Category: 8. Health

  • Impact of Assisted Reproductive Technology on Pregnancy Outcomes in Ad

    Impact of Assisted Reproductive Technology on Pregnancy Outcomes in Ad

    Advanced maternal age (AMA), typically defined as maternal age ≥35 years at delivery, has become a global public health concern with significant demographic shifts observed in both developed and developing nations.1 In China, the average age of first pregnancy has increased by 1.65 years between 2013–2019, reflecting an annual delay of 0.3 years.2 This trend is driven by complex socioeconomic factors, including rising costs of living, educational attainment, career prioritization, and declining fertility intentions.3 Concurrently, ART has emerged as a critical intervention, with over 10 million children born through ART procedures worldwide since 1987.4 However, the intersection of AMA and ART presents unique clinical challenges that warrant rigorous investigation.

    While ART enables pregnancy achievement in older women, its impact on perinatal outcomes remains controversial. Existing evidence underscores AMA as an independent risk factor for adverse maternal outcomes including gestational hypertension, preeclampsia, and gestational diabetes mellitus.5 Neonatal risks are equally pronounced, with meta-analyses demonstrating elevated rates of preterm birth and low birth weight in AMA pregnancies.6 These risks may be compounded by ART, which has been associated with placental dysfunction through mechanisms such as impaired trophoblast invasion and epigenetic modifications.7 Notably, For AMA women, IVF-ET pregnancy may lead to a higher incidence of pregnancy complications and adverse delivery outcomes, but this might be due to an increased rate of multiple pregnancies.8

    Some studies report that ART does not independently increase risks when controlling for age,9 whereas others demonstrate higher rates of placental-mediated complications in ART pregnancies.10 These discrepancies may stem from heterogeneous study populations, with most evidence derived from mixed-age cohorts or multifetal pregnancies.

    Notably, primiparous AMA women represent a distinct high-risk subgroup. Primiparity compounds age-related risks due to nulliparous uterine vascular adaptation,5 yet limited data exist focusing exclusively on this population. Existing studies either combine multiparous women11 or lack adjustment for critical confounders like parity.12 This knowledge gap impedes evidence-based counseling for the growing cohort of AMA primiparas opting for ART.

    To address these limitations, we conducted this retrospective cohort study comparing 2329 AMA primiparous women with singleton pregnancies, rigorously controlling for maternal age and parity. Our study aims to: Quantify the independent effect of ART on maternal and neonatal outcomes in AMA primiparas; Identify risk profiles specific to this population to guide clinical management.

    Patients and Methods

    Study Design and Population

    This retrospective cohort study was conducted at Northwest Women’s and Children’s Hospital, a tertiary care center in Xi’an, China. We analyzed data from 2329 primiparous women aged ≥35 years who delivered singleton live births between January 1, 2016, and January 1, 2020. Participants were stratified into two groups based on conception method: the ART group (n=422) comprising women who underwent in vitro fertilization and embryo transfer (IVF-ET), and the spontaneous conception (SC) group (n=1907).

    Inclusion and Exclusion Criteria

    Inclusion criteria: Primiparous women aged ≥35 years at delivery. Singleton pregnancy ≥28 weeks gestation. Complete medical records available. For ART group: only IVF-ET cycles included (excluding cases with fetal reduction). Exclusion criteria: (1) Pre-pregnancy comorbidities of serious medical conditions (cardiovascular, hepatic, renal, or immune system diseases); (2) Multifetal pregnancies or incomplete clinical data. The general maternal conditions, maternal outcomes and infant outcomes of the two groups were retrospectively analysed. This retrospective study utilized anonymized clinical data extracted from electronic medical records. The Ethics Committee of Northwest Women’s and Children’s Hospital waived the requirement for individual informed consent as the research involved no more than minimal risk to participants and used pre-existing de-identified data (Approval No. 2022-049). This study complies with the Declaration of Helsinki.

    Diagnostic Criteria

    All diagnoses were made according to the 9th edition of Chinese “Obstetrics and Gynecology”.13 Comparing the following outcomes in two groups: hypertensive disorders of pregnancy, pre-eclampsia, gestational diabetes mellitus, diabetes mellitus combined with pregnancy, anaemia, placental abruption, premature rupture of membranes, intrahepatic cholestasis in pregnancy, post-partum haemorrhage, stillbirths, foetal distress, low birth weight babies, macrosomic babies and preterm births.

