Category: 8. Health

  • The Effect of Minimal-dose S-ketamine on Opioids Consumption in Postop

    The Effect of Minimal-dose S-ketamine on Opioids Consumption in Postop

    Introduction

    Thoracic surgery is frequently associated with acute postoperative pain, with a prevalence of moderate-to-severe pain reported to be as high as 62.9%.1,2 Inadequate perioperative pain management following thoracoscopy can worsen respiratory function, potentially leading to postoperative pulmonary complications, chronic post-thoracotomy pain syndrome (CPTPS), and delayed recovery in patients.3 Among thoracic surgeries, radical resection of esophageal cancer is known to cause severe acute postoperative pain due to the extensive trauma of the procedure.

    Opioids have traditionally served as the primary treatment for moderate to severe acute postoperative pain.4 Current recommendations advocate for the implementation of multimodal analgesic regimens and non-opioid interventions to minimize perioperative opioid consumption and mitigate opioid-related adverse effects, such as nausea, vomiting, over sedation, ileus, pruritus, and respiratory depression, enhancing and expediting patients’ postoperative recovery.5

    (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (S-ketamine).6,7 S-ketamine is used as an anesthetic in several countries, including China. The 2018 guideline “Intravenous Ketamine for Acute Pain Treatment”, jointly issued by the American Society of Regional Anesthesia (ASRA), the American Academy of Pain Medicine (AAPM) and the American Society of Anesthesiologists (ASA), advocates for integrating subanesthetic ketamine doses (not exceeding 0.35 mg/kg or 1 mg/kg/h) into postoperative PCIA for surgeries anticipating severe acute postoperative pain in patients. The guidelines suggest that subanesthetic ketamine doses could lead to a 20% reduction in opioid usage for acute postoperative pain management.8 Nevertheless, the effect of S-ketamine, which exhibits a higher affinity for NMDAR than (R,S)-ketamine and R-ketamine, on opioid consumption for managing acute postoperative pain in patients undergoing radical esophageal cancer resection remains uncertain. The study by Bornemann-Cimenti in 2016 indicated that the dosage of S-ketamine (0.015 mg/kg/h×48h) was similar to that of (R, S)-ketamine (0.25 mg/kg/h×48h) for managing acute postoperative pain.9 This study aims to investigate the effect of minimal-dose S-ketamine (0.015 mg/kg/h×48h) for acute postoperative pain management on reducing opioid consumption, enhancing analgesic quality, and facilitating postoperative recovery in patients undergoing radical esophageal cancer resection.

    Materials and Methods

    Study Design

    This randomized double-blinded controlled trial was conducted at Zhongda Hospital affiliated with Southeast University. The study protocol was approved by the Ethics Committee of Zhongda Hospital affiliated with Southeast University (No. 2022ZDSYLL138-P01) and registered in the Chinese Clinical Trial Register (ChiCTR2100048311, http://www.chictr.org.cn/). Written informed consent was obtained from all participants or their legal representatives before recruitment. This study complies with the Declaration of Helsinki and adhered to the 2010 Consolidated Standards of Reporting Trials (CONSORT).10

    Participants

    The investigators screened eligible patients the day before surgery (or on Friday if they underwent surgery the following Monday). Patients who met the following criteria were included: aged 18–80 years, ASA status I–III and were scheduled to undergo minimally invasive radical resection of esophageal cancer. Patients who met any of the following criteria were excluded: allergy to S-ketamine or oxycodone, unstable ischemic cardiac disease, increased intracranial or intraocular pressure, untreated or poorly treated hyperthyroidism, psychiatric disease, severe hepatic dysfunction (Child–Pugh grade C), renal failure (requiring renal replacement therapy), severe respiratory dysfunction (respiratory failure type I or type II), previous long-term use of analgesics, previous basic pain (chronic pain), conversion to thoracotomy, transfer to the intensive care unit (ICU), unwillingness or inability to use a PCIA device, and cognitive impairment or inability to communicate.

    Randomization and Blinding

    This study included 216 patients who underwent minimally invasive radical resection of esophageal cancer under general anesthesia. Participants were numbered sequentially based on their enrollment order. A nurse used IBM SPSS Statistics 27 to generate random numbers and randomly allocate participants to one of the two groups in a 1:1 ratio. The randomization sequence was generated and placed in sequentially numbered sealed radiopaque envelopes. Once the investigator confirmed eligibility, the envelopes were opened sequentially and participants were assigned to their respective groups by the designated nurse who performed numerical randomization. Intravenous pumps of the drugs were used by the coded PCIA device (with a fixed background infusion rate of 2 mL/h) delivered to the operating rooms by a pharmacist and were started at the end of surgery: Group E, S-ketamine 0.015 mg/kg (diluted to 96 mL with 0.9% NS); Group C, 96 mL with 0.9% NS. This study was double blinded. The patients, researchers who performed data collection and postoperative follow-up, and clinical staff were blinded to group allocation throughout the study.

    Intervention

    Intraoperative Management

    General anesthesia was standardized, and no premedication was administered. Anesthesia was induced intravenously with midazolam (0.03–0.05 mg/kg), propofol (1.5–2.5 mg/kg), sufentanil (0.3–0.5 μg/kg), and rocuronium (0.6–0.9 mg/kg). Mechanical ventilation was performed after tracheal intubation, and the respiratory rate and tidal volume were adjusted to maintain the PETCO2 at 35–45 mmHg. Intravenous Ketorolac 30 mg was administered to the patients before the surgical procedure. Anesthesia depth was adjusted by target-controlled infusion of propofol and inhalation of a sevoffurane/oxygen/air mix to maintain a bispectral index value between 40 and 60. The remifentanil infusion rate was adjusted based on the mean arterial pressure and heart rate (within 20% of the baseline values).

    Postoperative Management

    The coded PCA with a fixed background dose of 2 mL/h were started at the end of surgery: Group E, S-ketamine 0.015 mg/kg (diluted to 96 mL with 0.9% NS); Group C, 96 mL 0.9% NS. All the patients were transferred to the post-anesthesia care unit (PACU) for extubation.

    Postoperative Multimodal Analgesia

    After extubation in the PACU, a fixed anesthesiologist performed ultrasound-guided paravertebral nerve block and another PCIA device (oxycodone 50 mg diluted to 100 mL with 0.9% NS) was administered to all patients. An ultrasound-guided paravertebral nerve block was performed by a specialized anesthesiologist with expertise in acute pain management. The ultrasound probe was positioned perpendicularly to the dorsal midline at the spinous processes of the target thoracic vertebrae (T5 and T8), with the inner end of the probe aligned on the dorsal midline. The imaging demonstrated the spinous process of the target thoracic vertebra and the transverse process of the adjacent thoracic vertebra. The probe was then adjusted cephalad to avoid interference with the transverse process of the adjacent thoracic vertebra, ensuring its placement between the two transverse processes and parallel to them. The paravertebral space of the thoracic vertebrae was identified as the region enclosed by the deep portion of the articular process, approximately 1 cm lateral to it, and bounded externally by the pleura. A needle was inserted lateral to the probe, carefully avoiding contact with the pleura, and advanced into the space between the articular process and the pleura. After confirming the absence of blood or cerebrospinal fluid upon aspiration, 10 mL of 0.187% ropivacaine was administered to the paravertebral regions of the target thoracic vertebrae. Oxycodone PCIA was programmed at a background dose of 0–2 mL/h and a single bolus dose of 4 mL, followed by a 10-min interval lockout. All patients received ketorolac (30 mg) intravenously daily. How to use oxycodone PCIA, postoperative follow-up and the adjustment of the PCIA were performed by a fixed nurse and a fixed anesthesiologist: if the NRS pain scores at rest was 0, the background dose would be reduced; otherwise, if the NRS pain scores at rest was > 3, the background dose would be increased until the score was ≤ 3. If the FAS was still grade C after one bolus injection, a bolus dose would be administered again 10 min later and so on until the FAS decreased to grade A/B. The PONV was treated with intravenous tropisetron (2 mg). When the liquid in the pump box of the oxycodone PCIA was exhausted, the original concentration of the medical solution could be added under aseptic conditions. If delirium occurred, dexmedetomidine (0.5 μg/kg) was pumped intravenously within 15 minutes and then infused at a rate of 0.2 to 0.7 μg/kg/h until the symptoms were controlled.

    Outcomes

    The primary outcome was cumulative opioid consumption in the first 48 h postoperatively. The main secondary outcomes included FAS scores (after one bolus administration) at postoperative hour 12 (T3), postoperative hour 24 (T4), postoperative hour 48 (T5), postoperative hour 72 (T6), NRS pain scores (at rest and when coughing) at postoperative hour 2 (T1), postoperative hour 6 (T2), T3,T4,T5,T6, and the cumulative opioid consumption in different periods (postoperative 0–24 hours, 24–48 hours, 48–72 hours). Other pre-specified secondary outcomes included LOS scores at T2 – T6, time of first postoperative flatulation, BI, incidence of PONV, postoperative delirium, pulmonary complications and other complications, duration of chest tube use, length of postoperative hospital stay, and satisfaction of medical workers and patients. Postoperative pain was evaluated using the NRS (11- point scale: 0 [no pain], 0 < NRS < 4 [mild pain], 4 ≤ NRS < 7 [moderate pain], 7 ≤ NRS < 10 [severe pain], 10 [worst pain imaginable]). Patients regularly used an external vibration expectoration machine (one bolus administration would be given in advance) from postoperative hour 12 and FAS scores (Grade A: no limitation [pain does not limit functional activity at all]; Grade B: mild limitation [pain slightly limits functional activity]; Grade C: Severe limitation [pain severely limits functional activity]) were used to evaluate the effect. Postoperative sedation was assessed using LOS scores (Grade 0: awake and responsive; Grade 1: slightly drowsy, but easy to wake up [Grade 1S: normal sleep state]; Grade 2: frequent drowsiness, easy to wake up, but not continuously awake; Grade 3: difficult to awaken). Activities of daily living were assessed using the Barthel Index (BI), with a total score of 100 points (≥ 60 points, can take care of themselves; 41–59 points, moderate dysfunction, need assistance in daily life; 21–40 points, severe dysfunction, requiring assistance in daily life, and ≤ 20 points requiring assistance in daily life). Postoperative delirium was diagnosed based on the Intensive Care Delirium Screening Checklist (ICDSC) (total scores ≥ 4). Pulmonary complications include pulmonary infection, atelectasis, pulmonary edema and pneumothorax. Other complications include anastomotic leakage and abnormal bleeding. The satisfaction levels of the medical staff and patients were assessed using NRS scores from 0 to 10 points (the higher the score, the better the satisfaction).

    Sample Size Calculation

    Oxycodone consumption after minimally invasive radical resection of esophageal cancer in the previous year was calculated for the control group. We calculated the standard deviation (29.6 mg) and mean oxycodone consumption (66.5 mg) (postoperative 0–48 h). The guideline “Intravenous Ketamine for the treatment of Acute Pain” suggested that the addition of subanesthetic doses of ketamine can reduce opioid use by 20%.8 So the expected reduction in oxycodone consumption would be 13.3 mg (66.5 mg × 20%). With the power set at 90% and a one-sided significance level of 0.05, 172 patients were required to detect differences. Owing to the 20% dropout rate, 216 patients were enrolled in the trial.

    Statistical Analysis

    Statistical analyses were performed using a modified intention-to-treat approach, which excluded patients deemed ineligible after enrollment. All data were checked for normal distribution using the Kolmogorov–Smirnov test. Continuous variables are presented as mean (standard deviation, SD) or median (interquartile range, IQR), and Student’s t-test or Mann–Whitney U-test was performed to compare the difference between the two groups according to the Kolmogorov–Smirnov test. Categorical variables are presented as numbers (percentages) and were compared using Pearson’s χ2 test or Fisher’s exact test as appropriate.

    For the primary outcome, cumulative opioid consumption at postoperative 0–48 hours, Mann–Whitney U-tests were performed to compare the difference between the two groups and the median difference and its 95% CI were estimated using the Hodges-Lehmann estimator. Generalized estimating equations (GEEs) with robust standard error estimates were used to account for repeated measures of pain and FAS scores.

    Statistical significance was set at P < 0.05. Statistical analyses were performed using IBM SPSS version 27 or GraphPad Prism 10.0.

    Results

    Study Population

    A total of 325 patients were assessed for eligibility between January 1, 2022, and October 30, 2024. Of these, 216 were eligible and randomized. The final intention-to-treat analysis included 202 patients (Figure 1). Overall, the patient demographics and surgical and anesthetic characteristics were balanced between the groups (Table 1).

    Table 1 Demographic and Clinical Characteristics at Baseline

    Figure 1 CONSORT diagram for the study.

    Abbreviations: ICU, intensive care unit; Group E, S-ketamine group; Group C, control group.

    Primary Outcome Analysis

    The postoperative opioid consumption within 48 hours in S-ketamine group was significantly lower than those in placebo group (P <0.001) (Table 2, Figure 2), and the difference between the two groups was 40% (mean: 44.5 mg vs 74.8 mg).

    Table 2 Comparison of Oxycodone Consumption (Mg) Between the Two Groups

    Figure 2 Comparison of indicators of the analgesic efficacy between the two groups. (A). Oxycodone Consumption; (B). Probability of FAS A/B after 1 bolus; (C). NRS score for pain at Rest; (D) NRS of pain when coughing.

    Abbreviations: Group E, S-ketamine group; Group C, control group; POD 1, postoperative 0–24 h; POD 2; postoperative 24–48 hours; POD 3: postoperative 48–72 hours; T1, postoperative hour 2; T2, postoperative hour 6; T3, postoperative hour 12; T4, postoperative hour 24; T5, postoperative hour 48; T6, postoperative hour 72.

    Notes: Compared with T1 in the same group, #P <0.05; compared with Group C at the same time point, *P <0.05, **P <0.01, ***P<0.001.

    Secondary Outcomes Analyses

    The NRS pain scores at rest were all ≤ 3, and the FAS (after 1–3 bolus dose administrations) was grade A/B in both groups, which met the requirements for postoperative analgesia. At T3,T4, T5, and T6, the proportion of FAS (after one bolus dose administration) with grade A/B in group E was significantly higher than that in group C (P < 0.001, P= 0.007, P < 0.001, P < 0.001, respectively) (Table 3, Figure 2). The NRS pain scores at rest at T5 in group E were lower than those in group C (P = 0.001) and the NRS pain scores when coughing at T3 in group E were larger than those in group C (P = 0.011) with mean differences of −0.3 and 0.4 respectively (Table 3, Figure 2). The AUC of the NRS pain scores at rest in group E was smaller than that in group C within 72 hours after surgery (P = 0.027) (Table 3). Oxycodone consumption in group E was significantly lower than that in group C within 24, 24–48 and 48–72 hours after surgery (P < 0.001, P < 0.001, P < 0.001, respectively) (Table 2, Figure 2), and the differences between the two groups were 40%, 41% and 47% respectively (mean: 23.6 mg vs 39.4 mg, 21.0 mg vs 35.4 mg, 16.9 mg vs 31.8 mg).

