Category: 8. Health

A 34-year-old woman of childbearing age came to the local hospital for her annual well-woman visit, and an ultrasound revealed a cystic solid pelvic mass. The patient was subsequently admitted to our hospital. The patient exhibited no symptoms indicative of abdominal discomfort, vaginal bleeding, change in bowel habits, or change in urination. The absence of clinical manifestations precluded determination of its onset time or progression timeline. Moreover, she had undergone one cesarean section and had no history of uterine fibroids. Furthermore, the patient reported no prior use of hormonal treatments or oral contraceptive pills. Additionally, she had no significant history or family history of hypertension or diabetes mellitus, and no history of smoking or alcohol consumption. Her vital signs were within normal limits. A specialized gynecological examination was conducted, during which the uterus was found to be anteriorly positioned, of normal size and shape, and free of tenderness. Additionally, no palpable mass was identified in the left adnexal region, and no tenderness was observed. On the right side, a mass of approximately 5.0 × 6.0 cm was detected in the adnexal region, exhibiting distinct boundaries, a smooth surface, and no evidence of pressure pain.

The blood routine, blood coagulation, liver and kidney function, electrolytes, and glucose levels were within the normal limits. The tumor marker alpha-fetoprotein (AFP) was elevated at 10.90ng/ml. The remaining tumor markers, carcinoembryonic antigen (CEA), carcinoma antigen (CA) 15 − 3, CA 19 − 9, and CA 12 − 5, were within the normal range.

Transvaginal ultrasound demonstrated a cystic solid echogenic mass of approximately 5.2 × 4.5 × 5.7 cm in the right adnexal region with well-defined borders and peripheral blood flow signal in the form of punctate streaks. The bilateral ovaries were visible, and the uterus appeared normal. Given concerns for ovarian malignancy, contrast-enhanced pelvic CT was performed, demonstrating an irregular cystic solid hypodense shadow of about 6.2 × 5.3 cm in the right adnexal area, with a slightly unclear border. Figure 1(A) displays the arterial phase, while Fig. 1(B) indicates that the mass has sufficient blood supply. Contrast enhancement revealed mild, uniform enhancement of the cystic wall and inner solid components, without nodular hyperenhancement. The intracystic fluid region was not of homogeneous density. Rectal walls were normal, with no pelvic lymphadenopathy. Chest CT prior to surgery was unremarkable.

The patient was a 34-year-old female of childbearing age with a well-defined cystic solid pelvic mass of unknown nature, indications for surgery, and the patient’s desire for surgery. There were no contraindications to surgery, adequate preoperative preparation, and laparoscopic exploration was performed. Intraoperatively, a small amount of yellowish fluid was visible in the pelvis. The anterior position, morphology, and size of the uterus were normal, and no masses were seen in the bilateral adnexa. The peritoneum was intact, and a retroperitoneal mass of about 5.0 × 6.0 cm in size with irregular morphology and a smooth surface was observed on the surface of the right retroperitoneal iliac vessels and ureter. Additionally, anomalous vessels were identified (Fig. 2(A)). A thorough examination of the pelvic, abdominal, and bowel walls did not reveal any evidence of abnormal nodules. The tumor is located on the surface of the ureter and iliac vessels, necessitating meticulous separation to avoid damage. Therefore, we opened the peritoneum close to the root of the tumor, and the tumor margins were clear. The specimen was then removed in a specimen bag (Fig. 2(B)). Intraoperative cytopathology suggested that the tumor was a spindle cell tumor, which was a smooth muscle tumor with cystic degeneration. Macroscopically, the tumor was a 5.0 × 6.0 cm cystic-solid mass with swirling structures visible in profile. In addition, a cystic cavity with clear fluid was observed (Fig. 2(C)). Microscopically, the lesion consisted of spindle-shaped smooth muscle cells with bluntly rounded nuclei at both ends, uniformly fine chromatin, and no apparent anisotropy or nuclear division. Some areas showed cystic degeneration and the tumor cells’ fascicular arrangement. This finding confirmed the intraoperative frozen section diagnosis of a spindle cell tumor, a smooth muscle tumor with cystic changes(Fig. 3(A)). Moreover, the excised margins of the mass were free of tumor cells. Immunohistochemical staining showed tumor cells positive for desmin (Fig. 3(B)), smooth muscle actin, estrogen receptor (ER), and progesterone receptor(PR). However, they were negative for the cluster of differentiation (CD) 34 and CD117, findings consistent with a diagnosis of pelvic retroperitoneal leiomyoma. Notably, we also observed the occurrence of cystic degeneration in tumor cells(Fig. 3(C)).

The patient recovered uneventfully and was discharged on postoperative day 4. Therefore, the patient is required to undergo gynaecological ultrasound examinations at the outpatient clinic on a 3 to 6-month basis post-surgery. No evidence of tumor recurrence was observed on the ultrasound six months after surgery. However, it is important to note that regular follow-up is still necessary.

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Computed tomography (CT) colonography has been shown to be both cheaper and clinically more effective than multitarget stool DNA (mt-sDNA) testing for population-level colorectal cancer screening, according to peer-reviewed research published in the journal of the Radiological Society of North America.

Colorectal cancer is the world’s second leading cause of cancer-related mortality. Routine examination of the colon and rectum enables early removal of precancerous polyps, thereby reducing the need for late-stage therapies and their associated higher costs and greater risk to patients. In response to rising incidence among younger adults, the United States Preventive Services Task Force, and several professional bodies, have now recommended that screening programmes commence at 45 years of age.

“Conventional optical colonoscopy remains the dominant screening test in the United States, yet it is the most expensive and invasive option,” said lead author Dr Perry J. Pickhardt, John R. Cameron Professor of Radiology and Medical Physics at the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Dr. Perry emphasised that recent Medicare coverage expansions have improved access to less invasive modalities, including mt-sDNA testing – which analyses stool for cancer-specific biomarkers – and CT colonography, which employs imaging technology to render non-invasive visualisation of the colon polyps and tumours.

Using a Markov model, the investigators simulated colorectal disease progression in 10,000 individuals aged 45 at baseline, assuming perfect adherence to recommended screening and follow-up until 75 years. Without screening, 7.5 per cent of the cohort developed colorectal cancer.

Both strategies substantially lowered disease incidence versus no screening, but CT colonography achieved a 70–75 per cent reduction, compared with 59 per cent for mt-sDNA. Cost-effectiveness was measured in quality-adjusted life-years (QALYs). Mt-sDNA yielded an incremental cost of nearly US$9,000 per QALY gained, well below the accepted US$100,000 threshold; CT colonography, by contrast, was cost-saving relative to no screening.