    Statistical Analysis

    Data analysis was performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation (SD) and compared using Student’s t-test or Mann–Whitney U-test, as appropriate. Categorical variables were expressed as frequencies (%) and analyzed using the chi-square test or Fisher’s exact test. Multivariate logistic regression was performed to adjust for maternal age, BMI, and parity. Variables with p<0.1 in univariate analysis were included in the final model. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated to determine independent associations. A two-tailed P-value <0.05 was considered statistically significant.

    Results

    Baseline Characteristics

    The ART group demonstrated significantly higher maternal age (37.48±2.44 years vs 36.65±1.90 years, p<0.001) and BMI (27.79±3.34 kg/m² vs 27.61±8.12 kg/m², p=0.016) compared to the spontaneous conception (SC) group. The proportion of women aged ≥40 years was markedly higher in the ART group (22.04% vs 8.65%, p<0.001). Gestational age at delivery was significantly shorter in ART pregnancies (38.49±1.95 weeks vs 38.97±1.71 weeks, p<0.001), while neonatal birth weights showed no statistical difference between groups (3224.45±575.56g vs 3275.90±513.07g, p=0.312) (Table 1).

    Table 1 Comparison of Baseline Characteristics Between ART and Spontaneous Conception (SC) Groups

    Maternal Outcomes

    The ART group exhibited significantly higher rates of: Preeclampsia (9.24% vs 5.14%, χ²=10.51, p=0.001), Cesarean delivery (80.09% vs 63.08%, χ²=44.67, p<0.001); Conversely, the SC group demonstrated higher incidence of: Preterm premature rupture of membranes (PPROM) (26.43% vs 17.30%, χ²=15.46, p<0.001), No significant differences were observed in: Gestational hypertension (11.61% vs 9.28%, p=0.143), Gestational diabetes mellitus (33.18% vs 31.31%, p=0.455), Placental abruption (0.95% vs 1.42%, p=0.313) Postpartum hemorrhage (1.42% vs 2.36%, p=0.234) (Table 2).

    Table 2 Comparison of Pregnancy Complications and Neonatal Outcome Between the Two Groups [n (%)]

    Neonatal Outcome

    ART-conceived neonates showed significantly higher rates of: Low birth weight (9.24% vs 6.14%, χ²=5.34, p=0.021), Preterm birth (11.85% vs 8.02%, χ²=6.36, p=0.012), NICU admission (13.27% vs 6.08%, χ²=26.13, p<0.001), No significant differences were found in: Stillbirth (0% vs 0.26%, p=0.368), Fetal distress (3.08% vs 2.99%, p=0.921), Macrosomia (6.16% vs 6.03%, p=0.919), Neonatal malformations (1.18% vs 0.89%, p=0.367). Key findings are summarized in Tables 1 and 2, presenting both unadjusted and adjusted analyses for comprehensive assessment of outcomes (Table 2).

    To control for potential confounders including maternal age, BMI, and parity, we performed multivariate logistic regression analysis (Table 3). ART remained independently associated with:

    • Preeclampsia (adjusted odds ratio [aOR] 1.89, 95% confidence interval [CI] 1.25–2.86)
    • Cesarean delivery (aOR 2.31, 95% CI 1.74–3.06)
    • Preterm birth (aOR 1.55, 95% CI 1.10–2.19)
    • NICU admission (aOR 2.38, 95% CI 1.68–3.37)

    Table 3 Multivariate Logistic Regression Analysis of ART-Associated Outcomes (Adjusted for Maternal Age and BMI)

    No significant associations were found between ART and gestational diabetes mellitus (aOR 1.12, 95% CI 0.89–1.41), placental abruption (aOR 0.67, 95% CI 0.23–1.95), or postpartum hemorrhage (aOR 0.60, 95% CI 0.26–1.39).

    Discussion

    This large retrospective cohort study of 2329 advanced maternal age (AMA) primiparous women demonstrated that ART-conceived pregnancies were independently associated with increased risks of preeclampsia (aOR 1.89), cesarean delivery (aOR 2.31), preterm birth (aOR 1.55), and NICU admission (aOR 2.38) compared to spontaneous conceptions, even after adjusting for maternal age and BMI. These findings align with existing evidence highlighting the interplay between ART and placental dysfunction,10 while also revealing unique insights specific to AMA primiparas—a population that has been understudied in prior research.8,14