    Table 3 Comparison of Postoperative Pain Between the Two Groups

    Safety and Other Outcomes Analyses

    The proportion of flatulation within 48 h postoperatively in group E was higher than that in group C (P = 0.029), the BI at 48 h postoperatively in group E was higher than that in group C (P = 0.008) and the postoperative hospital stay in group E was shorter than that in group C (P = 0.044) (Table 4). There was no statistically significant difference in postoperative pulmonary complications between the two groups; however, the incidence of postoperative pulmonary complications in group E (3.7%) was lower than that in group C (10.2%). The LOS scores were all grade 0 or 1 in the two groups, which met the requirements for postoperative analgesia and did not differ significantly between the two groups (Table 4). There were no significant differences in incidence of PONV, other complications, duration of chest tube placement, and satisfaction levels of medical staff and patients between two groups (Table 4).

    Table 4 Comparison of Safety and Other Outcomes Between the Two Groups

    Discussion

    The main findings of the study are as follows. First, Opioid consumption within the first 48 h postoperatively for acute pain management was significantly lower in the S-ketamine group than in the control group in patients undergoing radical resection for esophageal cancer. Second, the FAS and BI scores were notably higher in the S-ketamine group than in the control group. Moreover, there was a statistically significant difference in the NRS pain scores between the two groups of patients; however, the score differences were less than 1 point. Given that the minimum unit of the NRS score is 1 point and prior studies have demonstrated that a decrease of at least 1.3 points in the NRS pain score relative to baseline pain intensity is required for clinically meaningful pain relief, the observed differences in this study lacked clinical significance despite being statistically significant.12–14 Time to first postoperative flatulence and length of postoperative hospital stay were lower in the S-ketamine group than in the control group. There were no significant differences in the incidence of PONV, LOS, postoperative delirium, pulmonary and other complications, duration of chest tube placement, or satisfaction levels of medical staff and patients between the two groups.

    Selection of the Study Population

    The addition of subanesthetic doses of ketamine is supported by the guidelines for patients undergoing thoracic surgery expected to cause severe postoperative pain.8 Postoperative pain following thoracic surgery, particularly radical resection of esophageal cancer, is known to be severe, with incidence rates of moderate to severe pain reaching 62.9%.2 Given the high demand for analgesia observed in patients undergoing minimally invasive radical resection of esophageal cancer, often necessitating patient-controlled analgesia (PCIA) for over 72 h post-surgery, this study focused on this specific patient population to enhance postoperative pain management.

    Selection of the Primary Outcome and the Secondary Outcome FAS

    The perioperative analgesia guidelines aim to achieve postoperative pain tolerance or a pain level of NRS ≤ 3.15–17 Our department implemented artificial intelligence patient-controlled analgesia (Ai-PCA) in 2012 and established the Acute Pain Service (APS) in 2017. Due to clinical and ethical considerations, to ensure adherence to the analgesic goal, we strived for homogeneity in pain scores: NRS scores at rest were ≤ 3 and FAS levels were grade A or B. Therefore, the primary outcome of this study was opioid consumption, which served as an indirect indicator of analgesic efficacy.

    In this study, all patients achieved FAS levels of grade A/B following 1–3 bolus administrations and we chose the FAS levels obtained after one bolus administration as the secondary outcome to assess the difference in functional exercise between the two groups. Conventional clinical studies frequently integrate both S-ketamine and opioids into PCIA.18–20 Moreover, unlike typical clinical studies, we did not incorporate S-ketamine into PCIA because it would result in discrepancies in the bolus between the two groups.

    Selection of S-Ketamine Dosage

    S-ketamine, being more potent and less prone to adverse effects than racemic ketamine, is a viable alternative during the perioperative period. A recent meta-analysis by Wang et al21 indicates that intravenous S-ketamine, when used as an adjunct to general anesthesia, effectively enhanced analgesia, reduced postoperative pain intensity, and minimized opioid requirements in the short term. However, it may also increase the incidence of psychotomimetic adverse events. Notably, the risk of such adverse events is significantly higher in the intra- and postoperative group compared to the intraoperative-only group, possibly due to higher postoperative infusion rates (doses ranged from 0.075 to 0.5 mg/kg for boluses and 1.25 to 10 μg/kg/min for infusions).21 Studies by Bornemann-Cimenti9 and Zhang20 have shown that minimal-dose S-ketamine (0.015 mg/kg/h for 48 hours) yields comparable analgesic effects to conventional low-dose S-ketamine regimens, while also demonstrating similar outcomes to a placebo in terms of postoperative delirium and sedation. Therefore, in light of the literature and the outcomes of preliminary experiments, the minimum dose of S-ketamine (0.015 mg/kg/h for 48 h) was selected for this study to achieve the desired therapeutic effect while minimizing the dosage.

    Exploratory Outcomes Analyses

    Exploratory Primary Outcome Analysis

    Our findings indicate that the addition of a minimum dose of S-ketamine to postoperative analgesia reduces the postoperative opioid requirements. Our study showed an approximate 40% decrease in postoperative opioid requirements in the S-ketamine group compared to the control group, consistent with previous research and surpassing the anticipated 20% reduction, confirming the study’s statistical power to detect differences between groups.9,22

    Exploratory Main Secondary Outcomes Analyses

    Multimodal pain management, a key element in Enhanced Recovery After Surgery (ERAS) protocols, often includes the NMDA receptor antagonist ketamine because of its efficacy in reducing opioid consumption and pain levels.5,21,23,24 The primary aim of analgesia is to enhance postoperative rehabilitation, as indicated by the FAS assessment. Our findings revealed significantly improved FAS scores in the S-ketamine group compared to the control group, highlighting the superior analgesic efficacy of S-ketamine in functional exercises.

    Safety and Other Outcomes

    The time to first postoperative flatulence, bowel movements, and length of hospital stay were significantly better in the S-ketamine group than in the control group, possibly because of the reduced postoperative opioid use and enhanced mobilization. No significant differences were observed in LOS scores or postoperative delirium between the groups, consistent with previous studies.9,20 The incidence of postoperative nausea and vomiting did not differ between the groups, aligning with conflicting findings in the literature.21,25 Although a decrease in pulmonary complications was noted, it was not statistically significant, nor were other complications. Previous studies suggest that perioperative administration of S-ketamine or ketamine in various surgeries may confer anti-inflammatory and immunoprotective effects with efficacy potentially dose-dependent.26–29 Inconclusive results may be attributed to inadequate power analysis for this outcome, limiting the study’s ability to detect differences.

    Limitations

    First, continuous constant-rate intravenous infusion was selected to ensure that the hourly dosage of S-ketamine remained at its minimum level. Nonetheless, incorporating S-ketamine into the PCIA may offer greater clinical convenience. Further studies and design improvements are necessary to build this foundation. Second, this trial was conducted at a single center. Therefore, the generalizability of our findings to other patient populations remains unclear. Third, we did not design multiple dosage groups to determine the optimal dose. The minimal-dose of S-ketamine used in this protocol was based on previous studies. Given the relatively small number of patients undergoing esophageal cancer surgery, it took approximately three years to complete this study. Comparing multiple groups would have further prolonged the research period. Clinically, treatment modalities for various diseases and postoperative analgesia management are continually evolving. A protracted research timeline may introduce potential biases into the results. These limitations could be addressed through multicenter collaboration in future studies. Fourth, no quantitative indicators of hyperalgesia were used in this study. In the pilot study, von fair silk was used to measure the area of pain sensitivity. However, the patients refused because they used a band to fix their chest to relieve pain after surgery, and the process of removing the band was complicated and inconvenient. This limitation should be fully considered in future studies, and alternative methods such as the pressure pain threshold (PPT) assessment are recommended. Fifth, the sample size was calculated based on the primary outcomes. Therefore, it is highly likely that our relatively small sample size underpowered the secondary outcomes (such as the incidence of pulmonary complications and PONV). Large-scale randomized controlled trials should be conducted to address these limitations.

    Conclusion

    In conclusion, the minimum dose of S-ketamine for managing acute postoperative pain in patients undergoing radical resection of esophageal cancer leads to a 40% reduction in opioid use and promotes postoperative functional exercise and rehabilitation, which is worthy of clinical promotion.

    Data Sharing Statement

    All data generated or analyzed during this study have been included in the published article. Further inquiries regarding the datasets can be directed to the corresponding author upon reasonable request.

    Funding

    This work was supported by the Nanjing Health Science and Technology Development Special Fund Project (Grant No.: YKK21264) and Beijing Medical Award Foundation (Grant No.: YXJL-2021-0307-0737).

    Disclosure

    The authors declare no conflicts of interest in this work.

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  • “At home, I never felt included, I always felt on the outside”: Deaf peoples’ perspectives on how inadequate access to childhood communication influences mental health outcomes | BMC Public Health

    “At home, I never felt included, I always felt on the outside”: Deaf peoples’ perspectives on how inadequate access to childhood communication influences mental health outcomes | BMC Public Health

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  • Investigation of appropriate mortality due to clinically diagnosed Alz

    Investigation of appropriate mortality due to clinically diagnosed Alz

    Introduction

    The prevalence of dementia is increasing worldwide, with projections estimating that the number of individuals affected will reach 150 million by 2050.1,2 Alzheimer’s disease (AD) and other major forms of dementia are progressive neurodegenerative disorders that affect the entire body, ultimately leading to death from complications and associated conditions.3,4 Patients with Vascular dementia (VD) often succumb to cerebrovascular disease or myocardial infarction; however, VD itself can result in pathologies such as aspiration pneumonia, which can also be fatal.5

    As awareness grows regarding dementia as a terminal condition, it has become a focus of palliative care in many countries.6,7 Consequently, AD and other dementias rank among the leading causes of death in European countries and the United States (US). Notably, AD is the most common form of dementia, accounting for approximately 60% of all cases, with a reported death rate of 13% in France, 12% in the United Kingdom, and 7% in the US.8

    Although the prevalence of dementia increases with age, Japan, despite having one of the longest life expectancies globally, reports a lower ranking of dementia as a cause of death compared to that in other countries. The reported mortality rate for AD and other dementias in Japan is 1.6% for both, significantly lower than rates observed in Western countries.9 Conversely, “senility” ranked as the third leading cause of death in Japan’s 2018 mortality statistics, accounting for 8% of deaths. This discrepancy has sparked debate over whether deaths caused by dementia are being inaccurately documented as senility on death certificates.10,11

    The idea that dementia should be recognized as a cause of death was proposed by Molsa et al5 in 1986 and is now well established in many countries. However, even in the US, where dementia ranks higher as a cause of death than in Japan, the underreporting of dementia-related mortality remains a contentious issue.12 Research has estimated that the actual death rate due to dementia in the US is approximately 14%, whereas only approximately 5% is officially recorded.13 Japanese death statistics are compiled based on death certificates issued by physicians. The first author, a psychiatrist with extensive experience in internal medicine, observed that in psychiatric hospitals, where many patients with dementia are admitted, the cause of death listed on death certificates was often recorded as another condition, even when the patient had died of dementia. Although the proportion of deaths occurring in hospitals in Japan has been gradually decreasing, it still accounts for nearly 70% of all deaths. According to a 2020 survey by the Ministry of Health, Labour and Welfare (MHLW), a total of 75,900 individuals with dementia were hospitalized in Japan, including 50,600 with AD and 25,300 with other dementias. Of these, 39,200 patients with AD and 18,800 with other dementias were admitted to psychiatric hospitals, resulting in a total of 58,000 patients with dementia hospitalized in such facilities.14 According to statistics from the MHLW, 76% (58,000) of all hospitalized Japanese patients with dementia are admitted to psychiatric hospitals. Japan has approximately 1.58 million hospital beds, of which approximately 20%, or 323,000 beds, are designated for psychiatric care. Of these, 244,000 beds are in psychiatric hospitals, and 79,000 are in general hospitals.15 The majority of inpatient psychiatric care is provided in psychiatric hospitals. In recent years, there has been an increasing trend of patients with dementia being admitted to psychiatric hospitals and remaining there until death.16,17

    We hypothesized that the low proportion of deaths attributed to dementia in Japanese mortality statistics may be due to the omission of AD and other dementias in the direct cause of death section on death certificates. To explore this, we aimed to investigate whether dementia was accurately recorded as the main diagnosis or direct cause of death on death certificates, focusing on psychiatric hospitals with a high number of inpatients with dementia. This analysis utilized both death certificates and medical records.

    Methods

    Participants

    We examined the death certificates of patients who died in 11 psychiatric hospitals in the northern Kanto region of Japan between fiscal years (FY) 2010 and 2020. During this period, 942 deaths were recorded, with death certificates available for all cases and medical records accessible for 653 cases. Therefore, the 653 cases with both death certificates and medical records were selected for the present study (Figure 1).

    Figure 1 Consort flow diagram of study patients.

    All data used in this study were anonymized during the collection process to ensure individuals’ confidentiality and informed consent was obtained from participants in the form of opt-out on the website. The study was approved by the Ethical Review Committee of Jichi Medical University (approval number: 23–139). The study protocol adhered to the Declaration of Helsinki guidelines.

    Survey Items

    The investigation of death certificates and medical records was conducted by Sato, a Board Certified Member of the Japanese Society of Internal Medicine. In cases where uncertainties arose during the review of medical records, particularly in determining the direct cause of death, the final determination was made in consultation with Shioda, who had worked as a general physician for many years.

    From the total of 653 death certificates (male: 393; female: 260), we extracted the following information: age at death, sex, column I of the death certificate (Disease or condition directly leading to death), and column II of the death certificate (Other significant conditions contributing to death but not related to the disease or condition causing it). The direct cause of death was defined as the disease listed at the bottom of column I, in accordance with the methods prescribed by the World Health Organization (WHO) and the MHLW for identifying causes of death. The names of the direct causes of death were classified using the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), which is the standard classification system used in official death statistics in Japan.

    We analyzed 653 medical records (male: 393; female: 260) of patients for whom records were available, focusing on the disease that led to admission, the presence of AD as a comorbidity, and the categorization of dementia as a cause of hospital admission (AD or other dementias). Additionally, we examined whether dementia was accurately documented in column I of the death certificate when AD or any other dementia was identified as the cause of death. The medical records were further reviewed to determine whether dementia had progressed to become a direct cause of death. In this study, death due to dementia was defined using two criteria:1 the patient’s condition prior to death met the National Hospice and Palliative Care Organization (NHPCO) definition of hospice care induction criteria (Table 1); and2 the patient died from a condition attributable to dementia, such as pneumonia, asphyxia resulting from impaired swallowing, urinary tract infections and kidney failure due to dysuria, or infections related to pressure ulcers and other recurring conditions. Cases in which patients with dementia died from apparent malignant diseases, heart diseases, or cerebrovascular diseases were excluded.

    Table 1 Hospice Criteria for Dementia

    Analysis

    We categorized the mental disorders causing hospitalization into the following groups: AD (F00), other dementias (F0 excluding F00), mood disorder spectrum (F3), schizophrenia disorder spectrum (F4), and other mental disorders. The age at death was compared across these categories.

    Based on the death certificates, we classified the direct causes of death for the 653 cases using the ICD-10 codes. The number of deaths for men, women, and the overall death rates were identified by ICD codes.