Because advanced polyps ≥10 mm pose the greatest malignant risk, the authors evaluated a hybrid CT-based pathway: three-year CT colonography surveillance for small polyps (6–9 mm) and colonoscopic referral only for lesions ≥10 mm. This approach offered the best balance of cost and clinical benefit. Referring all polyps ≥6 mm for colonoscopy was not cost-effective, owing to higher procedural expenses and minimal QALY gains.

“Among safe, minimally invasive options, CT colonography prevents and detects colorectal cancer more effectively – and at lower overall cost – than stool DNA testing,” Dr Pickhardt said.

“Furthermore, CT colonography can simultaneously screen for extracolonic conditions such as osteoporosis and cardiovascular disease.”

The findings bolster the case for wider adoption of CT colonography within national screening programmes, particularly where resource allocation and patient comfort are paramount.

Workers spend long hours at the workplace, limiting opportunities to learn about healthy lifestyles and nutrition. A multimodal nutrition intervention can thus improve their health factors. This study showed that after 6 months, mean weight, BMI, total cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure significantly decreased, while HDL cholesterol increased (p < 0.001). However, fasting blood sugar and liver enzymes did not change significantly.

In line with these results, Hassani et al. reported significant reduction in weight and BMI after three months of nutritional education among workers with dyslipidemia, though their intervention was shorter and limited to education [20]. A systematic review of 23 studies, confirmed the efficacy of workplace weight management programs. It is noteworthy that a majority of the studies reviewed predominantly originated from North America and Europe, reflecting a concentrated geographic focus on these continents. [21]. Also a meta-analysis study investigated the effect of dietary interventions in the workplace on obese and overweight employees, the results of which indicated a significant reduction in weight, BMI, and total cholesterol and a non-significant reduction in systolic and diastolic blood pressure [22]. Another study showed that the worksite wellness program improves blood pressure and total cholesterol control, but has no improvement in weight control [11]. In another study involving a 4-month nutritional education intervention with 75 male workers, the findings indicated a significant reduction in fasting blood glucose levels, total cholesterol, and LDL cholesterol after the intervention was implemented [17]. In their assessment of nutritional interventions conducted in the workplace, Steyn and colleagues concluded that interventions focusing on altering nutritional knowledge and dietary behaviors lead to improved health and employee behaviors [23]. On the other hand, in the study of Song et al., although the multicomponent workplace wellness program improved some behavioral factors, no significant changes were observed in clinical factors including blood glucose levels, blood cholesterol levels, blood pressure, and BMI [24]. Like the present study, the results of other studies show the effect of these interventions on the mentioned factors, although some contradictions in the results can be explained by the difference in the methods of the interventions, the duration of studies and the number of participants.

Contrary to expectations, no significant decrease in fasting blood sugar of the participants was observed in the current study. It seems that the high impact of food intake the day before the blood test on this factor can justify it. If the amount of hemoglobin A1 C, which is less influenced by people’s recent food intake, was measured, more complete results would be obtained.

One of the aspects of our intervention was nutrition education for the workers. Nutrition education interventions have been shown to increase nutritional awareness among workers in various studies. Workplace-based nutrition education, such as integrating nutrition education, improving factory canteen services, and enhancing health services, effectively enhances workers’knowledge and practices of balanced nutrition and healthy habits [15]. Nutrition counseling was one of the other aspects of the present study. Workplace nutritional interventions, including counseling by Registered Dietitian Nutritionists (RDNs), have been associated with positive impacts on dietary habits and weight loss among employees [25]. Additionally, nutritional counseling has been found to contribute to reductions in anthropometric measurements, glycemia indices, lipid profiles, and insulin resistance, ultimately improving overall health indicators [26]. Another of our interventions was the nutritional improvement of the company’s food menu. Modifying the factory food menu can significantly impact workers’health factors [27]. Implementing nutritional interventions and changes in the food service system can lead to improved weight management among staff, as evidenced by a decrease in BMI and weight in the intervention group [28]. Additionally, the satisfaction level with the food service increased following menu modifications, indicating a positive impact on workers’dietary habits and overall well-being [29]. Therefore, optimizing the factory food menu through nutritional interventions and system-level modifications can contribute to enhancing workers’health and well-being, ultimately benefiting both employees and employers.

The current study has several advantages. Unlike many studies in this field, which limit themselves to one-dimensional intervention, in this study, we tried to achieve the maximum effect by using education, counseling, and diet changes by creating a multimodal intervention. Providing nutrition education to the workers’families was also one of the strengths of this study, which, considering the important role of the family in the workers’lifestyle, helped them to comply more with the intervention. In the present study, all educational programs, consultations, interviews, and measurements were done by a trained physician and registered dietitian. Also, all the biochemical parameters were measured by trusted laboratories and checked again by the physician. The type of this study is prospective follow-up and has an acceptable sample size compared to similar studies in this field. The study maintained a high retention rate, with only 4 out of 1097 participants (0.36%) excluded due to cancer diagnosis and none due to leaving employment, both unrelated to the nutritional intervention, suggesting minimal risk of attrition bias. However, this investigation had several limitations. The absence of a control group in this study is one of these issues which prevents definitive attribution of all observed changes to the nutritional intervention alone. This was unavoidable due to ethical and practical considerations, and historical control data from similar populations were unavailable. To address this, we calculated effect sizes (Cohen’s d) for all continuous outcomes, which ranged from small to medium (Tables 3 and 4). These consistent and meaningful effect sizes suggest that the observed improvements in anthropometric and laboratory parameters are unlikely to result solely from natural variation or unmeasured confounders, supporting the intervention’s effectiveness. Nevertheless, without a control group, alternative explanations (e.g., temporal trends) cannot be fully ruled out, and future studies with comparative designs could further confirm these findings. Furthermore, the lack of evaluation of participants’dietary intake and their nutritional knowledge before and after the intervention is acknowledged. While our study did not include formal assessments of dietary changes using methods such as food frequency questionnaires or dietary recall, this limitation impacts the direct correlation between observed health improvements and specific dietary modifications. To enhance future research in this area, incorporating comprehensive dietary assessments like food frequency questionnaires or dietary recall methods is recommended. A notable limitation of our study is the absence of hemoglobin A1 C (HbA1c) measurements, which could have provided valuable insights into long-term glycemic control. Unfortunately, due to resource constraints, we were unable to assess HbA1c levels in this study. we recommend that future studies prioritize the inclusion of HbA1c measurements to enhance the depth of analysis and strengthen the robustness of conclusions drawn regarding glycemic status. The study focuses on male workers (> 99%) due the factory’s predominantly male workforce, not intentional bias,, potentially limiting the generalizability of the findings to female populations. It is important to acknowledge this demographic imbalance as a notable limitation. Future research efforts could aim to include a more diverse sample to enhance the overall applicability and relevance of the study’s outcomes across different gender groups. A limitation of this study is the lack of adjustment for potential time-varying confounders. However, given the uniform application of the nutritional intervention across the entire population and the absence of reported external influences, we believe the impact of such factors was minimal.