    Characteristics of Pregnancy Risks for AMA Primiparous Women

    AMA primiparous births are now becoming more common, with an increase in the age of first-time births possibly associated with women marrying later,15 and anxiety during pregnancy and negative overall experiences of labour are more common among older first-time parents.16 Older women have a higher risk of delivering preterm and low birth weight babies, which have long term negative effects on both the child and the mother.17 The present study, after excluding twin births and repeat pregnancies in advanced maternal age, showed that the mean age (37.48 years) and the percentage of ultra-advanced age (≥40 years) was significantly higher in the ART group (22.04%), which is in line with the findings of another study of ultra-AMA and these differences may be related to defective placenta function in pregnant women on ART.14 Placental hypofunction due to advanced age may explain the shorter gestational weeks of delivery in the ART group (38.49 weeks vs 38.97 weeks, p<0.001). Of note, despite a higher BMI in the ART group (27.79 kg/m2 vs 27.61 kg/m2), there was no significant difference in the incidence of gestational diabetes mellitus (33.18% vs 31.31%, P=0.455), suggesting that age, rather than ART per se, may be the main cause of metabolic disturbances.

    Selective Risks of ART

    ART has been widely used in elderly primigravid women, in this study, the percentage of super-elderly primigravid women with ART pregnancies reached 22%, while the percentage of super-elderly primigravid women with natural pregnancies was only 8.65%, which indicates that the percentage of super-elderly primigravid women opting for ART pregnancies is more significantly higher, which is in line with the conclusions of other studies.18,19 Some studies have concluded that assisted reproductive pregnancies do not appear to increase the risk of complications during pregnancy and perinatal outcomes in advanced maternal age,20 while others have concluded the opposite,21,22 that women with ART pregnancies have a higher cesarean section rate, obstetrical complications, and the risk of adverse fetal outcomes relative to spontaneous conception among women of advanced maternal age, but that these risks may be associated with an increase in the rate of twin pregnancies,8 the cesarean section rate in the ART group in this study was 80.09% vs 63.08%, which, in addition to the factor of advanced age, may be related to the excessive intervention of doctors and patients on the “precious child”, and we need to be vigilant about the long-term complications associated with non-medically indicated cesarean section.

    In this study, after excluding the influence of multiple pregnancy factors, we found that among perinatal complications, only the incidence of premature rupture of membranes was significantly different between the two groups, and the pregnant women with natural pregnancy were significantly higher than those in the ART group (26.43% vs 17.30%), while no significant differences were observed in other aspects, which may be related to the higher average age of ART pregnant women and more medical treatment received before pregnancy, both the Pregnant women and doctors psychologically attached more importance to the outcome of this pregnancy and more often chose elective caesarean section delivery rather than waiting for spontaneous labour.

    The incidence of perinatal complications such as hypertensive disorders of pregnancy and gestational diabetes mellitus in the present study did not differ between the two groups, which is in line with the findings of other studies.8,23 The significantly elevated risk of preeclampsia in ART pregnancies (aOR 1.89, 95% CI 1.25–2.86) aligns with current understanding of ART-associated placental dysfunction,10 the potential mechanisms may explain this association: Corpus luteum deficiency: Most ART cycles in our cohort used GnRH agonist protocols, which are known to suppress endogenous luteal function, potentially limiting production of vasoactive relaxin crucial for maternal cardiovascular adaptation.24 Trophoblast invasion impairment: The supraphysiological hormonal environment during ovarian stimulation may disrupt normal trophoblast invasion and spiral artery remodeling.25 Epigenetic modifications: In vitro culture conditions could induce epigenetic changes affecting placental development.8

    Neonatal Outcomes: Reconciling Controversies

    While ART-conceived neonates had higher rates of preterm birth and NICU admission, other outcomes (eg, stillbirth, fetal distress, macrosomia) showed no significant differences compared to SC neonates. This selective risk profile aligns with recent studies suggesting that ART primarily impacts fetal growth restriction and prematurity rather than congenital anomalies.12,26,27 However, the twofold increase in NICU admissions highlights the need for enhanced postnatal surveillance in this population.28

    Research Strengths and Limitations

    The strengths of this study are: (1) focusing on singleton pregnancy and excluding the confounding factors of multiple pregnancies; (2) large sample size (n=2329), more representative data; (3) the first systematic analysis of elderly primigravid women in Northwest China. However, the study has the following limitations: (1) it did not differentiate between fresh and frozen-thawed embryo transfer cycles, which may have different effects on pregnancy outcomes; (2) Absence of placental pathology data to explore preeclampsia mechanisms; and (3) the retrospective design may introduce selection bias. Future multicentre prospective studies combining placental pathology and long-term follow-up data in children are needed to further validate the findings.