    The medical records of 148 patients hospitalized for AD were reviewed to determine the appropriate direct cause of death. For each ICD code, we calculated the difference between the number of deaths recorded on the death certificate and the number of deaths corrected based on the medical record review.

    The medical records of 124 patients hospitalized for other dementias were reviewed to determine the appropriate direct cause of death. For each ICD code, the difference between the number of deaths recorded on the death certificate and the number of deaths corrected through medical record review was calculated.

    The medical records of 13 patients with comorbid AD who were admitted for other mental disorders were reviewed to determine the appropriate direct cause of death and the mental disorder leading to hospitalization. Discrepancies between the number of deaths recorded on death certificates and the corrected number of deaths based on medical record investigations were identified.

    We examined whether there were differences in the number of deaths attributed to AD between death certificates and the corrected number of deaths. The proportions of AD deaths, as recorded on death certificates and as determined by medical record review, were compared overall and by sex. Ratios were analyzed using the chi-squared (χ2) test. Additionally, the χ2 test was used to determine whether there were significant differences in AD mortality by sex.

    We investigated whether there were differences in the number of deaths attributed to all dementias between death certificates and the corrected number of deaths. The proportion of dementia-related deaths, as recorded on death certificates and as determined by medical record review, were compared overall and by sex. Ratios were analyzed using the χ2 test. Additionally, the χ2 test was used to assess whether there were significant differences in dementia-related mortality by sex.

    A P-value of <0.05 was considered statistically significant. All statistical analyses were conducted using IBM SPSS statistics for Windows, version 26.

    Results

    A total of 942 death certificates were identified for patients who died between FY 2010 and FY 2020 in 11 psychiatric hospitals. Of these, 393 were male, and 260 were female, resulting in a total of 653 patients for which both death certificates and medical records were verified (Figure 1).

    Mental Disorders Causing Hospitalization and Associated Age of Death

    We categorized mental disorders causing hospitalization into AD (F00), other dementias (F0 excluding F00), mood disorder spectrum (F3), schizophrenia disorder spectrum (F4), and other psychiatric disorders. The age at death was analyzed for each disorder.

    The most common mental disorder was schizophrenia (293 cases), followed by AD (148 cases) and other dementias (124 cases) (Table 2). The average age at death for patients with AD and other dementias was over 80 years. In contrast, the average age at death for patients with other conditions was approximately 70 years (Table 2).

    Table 2 Mental Disorders Causing Hospitalization and Associated Age of Death

    Causes of Death Based on Death Certificates (by ICD Code)

    The results derived from death certificates showed that the leading cause of death was classified under ICD-10 code J, with pneumonia and aspiration pneumonia accounting for 40.3% (263 cases) of all deaths. The second most common cause was ICD-10 code I, representing heart failure and other diseases of the circulatory system, which accounted for 17.6% (115 cases) of deaths. Neoplasms, categorized under ICD-10 code C, were the third most common cause, comprising 12.6% (82 cases) of total deaths. AD accounted for 5.2% (34 cases) of total deaths, while other dementias combined accounted for 6.9% (45 cases).

    Furthermore, 6.6% (43 cases) were classified as others (code R), including 5.4% (35 cases) attributed to senility (Table 3).

    Table 3 Causes of Death Based on Death Certificates (by ICD Code)

    Changes in Direct Cause of Death Before and After Medical Record Confirmation for Patients Admitted with AD

    We examined whether patients admitted with AD were accurately reported as having died from AD. Among 148 cases of patients hospitalized with AD, only 34 death certificates listed AD as the direct cause of death. However, after reviewing the medical records and identifying cases that met the definition of death due to dementia, it was determined that AD should have been listed as the direct cause of death in 116 of the 148 cases.

    A review of medical records where AD was already listed as the direct cause of death on the death certificate confirmed that all these cases met the criteria for dementia-related death, supporting the accuracy of AD as the direct cause of death. For other cases, the direct cause of death was revised as follows: in 43 out of 47 cases of pneumonia and all nine cases of aspiration pneumonia, the direct cause of death was corrected to AD; all 11 cases classified as senility were corrected to AD; 6 out of 9 cases of heart failure were corrected to AD; all 3 cases of renal failure and 3 of urinary tract infections were corrected to AD; one case of infectious and parasitic diseases and one case of diseases of the skin and subcutaneous tissue were corrected to AD; 2 cases classified under external causes of morbidity and mortality were corrected to AD; one case initially labeled as dementia was corrected to AD, as the diagnosis in the medical record specified AD (Table 4).

    Table 4 Changes in Direct Cause of Death Before and After Medical Record Confirmation for Patients Admitted with AD

    Changes in Cause of Death Before and After Medical Record Confirmation for Patients Admitted with Dementias Other Than AD

    The study included 124 patients admitted with dementias other than AD (other dementias). Among these, the primary cause of death listed on the death certificate was dementia in only 10 cases, accounting for less than one-tenth of the total. After reviewing the medical records and identifying cases that met the definition of death due to dementia, it was determined that dementia should have been listed as the direct cause of death in an additional 64 of the 124 cases.

    A review of medical records where dementia was already listed as the direct cause of death on the death certificate confirmed that all these cases met the criteria for dementia-related death, supporting the accuracy of dementia as the direct cause of death. For other cases, the direct cause of death was revised as follows: in 31 out of 46 cases of pneumonia and all 11 cases of aspiration pneumonia, the direct cause of death was corrected to dementia; all 9 cases initially classified as senility were corrected to dementia; 8 of 15 cases of heart failure were corrected to dementia; one case categorized under ICD-10 code R (multi-organ failure) was corrected to dementia; a case of urinary tract infections was corrected to dementia; 2 cases of infectious and parasitic diseases were corrected to dementia; one case classified under external causes of morbidity and mortality was corrected to dementia; 5 cases diagnosed with other dementias at the time of admission were reclassified as AD, and their cause of death was corrected to AD (Table 5).

    Table 5 Changes in Cause of Death Before and After Medical Record Confirmation for Patients Admitted with Dementias Other Than AD

    Causes of Death in Cases of Comorbid AD and Hospitalization for Other Mental Disorders

    The same investigations were conducted for cases where the primary reason for hospitalization was a mental disorder other than AD or other dementias but where AD was present as a complication. Among these, 11 patients were admitted with schizophrenia and 2 with bipolar disorder, both complicated by AD. For the 11 patients with schizophrenia, the direct causes of death listed on death certificates were as follows: pneumonia (five cases), aspiration pneumonia (two cases), senility (two cases), and heart failure (two cases). After a medical record review, all 11 cases were corrected to AD as the direct cause of death. For the two patients with bipolar disorder, the direct causes of death listed on death certificates were pneumonia and aspiration pneumonia. Both cases were also corrected to AD as the direct cause of death.

    Appropriate AD Death Rate in Psychiatric Hospital Inpatients

    The results showed that AD was the direct cause of death in 116 patients hospitalized with AD, 5 patients hospitalized with other dementias, and 13 patients hospitalized with other mental disorders. The proportion of AD-related deaths reported on death certificates and the corrected number of AD-related deaths after medical record confirmation were compared overall and by sex. In total, 134 of the 653 cases (20.5%) were determined to have AD as the direct cause of death, a significant increase from the 34 cases initially identified from death certificates alone (P<0.01). Similarly, by sex: among male patients, 20 of 393 cases (5.1%) were recorded as AD-related deaths before medical record confirmation, while 78 cases (19.8%) were identified after confirmation (P<0.01). Among female patients, 14 of 260 cases (5.4%) were recorded as AD-related deaths before medical record confirmation, while 56 cases (21.5%) were identified after confirmation, also showing a significant difference (P<0.01). The mortality rate due to AD after medical record review was significantly higher in men than in women (P=0.035) (Table 6).

    Table 6 Difference in the Number of Patients Considered to Have AD as the Cause of Death

    Appropriate Dementia-Related Death Rates in Psychiatric Hospital Inpatients

    After reviewing the medical records of 653 patients, 203 (134 with AD and 69 with other dementias) were identified as having dementia as the direct cause of death, representing 31.1% of all deaths. This rate was significantly higher than the rate identified before the medical record review (P<0.01).

    When examining dementia-related deaths by sex: among males, 122 out of 393 patients (31%) were determined to have dementia as the direct cause of death, a significant increase compared to the rate before the medical record review (P<0.01). Among females, 81 out of 260 (31.1%) patients were determined to have dementia as the direct cause of death, also showing a significant increase (P<0.01) (Table 7). The mortality rate due to all dementias after the medical record review showed no significant difference between males and females (P=0.975).

    Table 7 Difference in the Number of Patients Considered to Have Dementia (Including AD) as the Cause of Death

    Discussion

    A survey of the causes of death based on death certificates, categorized by ICD code, revealed that respiratory diseases accounted for approximately 40% of all deaths, followed by cardiovascular diseases at 17.6%, with half of these cases listed as heart failure.

    The underlying cause of death, which forms the foundation for mortality statistics, is determined according to WHO guidelines. Under these guidelines, the illness or injury listed at the bottom of column I on the death certificate is considered the direct cause of death. However, the WHO specifies that terminal conditions, such as heart failure or respiratory failure, are not appropriate as direct causes of death.8

    Additionally, 6.6% of deaths were categorized under the ICD-10 R code, which were found to be inappropriate as direct causes of death, with senility alone accounting for 5.4% of these cases. This indicates that inappropriate causes, such as heart failure and senility, were frequently listed as the direct cause of death. These findings highlight that death certificates in Japanese psychiatric hospitals are often not completed in accordance with proper standards.

    Patients admitted with AD or other dementias accounted for 42% of the total, but only approximately 7% of the total deaths. Among patients admitted with AD, only 25% had AD listed as the cause of death on their death certificate. Respiratory diseases were the most common cause of death, accounting for approximately 40%, with most cases involving pneumonia, including aspiration pneumonia. This finding aligns with those of previous studies.18–21 However, in 91% of the cases where pneumonia and aspiration pneumonia were listed as the cause of death, it was believed that the progression of AD led to impaired swallowing and other functional declines, ultimately resulting in pneumonia.

    Clinically, determining whether complications or the underlying disease is the true cause of death is often challenging. This determination also depends on the country’s rules for selecting the underlying cause of death. For example, in Canada and the United Kingdom22,23 the rule is that if a patient with dementia dies of aspiration pneumonia, dementia is considered the cause of death. While similar rules have been adopted in Japan, they are not widely recognized in clinical practice.

    This discrepancy is also evident in the US, where dementia is reported on death certificates for only a quarter of dementia-related deaths despite being a leading cause of death. A US cohort study reported a significant increase in mortality associated with the incidence and progression of AD, suggesting that AD contributes to more deaths than are officially recorded.24,25

    In contrast, countries such as France and Italy report higher rates of dementia as the underlying cause of death. In Italy, dementia is listed in approximately 12–19% of cases, while in France, it is listed in approximately 26–33% of cases. These differences highlight how the tendency to underreport dementia as a cause of death may vary by country.26

    In this study, approximately 7% of patients hospitalized for AD had “senility” listed as the cause of death. Unlike in other countries, senility is a leading cause of death as per Japan’s mortality statistics. Originally, senility was defined as “symptoms, signs, and abnormal clinical or detection findings that are not classified elsewhere”, making it a condition with an unclear diagnosis. In Japan, it is generally considered acceptable to record “senility” as the cause of death on death certificates, particularly in settings such as nursing homes and home-based palliative care.27

    In contrast, in Europe and the United States, listing only terms such as “senility” or “natural causes” is typically regarded as insufficient for determining the underlying cause of death. This practice may also complicate postmortem investigations or insurance procedures; hence, physicians are strongly encouraged to specify a definitive medical diagnosis.28

    In Japan, the rate of deaths attributed to senility has quadrupled, rising from 2.6% in 2000 to 10.3% in 2020. In contrast, the rate is only 0.8% in France and 0.2% in the US, highlighting a significant international discrepancy.29 In many cases, listing senility as the primary cause of death is inappropriate, particularly when dementia is the underlying condition that leads to a gradual decline and eventual death. Nevertheless, in this study, there were cases where only senility was recorded as the primary cause of death.

    Hayashi et al reported that 90% of death certificates listing senility as the cause of death did not mention any other causes, and this percentage has been increasing over time.29 This raises an important question: was senility truly the sole cause of death, or were there underlying diseases that went unlisted? Based on our investigation, it is likely the latter, indicating a need for a better understanding of dementia, clearer definitions of senility, and greater public awareness about the proper completion of death certificates.

    Additionally, the results of the medical record survey revealed six cases where heart failure was described as a terminal condition without detailed examination. The underlying cause of death, which serves as the basis for mortality statistics, is determined by the guidelines set by the WHO. According to these rules, if the condition listed in the bottom line of column I is likely to have caused all the other conditions listed above, it is considered the underlying cause of death. However, if an inappropriate condition is listed in column II as the cause of death, it may be inaccurately classified as such. Furthermore, the WHO guidelines advise against listing terminal conditions, such as cardiac failure or respiratory failure, as the cause of death.

    In this study, 124 patients with non-AD dementia were found to have psychiatric disorders that led to their hospitalization. Among the patients whose death certificates listed pneumonia and aspiration pneumonia as the cause of death, 74% may have developed pneumonia and aspiration pneumonia due to the deterioration of swallowing and other functions caused by the progression of dementia. Additionally, as seen in AD cases, there were nine instances where only senility was listed as the cause of death on the death certificate. Many cases also featured a diagnosis of dementia without further classification. In such instances, AD was often considered the underlying cause of death. These findings suggest that a significant number of cases may have had AD as the actual cause of death.

    The results of the medical record survey indicated that in cases where AD was diagnosed alongside other psychiatric disorders, the cause of death was frequently misattributed, with some instances where it should have been recognized as resulting from AD. Notably, a significant number of patients with schizophrenia were identified with complications related to AD.

    The risk of developing dementia among patients with ataxia is reported to be approximately twice as high as that in the general population.30 Specifically, it is hypothesized that patients with schizophrenia who develop AD may experience heightened susceptibility to schizophrenia-like symptoms due to the progressive decline in cognitive function.31

    In diagnosing dementia, cognitive dysfunction observed in patients with schizophrenia during the early stages of their illness can complicate the timely diagnosis of dementia. This delay can hinder accurate estimation of the co-occurrence rates of schizophrenia and AD.32 Comprehensive patient interviews and detailed examination findings are essential for differentiating schizophrenia from dementia. However, distinguishing schizophrenia from dementia based solely on clinical symptoms remains challenging.33,34 This diagnostic difficulty may lead to underdiagnosis or misdiagnosis of both conditions, as the perceived benefit of differentiating between them might be minimal.

    There was a significant increase in deaths attributed to AD across both sexes before and after the medical record survey. This rise can largely be attributed to complications of AD, such as pneumonia, being documented as the immediate cause of death, while AD, as the underlying condition, was often omitted from the records.

    Overall, in this study, the appropriate cause of death was identified by analyzing the diseases and medical conditions listed in patients’ medical records and comparing them to the information documented on death certificates. This analysis revealed a significant increase in the reported mortality rate of AD and overall dementia. The findings suggest that while physicians often diagnose AD and dementia, there is insufficient recognition of dementia as a direct cause of death, leading to incomplete or inaccurate death certificates. Given that Japan’s death statistics are based on these certificates, the actual number of dementia-related deaths in Japan is likely substantially higher than that officially reported.