The findings of this study show the significant effect of multimodal nutrition intervention on the improvement of anthropometric indicators and lipid profiles of Arfa Iron and Steel Company workers. These results suggest that implementing similar interventions (encompassing nutritional education, modification of the factory dining menu to include healthier options, healthy cooking method education, and nutritional counseling) in similar industrial settings may have the potential to improve the overall health and well-being of workers, potentially enhancing their productivity levels. The positive outcomes observed in this study highlight the feasibility of such interventions as a health promotion strategy within comparable occupational contexts. However, given the absence of a control group and other methodological limitations, broader application to diverse workplace environments should be approached cautiously. Further research incorporating control groups and extended follow-up periods is essential to validate these findings and assess the sustained effectiveness of such interventions across varying work settings.

Training sessions on Go.Data for health professionals from various states of Brazil to support the response to outbreaks and health emergencies [2022]. © Pan American Health Organization, Brazil.

Brazil, a vast country covering approximately 8.5 million km², is divided into 27 states and 5570 municipalities across five regions: North, Northeast, Central-West, Southeast, and South. These regions are home to about 212 million people. Given this extensive territory, implementing new technologies and innovations to ensure quality healthcare access throughout the country is a significant challenge. 

The COVID-19 pandemic exposed several gaps in the public health system, particularly the need for an effective contact tracing strategy. In Brazil, there were no specific tools available for this purpose, prompting many localities to rely on monitoring spreadsheets or develop their own strategies. 

In response, the first implementations of the Go.Data tool began in August 2021. Developed by the World Health Organization (WHO) in collaboration with partners at the Global Alert and Response Network (GOARN), Go.Data is a software designed to support outbreak response, particularly contact tracing efforts. It enables users to identify exposed individuals, monitor their health status, and visualize transmission chains. Two municipalities stood out in their use of the tool, applying it to investigate contacts in various situations, including within educational institutions. In these instances, more than 30 000 contacts were recorded. The implementation of the tool facilitated standardized contact tracing, allowing multiple professionals to collaborate concurrently. Furthermore, it supported the real-time creation of transmission chains, thereby offering crucial support in informed decision-making. 

Following the success of various initiatives and the emergence of mpox in Brazil in 2022, efforts were made to implement state-level servers with support from the National Council of Health Secretaries. As a result, approximately 15 states installed the tool within their infrastructures, expanding its use across different contexts. Subsequently, the Ministry of Health also adopted the tool, integrating it into its infrastructure while complying with all necessary security protocols and requirements. This marked a significant milestone for Brazil, enabling all states to access the tool. 

In 2023, once the server was established at the Ministry of Health, Go.Data was utilized to monitor individuals exposed to animals with avian influenza. During this process, a centralized server was recommended to consolidate information, allowing 15 states to access the same server. This model represented progress in hierarchical access management and the geographic distribution of information, thereby strengthening epidemiological surveillance in the country. 

Building on this experience, since 2024, the Ministry of Health, in partnership with the states, has been working to structure the national adoption of the tool in the context of measles and other diseases. To support this effort, two focal points have been trained in each state to ensure a timely response to epidemiological investigations in November 2023 by Pan American Health Organization (WHO Regional Office for the Americas or PAHO) and the Ministry of Health. 

Epidemiology team from the state of Rio de Janeiro using Go.Data in response to an outbreak [2025]. © Pan American Health Organization, Brazil.

The implementation of Go.Data has streamlined contact investigations by providing a single online platform with regional access permissions, which enhances tracking and monitoring efforts. Brazil has successfully integrated this tool into its official case notification system, ensuring alignment with national guidelines. Furthermore, Go.Data is equipped with integrations for Power BI and Shiny, which improve data analysis and visualization capabilities. The development of guides and training courses focused on operational procedures has standardized processes and strengthened user competencies. 

Felipe Lopes Vasconcelos, a national consultant for PAHO, reflects on the tool’s progress in the country. “We had the opportunity to understand the various realities at the state level in Brazil. Before introducing Go.Data, contact tracing was slow and lacked standardization. Today, we have already seen significant advances at different levels, and I believe we are moving toward a more timely response to outbreaks,” Felipe says.  

The technical support provided by the WHO has been crucial in this process. Since 2020, the WHO team has offered continuous assistance, addressing all questions, needs, and suggestions from Brazil, which has contributed to the tool’s development over the years. 

 

 

Professor Fornstedt is internationally recognized for his pioneering contributions to the field of separation science, particularly in advancing our understanding of liquid chromatography theory and its practical applications in complex molecular analysis.

With the growing demand for precision in therapeutic development—especially in the realm of oligonucleotide-based drugs—analytical scientists face mounting challenges in resolving and characterizing structurally similar and high-mass molecules. In Part 1, Professor Fornstedt shared his insights on how modern chromatographic techniques are evolving to address these obstacle of analysing, oligonucleotides.

In part two of this i video interview Torgny answered the following questions:

• How do small interfering ribonucleic acidsd (siRNAs) separations differ from antisense oligonucleotides (ASOs), and what analytical adjustments are typically needed?

• How are digital modeling or machine learning tools helping chromatographers?

Biography
Torgny Fornstedt is a professor at Karlstad University in Sweden. His research combines theory and practice to understand molecular interactions in separation media, focusing on reliable analysis and purification of drug molecules using high-pressure liquid and supercritical fluid systems. Recent work with industry partners tar- gets therapeutic oligonucleotides (ASOs, siRNA) and digital technology applications for quality assurance of next-generation drugs.

Introduction

With continuous advancements in cardiac surgical techniques in recent years, cardiopulmonary bypass (CPB) has become a fundamental approach for managing complex congenital heart diseases (CHD). However, CPB is associated with complex alterations in cardiopulmonary functions and may cause structural and functional damage to the pulmonary vascular endothelium, potentially resulting in pulmonary hypertension, increased pulmonary vascular resistance, and other complications.¹ This is particularly significant in infants and children with CHD, whose respiratory systems have not yet fully matured, amplifying the impact of CPB on lung function.²

Given the insufficient research on changes in respiratory function before and after CPB in pediatric patients with CHD with different shunt types, and considering that distinct pulmonary pathological changes have been noted in CHDs with different types of shunts,³ this study retrospectively analyzed changes in respiratory function before and after CPB in children with CHD admitted to a hospital between January 2022 and December 2023, stratified by shunt type (increased vs decreased pulmonary blood flow), to provide evidence for optimizing perioperative respiratory management.