    Conclusion

    In conclusion, our findings substantiate that ART in AMA primiparas confers selective perinatal risks requiring tailored clinical pathways. These results should inform international guidelines while highlighting the need for continued research into optimizing outcomes for this growing patient population.

    Author Contributions

    All authors made significant contributions to conception, study design, data acquisition, analysis, and interpretation; participated in drafting or critically revising the article; approved the final version; agreed on the target journal; and take responsibility for all aspects of the work.

    Disclosure

    All authors report no conflicts of interest in this work.

    References

    1. Office for National Statistics (ONS), released 17 May 2024, ONS website, statistical bulletin, Birth characteristics in England and Wales: 2022. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthcharacteristicsinenglandandwales/2022. Accessed July 31, 2025.

    2. Mao Y, Zeng S, Han C, et al. Analysis of pregnancy age of rural planned pregnancy primigravida in Min xian County, Gansu Province, 2013_2019. China Fam Plann Obstet Gynaecol. 2021;13(12):83–86.

    3. Ren ZP, Xiong C, Zhou Z. China fertility report 2019. Dev Res. 2019;2019(06):20–40.

    4. Adamson GD, Creighton P, de Mouzon J, Zegers-Hochschild F, Dyer S, Chambers GM. How many infants have been born with the help of assisted reproductive technology? Fertil Steril. 2025;124:40–50. doi:10.1016/j.fertnstert.2025.02.009

    5. Morton JS, Care AS, Kirschenman R, Cooke CL, Davidge ST. Advanced maternal age worsens postpartum vascular function. Front Physiol. 2017;8:465. doi:10.3389/fphys.2017.00465

    6. Saccone G, Gragnano E, Ilardi B, et al. Maternal and perinatal complications according to maternal age: a systematic review and meta-analysis. Int J Gynaecol Obstet. 2022;159(1):43–55. doi:10.1002/ijgo.14100

    7. Choux C, Carmignac V, Bruno C, et al. The placenta: phenotypic and epigenetic modifications induced by Assisted Reproductive Technologies throughout pregnancy. Clin Epigenet. 2015;7:87. doi:10.1186/s13148-015-0120-2

    8. Lang M, Zhou M, Lei R, Li W. Comparison of pregnancy outcomes between IVF-ET pregnancies and spontaneous pregnancies in women of advanced maternal age. J Matern Fetal Neonatal Med. 2023;36(1):2183761. doi:10.1080/14767058.2023.2183761

    9. Kalayci H, Ozdemir H, Alkas D, Cok T, Tarim E. Is primiparity a risk factor for advanced maternal age pregnancies? J Matern Fetal Neonatal Med. 2016;30(11):1283–1287. doi:10.1080/14767058.2016.1211633

    10. Chih HJ, Elias FTS, Gaudet L, Velez MP. Assisted reproductive technology and hypertensive disorders of pregnancy: systematic review and meta-analyses. BMC Pregnancy Childbirth. 2021;21(1):449. doi:10.1186/s12884-021-03938-8

    11. Marozio L, Picardo E, Filippini C, et al. Maternal age over 40 years and pregnancy outcome: a hospital-based survey. J Matern Fetal Neonatal Med. 2019;32(10):1602–1608. doi:10.1080/14767058.2017.1410793

    12. Kawwass JF, Badell ML. Maternal and fetal risk associated with assisted reproductive technology. Obstet Gynecol. 2018;132(3):763–772. doi:10.1097/AOG.0000000000002786

    13. Xie X, Kong B, Duan T. Obstetrics and Gynaecology. 9th ed. Beijing: People’s Health Publishing House; 2018.

    14. Jackson S, Hong C, Wang ET, Alexander C, Gregory KD, Pisarska MD. Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology. Fertil Steril. 2015;103(1):76–80. doi:10.1016/j.fertnstert.2014.09.037

    15. Chen W, Duan Y. Recent levels and trends of fertility in China. Popul Res. 2019;43(1):3–17.

    16. Waldenström U. Postponing parenthood to advanced age. Ups J Med Sci. 2016;121(4):235–243. doi:10.1080/03009734.2016.1201553

    17. Sydsjö G, Lindell Pettersson M, Bladh M, Skoog Svanberg A, Lampic C, Nedstrand E. Evaluation of risk factors’ importance on adverse pregnancy and neonatal outcomes in women aged 40 years or older. BMC Pregnancy Childbirth. 2019;19(1):92. doi:10.1186/s12884-019-2239-1