    Prior to the survey, 34 out of 653 deaths (5.2%) were attributed to AD, whereas post-survey, this number increased to 134 out of 653 (20.5%), representing nearly a fourfold rise. These findings imply that while the official number of deaths due to AD in Japan is approximately 25,000, the actual figure could be closer to 100,000. Similarly, deaths attributed to total dementia increased from 45 out of 653 (6.9%) before the survey to 203 out of 653 (31.1%) after the survey, approximately 4.5 times higher. These results suggest that the actual number of dementia-related deaths in Japan might be approximately 220,000, surpassing the approximately 190,000 deaths reported due to senility and potentially making dementia the third leading cause of death in the country.

    These findings indicate that the number of deaths due to dementia, including AD, is significantly underreported on death certificates. As approximately 30% of the deaths in psychiatric hospitals analyzed in this study were attributed to dementia, it is imperative for medical personnel involved in psychiatric care to be well-informed about dementia, including AD. Furthermore, death certificates serve as foundational data for death statistics and are critical for national healthcare administration and policy decision-making. Therefore, even psychiatrists must possess adequate knowledge on how to accurately complete death certificates.

    Additionally, in this study, heart failure was often not diagnosed following a thorough examination immediately prior to death, and some death certificates listed heart failure as a terminal condition for convenience. Villar et al reported that 56.8% of death certificates listed respiratory or cardiac arrest as the direct cause of death prior to educational interventions, whereas none listed these causes following such education.35 This emphasizes the importance of proper training on accurate death certificate entries in Japan.

    This study has some limitations. The result lacks broader applicability. It was conducted exclusively in the northern Kanto region of Japan, which may limit the applicability of its findings to other regions, as the practices for completing death certificates could vary geographically. Additionally, the study focused exclusively on psychiatric diseases, without including a death certificate survey in general hospitals or home care settings. Therefore, generalizing these findings to estimate the national mortality rate of dementia, including AD, across Japan may not be appropriate. Furthermore, It has been suggested that individuals with mental disorders receive less frequent medical evaluations.36 Since the patients in this study were also hospitalized in psychiatric facilities, it is possible that serious conditions such as cancer and myocardial infarction were insufficiently investigated. Consequently, the potential for an elevated mortality rate for dementia, including Alzheimer’s disease, in the medical record survey cannot be ruled out.

    Although not relevant to the present study, we found that patients hospitalized with schizophrenia spectrum disorders, mood disorder spectrum disorders, and other mental disorders had shorter life expectancies than did those with AD or other dementias. Patients with schizophrenia have reduced life expectancies. Kiviniemi et al reported that patients with schizophrenia have a 4.45-fold higher risk of death than that in the general population,37 and Owens et al noted that these patients have a life expectancy approximately 20% shorter than that of the general population.38 In the present study, the age at death for patients with schizophrenia was approximately 10 years younger than for those with dementia.

    In recent years, individuals with various mental disorders reportedly have significantly shorter life expectancies than do those without mental illness. Patients with organic mental illnesses, including dementia, experience reduced life expectancy, but the extent of reduction is reported to be smaller than that for other psychiatric disorders. Consequently, the age at death for patients with AD and other dementias is higher than for those with other psychiatric disorders.39 The results of our study align with these previous findings.

    Conclusion

    We investigated whether dementia was accurately recorded as the main diagnosis or direct cause of death on death certificates, focusing on psychiatric hospitals with a high number of inpatients with dementia. Dementia including AD was not accurately recorded on death certificates and the actual mortality rate for dementia including AD was estimated to be higher than currently reported. These findings underscore the critical need to increase awareness about dementia as a cause of death and to educate the public and healthcare professionals on accurately documenting it on death certificates.To further validate the findings of this study, it is necessary to expand the scope of the research to include general hospitals and nursing care facilities in future investigations and to examine the actual conditions more comprehensively.

    Acknowledgments

    This work was supported by Ministry of Education, Culture, Sports, Science and Technology Japan Society for the Promotion of Science Grant Number JP20K23203. We would like to thank Editage for English language editing and all the participants for their cooperation.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Disclosure

    The authors declare no conflicts of interest in this work.

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    26. Désesquelles A, Demuru E, Salvatore MA, et al. Mortality from Alzheimer’s disease, Parkinson’s disease, and dementias in France and Italy: a comparison using the multiple cause-of-death approach. J Aging Health. 2014;26(2):283–315. doi:10.1177/0898264313514443

    27. Ministry of Health. Labour and welfare. manual to fill in a death certificate: Available from: https://www.mhlw.go.jp/toukei/manual/dl/manual_r03.pdf. Accessed December, 2024.

    28. Centers for Disease Control and Prevention. Physicians’ handbook on medical certification of death. Available from: https://www.cdc.gov/nchs/data/misc/hb_cod.pdf. Accessed December, 2024.

    29. Hayashi R, Beppu M, Ishii F, et al. Statistical analysis of senility death in Japan. J Popul Probl. 2023;78(1):1–18.

    30. Lin CE, Chung CH, Chen LF, et al. Increased risk of dementia in patients with schizophrenia: a population-based cohort study in Taiwan. Eur Psychiatry. 2018;53:7–16. doi:10.1016/j.eurpsy.2018.05.005

    31. Harrison PJ. The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain. 1999;122(4):593–624.

    32. Radhakrishnan R, Butler R, Head L. Dementia in schizophrenia. Adv Psychiatr Treat. 2012;18(2):144–153. doi:10.1192/apt.bp.110.008268

    33. Tsuang MT, Stone WS, Faraone SV. Toward reformulating the diagnosis of schizophrenia. Am J Psychiatry. 2001;158(5):670–676.

    34. McKeith IG, Cummings J. Behavioural changes in dementia with Lewy bodies. Lancet Neurol. 2005;4(1):19–27.

    35. Villar J, Pérez-Méndez L. Evaluating an educational intervention to improve the accuracy of death certification among trainees from various specialties. BMC Health Serv Res. 2007;7(1):183. doi:10.1186/1472-6963-7-183

    36. Goldman ML, Mangurian C, Corbeil T, et al. Medical comorbid diagnoses among adult psychiatric inpatients. Gen Hosp Psychiatry. 2020;66:16–23.

    37. Kiviniemi M, Suvisaari J, Pirkola S, et al. Regional differences in five-year mortality after a first episode of schizophrenia in Finland. Psychiatr Serv. 2010;61(3):272–279. doi:10.1176/ps.2010.61.3.272

    38. Owens DG, Cunningham EC, Johnstone EC. Treatment and management of schizophrenia. In: Gelder M, editor. New Oxford Textbook of Psychiatry. 2nd ed ed. Oxford, UK: Oxford University Press; 2012.

    39. Peritogiannis V, Ninou A, Samakouri M. Mortality in schizophrenia-spectrum disorders: recent advances in understanding and management. Healthcare. 2022;10(2366):2366. doi:10.3390/healthcare10122366

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  • Cambodia confirms 12th H5N1 case—Doctors warn early signs of bird flu you shouldn’t ignore – Healthcare News

    Cambodia confirms 12th H5N1 case—Doctors warn early signs of bird flu you shouldn’t ignore – Healthcare News

    Cambodia has confirmed yet another human case of the H5N1 bird flu virus, this time, in a 5-year-old boy from Kampot province. This marks the 12th reported case in the country this year, according to a translated update posted by the Center for Infectious Disease Research and Policy (CIDRAP), University of Minnesota.

    H5N1 bird flu cases have been rising in the US, raising concerns among health experts. The virus can cause serious illness in people. It usually spreads from infected birds or animals, and human-to-human transmission is rare. However, doctors are closely monitoring the situation because the infection can turn severe if not treated early.

    What is H5N1?

    H5N1, commonly known as bird flu, is a type of influenza virus that primarily affects birds but can sometimes jump to humans through direct or indirect contact with infected animals or contaminated environments. The virus has been around for decades, but what makes it dangerous is its high mortality rate in humans.

    Unlike regular flu viruses, which often cause mild to moderate symptoms, H5N1 can trigger severe respiratory illness. According to the World Health Organization (WHO), more than 50 per cent of confirmed human cases of H5N1 have resulted in death.

    What are the early signs of H5N1 infection?

    Initial symptoms of H5N1 are similar to those of the common flu, which makes early detection difficult. Look out for:

    • High fever
    • Cough
    • Sore throat
    • Body aches
    • Fatigue

    As the infection progresses, more severe symptoms may appear, such as:

    • Shortness of breath
    • Chest pain
    • Diarrhea
    • Seizures
    • Altered mental status or confusion

    In some cases, H5N1 can rapidly develop into pneumonia, acute respiratory distress, and multi-organ failure, especially if medical care is delayed.

    The H5N1 US outbreak

    In the US, the virus recently made headlines after being detected in dairy cattle. A few human cases have also been confirmed among farm workers who had direct exposure. Fortunately, the symptoms in these cases were mild. Still, experts warn that the virus is mutating and must be closely watched to prevent a larger outbreak.

    After-effects and complications of H5N1

    People who recover from H5N1 may still experience lingering effects, including:

    • Fatigue
    • Lung damage
    • Depression or anxiety
    • Increased vulnerability to other infections

    These after-effects can last for weeks or even months, depending on how severe the illness was.

    When to see a doctor

    If you’ve been in close contact with poultry and start experiencing flu-like symptoms, it’s important to seek medical care immediately. Let your doctor know about your exposure history, as early antiviral treatment can reduce the severity of the illness and lower the risk of complications.

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  • Prevalence and patterns of multiple long-term conditions among lymphatic filariasis patients in Odisha, India: a community-based cross-sectional study | BMC Public Health

    Prevalence and patterns of multiple long-term conditions among lymphatic filariasis patients in Odisha, India: a community-based cross-sectional study | BMC Public Health

    This is the first study to use a random sample to look into the prevalence of MLTC in patients with lymphatic filariasis. We observed hypertension to be the most common comorbid chronic condition, followed by peptic ulcer disease, visual impairment, arthritis, and diabetes, which is in contrast with the findings of another study conducted among 323 tuberculosis patients in two states of India that reported depression to be the most prevalent condition, followed by diabetes, peptic ulcer disease, and hypertension [29]. Nonetheless, hypertension, diabetes, and peptic ulcer disease had the highest prevalence across both studies that looked at the interface of chronic infectious disease with non-communicable diseases. A probable reason for this could be that patients with lymphatic filariasis share the exposure to the drivers of NCDs in India. Moreover, a few studies also highlight that lymphatic filariasis patients have chronic inflammation due to lymphedema and elephantiasis, which may contribute to the development of cardiometabolic diseases, as proinflammatory immune responses increase the onset of these conditions [30]. Additionally, arthritis attributable to Wuchereria bancrofti has been reported among Indian patients, and its pathogenesis is linked to immune complex deposition or inflammation due to the presence of adult worms in the joint space [31].

    The prevalence of MLTC in our study was greater than that reported in a study conducted in two states of India i.e. Telangana and Odisha, in which the prevalence of multimorbidity among tuberculosis patients was approximately 52% [29]. Additionally, a study conducted among human immunodeficiency virus (HIV) patients reported that the prevalence of multimorbidity was approximately 48% [32]. Nonetheless, the prevalence of MLTC among lymphatic filariasis patients is greater than the global pooled prevalence of multimorbidity, which is approximately 37%, as reported by a recent systematic review based on 126 peer-reviewed studies [33].However, it is worth noting that that the mean age of participants in our study was around 62.1 years which may be one of the reasons for higher prevalence of MLTCs in this study. However, this highlights the need for the assessment of MLTCs among lymphatic filariasis patients to design evidence-based policies in the future to provide continuity of care for these individuals.

    The chances of having MLTC increased with increasing age, which is consistent with the findings of a systematic review that identified older age to be a risk factor for multimorbidity [34], while another systematic review conducted with the aim of identifying risk factors for multimorbidity also showed that increased age was positively associated with multimorbidity [35]. A study conducted in Delhi, India also reported that multimorbidity increased with age, which is in agreement with the findings of our study [36]. This finding highlights two major areas to be focused upon, the first being the demographic shift, which will lead to the addition of an aging population who will require healthcare services. Second, India is attempting to eliminate lymphatic filariasis by 2027 (three years ahead of the global target), which means that further transmission will be interrupted with no new cases [10]. However, patients with existing lymphatic filariasis can survive for many years. Additionally, the burden of MLTC, as indicated by the present study, is high in this group; hence, these individuals will require quality healthcare facilities, thus warranting the strengthening of primary care.

    In our study, males were identified to be at a greater risk of having MLTC than their female counterparts, which is incongruous with the existing MLTC literature in India [21, 22, 36]. All studies to date have reported that females are at greater risk of having MLTC, whereas the present study showed that males are at greater risk of having MLTC, which is a novel finding. A probable reason for this could be the gender roles assigned by society in India and other similar cultures. Despite having lymphatic filariasis, females perform household chores that involve physical activity, whereas males will rest if they are diagnosed with a disease leading to reduced physical activity, increased obesity and other risk factors for developing MLTC.

    We observed that participants with more years of schooling had a greater chance of having MLTC, which is consistent with the findings of a systematic review that also revealed higher education to be directly associated with multimorbidity in Southeast Asia [37]. A probable reason for this could be that with education, people tend to be more health conscious and hence have better chances of being diagnosed and self-reported with chronic conditions. Nonetheless, this finding implies that health literacy should be provided to people with no formal education or fewer years of education.

    We observed that participants who did not work were at a greater risk of having MLTC, which is consistent with the findings of a systematic review that reported that not working or being unemployed increased the risk of having multimorbidity, particularly substance use patterns [38]. Moreover, studies have reported that socioeconomic marginalization increases the risk of multimorbidity, which stands true for patients with lymphatic filariasis, as this disease mostly affects the poorest people of the poor population and often leads to disability, contributing to a loss of livelihood opportunities [20,21,22, 39]. Hence, it is crucial to identify the care-seeking pathways of these patients to make the existing programmes more equitable.

    The most commonly occurring pattern among patients with lymphatic filariasis was hypertension and diabetes, which is congruent with the findings of a systematic review that reported that cardiovascular and metabolic diseases were the most commonly observed multimorbidity patterns in Asia [40]. Our findings also align with the findings of another systematic review showing hypertensive diseases were the most frequent condition in all dyads, followed by gastrointestinal conditions, arthropathies and diabetes mellitus, in India and China [41].

    There was a per unit decrease in self-rated health with an increase in the number of chronic conditions, which is in agreement with the findings of a systematic review that reported a mean decrease of -1.5% to -4.4% (varied depending on the scale used) in health-related quality of life (HRQoL) per added disease [42]. Notably, poor quality of life among our study population was a cumulative effect of MLTC, along with existing disability and functional decline due to chronic lymphatic filariasis, which needs to be addressed.