Study Participants and Methods

General Characteristics of Study Participants

With approval from the Ethics Committee of the medical institution, a retrospective analysis was conducted on the clinical data of 60 pediatric patients with CHD who were admitted between January 2022 and December 2023. Patients were consecutively recruited based on predefined inclusion/exclusion during the study period criteria. The patients were divided into Group A (increased pulmonary blood flow, n = 30) and Group B (decreased pulmonary blood flow, n = 30) based on their shunt types. Group A consisted of 12 male and 18 female pediatric patients, while Group B had 16 male and 14 female pediatric patients.

Inclusion criteria: (1) aged under 12 years; (2) diagnosis of CHD was confirmed by echocardiography or other imaging modalities, requiring cardiac surgery under CPB; and (3) signed informed consent was obtained from parents of the patients.

Exclusion criteria: (1) a history of previous cardiac surgery; (2) congenital immunodeficiency; (3) diagnosed with a genetic disease known to affect the respiratory system; and (4) allergy to drugs or materials used in CPB.

Methods

A standardized anesthesia protocol was used all pediatric patients in both groups. General tracheal intubation combined anesthesia was used, with similar agents administered for both induction and maintenance. Depending on the severity of the malformation, CPB under mild hypothermia was used for mild malformations, while CPB under deep hypothermia was utilized for severe malformations. Following the procedure, the pediatric patients were transferred to the intensive care unit (ICU) once hemodynamic parameters were stabilized. The patients received similar medication regimens before and after operation, thereby excluding variability caused by differences in drug administration.

Observation Indexes

Differences in general characteristics of patients, external diameters of the pulmonary artery and aorta, and respiratory mechanics were assessed before and 24 hours after CPB drainage. General characteristics included age, body weight, duration of the bypass procedure, and findings from X-ray examinations. Respiratory mechanics parameters, including peak airway pressure, plateau airway pressure, inspiratory resistance, expiratory resistance, and lung-thorax compliance, were measured before and after CPB drainage using a pulmonary mechanics monitor. Measurements were taken during mechanical ventilation under standardized ventilator settings.

Statistical Analysis

Sample size was determined based on previous literature and preliminary data. The research data were analyzed using SPSS 22.0 statistical software. Measurement data were expressed as mean ± standard deviation () and analyzed using t-tests. Categorical data were presented as frequency and percentage (n,%) and analyzed using χ² tests. A p-value < 0.05 was considered statistically significant.

Results

Comparison of General Characteristics Between the Two Groups

As shown in Table 1, there were no statistically significant differences (p > 0.05) between the two groups of pediatric patients in terms of age, body weight, duration of the bypass procedure, or X-ray examination results.

Table 1 Comparison of General Characteristics Between the Two Groups of Pediatric Patients ()

Comparison of the Diameters of the Pulmonary Artery and Aorta Between the Two Groups

As presented in Table 2, the external diameter of the pulmonary artery among patients in Group A was significantly larger than that in Group B (2.50±0.38 vs 1.31±0.29 cm, p < 0.05), while the external diameter of the aorta was significantly smaller compared to Group B (1.60±0.26 vs 1.91±0.37 cm, p < 0.05).

Table 2 Comparison of the Diameters of Pulmonary Artery and Aorta Between the Two Groups of Pediatric Patients ()

Comparison of Respiratory Mechanics Parameters Before and After CPB Drainage Between the Two Groups

As indicated in Table 3, significant differences were observed in various respiratory mechanics indexes before and after CPB drainage within and between the two groups, including peak airway pressure, plateau airway pressure, inspiratory resistance, expiratory resistance, and lung-thorax compliance (p < 0.05).

Table 3 Comparison of Respiratory Mechanics Before and After CPB Drainage Between the Two Groups of Pediatric Patients ()

Discussion

CHD is one of the most common congenital anomalies in neonates, with an incidence rate of approximately 0.8 to 1.2%.⁴ CHD can be categorized into various types based on its complexity, necessitating surgical intervention in early childhood in some cases to improve physiological function and quality of life. CPB is a commonly employed technique in surgical management that can temporarily substitute cardiopulmonary function and provide essential conditions for the procedure.⁵ However, the use of CPB induces a series of physiological changes in pediatric patients, particularly affecting respiratory function. These changes may vary considerably among patients with different types of CHD.^6,7 In this study, there were no statistically significant differences between the two groups of pediatric patients with regard to age, body weight, duration of the bypass procedure, and X-ray examination results (p > 0.05). However, the external diameter of the pulmonary artery among patients in Group A was significantly larger than that in Group B, while the external diameter of the aorta was significantly smaller compared to Group B (p < 0.05).

CHD is typically classified into three types based on the direction and mechanism of blood flow: left-to-right shunt, right-to-left shunt, and non-shunt. CHD with a left-to-right shunt is associated with increased pulmonary blood flow, whereas CHD with a right-to-left shunt results in decreased pulmonary blood flow. An increase in pulmonary blood flow can cause elevated pulmonary artery pressure, and prolonged pulmonary hypertension may induce structural changes in the pulmonary artery wall, including thickening and dilation.⁸ Conversely, decreased pulmonary blood flow may result in lower pulmonary artery pressure. Since the pulmonary artery does require dilation to accommodate high blood flow under these conditions, a significant increase in its external diameter is typically not observed.⁹

From additional analyses in the current study, statistically significant differences were noted in respiratory mechanics indexes, including peak airway pressure, plateau airway pressure, inspiratory resistance, expiratory resistance, and lung-thorax compliance, both before and after CPB drainage within and between the two groups of pediatric patients (p < 0.05). These variations were closely associated with systemic and pulmonary pathophysiological changes induced by CPB. During CPB, blood comes into contact with non-endothelial surfaces, potentially activating the complement system, leukocytes, and other inflammatory mediators. These inflammatory mediators subsequently enter the pulmonary tissue via the bloodstream, triggering pulmonary inflammation and leading to pulmonary edema. The formation of pulmonary edema increases the elastic resistance of lung tissue, resulting in elevated peak airway pressure and plateau airway pressure, along with decreased lung-thorax compliance.¹⁰ Additionally, CPB has been reported to affect pulmonary surfactant function and pulmonary vascular resistance, further influencing respiratory mechanics indexes in pediatric patients.¹¹ It has also been indicated in previous studies^12,13 that the decrease in lung-thorax compliance after CPB is primarily attributable to pulmonary edema, atelectasis, and increased elastic resistance of lung tissue—all of which can also contribute to the overall increase in peak airway pressure and plateau airway pressure. Furthermore, respiratory mechanics indexes can be influenced to a certain extent by adjustments in mechanical ventilation parameters. These findings highlight the need for clinicians to implement more refined intraoperative and postoperative management strategies to optimize pulmonary function and improve overall prognosis in pediatric patients undergoing CPB.