    18. Tambvekar SE, Adki S, Sheriar NK. Pregnancies in elderly mothers over 40 years: what to expect from the rising new age high-risk cohort? J Obstet Gynaecol India. 2023;73(4):358–362. doi:10.1007/s13224-022-01701-3

    19. Juneja SK, Tandon P, Kaur G. To evaluate the effect of increasing maternal age on maternal and neonatal outcomes in pregnancies at advanced maternal age. Int J Appl Basic Med Res. 2022;12(4):239–242. doi:10.4103/ijabmr.ijabmr_193_22

    20. Kalayci H, Ozdemir H, Alkas D, Cok T, Tarim E. Is primiparity a risk factor for advanced maternal age pregnancies? J Matern Fetal Neonatal Med. 2017;30(11):1283–1287. doi:10.1080/14767058.2016.1211633

    21. Wu Y, Chen Y, Shen M, et al. Adverse maternal and neonatal outcomes among singleton pregnancies in women of very advanced maternal age: a retrospective cohort study. BMC Pregnancy Childbirth. 2019;19(1):3. doi:10.1186/s12884-018-2147-9

    22. Frati P, Foldes-Papp Z, Panici PB, et al. A retrospective study on advanced maternal age and assisted reproductive techniques, medico-legal advice, “Food for Thought”. Curr Pharm Biotechnol. 2016;17(4):330–336. doi:10.2174/1389201017666151231095546

    23. Yuan CL, He MR, He SM, Huang JC, Jian WQ, Zhao KS. Differences in pregnancy outcomes between in vitro fertilization and natural conception in nulliparous singleton pregnancies of advanced maternal age: a study based on propensity score matching and cohort retrospective analysis. Int J Womens Health. 2025;17:947–954. doi:10.2147/IJWH.S510393

    24. Dall’Agnol H, García Velasco JA. Frozen embryo transfer and preeclampsia: where is the link? Curr Opin Obstet Gynecol. 2020;32(3):213–218. doi:10.1097/GCO.0000000000000624

    25. Chang KJ, Seow KM, Chen KH. Preeclampsia: recent advances in predicting, preventing, and managing the maternal and fetal life-threatening condition. Int J Environ Res Public Health. 2023;20(4):2994. doi:10.3390/ijerph20042994

    26. Harlev A, Walfisch A, Oran E, et al. The effect of fertility treatment on adverse perinatal outcomes in women aged at least 40 years. Int J Gynaecol Obstet. 2018;140(1):98–104. doi:10.1002/ijgo.12345

    27. Lagrew DC, Morgan MA, Nakamoto K, Lagrew N. Advanced maternal age: perinatal outcome when controlling for physician selection. J Perinatol. 1996;16(4):256–260.

    28. Pettersson ML, Bladh M, Nedstrand E, Svanberg AS, Lampic C, Sydsjö G. Maternal advanced age, single parenthood, and ART increase the risk of child morbidity up to five years of age. BMC Pediatr. 2022;22(1):39. doi:10.1186/s12887-021-03103-2

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  • Vagus nerve stimulation enhances the effects of compassion meditation training

    Vagus nerve stimulation enhances the effects of compassion meditation training

    Stimulating the vagus nerve with a device attached to the outer ear can help make compassion meditation training more effective at boosting people’s capacity for self-kindness and mindfulness, finds a new study led by University College London (UCL) researchers.

    The study, published in Psychological Medicine, adds to evidence of the potential benefits of stimulating this key nerve that connects the brain with major organs in the chest and abdomen.

    The vagus nerve plays a crucial role in the ‘rest-and-digest’ (parasympathetic) system, counteracting the ‘fight-or-flight’ (sympathetic) stress response, and allows the brain to communicate with all major organs in the body. By transmitting signals from the body up to the brain, the vagus nerve can also regulate a range of psychological processes, including some involved in social interactions and emotional control.

    The researchers stimulated study participants’ vagus nerve by delivering a painless electric pulse to the tragus, the small cartilaginous flap located in front of the ear canal on the outer ear. This electronic pulse was designed to activate nerve fibres that pass close to the skin surface.

    The academics tested 120 healthy participants who either received vagus nerve stimulation through the skin on their tragus, or a placebo stimulation to another part of the ear. This was combined either with self-compassion meditation training or another form of training not designed to promote compassion.