    Implications for policy and practice

    The findings suggest MLTC to be common among lymphatic filariasis patients, which calls for linking these patients to their nearest Ayushman Arogya Mandir (AAM) or primary healthcare centers formerly known as Health and Wellness Centers for continuity of care. AAMs are established with a vision to strengthen primary care by providing preventive and curative services in the patient’s vicinity with an expanded range of services, especially those curated for chronic conditions. However, lymphatic filariasis is not included in this list despite being prevalent in 339 out of 766 districts across 20 states and Union Territories of India. Hence, the states should be directed to add locally important diseases to the list of AAMs, as health is a state subject in India. This will help in providing quality care to these patients who would eventually help in achieving universal health coverage.

    Individuals with lymphatic filariasis, as seen in our study, mostly belong to deprived strata of society and hence need additional support, which may cause them to incur out-of-pocket expenditures and the risk of impoverishment during treatment. Hence, MLTC among these patients is far more challenging and requires additional efforts to combat. Here, patient-centered holistic care for all ailments at one point/facility is of utmost importance as multiple (self-) referrals to a variety of specialists is not realistic due to disability and low socio-economic status.

    Community health workers (newly recruited cadre of trained nurses) can play a major role in keeping track of these patients by regularly screening for common chronic conditions and managing multiple morbidities through periodical investigations, motivating regular physician visits and helping them in procurement as well as taking their medications. This could be brought under the ambit of the existing Morbidity Management and Disability Prevention (MMDP) component of the Lymphatic Filariasis Elimination Programme by further increasing its scope. Moreover, diabetes (via polyneuropathy) and hypertensive disease (via heart failure ) might aggravate disability of lower extremities in LF patients making effective control of these co-morbidities essential for long term success of LF care.

    Additionally, there is a need for family-based approaches for reducing shared risk factors for MLTCthat may require behavioral change interventions. Future studies should develop interventions to manage MLTC in this population. Addressing disparities in accessing healthcare and improving access to integrated healthcare services at a single platform may help in mitigating the burden of multiple chronic conditions among lymphatic filariasis patients [43].

    Strengths and limitations

    This novel study has a number of strengths, including the use of a random sample, the assessment of common MLTCs, a high response rate, and associations with a number of risk factors, but it was conducted in only one state of India. We used a pre-validated tool to assess MLTC, which was also one of the strengths of this study, but our data were limited by self-reported chronic conditions that may have resulted in recall bias. Nonetheless, we triangulated the self-reported data with those of community healthcare workers. We did not include phenotypic measurements, which was another limitation of the study. Additionally, we could not establish causality, as our study was cross-sectional in nature.

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  • Post-cancer exercise plan lowers death and recurrence rates, according to a study |

    Post-cancer exercise plan lowers death and recurrence rates, according to a study |

    Regular exercise has numerous benefits, including reducing the risk of chronic diseases like diabetes and heart disease. A recent study published in the New England Journal of Medicine found that cancer patients who participated in a structured exercise program had better outcomes, living longer without cancer recurrence and having a lower risk of death. The study’s findings suggest that exercise should be a key component of cancer treatment, helping patients live longer and healthier lives. By incorporating exercise into their care plan, cancer patients can potentially improve their survival rates and reduce the risk of recurrence of cancer.

    The study tells how regular exercise lowers the risk of cancer recurrence

    The clinical trial, conducted across multiple countries, followed nearly 900 patients diagnosed with stage II and stage III colon cancer. Participants had completed surgery and chemotherapy and were split into two groups: one group received structured exercise coaching twice monthly for the first six months, then monthly for three years, and the other group received usual care without specific exercise guidance.

    The results of the study were striking

    Those in the exercise group had a 28% lower risk of cancer recurrence or developing a new cancer. More significantly, they had a 37% lower risk of death from any cause during an eight-year follow-up period. Cardiovascular fitness and endurance also improved in the exercise group, as shown by a better six-minute walk test and VO₂ max results.

    Experts suggest structured exercise should be a part of a cancer recovery plan

    As CNN spoke with Dr. Leana Wen, the potential for exercise to revolutionize cancer treatment became clear. The study’s findings are significant, showing that exercise can substantially reduce the risk of recurrent or new cancers and death. According to Dr. Wen, these results could change cancer treatment protocols. Currently, patients often receive general advice to exercise after treatment, but many don’t receive structured support. She suggests that patients should have “exercise prescriptions” and healthcare providers should track their progress. Insurance companies might also consider covering health coaching for cancer patients, potentially reducing the need for costly treatments.

    Why exercise helps fight cancer

    According to Dr. Leana Wen, exercise doesn’t just make you feel good, it alters your body at a cellular and hormonal level, helping to:

    • Regulate hormones like insulin and estrogen that are linked to cancer growth.
    • Reduce chronic inflammation, which contributes to cancer progression.
    • Enhance immune function, supporting your body’s ability to detect and destroy abnormal cells.
    • Support a healthy body weight, which is a major factor in cancer recurrence.
    • This multi-layered impact makes exercise a powerful, non-pharmacological tool for improving cancer outcomes.


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  • U.S. researchers develop AI model to improve sudden cardiac death prediction – news.cgtn.com

    U.S. researchers develop AI model to improve sudden cardiac death prediction – news.cgtn.com

    1. U.S. researchers develop AI model to improve sudden cardiac death prediction  news.cgtn.com
    2. Multimodal AI to forecast arrhythmic death in hypertrophic cardiomyopathy  Nature
    3. This Model Beats Docs at Predicting Sudden Cardiac Arrest  Medscape
    4. US researchers develop AI to better predict sudden cardiac death  tripuratimes.com
    5. AI predicts patients likely to die of sudden cardiac arrest  Johns Hopkins University

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  • Inflammatory Markers as Predictors of Diabetes Mellitus in Patients wi

    Inflammatory Markers as Predictors of Diabetes Mellitus in Patients wi

    Introduction

    As an ancient disease, tuberculosis (TB) has existed for thousands of years since the origin and evolution of mankind.1 Pulmonary tuberculosis (PTB) is caused by the infection with Mycobacterium tuberculosis (Mtb), which primarily spreads among people through the air and affects the lung.2 PTB was classified as a Global Health Emergency by the World Health Organization (WHO) in 1993, and it was the world’s second leading cause of death from a single infectious agent, after Coronavirus disease 2019 (COVID-19) in 2022. According to the statistics of the WHO, the number of people who developed TB was approximately 10.6 million and the number of people newly diagnosed with TB was 7.5 million in 2022, of which TB patients newly diagnosed in China were approximately 748,000 (accounted for 7.1%),3 ranking third among the 30 countries with a high TB burden.4 Although the global incidence of TB has been well controlled, it still poses a severe challenge to global public health because of the poor prognosis caused by such as rising resistance rates and the severe complications. Currently, the epidemic situation of TB epidemics in China remains very serious. The risk factors for tuberculosis include overcrowding, poverty, malnutrition, and immunosuppression including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).5 Diabetes mellitus (DM) is increasingly being recognized as an independent risk factor for tuberculosis.6,7 DM is a chronic metabolic disease resulting from a combination of genetic and environmental factors.8,9 The main pathogenesis of DM is an absolute or relative reduction in insulin secretion, which affects the metabolism of carbohydrates, proteins, fats, electrolytes, and water, resulting in chronic organ injury and dysfunction.10,11 DM epidemic has grown worldwide and is associated with high morbidity and mortality.12 During recent decades, the prevalence of DM has been sharply increased owing to an aging population, urbanization, physical inactivity and obesity caused by lifestyle changes.13 According to International Diabetes Federation (IDF) reports in 2019, the number of patients with DM worldwide was as high as 463 million, with the most rapid increase occurring in low- and middle-income countries (LMICs).14 Simultaneously, these countries face serious TB situations. The rising prevalence of diabetes may be contributed to the persistently high incidence of TB in countries with a high TB burden.

    The bidirectional association between PTB and DM is well established, and the relationship between them is bidirectional. Studies have shown that the overall risk of PTB in patients with DM is three times higher than in the general population,15,16 and the prevalence of DM among PTB patients ranges from 1.9% to as high as 35%.17 Nearly 80% of adult DM cases are expected to occur in developing countries, and the convergence of these two epidemics may lead to an increased incidence of PTB.18 The patients with PTB and DM lead to treatment failure, longer sputum conversion time to normal, relapse, increased risk of developing multidrug-resistant tuberculosis (MDR-TB), and high mortality.19 According to the WHO PTB screening guidelines, uncontrolled diabetes doubles the risk of TB treatment failure, relapse, and death.20 There are significant challenges in the treatment and care of patients with DM and TB. Systematic evaluation of Asian countries showed that the prevalence of diabetes among PTB patients is between 5% and 50%, while the prevalence among DM patients in developing Asian countries is 1.8–9.5 times the general population.21 China has experienced the largest dual DM and TB epidemic globally, and DM combined with PTB poses a major public health problem. The incidence rates of DM and PTB comorbidity (PTB-DM) among Chinese individuals increased from 19.3% to 24.1%.22 Therefore, clarifying the diagnostic value of clinical laboratory indices for PTB-DM is of great clinical significance.

    Inflammation has long been identified as an essential component of both DM and TB.23,24 DM increases the risk of TB infection by inducing chronic inflammation and immune deficiency. TB infection aggravates abnormal blood glucose through inflammatory responses, forming a bidirectional worsening cycle of “DM-tuberculosis”. Inflammation is the core mechanism connecting diabetes and tuberculosis, running through the entire process of disease occurrence and development. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) have been found to be useful markers for the diagnosis and differential diagnosis of TB,25,26 and DM related disease and prognosis.27–29 In addition, system immune inflammation index (SII) and system inflammation response index (SIRI) are two markers of system immune inflammation, and their links to DM are being revealed.30,31 However, the association between immunoinflammatory markers and PTB-DM remains unclear. In the present study, we aimed to investigate whether these immunoinflammatory markers and clinical features are associated with the risk of DM in patients with PTB. It would provide a scientific basis for the prevention and control of PTB in patients with DM.

    Materials and Methods

    Study Population

    A total of 1106 patients with PTB were selected as the case group at Meizhou People’s Hospital between April 2016 and December 2020 were retrospectively. During the study period, 326 cases with PTB (observation group) of DM patients with PTB were randomly selected, and compared with 780 PTB patients without DM during the same period (control group). PTB patients were diagnosed according to the criteria of “WS 288–2017 Pulmonary Tuberculosis Diagnosis”32 by microbiological diagnosis. The diagnostic criteria for T2DM were as follows: (1) There were typical clinical symptoms of DM (polydipsia, polydipsia, polyuria, polydipsia, and unexplained weight loss), and random intravenous plasma glucose ≥11.1mmol/L; or fasting blood glucose (FBG) ≥7mmol/L; or blood glucose level at the 2-hour oral glucose tolerance test ≥11.1mmol/L.33 Patients with leukemia, HIV infection, septic shock, organ failure, malignancy, or mental disorders; those with diseases that can affect immune function, such as AIDS, malignant tumor, chronic hepatitis, cirrhosis, primary kidney disease, renal failure, blood disease, renal transplantation, gastrectomy, or use of hormones and immunosuppressants within four months were also excluded. Clinical data, including age, sex, cough, fever, respiratory symptoms, expectoration, and extrapulmonary tuberculosis, were collected from all study subjects. This study was approved by the Human Ethics Committee of Meizhou People’s Hospital.

    Data Collection

    Data on clinical characteristics, laboratory outcomes, and inflammation indices were systematically collected from the medical record system of Meizhou People’s Hospital. Clinical symptoms recorded included fever (defined as a body temperature ≥38°C, measured using a standard clinical thermometer), sputum production (assessed based on the presence and quantity of sputum, categorized as mild, moderate, or severe), shortness of breath/difficulty breathing (evaluated using clinical assessment tools such as the Respiratory Distress Observation Scale or the Modified Borg Dyspnea Scale), and extrapulmonary tuberculosis (diagnosed based on clinical presentation, imaging studies, and laboratory confirmation). Laboratory outcomes included erythrocyte sedimentation rate (ESR), measured using the Westergren method and reported in millimeters per hour (mm/hr); C-reactive protein (CRP), quantified using high-sensitivity CRP assays and reported in milligrams per liter (mg/L); and complete blood count (CBC), analyzed using automated hematology analyzers to record absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), and platelet count (reported as cells per microliter). Inflammation indices were calculated as follows: neutrophil-to-lymphocyte ratio (NLR=ANC/ALC), platelet-to-lymphocyte ratio (PLR=Platelet count/ALC), monocyte-to-lymphocyte ratio (MLR=AMC/ALC), systemic immune-inflammation index (SII=Platelet count × ANC/ALC), and systemic inflammation response index (SIRI = AMC × ANC/ALC). These indices were used to assess systemic inflammation and immune response.

    Data Processing and Statistical Analysis

    SPSS 26.0 and GraphPad Prism software were used for the statistical analysis of the experimental data. Data with non-normal distributions were described as median and interquartile range (IQR) values, and evaluated using the Mann–Whitney U-test. Categorical variables were represented numerically and as percentages, and were compared using the chi-squared test. Univariate regression analysis (Pearson) and Spearman correlation analysis were used to analyze the relationship between the correlation test indicators. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values of ESR, NLR, MLR, PLR, SII, and SIRI for differentiating whether pulmonary tuberculosis patients developed DM or not, and the area under the ROC curve (AUC) was calculated. In addition to the logistic regression model, a 95% confidence interval (95% CI) was used to determine the diagnostic probability of PTB combined with DM. The significance level was set at P < 0.05.

    Results

    General Characteristics in PTB Patients with or without DM

    A total of 1106 patients diagnosed with PTB were enrolled, including 326 (29.5%) PTB patients with DM and 780 (70.5%) without DM. The clinical characteristics of the two patient groups of patients are shown in Table 1. The majority of PTB patients were male (84.6%), and most had no fever (83.7%) or shortness of breath/difficulty breathing (76.9%). There were 39 (3.5%) had concurrent extrapulmonary tuberculosis. The differences in gender distribution, age distribution, and clinical manifestations including fever, shortness of breath/difficulty breathing, and expectoration, and extrapulmonary tuberculosis between the two groups were not statistically significant. The level of ESR (44.00 (22.00, 80.00) vs 30.00 (12.00, 54.00), p<0.001) was higher while the levels of NLR (4.61 (2.90, 7.64) vs 6.43 (3.62, 11.20), p<0.001), MLR (0.50 (0.31, 0.75) vs 0.64 (0.38, 1.00), p<0.001), PLR (197.38 (135.53, 299.16) vs 248.44 (149.74, 396.43), p<0.001), SII (1333.06 (712.37, 2289.35) vs 1603.72 (844.73, 3224.20), p<0.001), and SIRI (3.13 (1.73, 6.42) vs 3.93 (2.00, 8.79), p<0.001) were lower in PTB-DM patients than those in non-DM PTB patients.