This study has several limitations. As a retrospective, single-center study with a relatively small sample size, its findings may not be widely generalizable. Additionally, only one postoperative time point (24 hours after CPB) was analyzed, which cannot reflect the dynamic changes in respiratory function over time. Important confounding factors such as postoperative complications were not accounted for. Future studies using a prospective, multicenter design with larger cohorts and include multiple postoperative time points are needed. Incorporating additional clinical parameters such long-term respiratory outcomes may further inform individualized respiratory management strategies in children with congenital heart disease undergoing CPB.

In summary, in this study on pediatric patients with CHD, it was found that patients with different types of shunts exhibited significant differences in the external diameter of the pulmonary artery and aorta. Dynamic monitoring of respiratory mechanics indexes before and after CPB is essential in clinical respiratory management to promptly assess changes in pulmonary function and adjust respiratory support strategies accordingly.

Data Availability Statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Ethics Approval and Consent to Participate

This study was conducted with approval from the Ethics Committee of Shanxi Children’s Hospital, Shanxi Women and Children Hospital.(Approval number: IRB-KYYN-2021-005) This study was conducted in accordance with the declaration of Helsinki. Written informed consent was obtained from all participants.

Consent for Publication

All patient guardians signed a document of informed consent.

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Funding

No external funding received to conduct this study.

Disclosure

The authors declare that they have no competing interests in this work.

References

1. Lin Y. Nursing research on ventilator-associated pneumonia after cardiopulmonary bypass surgery for congenital heart disease. Jilin Med J. 2021;42(10):2550–2551.

2. Shibata T, Kondo M, Fukushima Y, et al. Epilepsy in children with congenital heart disease: risk factors and characteristic presentations. Pediatric Neurol. 2023;32(6):918–924.

3. Foote H, Hornik C, Hill KD, Rotta AT, Chamberlain R, Thompson EJ. A systematic review of the evidence supporting post-operative diuretic use following cardiopulmonary bypass in children with congenital heart disease. Cardiology in the Young. 2021;31(5):699–706. doi:10.1017/S1047951121001451

4. Marwali EM, Caesa P, Purnama Y, et al. Thiamine levels in Indonesian children with congenital heart diseases undergoing surgery using cardiopulmonary bypass machine. Asian Cardiovascu Thoracic Ann. 2021;30(3):307–313.

5. Schlapbach LJ, Gibbons KS, Horton SB, et al. Effect of nitric oxide via cardiopulmonary bypass on ventilator-free days in young children undergoing congenital heart disease surgery. NITRIC Randomized Clin Trial JAMA. 2022;328(1):38–47.

6. Padalino MA, Luca V, Manuela S, et al. Protective continuous ventilation strategy during cardiopulmonary bypass in children undergoing surgery for congenital heart disease: a prospective study. Interactive CardioVascu Thoracic Surg. 2022;35(2):84–92.

7. Chu WY, Nijman M, Stegeman R, et al.Population pharmacokinetics and target attainment of allopurinol and oxypurinol before, during, and after cardiac surgery with cardiopulmonary bypass in neonates with critical congenital heart disease. Clin Pharmacokinet. 2024;(8):63–70.

8. Erdem Graaff JDD, de Graaff JC, Hilty MP, et al.. Microcirculatory monitoring in children with congenital heart disease before and after cardiac surgery. J Cardiovascu Transl Res. 2023;16(6):1333–1342. doi:10.1007/s12265-023-10407-4

9. Puwei S, Siyu M, ZhuoGa D. et al. The potential value of cuprotosis in myocardial immune infiltration that occurs in pediatric congenital heart disease in response to surgery with cardiopulmonary bypass. Immun Inflamm Dis. 2023;11(3):795–803. doi:10.1002/iid3.795

10. Holladay J, Winch P, Morse J, et al. Acetaminophen pharmacokinetics in infants and children with congenital heart disease. Paedia Anaesth. 2023;33(1):46–51. doi:10.1111/pan.14579

11. Qian X, Chen Y, Liang W, Song S, Li J, Dou L. Setup of extracorporeal membrane oxygenation from cardiopulmonary bypass in infants undergoing cardiac surgery. Chin J Pedia Surg. 2024;45(3):199–202.

12. Jiang L, Wang W, Yang Y, et al. Effect of postoperative cardiopulmonary resuscitation on the prognosis of extracorporeal membrane oxygenation in children with congenital heart disease. Chin J ExtracorpCircul. 2021;19(5):270–274.

13. Kong Y, Zhang M, Chen X, Wang L, Xu Z, Pan Y. Changes of cytokines after cardiopulmonary bypass in children with congenital heart disease. Chin Pediatric Emerg Med. 2022;29(5):359–362.

Can probiotics reverse early ovarian decline? A new study in mice suggests they might restore hormonal balance and microbial health after chemotherapy-induced damage.

Study: Probiotics may improve vaginal microbiota, metabolic disorders and ovarian function-related markers by modulating gut microbiota in POI mice. Image credit: ALIOUI MA/Shutterstock.com

A study conducted by Nanjing Medical University researchers revealed that probiotics can potentially improve ovarian functions and gut and vaginal microbiota compositions in mice with premature ovarian insufficiency, a condition characterized by early deterioration of ovarian function. The study was published in BMC Microbiology. 

Background

Premature ovarian insufficiency (POI) is a condition of premature menopause, causing deterioration of ovarian functions before the age of 40 years. The condition is characterized by abnormal menstruation and hormonal imbalance.

Women with POI experience a range of short-term and long-term health complications, which collectively affect their mental health and overall quality of life. Apart from increasing the risk of osteoporosis, cardiovascular disease, and cognitive impairment, POI can potentially affect fertility.

Existing evidence on the pathophysiology of POI indicates that the condition can lead to changes in gut and vaginal microbiota compositions, and that these changes are associated with hormonal imbalance observed in women with POI.

Given the potential link between microbial composition and POI pathophysiology, researchers at the Nanjing Medical University, China, conducted this study in a chemotherapy-induced mouse model of POI to investigate the effect of probiotics on the composition of gut and vaginal microbiota, markers of ovarian function, and markers of lipid metabolism.

Probiotics are a class of microorganisms that promote the growth of beneficial bacterial populations and suppress the growth of harmful bacteria. This leads to improvements in gut microbiota and a range of physiological processes in the host’s body. 

The study

The researchers generated a mouse model of POI by injecting cyclophosphamide, a chemotherapeutic drug that damages ovarian follicles. They randomly divided these mice into the POI and probiotic-treated POI groups and used healthy mice as controls.

The mice in the treatment group received a mixture of 12 probiotics for 28 consecutive days, while the control and the POI group mice received normal saline for the same duration.

Blood samples collected from the mice following treatment completion were analyzed for anti-Müllerian hormone (a crucial hormone for reproductive development) and sex hormone levels, the number of follicles, and serum levels of total cholesterol and triglycerides. The gut and vaginal microbiota compositions were analyzed using fecal and vaginal samples, respectively.