    The participants who received the vagus nerve stimulation alongside the self-compassion training experienced a larger and more immediate increase in self-compassion than those in the other three groups. The participants’ level of mindfulness (awareness of the present moment and calm acknowledgement of one’s thoughts and feelings) was also measured, and the benefits to mindfulness accumulated across multiple training sessions, suggesting that while some effects of stimulation and training are immediate, others build over time.

    We found that delivering a small shock to the ear, to stimulate the vagus nerve, can amplify the benefits of certain meditation techniques, particularly those involved in cultivating self-compassion.


    Our findings reveal how neuroscience technology may have a meaningful impact on how we feel about ourselves. Neurostimulation alone had limited benefits, but it may have an important role to play in supporting meditation therapies, which are increasingly used to help people with mental and physical health problems. Meditation can be hard work, requiring persistence and dedication, so a way to boost and accelerate its impacts could be a welcome development for therapists and patients alike.”


    Professor Sunjeev Kamboj, Lead author, UCL Psychology & Language Sciences

    The researchers say that further research is needed to refine the technique and to see how long the effects last. Additionally, as this study only investigated healthy participants without a diagnosed psychological disorder, further research is needed to see if this approach could benefit people with conditions such as anxiety, depression or trauma.

    In a separate study published last week, a separate team co-led by a UCL researcher also found that vagus nerve stimulation could help to improve fitness and exercise tolerance.

    Source:

    University College London

    Journal reference:

    Kamboj, S. K., et al. (2025) Electroceutical enhancement of self-compassion training using transcutaneous vagus nerve stimulation: results from a preregistered fully factorial randomized controlled trial. Psychological Medicine. doi.org/10.1017/S0033291725101013.

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  • Gfi1 regulates exhausted CD8+ T cells to improve cancer immunotherapy

    Gfi1 regulates exhausted CD8+ T cells to improve cancer immunotherapy

    Killer immune cells destroy cancer cells and cells infected by virus. These CD8+ T cells are activated after detection of viral infection or growth of “non-self” tumor cells. However, in chronic viral infection and cancer, the killer cells often lapse into “exhausted” CD8+ T cells that no longer can stem disease.

    This exhaustion is a major barrier in the new immunotherapies for cancer, including immune checkpoint blockers and CAR T cell therapy. In a detailed study of exhausted T cell subsets reported in Nature Communications, University of Alabama at Birmingham researchers led by Lewis Z. Shi, M.D., Ph.D., show that a transcriptional repressor called Gfi1, or growth factor independent-1, is a key regulator of the subset formation of exhausted CD8+ T cells and may offer a key to reducing exhaustion.

    Our study identifies an important role of Gfi1 in orchestrating CD8+ T cell response to anti-CTLA-4 therapy, the very first U.S. Food and Drug Administration-approved immune checkpoint blocker to treat patients with advanced cancer. We reason that fine-tuning Gfi1 activity in T cells may prevent or reverse T cell exhaustion to bolster immune checkpoint blockade efficacy.”


    Lewis Z. Shi, M.D., Ph.D., Professor in the UAB Department of Radiation Oncology

    Exhausted CD8+ T cells are a complex population of subsets composed of progenitor cells and “effector-like” or “terminally exhausted” cells. Effector-like cells still retain some killer ability. The UAB researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108+CX3CR1+ subset that expresses low levels of Gfi1, while other established subsets have high expression.

    Notable key features of the Ly108+CX3CR1+ subset include: First, the Ly108+CX3CR1+ subset has a distinct chromatin profile from the other sets, meaning a changed accessibility to certain genes on the chromosome. Second, that subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. Third, this process depends on Gfi1.

    To demonstrate a role for Gfi1 in immune checkpoint blockade therapy, the UAB team tested anti-CTLA-4 therapy in a mouse bladder cancer model, comparing mice that had T cells with either wild-type Gfi1 or Gfi1 knockout. They found that the anti-CTLA-4 therapy significantly inhibited tumor growth in wild-type but not Gfi1 knockout mice. Similarly, anti-CTLA-4 therapy promoted infiltration and/or expansion of CD4+ and CD8+ tumor-infiltrating lymphocytes in wild-type but not Gfi1 knockout mice. These observations were largely corroborated in a second mouse model of colorectal adenosarcoma, MC38.

    “Considering Gfi1 downregulation is associated with the active differentiation of CD8+ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108+CX3CR1+ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors,” Shi said.