    Table 1 Comparison of Clinical Features and Peripheral Blood Inflammatory Markers Between Non-DM PTB Group and PTB-DM Group

    Logistic Regression Analysis of Related Factors for DM in Patients with PTB

    Logistic regression analyses of the association between PTB-DM and related factors were performed (Table 2). Univariate logistic regression analysis showed that PTB patients with DM were more likely to have a higher ESR (odds ratio (OR): 1.024, 95% CI: 1.018–1.30, p<0.001), lower levels of NLR (OR: 0.964, 95% CI 0.945–0.983, p<0.001), MLR (OR: 0.440, 95% CI 0.319–0.607, p<0.001), PLR (OR: 0.998, 95% CI: 0.998–0.999, p<0.001), and SIRI (OR: 0.965, 95% CI: 0.944–0.987, p=0.002). Clinical features such as gender, age, fever, expectoration, shortness of breath/difficulty breathing, extrapulmonary tuberculosis, and other blood indicators were not associated with DM in PTB patients. Multivariable logistic regression analyses indicated that a high ESR (OR: 1.024, 95% CI: 1.018–1.030, p<0.001), low levels of MLR (OR: 0.352, 95% CI 0.145–0.856, p=0.021), and PLR (OR: 0.997, 95% CI: 0.995–0.999, p=0.003) were independent risk factors for DM in patients with PTB.

    Table 2 Logistic Regression Analysis of Related Factors for DM in Patients with PTB

    The Value of Different Indexes and Their Combined Detection in the Differential Diagnosis of PTB-DM

    To analyze the discriminating ability of these inflammatory parameters in the PTB-DM versus PTB groups, ROC curves for the related parameters were plotted (Figure 1). Results revealed the AUC value of ESR was 0.619 (95% CI: 0.590–0.648, cut-off value: 45.5), MLR was 0.600 (95% CI 0.570–0.629, cut-off value: 0.765), PLR was 0.584 (95% CI: 0.554–0.613, cut-off value: 239.615), ESR+MLR was 0.689 (95% CI: 0.661–0.716), ESR+PLR was 0.694 (95% CI: 0.666–0.721), MLR+PLR was 0.610 (95% CI: 0.574–0.645), and ESR+MLR+PLR was 0.712 (95% CI 0.685–0.739), respectively. The PTB-DM and PTB groups could be well discriminated by the combination of indicators ESR, MLR and PLR, with sensitivity and specificity of 63.8% and 70.6%, respectively. Table 3 presents the comprehensive features of ESR, MLR, and PLR for the diagnosis.

    Table 3 The Diagnostic Efficacy of ESR, MLR, PLR, and Their Combination on PTB-DM

    Figure 1 The ROC curve of ESR, MLR, PLR, and their combination on PTB-DM.

    Discussion

    This study compared the characteristics of the PTB patients with and without DM. Among the patients diagnosed with PTB, 29.5% had DM. The results showed that there were no significant differences in clinical manifestations including gender distribution, age distribution, fever, shortness of breath/difficulty breathing, expectoration, and extrapulmonary tuberculosis. ESR was higher, while NLR, MLR, PLR, SII, and SIRI were lower in PTB-DM patients than in non-DM PTB patients. In addition, high ESR and low MLR and PLR were independent risk factors for PTB-DM.

    The high prevalence of DM creates more pressure on the PTB burden. DM increases the risk of PTB, posing a significant threat to the public health, particularly, in countries with a high burden of both diseases.34 Thus, experts have raised concerns regarding the co-prevalence of PTB and DM. PTB patients with DM often have nutritional deficiency, leading to body injury and disease recurrence, which ultimately affects prognosis and increases the risk of mortality.22,35 In many studies on the Chinese population, male sex and advanced age were identified as factors associated with PTB with DM;36–38 however, in this study, age and gender were not statistically different. In addition, the presence of symptoms such as fever, cough, sputum, shortness of breath, difficulty breathing, or extrapulmonary tuberculosis was similar between patients with and without DM. Therefore, we cannot estimate whether TB patients are at risk for diabetes based on simple clinical manifestations.

    Chronic infection with Mtb can induce hematopoietic stem cell proliferation and immune changes, which in turn cause changes in the proportion of lymphocyte and other cells.39 There is a correlation between the immune status (including ESR, NLR, MLR, PLR, SII, and SIRI) and clinicopathological features of PTB patients,40 which are some of the more novel inflammatory markers currently available.41 ESR is a sensitive marker of the inflammatory response, and is often used to obtain information regarding disease progression and retrogression.42 The ESR value was significantly higher in tuberculosis patients with tuberculosis, and was even elevated in 98% of the patients.43,44 MLR has been proven to be associated with the diagnosis of PTB and the predictive value of MLR in patients with tuberculosis, and higher MLR levels are associated with more severe disease and poorer prognosis.45,46 The importance of PLR has been emphasized as a marker in some disorders such as non-small-cell lung cancer, acute coronary syndrome, end-stage renal disease, and so on.47,48 PLR could be developed as a valuable maker for identifying tuberculosis infection in chronic obstructive pulmonary disease (COPD) patients,40 indicating that PLR is a convenient, and easily measured prognostic indicator. In this study, the inflammation index of ESR was significantly increased, MLR, PLR, SII, and SIRI were significantly decreased in the PTB patients with DM compared to those in PTB patients alone. Further regression analysis indicated that the ESR, MLR, and PLR were relevant factors for PTB-DM. It indicates that a higher ESR and lower MLR and PLR may indicate PTB-DM.

    However, these indicators fluctuate to a certain extent and do not have the significance of an independent diagnosis in patients with PTB-DM. Hence, these factors need to be combined to improve the diagnostic value of PTB complicated by DM. Thus, we analyzed the diagnostic efficacy of ESR, MLR, and PLR in PTB patients with DM, and found that ESR has low sensitivity and MLR has low specificity, while PLR has slightly higher sensitivity and specificity. In addition, we also analyzed the sensitivity and specificity of ESR, MLR, and PLR combined tests, and found that the combined tests of these indicators were superior to the single indicator in both sensitivity and specificity. Therefore, the combined detection of ESR, MLR, and PLR is helpful in the differential diagnosis of PTB with DM and non-DM PTB. The results of this study provide a convenient method for clinicians to assess the risk of developing DM in patients with PTB.

    This study offers valuable insights into the relationship between hematological markers and DM in patients with PTB, though there are opportunities for further exploration. Firstly, the relationship between these indicators and the severity of DM has not been studied. Future research could investigate the association between inflammation markers (ESR, MLR, and PLR) and the severity of DM. Secondly, the research subjects included in this study were from a single medical structure. Due to the incomplete representativeness of the research subjects, the application of the results of this study in other populations was limited. So, expanding the study to multiple centers would provide a more diverse sample, enhancing the generalizability of the results. Thirdly, this study only analyzed the differences in ESR, NLR, MLR, PLR, SII, and SIRI levels, and did not investigate the role of other factors in the occurrence of DM in patients with PTB, especially some confounding factors. Lastly, collecting data at multiple time points, rather than a single pre-treatment measure, would allow for a more comprehensive analysis of the dynamic changes in these hematological indicators and their clinical significance throughout the treatment process. Addressing these factors would provide a more complete understanding of the role of these markers in DM and PTB, which depends on more research in the future.

    Conclusion

    ESR, MLR, and PLR were associated with the risk of DM in patients with PTB. In particular, combined tests of these indicators were superior to the single indicator in both sensitivity and specificity in the diagnosis of DM among patients with PTB. It provides a convenient method for clinicians to assess the risk of developing DM in patients with PTB. Specifically, during the treatment of tuberculosis, it is necessary to closely monitor the changes in the patient’s blood sugar, adjust the diabetes treatment plan in a timely manner, and reduce the fluctuations in blood sugar caused by inflammation. Secondly, for pulmonary tuberculosis patients with abnormal inflammatory indicators, their association with diabetes should be emphasized. Through anti-inflammatory treatment or immunomodulatory measures, insulin resistance can be improved, immune balance can be regulated, and the risk of disease progression can be reduced.

    Data Sharing Statement

    The data that support the findings of this study are available from the corresponding author upon reasonable request.

    Ethics Approval and Consent to Participate

    The study was approved by the Ethics Committee of Medicine, Meizhou People’s Hospital number. All participants signed informed consent in accordance with the Declaration of Helsinki.

    Acknowledgments

    The author would like to thank other colleagues whom were not listed in the authorship of Meizhou People’s Hospital for their helpful comments on the manuscript.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Funding

    This study was supported by the Science and Technology Program of Meizhou (Grant No.: 2019B0202001).

    Disclosure

    The authors declare that they have no competing interests.

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  • Male Breast Cancer: Evaluating the Current Landscape of Diagnosis and

    Male Breast Cancer: Evaluating the Current Landscape of Diagnosis and

    Introduction

    Male breast cancer is a rare malignancy, accounting for 0.5–1% of all breast cancer cases worldwide, with approximately 2,500 new cases diagnosed annually in the United States.1 Clinical presentation most often involves a painless breast mass, and approximately half of patients have lymph node involvement at diagnosis.2 Diagnostic evaluation relies on mammography and ultrasonography when a breast mass is suspected, since routine screening is not recommended for asymptomatic men.3,4 Pathologic confirmation is essential, and genetic counseling and testing are recommended for all men with breast cancer due to the high prevalence of hereditary mutations.5,6 Treatment strategies for MBC are largely extrapolated from female breast cancer (FBC) due to the paucity of prospective, male-specific trials.2,5 According to Corrigan et al, male patients accounted for only 0.087% of participants across 131 breast cancer clinical trials.7 Mastectomy remains the most common surgical approach, though breast-conserving surgery with sentinel lymph node biopsy is a safe alternative in selected cases.4,6,8 Adjuvant endocrine therapy, primarily tamoxifen for 5–10 years, is the mainstay for hormone receptor–positive disease, while an aromatase inhibitor (AI) should only be used in combination with a gonadotropin-releasing hormone analog if tamoxifen is contraindicated.5,8,9 The role of chemotherapy and targeted therapies is determined by standard indications, with gene expression assays such as Oncotype DX increasingly used to guide adjuvant therapy decisions.4,5,10 This comprehensive narrative review synthesizes the latest research on MBC using literature searches of current best practices and aims to provide an up-to-date summary of diagnostic and therapeutic approaches, highlight knowledge gaps, and underscore the need for increased inclusion of men in breast cancer research and clinical trials.

    Epidemiology of MBC

    MBC is a rare malignancy, globally accounting for approximately 0.6–1% of all breast cancer cases and about 0.3% of all cancers in men.5 Incidence rates for MBC have increased modestly over recent decades, with age-adjusted rates rising from 0.85 per 100,000 in 1975 to 1.19 per 100,000 in 2015 in the United States.11 MBC patients are diagnosed at an older age than FBC patients (mean age 67 vs 62 years) and often present with more advanced disease.5 Comorbidities are more prevalent in MBC due to the older age at diagnosis, and these comorbid conditions may contribute to the observed differences in overall survival between men and women.12 In addition, men with breast cancer have an increased risk of second primary malignancies, including melanoma, prostate, and gastrointestinal cancers, which further complicates management and impacts long-term outcomes.12 Mortality rates for MBC are also higher than for FBC; large registry-based studies demonstrate that men have a 1.3- to 1.5-fold increased risk of death compared to women, even after adjustment for age, stage, and treatment.11,13 A population-based cohort study of patients from the United Kingdom diagnosed with breast cancer demonstrated the survival probability for females one, five, and ten years after diagnosis was 95.1%, 80.2%, and 68.4%, and for males 92.9%, 69.0%, and 51.3%.14 Despite propensity score matching for age, stage, and treatment, some studies report that the survival gap between MBC and FBC narrows, but does not disappear, signaling that comorbidities and other non-cancer-related factors are contributors to excess mortality in men.12,13,15,16 These findings underscore the need for tailored approaches to diagnosis and management in MBC, with particular attention to comorbidity assessment and optimization.

    Risk Factors for MBC

    Several risk factors have been identified for the development of MBC, including genetic mutations, hormonal imbalances, Black ethnicity, exposure to radiation, and family history.5 The most well-known genetic risk factors for MBC are BRCA2 and BRCA1 mutations, which are inherited in an autosomal dominant manner. Genetic predisposition to breast cancer is broadly similar between men and women, but there are important sex-specific features. BRCA2 is the predominant high-penetrance gene in MBC, while BRCA1 is more prominent in FBC.17 Recent large-scale analyses have affirmed that BRCA2 pathogenic variants confer a substantially higher risk of MBC than BRCA1, with relative risks of 44.0 for BRCA2 and 4.3 for BRCA1.18 Both BRCA1 and BRCA2 are associated with increased risks of pancreatic and stomach cancers, with BRCA2 further linked to elevated prostate cancer risk.18 A large Italian case-control study demonstrated that pathogenic variants in genes other than BRCA1/2, particularly moderate-penetrance genes such as PALB2 and ATM, are also associated with a significantly increased risk of MBC.19 PALB2 variants conferred a sevenfold increased risk (OR: 7.28), and ATM variants a fivefold increased risk (OR: 4.79).19 Carriers of these variants were more likely to have a personal or family history of cancer, supporting the use of multigene panel testing in MBC patients to guide risk management and clinical decision-making.19 Klinefelter syndrome also increases the risk of MBC due to the extra X chromosome, which increases estrogen levels.20 Other etiologies of hyperestrogenism in men that increase the risk of breast cancer include obesity, liver disease, or exogenous hormone exposure.1 Finally, family history of breast cancer is among the compelling risk factors for MBC, with approximately 15–20% of cases having a family member with the disease, compared with 7% in the general male population.21

    Clinical Presentation

    MBC is typically diagnosed at an older age than FBC, with average ages of 68 and 62 years, respectively.22 MBC is also diagnosed at more advanced stages, with larger tumors and more nodal involvement, and up to 47% of men having axillary nodal involvement at the time of diagnosis.22,23 The delayed stage at diagnosis may be due to limited awareness of presenting symptoms, which most commonly include a painless, firm breast lump and may be accompanied by nipple retraction, discharge, bleeding, or skin ulceration.22 Most MBC tumors are hormone-positive and ductal in etiology, reflecting the lower incidence of lobular carcinoma in men.22 For unknown reasons, papillary histology appears to be more frequent in men than in women.1 Other histological subtypes of breast cancer are rare in men.

    Diagnostic Approaches

    Mammography and ultrasonography are commonly used in the evaluation of MBC. The American College of Radiology recommends ultrasound for men aged <25 years with an indeterminate palpable mass, and mammography is performed if suspicious or indeterminate features are noted on the ultrasound.24 For men aged ≥25 years with an indeterminate palpable breast mass, a diagnostic mammogram is useful for distinguishing benign from malignant breast masses.24 Carrasco et al demonstrated in a series of 638 patients that ultrasonography had a lower sensitivity of 88.9% compared to 95% for mammography in distinguishing benign from malignant disease but had a similarly high specificity of 95.3%.25 There is no relevant literature regarding the use of breast MRI for the initial evaluation of MBC; therefore, it is not indicated for evaluation of palpable breast masses in men.24 Once a suspicious lesion is detected, a core needle biopsy or fine-needle aspiration is essential to confirm histopathological diagnosis.