Key findings

The analysis of mice with POI revealed significantly lower levels of anti-Müllerian hormone and growing ovarian follicles and significantly higher levels of atretic follicles (degenerated ovarian follicles) than healthy mice. The POI mice also exhibited impairments in gut and vaginal microbiota.

Regarding the effect of the study intervention, the study reported that 28-day probiotic treatment caused non-significant (P > 0.05) but trending improvements in ovarian function markers, including anti-Müllerian hormone and estradiol levels, in mice with POI. The treated mice also exhibited a slight increase in growing follicle numbers and a notable, though not statistically significant, decrease in degenerated follicle numbers compared to untreated mice with POI.

The probiotic treatment caused a slight reduction in serum levels of total cholesterol and triglycerides, with a statistically significant decrease observed in triglycerides, indicating possible metabolic improvements in POI mice.

Regarding microbial compositions, the study found that the probiotic treatment significantly altered the gut microbiota, leading to restoration of microbial compositions to levels that trended towards those of healthy mice.

While alpha diversity measure of gut and vaginal microbiota did not differ significantly amoung groups (P > 0.05), beta diversity and microbial composition showed notable shifts with probiotic treatment.

Probiotic treatment also increased the abundance of beneficial bacteria in the vagina, particularly Rodentibacter, with bacterial populations even exceeding those in the control group; however, the health implications of this increase require further study.

Study significance

The study highlights that probiotics may help mitigate ovarian dysfunction, improve lipid metabolism, and restore vaginal microbiota homeostasis in POI mice by modulating gut microbiota composition.

Existing evidence regarding reproductive endocrine diseases suggests a link between gut and vaginal microbiota disruption, which in turn is associated with the progression and outcome of diverse reproductive endocrine disorders, including polycystic ovary syndrome and endometriosis. The gut microbiota plays a vital role in shaping various physiological functions, including immune, neurological, metabolic, and endocrine functions. Recent evidence indicates that both gut and vaginal microbiotas are involved in the regulation of sex hormones and female reproductive system.

Scientific literature also documents that gut microbiota alterations can remotely affect vaginal immunity through the modulation of circulating immune cells. Gut microbiota-derived metabolites, such as short-chain fatty acids, can reach the vagina through circulation and modulate the vaginal microenvironment.

Given the study findings, the researchers suggest that probiotics could offer a promising avenue for future therapeutic development. However, they emphasize that clinical trials in humans are needed to confirm these effects. The current results are based on a preclinical mouse model, and direct clinical application in women with POI is not yet supported by sufficient evidence.

Probiotics may help alleviate clinical symptoms, such as atrophic vaginal inflammation and metabolic syndrome, and improve long-term quality of life in women living with POI.

Future studies should focus on exploring specific mechanisms involved in probiotic-mediated regulation of microbial composition and improvement of ovarian functions to clinically establish the therapeutic potential of probiotics in patients with chemotherapy-induced ovarian insufficiency. The researchers noted that clinical studies in human populations are currently underway.

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Introduction

Tuberculosis (TB) is a chronic respiratory infectious disease that seriously threatens human health and the quality of life. According to the Global Tuberculosis Report 2023, approximately 10 million new TB cases were reported worldwide, of which 748000 were in China, making China a country with high TB and rifampicin-resistant tuberculosis (RR-TB)/multidrug-resistant TB (MDR-TB) burden.¹ Long-term treatment is usually required to manage TB patients, which makes them prone to treatment noncompliance and drug resistance. The introduction of new drugs, such as bedaquiline and delamanid, into clinical practice has contributed to the control of MDR-TB,² but more innovative drugs are still required to further improve the management of MDR-TB.

Linezolid is the first generation of oxazolidinone drug and is mainly used for gram-positive bacterial infections. Linezolid also has good efficacy in the treatment of MDR-TB.³ Therefore, both the WHO Consolidated Guidelines on Drug-resistant Tuberculosis Treatment and Chinese expert consensus on the all-oral treatment of drug-resistant pulmonary tuberculosis have adopted linezolid as a core drug for the treatment of drug-resistant TB since 2019.^4,5 In particular, the Nix-TB study published in the New England Journal of Medicine in 2020 confirmed that the treatment success rate of the new drug regimen, including linezolid, pretomanid, and bedaquiline, reached 90% for the treatment of MDR-TB.⁶ However, a high percentage of patients had adverse events (AEs) related to linezolid in the Nix-TB trial. Myelosuppression (anemia, leukopenia, and thrombocytopenia) was reported in 49% of the patients, and peripheral neuropathy was reported in 81% of the patients receiving linezolid-containing anti-TB regimen; only 15% of the patients completed the 26-week course of linezolid without interruption or a reduction of 1200 mg/day,⁶ which severely limits the long-term use of linezolid. About 29% of patients discontinued linezolid due to adverse drug reactions in real-world settings. Linezolid-related myelosuppression frequently occurs within the first 2 months of treatment in most cases. Findings from programmatic experience in field conditions have also demonstrated similar results. A recent study conducted under programmatic conditions focused on a WHO-endorsed bedaquiline-containing all-oral regimen for MDR-TB treatment. Linezolid, serving as a key component of this regimen, was associated with adverse drug reactions in 42.45% of patients. Among these, 93.33% experienced peripheral neuropathy – an agonizing adverse reaction for people with MDR-TB in field conditions, often compromising their treatment outcomes.⁷ Therefore, there is an urgent need to develop safer drugs and regimens to address MDR-TB.

Contezolid is a new generation of oxazolidinone antibiotics originally developed and approved in China.⁸ Contezolid has shown good in vitro activity against M. tuberculosis strains (MIC₅₀/MIC₉₀ = 0.5/1 mg/L).^9,10 Additionally, the good antimicrobial activity is maintained and the safety profile is optimized for contezolid by improving its structure-activity relationship. Short-term treatment clinical trials also suggest a better safety profile than that observed with linezolid.¹¹ However, safety information on clinical use of contezolid is still limited. We conducted a randomized, active-controlled trial of contezolid vs linezolid in combination with other anti-TB drugs for the treatment of drug-resistant TB to characterize the safety and tolerability of contezolid treatment for two months.

Patients and Methods

Study Design

This study was designed as a randomized, active-controlled trial in patients with RR-TB who were treated at the Tuberculosis Department of Beijing Chest Hospital Affiliated to Capital Medical University from August 1, 2023, to March 31, 2024. The study protocol and informed consent form were reviewed and approved by the Institutional Review Board for Human Investigation of Beijing Chest Hospital of Capital Medical University (approval no. YJS-2021-022). This study was registered at https://www.chictr.org.cn (identifier: ChiCTR2300074234) on August 1, 2023. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Patients

All participants voluntarily participated in this study. Enrolled patients were randomized using a randomization table based on block randomization after signing an informed consent form. The inclusion criteria included 18–65 (inclusive) years of age and diagnosis of RR-TB based on molecular biology methods, and admission to the hospital to receive initial anti-TB treatment or retreatment. The patient did not show fluoroquinolone resistance based on a line probe assay (LPA). An acid-fast bacteria (AFB) smear was positive (at least 1+) in sputum samples. Patients receiving treatment with other anti-TB drugs were willing to discontinue all anti-TB drugs and agreed to undergo a 7-day wash-out period. The patients were closely monitored to address the concerns regarding potential disease progression or worsening symptoms during the 7-day wash-out.