    Along with a recent report by others of promising outcomes in small cell lung cancer from combining a lysine-specific histone demethylase inhibitor with the anti-PD-1 immune checkpoint blocker, “further testing of this combination approach should be conducted in melanoma, bladder cancer and colorectal adenocarcinoma, especially those resistant to immune checkpoint blockers,” Shi said.

    Co-authors with Shi in the study, “Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer,” are Oluwagbemiga A. Ojo, Hongxing Shen and James A. Bonner, UAB Department of Radiation Oncology; Jennifer T. Ingram and Allan J. Zajac, UAB Department of Microbiology; Robert S. Welner, UAB Department of Medicine Division of Hematology and Oncology; and Georges Lacaud, The University of Manchester, Manchester, United Kingdom.

    At UAB, Radiation Oncology, Microbiology and Medicine are departments in the Marnix E. Heersink School of Medicine. Shi is a scientist in the O’Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.

    Source:

    University of Alabama at Birmingham

    Journal reference:

    Ojo, O. A., et al. (2025). Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer. Nature Communications. doi.org/10.1038/s41467-025-59784-1.

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  • 5 things dental experts want you to do for healthy teeth and gums – The Washington Post

    1. 5 things dental experts want you to do for healthy teeth and gums  The Washington Post
    2. How to Keep Your Teeth Healthy for Life  Consumer Reports
    3. How does brushing your teeth protect your overall health?  News On 6
    4. I Asked Dentists How to Brush Better—Here Are the 4 Tips That Changed My Routine  Real Simple
    5. How teeth change as we age and ways to maintain a healthy smile  InYourArea

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  • Clinical and antibiotic resistance features for extended-spectrum beta

    Clinical and antibiotic resistance features for extended-spectrum beta

    Introduction

    Bloodstream infection (BSI) is a severe and often fatal complication linked to accelerated morbidity and mortality, with an annual incidence ranging from 150 to 309 cases per 100,000 population and a mortality rate ranging from 12.5% to 22.7.1–3 Neonates, in particular, face even higher risks and mortality rates of BSIs, with a mortality rate ranging from 19.7% to 30%.4–6 Escherichia coli (E. coli) and Klebsiella pneumonia (K. pneumoniae) stand as prominent pathogens responsible for neonatal BSIs, with significant mortality rates linked to their infectious impact, presenting a formidable obstacle to anti-infective treatment.6,7 Therefore, it is crucial in clinical practice to identify predictors associated with poor prognosis in E. coli and K. pneumoniae neonatal BSIs.

    The emergence of antimicrobial resistance (AMR), particularly in extended-spectrum β-lactamase (ESBL)-producing bacteria, constitutes a significant global health challenge. This is primarily due to its frequent association with the failure of empirical antibiotic therapy, leading to elevated morbidity and mortality rates.8 In 2019, an estimated 4.95 million deaths were associated with bacterial AMR, among which 1.27 million were attributable to bacterial AMR.9 ESBL is a Gram-negative bacterium of the Enterobacteriaceae family, which harbors ESBL genes either within its plasmids or integrated into its chromosomal DNA.10 It produces β-lactam hydrolyzing enzymes, providing resistance to penicillin, aztreonam, and first-, second-, and third-generation cephalosporins, while lacking the ability to hydrolyze carbapenems or cephamycin.11 Among a wide range of Gram-negative bacteria harboring ESBL genes, E. coli (ESBL-EC) and K. pneumoniae (ESBL-KP) are the most common hosts, causing infections such as BSIs, urinary tract infections, and diarrhea, particularly among neonates, in both hospital and community settings.12–14 Although our previous research demonstrated a notably high prevalence of K. pneumoniae infections among preterm neonates, coupled with suboptimal treatment outcomes and elevated antimicrobial resistance patterns,15 the existing literature on ESBL-EC and ESBL-KP neonatal bloodstream infections remains scarce. Significant knowledge gaps persist regarding their clinical manifestations, epidemiological characteristics, and antimicrobial resistance profiles. Addressing these gaps is critical for developing targeted strategies to mitigate the impact of ESBL-EC and ESBL-KP neonatal BSIs.

    The present study aims to bridge this knowledge gap by systematically investigating the clinical features and antimicrobial resistance profiles of ESBL-EC and ESBL-KP. Through analyzing clinical data, AMR patterns, and the production of ESBL, this research seeks to enhance our understanding of these pathogens, and facilitate the development of evidence-based containment strategies and optimized therapeutic interventions.