    Treatment Strategy for Early-Stage Disease

    Surgical treatment for early-stage MBC is based on early-stage FBC and has evolved over time. After reports demonstrated that sentinel lymph node sampling was as feasible and accurate in MBC as it was in FBC, it slowly replaced axillary lymph node dissection as the standard of care for staging MBC with a clinically node-negative axilla.26,27 Similarly, mastectomy has traditionally been considered the standard surgical approach for male breast cancer, whereas lumpectomy is less commonly performed due to limited breast tissue and the typical proximity of tumors to the nipple–areolar complex. However, a review of The Surveillance, Epidemiology, and End Results (SEER) database of MBC patients from 1983 to 2009 who underwent either mastectomy or lumpectomy demonstrated that lumpectomy was not independently associated with worse breast cancer-specific survival (odds ratio 1.09, 95% confidence interval 0.87–1.37) or overall survival (odds ratio 1.12, 95% confidence interval 0.98–1.27) after controlling for age, race, stage, grade, and administration of radiotherapy.28 In a retrospective analysis of 8,445 MBC patients from the National Cancer Database, breast-conserving therapy (BCT) was associated with improved survival compared to mastectomy.29 Additionally, a prospective multi-institutional cohort study reported low postoperative complication rates with BCT, comparable to those seen in the FBC population.30 While the underlying mechanisms of these associations require further investigation, current evidence suggests that BCT is a safe and feasible treatment option in MBC, offering clinically meaningful survival benefits.

    Guidelines for adjuvant radiotherapy in early-stage MBC are limited, and postoperative radiation therapy is frequently underutilized in patients with MBC. Cardoso et al demonstrated that 45% of MBC patients treated with BCT, regardless of nodal status, and 30.7% of patients with lymph node positive tumors treated with mastectomy were not provided adjuvant radiotherapy.31 Generally, adjuvant radiation therapy should be provided according to the guidelines developed for FBC as multiple studies have suggested a clinically meaningful benefit for radiation therapy in men with early and locally advanced stages.32 For example, a SEER database analysis of males with stage I–III breast cancer between 2010 and 2015 demonstrated that postoperative radiation therapy was associated with improved survival, especially after breast-conserving surgery, for those with four or more positive lymph nodes or large primary tumors (T3/T4).33 Similarly, a 2018 meta-analysis of 29 studies involving 10,065 men (23% with T4 tumors, 50% node-positive, and 93% having undergone mastectomy) found that 64% received adjuvant radiation, which was associated with improved locoregional control, overall survival, and distant metastasis-free survival.34 Further investigations are necessary to improve our understanding and wider utilization of adjuvant radiotherapy for MBC.

    In recent years, gene expression profile testing has guided adjuvant chemotherapy decisions and estimated the risk of distant recurrence in women with hormone receptor-positive, HER2 negative early-stage breast cancer. The use of Oncotype DX and other genomic assays in MBC is based on extrapolation from FBC data, due to the rarity of MBC and the lack of male-specific clinical trial evidence.10 A SEER database review of this assay in 322 MBC patients demonstrated a larger proportion of men had an RS >31 and RS <10 compared to women, suggesting differences in tumor biology between men and women; the analysis also reported that increasing RS risk categories (RS <18, 18–30, and ≥31) were associated with decreased 5-year breast cancer-specific survival (99%, 96%, and 81%, respectively) and overall survival (93%, 86%, and 70%, respectively).35 Among those with an RS ≥31, 67% of MBC patients and 71% of FBC patients received chemotherapy in the SEER analysis.35 Although these results suggest the prognostic value of genomic assays in MBC, there is a lack of clinical trial data demonstrating the benefits of chemotherapy. Therefore, chemotherapy with or without HER2-targeted therapy should be recommended for males with breast cancer according to the guidelines for females with breast cancer.36

    The majority of male breast cancers are hormone receptor–positive, with approximately 99% expressing estrogen receptors (ER) and 81% expressing progesterone receptors (PR).31 In early-stage MBC with hormone receptor positive tumors, tamoxifen, a selective estrogen receptor modulator, is the most utilized adjuvant endocrine therapy, and has been demonstrated to reduce recurrence risk and improve overall survival based on observational studies.37,38 A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group showed that tamoxifen significantly reduced the risk of recurrence in patients with MBC, corresponding to its efficacy in FBC. In contrast, retrospective studies have demonstrated worse survival outcomes among patients with MBC treated with an aromatase inhibitor (AI) than among those treated with tamoxifen.39 Thus, AI monotherapy is not preferred in MBC, although men with hormone receptor positive breast cancer who have contraindications to tamoxifen may be offered a gonadotropin-releasing hormone (GnRH) antagonist with an AI, which may help overcome the lack of estradiol suppression with AI monotherapy.12 Although there are no clinical trials on early-stage MBC to guide the optimal duration of adjuvant endocrine therapy, extrapolation from FBC studies suggests that the duration should be at least five years, with an extended duration of ten years in men with a high risk of recurrence.40 Adjuvant cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can also be used in MBC with a high risk of recurrence, as demonstrated in the MonarchE trial, which enrolled 21 male patients (0.7%) in the intent-to-treat population and showed that abemaciclib with endocrine therapy resulted in absolute improvements in 3-year invasive disease-free survival and distant recurrence-free survival rates of 5.4% and 4.2%, respectively.41

    Treatment Strategy for Advanced-Stage Disease

    According to NCCN guidelines, the management of advanced breast cancer in men is generally aligned with established approaches used in women. Metastatic hormone receptor positive disease is treated with endocrine therapies such as tamoxifen, a GnRH agonist combined with an AI, or fulvestrant.5 Unlike FBC, concurrent administration of a GnRH analog is recommended when an AI is used in MBC.36 A prospective, randomized Phase II study in MBC found that combining an AI with a GnRH agonist led to greater suppression of serum estradiol levels compared to historical controls treated with AI monotherapy.9 In addition, population studies have shown improved responses with the combination of an AI and a GnRH analog over AI monotherapy, likely due to the inadequate suppression of testicular estrogen production by AIs alone.42 Collectively, these findings support the use of combined AI and GnRH agonist therapy in men. A pooled literature analysis also demonstrated the efficacy of fulvestrant monotherapy, with a median progression-free survival of 5 months, comparable to efficacy in females.43 Finally, evidence supporting the use of CDK4/6 inhibitors in men remains limited, as the pivotal clinical trials evaluating these agents have predominantly included female participants. Kraus et al demonstrated that palbociclib combined with endocrine therapy was associated with a longer median treatment duration and higher real-world response rates compared to endocrine therapy alone, with a safety profile consistent with that observed in women, supporting the use of CDK4/6 inhibitors in metastatic hormone receptor positive MBC.44 Another retrospective study of MBC patients treated with either palbociclib (n=16) or ribociclib (n=9), in combination with a GnRH analog and either fulvestrant or an AI, reported a median progression-free survival of 10 months in the second-line setting—comparable to outcomes observed in the MONALEESA-3 and PALOMA-3 trials involving postmenopausal women.45–47 Other therapies, such as mTOR inhibitors, PIK3CA inhibitors, or other specific targeted agents, lack specific clinical trial data for MBC, and recommendations regarding these agents are extrapolated from studies of female participants and real-world data. Similarly, recommendations regarding chemotherapy, HER2-targeted agents, immunotherapy, and PARP inhibitors in advanced MBC have been extrapolated from FBC.48

    Conclusion

    In summary, MBC is a rare disease that is typically diagnosed at an older age and more advanced stage than FBC, with distinct risk profiles and unique challenges in diagnosis and management. Current therapeutic strategies for MBC are largely extrapolated from FBC due to the underrepresentation of men in clinical trials and the scarcity of male-specific prospective or randomized data. This review is limited by the current evidence base on MBC, which is largely derived from retrospective and registry-based studies characterized by small sample sizes and substantial heterogeneity across study design and outcome reporting. These methodological limitations reduce the generalizability of findings and hinder the ability to draw definitive conclusions about optimal management strategies in men. Furthermore, important biological and clinical differences between MBC and FBC—such as hormone receptor status, genetic predisposition, and tumor biology—may not be fully captured or addressed by current treatment paradigms that are primarily derived from studies in women. Future research should prioritize inclusion of men in clinical trials, promote multinational data collaboration, and support the development of tailored management strategies that reflect the distinct biology and clinical course of MBC. Addressing these gaps will be essential to improving outcomes and quality of life for men diagnosed with this disease.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in the drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

    Funding

    The authors did not receive support from any organization for the submitted work.

    Disclosure

    The authors report no conflicts of interest in this work.

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  • Impact of Comprehensive Nursing on the Respiratory System and Lungs of

    Impact of Comprehensive Nursing on the Respiratory System and Lungs of

    Traumatic brain injury (TBI) is a common yet serious trauma, which can have a significant impact on the physiological and psychological health of patients.1 Following TBI, some patients may require tracheostomy to ensure airway patency and facilitate adequate gas exchange.2 Tracheostomy is not a cure for TBI but rather a means to address the severe impact of brain injury on respiratory system function.3 However, studies4 have indicated that patients undergoing tracheostomy after TBI are at risk of various serious complications, including respiratory system infections, pulmonary inflammation, and neurological dysfunction. These complications may exacerbate the patient’s condition, prolong hospitalization, and increase the risk of mortality. Therefore, effective nursing care and management for such patients are crucial. Given the complexity of care required for TBI patients undergoing tracheostomy, interdisciplinary collaboration among physicians, nurses, respiratory therapists, and rehabilitation specialists is essential to ensure comprehensive and continuous care. Integrating diverse professional perspectives and skill sets can enhance patient monitoring, optimize airway management, and improve rehabilitation outcomes.

    Comprehensive nursing has shown significant advantages across various diseases and medical conditions.5,6 However, its application in patients with tracheostomy following TBI remains insufficiently studied. Thus, this study aims to investigate the effects of comprehensive nursing on the respiratory system and lungs of patients undergoing tracheostomy after TBI, with the aim of providing more effective nursing strategies and guidance for clinical practice.

    Data and Methods

    Basic Information

    A retrospective analysis of clinical data was conducted on 87 patients who underwent tracheostomy after TBI in our hospital from January 2022 to January 2024. Inclusion criteria: ① Confirmed history of TBI and imaging examination; ② Age ≥ 18 years, gender unspecified; ③ Time from injury to admission < 24 h; ④ Glasgow Coma Scale (GCS)7 score ≤ 5–12 points; ⑤ Meeting the surgical indications for tracheostomy (presence of aspiration or positive sputum culture within 24 h of admission) and successful completion of tracheostomy; ⑥ Postoperative requirement for mechanical ventilation; ⑦ Relative stability of the patient’s condition; ⑧ Complete clinical data available for analysis. Exclusion criteria: ① Death upon arrival or death within 24 h due to severe hemorrhagic shock or severe trauma; ② Severe organ dysfunction; ③ Severe cardiovascular or cerebrovascular diseases; ④ Severe infections, endocrine disorders, or malignant tumors; ⑤ Immunodeficiency, coagulation, or hematopoietic abnormalities; ⑥Severe malnutrition; ⑦ Prolonged deep coma; ⑧ Lung dynamic compliance affected by trauma-induced conditions such as pneumothorax, sternum, or rib fractures; ⑨ Allergic reactions or relevant contraindications to the treatment and intervention methods adopted in this study. Patients were divided into a control group (n = 43), which received routine nursing care, and an intervention group (n = 44), which received comprehensive nursing care, based on the nursing interventions received. The comparability of baseline data between the two groups (P>0.05) is shown in Table 1. This study was approved by the Medical Ethics Committee of The First Affiliated Hospital, Jiangxi Medical College. Informed consent was obtained from all study participants. All the methods were carried out in accordance with the Declaration of Helsinki.

    Table 1 Comparison of Basic Information

    To minimize the impact of potential confounding variables, efforts were made to ensure consistency in medical support across both groups. All patients were managed within the same neurosurgical intensive care unit during the study period, with standardized physician involvement and respiratory therapist coverage. Staffing levels, including nurse-to-patient ratios, were maintained according to institutional ICU protocols and did not differ between groups. However, detailed quantitative data on staffing ratios, physician contact hours, and respiratory therapist involvement were not separately recorded for each patient. To minimize variability in interdisciplinary care, all patients were treated in the same neurosurgical intensive care unit under uniform institutional protocols. Standardized access to respiratory therapists and attending physicians was maintained across both groups throughout the study period. However, quantitative metrics such as individual contact hours or staffing ratios were not separately recorded. Involvement of speech-language pathologists was limited, given that the majority of patients had moderate to severe impairment of consciousness (GCS ≤ 12), and thus were not appropriate candidates for routine speech or swallowing interventions during the early postoperative phase.

    Methods

    All surgeries were performed by the same team of doctors and nursing staff, and preoperative nursing methods were consistent. Although no formal checklist was used, all comprehensive nursing interventions were implemented according to predefined procedures outlined in departmental nursing guidelines to ensure consistency across cases. Postoperatively, the control group received routine nursing interventions, including intervention of the patient’s condition, monitoring of vital signs, nasal feeding care, skin care, manual percussion, and suctioning as needed. The intervention group received comprehensive nursing interventions, including the following components: (1) Ward Placement: Where conditions permitted, patients were preferably placed in single rooms to minimize the risk of cross-infection. The period from 3 to 7 days postoperatively is the peak period for complications. During this time, special attention was paid to the cleanliness of the ward environment and the patient’s bedridden position. Semi-recumbent positioning was recommended to maintain airway patency, reduce the risk of respiratory and pulmonary complications, and improve patient oxygen saturation. Ultraviolet disinfection was performed at least twice daily for approximately 30 minutes each time. Meanwhile, nursing staff ensured appropriate room temperature and humidity and regularly opened windows for ventilation to maintain fresh indoor air. Additionally, strict control of the number of visitors was enforced, and all visitors were required to wear isolation gowns to reduce the potential harm of external viruses to the patients. (2) Strict Aseptic Operation: Nursing staff must disinfect themselves and wear isolation gowns when performing tracheostomy tube changes and other routine care for patients. All tools and equipment used must be disinfected, and disposable items must be replaced immediately to prevent reuse. After completing the nursing procedure, nursing staff needed to disinfect again to prevent cross-infection. (3) Airway Humidification: Airway humidification plays an indispensable role in reducing the risk of patient-related complications. Physiological saline was used for airway humidification and changed regularly every day. Patients underwent airway humidification four times daily, with professional nursing staff monitoring each session to assess respiratory conditions based on the patient’s symptoms during humidification. If the patient experienced increased respiratory rate, increased respiratory resistance, and wheezing, suctioning was performed immediately. (4) Enhanced Positioning and Percussion: To improve patient recovery, nursing staff repositioned patients every 2 hours and performed percussion before suctioning. During percussion, nursing staff used the back of their hand to form a semicircle with four fingers together, percussing from top to bottom and around the lungs to enhance the repositioning effect. Suctioning was performed from inner to outer, with gentle and swift movements during each suctioning to reduce or avoid discomfort to the patient. (5) Observation of Vital Signs: Postoperatively, nursing staff regularly observed patients’ vital signs, including pupil size and light reaction. During suctioning, nursing staff also observed other vital signs such as changes in facial color, pupil constriction, and heart rate. If the patient showed any abnormal signs, suctioning was immediately stopped, and the doctor was contacted promptly for further management. (6) Pain Management: Nursing staff must be proficient in postoperative pain management methods, clarify the use and dosage of analgesic drugs, and take necessary preventive measures for pain management. Patients and their families should be informed about the impact of emotions on postoperative pain and helped to alleviate negative emotions through psychological intervention. (7) Health Education and Daily Care: Nursing staff regularly conducted health education sessions to educate patients and their families about disease-related treatment knowledge and precautions. In terms of daily care, nursing staff regularly assessed patients’ health and recovery status, developed nutrition diet plans and daily rehabilitation training programs, and provided personalized services such as dietary care and rehabilitation training based on the patient’s specific condition. For comatose patients, nursing staff and family members called the patient’s name every 2 hours to promote awakening. For conscious patients, comfort and encouragement were provided, and detailed explanations of postoperative rehabilitation were given to patients’ families. Health education was conducted through various means such as language, text, audio, and visual aids to answer patients’ and families’ questions and provide positive feedback to enhance treatment confidence. Massage and acupressure were used to relieve pressure on patients’ pressure points, and air mattresses were used to alleviate compression. Additionally, protective rails were added bedside to prevent accidents such as falling out of bed. Supplementary Table 1 summarizes the comprehensive nursing protocol.