Subjects were excluded if they met any of the following criteria: (1) A history of allergy to the study drug or any of its components, or an effective treatment plan was not available; (2) complicated with severe comorbidities such as respiratory failure, cardiac insufficiency, or liver and kidney dysfunction (serum creatinine level, ALT and/or AST levels higher than three times the upper limit of normal [ULN]); (3) significant electrocardiogram abnormalities (QT interval prolongation > 430 ms for males, or > 450 ms for females); (4) severe cardiovascular or cerebrovascular diseases; (5) pregnant or lactating women; (6) participation in any other clinical trial within three months before initiation of this study; and (7) positive for HIV antibody or AIDS patients.

Anti-TB Regimens

Patients were randomly assigned to receive linezolid or contezolid in combination with other background anti-TB drugs, such as linezolid-bedaquiline (pyrazinamide)-levofloxacin (moxifloxacin)-cycloserine-clofazimine or contezolid-bedaquiline (pyrazinamide)-levofloxacin (moxifloxacin)-cycloserine-clofazimine. Anti-TB drugs were purchased from the same manufacturer and provided in the same dosage form and strength. The specific dosage was linezolid 600 mg q12h, contezolid 800 mg q12h, bedaquiline 400 mg/d for 2 weeks, adjusted to 200 mg three times per week, moxifloxacin 400 mg/d, levofloxacin 600 mg/d, cycloserine 250 mg bid, and clofazimine 100 mg/d.

Safety Assessment

All patients were closely monitored during the treatment period for the occurrence and progression of AEs, including clinical symptoms, vital signs, electrocardiogram findings, and laboratory test abnormalities. Hematology tests, urinalysis, and biochemical assays, including liver and kidney function tests, were performed for all patients every two weeks. The clinical characteristics, severity, onset time, duration, management, and outcome of AEs were documented and drug relatedness was evaluated. The risk factors for AEs were also analyzed. The frequency of dose reduction or discontinuation owing to AEs was also evaluated.

All AEs were coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.¹² Grade 1 AE was defined as mild, asymptomatic, or mild symptoms; clinical or diagnostic observations only; and intervention not required. Grade 2 AE was defined as moderate, minimal, local, or noninvasive intervention indicated and limiting age-appropriate instrumental activities of daily living. Grade 3 AE was defined as severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, and limiting self-care activities of daily living. Grade 4 AE was defined as life-threatening consequences and urgent intervention was indicated. Grade 5 AE was defined as death related to AE.

Anti-TB Efficacy Monitoring

Anti-TB efficacy was analyzed in terms of microbiology diagnostic testing and imaging examinations. All patients underwent monthly sputum smear tests for AFB and sputum cultures for Mycobacterium tuberculosis. Chest CT scan was scheduled for all the patients at the end of the second month of treatment.

Statistical Analysis

Sample size calculation was based on superiority study design. The patients were randomly assigned to contezolid or linezolid group at a ratio of 1:1. Contezolid is expected to be safer than linezolid. The sample size was calculated using the following formula:

Set α = 0.05, 1- β = 0.80,

In our experience, the expected incidence of AEs was 2.5% in contezolid group and 49% in linezolid group, based on the safety profiles of such regimens. At least 10 evaluable cases were required in contezolid and linezolid groups to test the superiority of contezolid, assuming two-sided α = 0.05, β = 0.2, superiority threshold δ = 15%, and a 20% dropout rate.

Statistical analyses were conducted using SPSS 24.0 software. Data are expressed as mean ± standard deviation (SD) and compared between groups using Student’s t test or Wilcoxon’s signed rank test. The incidence of AEs was compared between groups using Chi-square test or Mehta’s modification of Fisher’s exact test.

Results

Baseline Patient Characteristics

A total of 35 smear-positive RR-TB patients were screened, and 29 patients were enrolled and randomized to receive treatment at Beijing Chest Hospital from August 1, 2023 to March 31, 2024. Of the 15 patients treated with contezolid, one patient was excluded from the analysis due to rifampicin-susceptible TB. One of the 14 patients in linezolid group was excluded from the analysis because of withdrawal of informed consent. Finally, 14 patients in contezolid group and 13 patients in linezolid group completed the study and were included in the safety analysis (Figure 1).

Figure 1 Disposition of the patients in the study. Abbreviation: RR-TB, rifampicin-resistant tuberculosis.

The median (range) age was 40.9 (26–65) years for the patients in contezolid group, and 36.7 (18–64) years for the patients in linezolid group. The baseline characteristics of the two groups of patients were comparable (Table 1).

Table 1 Demographic and Clinical Characteristics of Rifampicin-Resistant Tuberculosis Patients Receiving Contezolid or Linezolid for Anti-TB Treatment

AE Profiles of Contezolid Versus Linezolid

Overall, the incidence of treatment-emergent AEs (TEAEs) was 14.3% (2/14) in contezolid-treated patients and 92.3% (12/13) in linezolid group (P < 0.05). The most common TEAEs were peripheral neuropathy, myelosuppression, and gastrointestinal reactions in linezolid group, but only gastrointestinal reactions in contezolid-treated patients (Table 2).

Table 2 Treatment-Emergent Adverse Events of Contezolid and Linezolid During Anti-TB Treatment for 2 months

Patients in contezolid group did not experience any AEs related to bone marrow suppression (anemia, neutropenia, or thrombocytopenia) during the 2-month treatment period. AEs related to bone marrow suppression (anemia) were observed in 4 patients in linezolid group (30.8%), all of which were Grade 2 or higher (hemoglobin levels reduced from 132 to 48 g/L, 112 to 86 g/L, 142 to 59 g/L, and 128 to 89 g/L, respectively). Specifically, 2 cases (15.3%) of Grade 2 anemia completely resolved after linezolid dose reduction to 600 mg/day. One case of Grade 3 anemia occurred in a patient after linezolid treatment for one month. The patient discontinued linezolid and received blood transfusion. The remaining one case of Grade 4 anemia (hemoglobin level reduced from 132 g/L to 48 g/L) developed two months after linezolid treatment. The patient was managed with blood transfusion and permanent discontinuation of linezolid.

Peripheral neuropathy was not observed in any patient who received contezolid. Peripheral neuropathy (numbness and/or tingling in the limbs) was observed in 7 patients in the linezolid group (53.8%). Most of these cases (6/7) were Grade 2 AEs and the remaining one case was Grade 3. Two of these patients discontinued linezolid treatment due to concurrent Grade 4 and Grade 3 anemia, respectively. The peripheral neuropathy of these two patients was also resolved after discontinuation of linezolid. The peripheral neuropathy AE in three patients were not relieved, even after linezolid dose was reduced to 600 mg qd. Linezolid dose was reduced to 600 mg/day in one patient because of gastrointestinal reactions after treatment for 20 days. One month later, this patient experienced finger numbness. The symptoms did not resolve during treatment at this dose. One patient (7.7%) developed Grade 3 AE one and half months after linezolid treatment. The symptoms were partially resolved after permanent discontinuation of linezolid.

Two patients (14.3%) in contezolid treatment group developed Grade 2 gastrointestinal AEs. All symptoms were resolved completely after the dose was reduced to 400 mg q12h. Three patients (23.1%) in linezolid group experienced Grade 2 gastrointestinal AEs. All symptoms were resolved completely after the linezolid dose was reduced to 600 mg/day.

In summary, contezolid showed significantly lower incidence rates than linezolid for myelosuppression and peripheral neuropathy but not for gastrointestinal AEs. Furthermore, dose reduction or discontinuation owing to AEs was observed for linezolid in most patients (84.6%, 11/13).

Sputum Smear Conversion After 2-month Treatment

Both contezolid-containing and linezolid-containing anti-TB regimens showed good clinical efficacy. Overall, the sputum negative conversion rate was 92.9% (13/14) in contezolid group and 92.3% (12/13) in linezolid group. The imaging-confirmed lesion absorption rate was 85.7% (12/14) in contezolid group and 84.6% (11/13) in linezolid group. The clinical efficacy was similar between contezolid-containing and linezolid-containing regimens (Table 3).

Table 3 Anti-Tuberculosis Effect of Contezolid-Containing Versus Linezolid-Containing Regimens for Rifampicin-Resistant Tuberculosis Patients

Discussion

Contezolid is an innovative drug of a new generation of oxazolidinone antibiotics. It is derived from structural modification of linezolid to form a non-coplanar structure between the B ring and the A and C rings, which makes the structure-activity relationship of contezolid more favorable in terms of safety and efficacy. Structural modification enables contezolid with enhanced binding to bacterial target and so reduced risk of drug resistance, leading to more efficient antimicrobial activity.¹³ The optimized structure of contezolid is associated with lower somatic and mitochondrial permeability, and thus, the normal function of mitochondria is not damaged, which may effectively reduce the side effects of bone marrow suppression. The National Medical Products Administration of China approved contezolid in 2021 for the treatment of infections caused by susceptible pathogens after pivotal Phase III clinical trials in China provided favorable and supporting data.^14–17

Shoen et al demonstrated that contezolid was similar to linezolid in the in vitro and in vivo anti-TB activities in mouse infection models against drug-sensitive and drug-resistant M. tuberculosis.⁹ However, the safety and efficacy of contezolid treatment for MDR-TB patients have not yet been evaluated in China at present time. The Nix-TB trial targeting MDR-TB has shown that most of the adverse reactions of linezolid occur after treatment for approximately 8 weeks.¹⁸ Therefore, linezolid was used as the control group in this study to monitor the occurrence of any AEs during the 2-month anti-TB treatment with contezolid- or linezolid-containing regimens.

In this study, during the 2-month anti-TB treatment period, TEAE was reported in 12 of 13 subjects receiving linezolid treatment (92.3%). All AEs were considered to be related to linezolid treatment. Eleven of the 12 patients underwent dose reduction or discontinuation of linezolid owing to adverse drug reactions. Only one patient continued to complete 2-month treatment with linezolid at a dose of 600 mg q12h. Linezolid-related AEs included anemia, peripheral neuropathy, and gastrointestinal reactions. All AEs occurred 1–2 months after the initiation of linezolid treatment. In contrast, AE was reported in 14.3% (2/14) of the patients receiving contezolid. All AEs were gastrointestinal reactions, one case each of nausea and vomiting. Both AEs were related to contezolid and occurred within one month after the initiation of contezolid treatment. The symptoms were resolved after reducing the contezolid dose to 400 mg q12h. Contezolid was associated with a significantly lower incidence of bone marrow suppression and peripheral neuropathy AEs compared with linezolid. Our data support the good safety of contezolid in the treatment of patients with TB. These findings are consistent with those of previous reports on contezolid regimens for the treatment of TB patients.^19–23

The results of this study indicated that the sputum negative conversion rate (92.9%) after treatment with contezolid-containing regimens for two months was comparable to that in patients treated with linezolid-containing regimens (92.3%). Contezolid-containing anti-TB regimens and linezolid-containing regimens showed similar clinical efficacy in terms of sputum negative conversion rate and imaging-confirmed pulmonary lesion absorption rate.

This study has some limitations, such as the small sample size, single-center design, relatively short treatment duration of anti-TB regimens, potential selection bias, and the effect of background anti-TB drugs. Especially, the dosage of linezolid used in this study (600 mg q12h) exceeds the current WHO recommended dose of 600 mg/day for MDR-TB treatment. Following the Nix-TB trial, the ZeNix trial demonstrated that reducing both the dose and duration of linezolid to 600 mg/day for 26 weeks was associated with statistically significant treatment success. The higher dose used in this study may have contributed to the elevated adverse drug reaction rate (92.3%) observed in the linezolid group.^24,25 These limitations could impact the generalizability of the study conclusion. Therefore, adequate-designed multi-center clinical trials are needed to confirm the utility of contezolid versus linezolid for the long-term treatment of MDR-TB.

Conclusion

Preliminary data in this randomized controlled study further support that contezolid has a safer safety profile than linezolid in combination with other background anti-TB drugs for a 2-month treatment of patients with MDR-TB. Both drugs showed similar anti-TB efficacy. However, the long-term safety beyond the 2-month window is unclear yet. Contezolid is safer based on the body of evidence available even though small sample size in this study may weaken the robustness and generalizability of the conclusion. Adequate-designed multicenter long-term clinical trials are required to confirm our findings.

Data Sharing Statement

The original data have been included in this article. Further inquiries can be directed to the corresponding author.

Ethics Approval and Consent to Participate

This study was approved by the Ethics Committee of Beijing Chest Hospital of Capital Medical University (approval no. YJS-2021-022). Informed consent was obtained from all participants.

Acknowledgments

We would like to thank the sample bank of Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis, and Thoracic Tumor Research Institute for supporting this study.

Funding

This research was supported by Special “Sailing” Plan for Clinical Medical Development (Grant number: ZLRK202331) and the National Natural Science Foundation of China (Grant number: 8210002).

Disclosure

The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

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