    The selection and prioritization of comprehensive nursing interventions were based on a review of departmental nursing guidelines, clinical consensus among senior ICU nursing staff, and evidence from prior studies on postoperative care in tracheostomized patients. Interventions were prioritized according to their relevance to common complications observed in the early postoperative period, such as pulmonary infection, airway obstruction, and impaired consciousness. Specific measures (eg, aseptic procedures, airway humidification, and frequent repositioning) were implemented early and intensively during the critical window of 3–7 days post-tracheostomy, identified as the peak risk period for complications. Psychological support and education were emphasized throughout hospitalization to promote patient engagement and recovery.

    Observational Indicators

    Perioperative Indicators

    Including postoperative monitoring time, duration of mechanical ventilation, duration of tube placement, length of ICU stay, and total length of hospital stay were compared between the control and intervention groups.

    Hemodynamic Indicators

    Preoperatively and at 2 weeks postoperatively, using non-invasive hemodynamic monitoring equipment to measure patients’ systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and oxygen saturation (SpO2) levels.

    Sputum Clearance and Suctioning

    Including: daily sputum volume, frequency of suctioning, duration of suctioning.

    Neurological Function

    Pre-intervention and post-intervention, assessing patients’ neurological function using the Clinical Neurological Deficit Scale (CSS),8 which includes eight dimensions: consciousness, language, facial muscles, upper limb muscle strength, lower limb muscle strength, hand muscle strength, gaze function, and walking ability. The scale consists of 10 items with scores ranging from 0 to 45 points, with higher scores indicating worse neurological deficits.

    Prognosis

    Pre-intervention and post-intervention, evaluating patients’ prognosis using the Glasgow Outcome Scale (GOS)9 and the Acute Physiology and Chronic Health Evaluation II (APACHE II).10 GOS scores range from 1 to 5, with higher scores indicating better prognosis; the APACHE II scale includes 12 items scored from 0 to 4 points in a negative direction, with a total score of 71 points, and higher scores indicating poorer prognosis.

    Pain Assessment

    Pre-intervention and post-intervention, assessing patients’ pain using the Visual Analog Scale (VAS),11 where 0 indicates no pain and 10 indicates unbearable severe pain, with scores positively correlated with pain intensity.

    Complications

    Including: pulmonary infection, cerebral edema, airway injury, sputum blockage, bleeding.

    Statistical Analysis

    GraphPad Prism 8.0 software (GraphPad Software Inc., San Diego, CA, USA) was used for graphing, and SPSS 20.0 was used for data analysis. Descriptive statistics for continuous data were presented as mean ± standard deviation (), and normality was assessed using the Shapiro–Wilk test. For variables meeting the normality assumption (P > 0.05), group comparisons were performed using the independent samples t-test; categorical data were presented as n (%), and analyzed using the chi-square test. P-value < 0.05 indicated statistical significance. Given the number of outcome measures assessed, no formal correction for multiple comparisons (eg, Bonferroni correction) was applied. The primary aim of the analysis was exploratory and hypothesis-generating rather than confirmatory. Therefore, findings should be interpreted with caution, particularly for secondary outcomes, as the risk of type I error may be increased due to multiple statistical tests.

    Results

    Comparison of Perioperative Indicators

    The intervention group showed significantly shorter postoperative monitoring time, duration of mechanical ventilation, tube placement, ICU stay, and total hospital stay compared to the control group (P < 0.05), as shown in Table 2. In addition, no significant differences were found between the two groups in the prevalence of common comorbidities, including chronic obstructive pulmonary disease, diabetes mellitus, uremia, liver cirrhosis, coronary artery disease, and stroke (P > 0.05), indicating comparability in baseline health status.

    Table 2 Comparison of Perioperative Indicators

    Comparison of Hemodynamic Indicators

    As shown in Figure 1, in the intervention group, SBP and DBP levels decreased after two weeks, while SpO2 levels increased more significantly than that in the control group (P < 0.05).

    Figure 1 Comparison of Hemodynamic Indicator ().

    Notes: Comparison with preoperative levels, *P < 0.05; denotes mean ± standard deviation.

    Comparison of Sputum and Suctioning Conditions

    The intervention group had a higher daily sputum volume compared to the control group, with lower suctioning frequency and duration (P < 0.05), as shown in Table 3.

    Table 3 Comparison of Sputum and Suctioning Conditions

    Comparison of Neurological, Prognostic, and Pain Conditions

    As illustrated in Figure 2, post-intervention GOS scores significantly increased in both groups compared to baseline, whereas CSS, APACHE II, and VAS scores significantly decreased. The intervention group exhibited a greater magnitude of improvement across all indices (P < 0.05).

    Figure 2 Comparison of Neurological, Prognostic, and Pain Conditions (, score).

    Notes: Compared to before intervention, *P < 0.05; between groups, #P < 0.05. denotes mean ± standard deviation.

    Comparison of Complications

    The incidence of complications in the intervention group (9.09%) was lower than that in the control group (27.91%) (P < 0.05), as shown in Table 4. To ensure that the observed differences in complication rates were not confounded by pre-existing differences in patient condition, baseline severity was assessed by comparing the prevalence of common comorbidities between groups. No significant differences were found in the rates of chronic obstructive pulmonary disease, diabetes mellitus, uremia, liver cirrhosis, coronary artery disease, and stroke (P > 0.05), as reported in Section 2.1. This suggests that the two groups were comparable in terms of baseline health status, thereby strengthening the validity of the association between the comprehensive nursing intervention and the lower incidence of complications.

    Table 4 Comparison of Complications [n (%)]

    Discussion

    Patients with TBI are characterized by rapid onset, severe condition, rapid changes, and a high incidence of postoperative complications.12,13 The nursing care for these patients has certain specificity, and any problem in any link may lead to unnecessary losses for patients, even resulting in a vegetative state or death. Despite continuous improvements in modern medical equipment and treatment methods, patients with TBI still face potential life-threatening risks postoperatively. Tracheostomy, as an indispensable basic technique in emergency medicine for TBI, effectively saves patients’ lives. However, its application can also affect the normal physiological functions of some respiratory tract components, such as humidification, heating, and partial defense functions, thereby affecting the patient’s coughing and sputum ability, increasing the accumulation of respiratory secretions, and easily leading to complications such as pulmonary infections, which are one of the main reasons for the death of patients with TBI.14,15 Therefore, it is crucial to prevent complications in tracheostomized patients. Regarding the changes in hemodynamic parameters, the observed reductions in SBP and DBP in the intervention group may reflect improved cardiovascular stability and a reduction in sympathetic nervous system activity, which is crucial in critically ill patients. These changes are particularly important in the context of TBI, where managing blood pressure and preventing further cardiovascular stress are essential to improving patient outcomes. Additionally, the increase in SpO2 level observed in the intervention group suggests better pulmonary function and oxygenation, likely due to improved airway management and respiratory care provided as part of the comprehensive nursing intervention. Improved SpO2 level is clinically significant as it reduces the risk of hypoxia-related complications, such as organ dysfunction or secondary brain injury, and may contribute to faster recovery and shorter duration of mechanical ventilation. Finding targeted nursing interventions that match the specific characteristics of patients’ diseases is of great significance and clinical value. Comprehensive nursing, as an important part of comprehensive treatment measures, focuses on patients as the core, comprehensively improves patients’ physiological, psychological, and social functions through multidisciplinary cooperation and multilevel interventions.16 In patients with TBI who undergo tracheostomy, comprehensive nursing not only includes direct care for the respiratory system, such as proper airway management and assisted ventilation with a respirator, but also involves comprehensive assessment and intervention of the patient’s overall condition, such as pain management, nutritional support, and bed turning. Through this comprehensive nursing approach, the occurrence of complications can be minimized, and the quality of life and recovery rate of patients can be improved to the greatest extent.

    In the present study, although SpO2 levels in the control group increased two weeks after surgery, this should not be interpreted as a better outcome compared to the intervention group. The increase observed in the control group was relatively modest and may have reflected the natural recovery process or the effects of standard respiratory support. In contrast, the intervention group exhibited a more significant improvement in SpO2 level, which was consistent with better airway management, more efficient sputum clearance, and reduced suctioning frequency and duration under the comprehensive nursing model. These factors likely contributed to enhanced oxygenation efficiency and respiratory stability, thereby reflecting the superiority of the intervention over routine care. It is important to recognize that the observed improvements in clinical outcomes are not solely attributable to nursing care in isolation. Rather, comprehensive nursing interventions function synergistically in a broader interprofessional framework. In the context of tracheostomy management, respiratory therapists play a critical role in optimizing ventilatory support, maintaining airway patency, and facilitating sputum clearance through advanced techniques and equipment management. Moreover, speech-language pathologists are essential for assessing swallowing function and initiating communication strategies, particularly in patients recovering from neurological injury. Physicians and other allied health professionals also contribute significantly through diagnostic oversight and therapeutic decision-making. The effectiveness of the comprehensive nursing model, therefore, should be understood as integrated within this multidisciplinary ecosystem, thereby enhancing patient safety, recovery, and quality of care.

    Importantly, the improved outcomes observed in this study should be interpreted in the context of interprofessional collaboration, which has emerged as a cornerstone of modern tracheostomy care. The intervention implemented here reflects principles advocated by the Global Tracheostomy Collaborative (GTC), which emphasize multidisciplinary teamwork, standardized protocols, and patient-centered care as key drivers for improving safety and outcomes in tracheostomized patients.17,18 Notably, the comprehensive nursing model employed was not limited to nursing actions in isolation but was embedded within a collaborative care structure involving respiratory therapists, speech-language pathologists, physicians, and other allied health professionals. This team-based approach is supported by clinical practice guidelines and systematic reviews that highlight the effectiveness of interprofessional tracheostomy teams in reducing complications, improving communication, and facilitating earlier decannulation.19,20 Therefore, the success of the intervention group in terms of shorter hospital stays, improved hemodynamic stability, and reduced complication rates likely stems not only from high-quality nursing care, but also from the synergistic contributions of an interdisciplinary care model aligned with evidence-based global standards. A study21 found that factors such as postoperative tracheostomy decannulation and pain in patients with TBI can increase stress responses, causing abnormal fluctuations in hemodynamics, thereby prolonging maintenance and treatment time. In this study, a comprehensive nursing model was applied for intervention in the postoperative care of patients with craniocerebral trauma undergoing tracheostomy. The results showed that compared to routine care, the comprehensive nursing model significantly shortened the postoperative monitoring time, mechanical ventilation time, tracheostomy duration, ICU stay, and total hospital stay for patients. This is conducive to maintaining postoperative hemodynamic stability in the body. These results share commonalities with previous related studies.22,23 The reason for this may lie in the fact that comprehensive nursing promotes patient recovery from multiple aspects, such as timely encouragement and comfort for awakening patients, and softly waking up comatose patients; strengthening postoperative patient health education, providing suctioning, pain management, and other care to ensure patient airway patency, and accelerate postoperative recovery. Regarding prognosis, the results of this study showed that the CSS scores, APACHE II scores, and VAS scores in the intervention group were lower than those in the control group, while the GOS score was higher than that in the control group, indicating that comprehensive nursing intervention can effectively improve the quality of patient prognosis and alleviate patient suffering. The reason for this lies in the fact that the comprehensive nursing model formulates nursing measures from multiple aspects such as postoperative pain management, early rehabilitation training, psychological counseling, etc., to keep patients in a more comfortable physical and mental state after surgery.24 Nurses will guide family members to accompany patients, urge patients to undergo early rehabilitation training, maintain a comfortable environment in the ward, enhance cognition through health education, cooperate with treatment, and improve prognosis quality. In addition, patients after tracheostomy often suffer from significant pain. Comprehensive nursing will provide corresponding analgesic treatment based on the patient’s pain situation, while counseling patients on negative emotions, formulating pain management content, observing tracheal intubation conditions, etc., thereby ensuring that the patient’s vital signs remain stable, which is beneficial to the recovery of bodily functions. Regarding complications, the results of this study showed that the incidence of complications in the intervention group was lower than that in the control group. This result suggests that comprehensive nursing can reduce the risk of patient-related complications to a certain extent. Patients in a coma after surgery have no autonomous consciousness, and neurological and brain tissue damage. Tracheostomy can easily lead to infections in the respiratory tract and lungs.25 In comprehensive nursing, nurses will closely monitor the intubation situation and provide corresponding interventions throughout the process, thereby reducing the risk of complications such as sputum plug blockage, airway damage, and lung infection. In addition, comprehensive nursing interventions will also alleviate pressure on patient pressure points through massage, gentle pressing, etc., help patients avoid pressure injuries, and assist patients in recovering as quickly as possible through diet, rehabilitation exercises, etc., thereby further reducing the risk of complications.

    However, this study has several limitations that should be acknowledged. Firstly, the relatively small sample size might limit the statistical power and generalizability of the findings. Secondly, the retrospective study design might increase the risk of information bias and treatment selection bias. Specifically, the absence of randomization and prospective data collection might introduce selection bias, thereby compromising the internal validity and making it more difficult to draw definitive causal inferences. Thirdly, as a single-center study, the findings may not be widely generalizable to other healthcare settings with different patient populations or clinical practices. Finally, individual differences, such as baseline health status, lifestyle factors, and adherence to treatment were not fully considered, which might influence the observed outcomes. Future studies should aim to overcome these limitations by employing prospective, multicenter designs with larger and more diverse samples, while also accounting for patient-level variability to enhance the credibility and applicability of the results.

    Conclusion

    The findings of this retrospective study suggested that comprehensive nursing care could be associated with improved outcomes in patients undergoing tracheostomy after TBI. Patients in the intervention group demonstrated better recovery trajectories, including more stable hemodynamic parameters, reduced pain levels, fewer complications, and enhanced neurological and prognostic indicators. While these results are encouraging, it is important to recognize that, due to the non-randomized and retrospective nature of the study design, definitive conclusions about causality cannot be drawn. Nevertheless, the observed associations indicate that comprehensive nursing, implemented in a multidisciplinary framework, may contribute to more favorable perioperative and recovery outcomes. Future prospective and controlled studies are warranted to validate these findings and further explore the causal mechanisms underlying the observed improvements.

    Disclosure

    The authors report no conflicts of interest in this work.

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