    Methods

    Study Setting and Patients

    We conducted a retrospective cohort study from January 2017 to December 2023 at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, which is the largest children’s hospital in the region. During the study period, 180,297 blood culture tests were conducted, with a positivity rate of 1.88% (3394/180,297). In this study we focused on cases of BSIs caused by E. coli and K. pneumoniae in diagnosed patients. For each patient, only the first E. coli or K. pneumoniae BSI isolate was selected for analysis. The inclusion criteria were defined as follows: (a) patients aged 28 days or younger, (b) meets criteria indicative of neonatal bloodstream infections,16 (c) a positive blood culture for E. coli or K. pneumonia, (d) hospitalization with complete clinical data available. Conversely, the analysis systematically excluded outpatients with incomplete or unavailable medical records. The protocol for this study was approved by the research administration of Medical Ethics Committee of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region (No. 2023-3-42). This study used an anonymous method to protect the participants and obtained their permission.

    Data Collection and Definitions

    Various clinical features of the enrolled patients were collected from the hospital’s electronic health records system. The collected data encompassed essential demographic information (gender, gestational age, and weight), medical history (underlying diseases, cesarean sections, premature ruptures of membrane), interventions (invasive procedures and devices, antibiotic exposure), bloodstream infection type and outcomes.

    According to the gestational age at birth, neonates can be classified as follows: term infants, with a gestational age of 37 weeks or more to 42 weeks; late premature infants, with a gestational age between 28 weeks and 37 weeks; and extremely preterm infants, with a gestational age between 22 weeks and 28 weeks. Based on the weight at birth, newborns can be categorized as follows: extremely low birth weight (ELBW) denotes infants with a birth weight below 1000g; very low birth weight (VLBW) indicates infants with a birth weight ranging from 1000g to under 1500g; low birth weight (LBW) signifies infants with a birth weight between 1500g to less than 2500g; normal birth weight (NBW) pertains to infants with a birth weight between 2500g to 4000g; macrosomia describes infants with a birth weight exceeding 4000g. Hypoalbuminemia is generally defined as a serum albumin level of less than 35 g/L. Anemia refers to a peripheral hemoglobin (Hb) concentration of less than 120 g/L. Treatment outcomes were divided into two distinct groups based on clinical documentation. Patients who achieved clinical recovery or showed significant improvement upon discharge were classified as having a favorable prognosis, while those who died during hospitalization or were discharged in critical condition were classified as having a poor prognosis.

    Microbiological Methods

    In this investigation, all intentionally collected isolates were cultivated on blood agar plates at 37 °C in an incubator for 18–24 hours. The isolates were then identified using the Zhuhai DL-96IIautomatic bacterial identification drug sensitivity apparatus (Zhuhai DL Biotech Co., Ltd.,China) or the VITEK2 Compact system (BioMérieux, Marcy l’Etoile, France). The antibiotic susceptibility tests were performed on the isolates utilizing either the Kirby-Bauer methodology, the Zhuhai DL-96II automated bacterial identification drug sensitivity apparatus or the VITEK 2 Compact system. Each protocol was carried out according to the manufacturer’s guidelines. The minimum inhibitory concentrations (MICs) of common clinical antibiotics, including gentamicin, sulfamethoxazole, ciprofloxacin, ceftazidime, cefazolin, cefepime, meropenem, piperacillin-tazobactam, imipenem, amikacin, ampicillin-sulbactam, ceftriaxone, ticarcillin-clavulanic acid, chloramphenicol, amoxicillin, cefuroxime, minocycline, levofloxacin, and cefoxitin. The findings were elucidated in accordance with the protocols delineated by the Clinical and Laboratory Standards Institute M100 document, and ESBL screen was determined based on the susceptibility test for ceftriaxone and ceftazidime (MIC ≥ 2 μg/mL), excluding carbapenem-resistant strains.

    The confirmation of ESBL-producing isolates was conducted using the combination broth microdilution. A comparison of the MIC was made between ceftazidime and cefotaxime alone versus those of ceftazidime and cefotaxime containing clavulanic acid. Following the designated incubation period, a reduction of ≥3-fold in the minimum inhibitory concentration (MIC) of any antimicrobial agent when tested in combination with clavulanate, compared to its MIC value when tested independently, was identified as indicative of ESBL production, in accordance with the criteria established by the Clinical and Laboratory Standards Institute (CLSI). The quality control strains employed were E. coli ATCC 25922 and K. pneumoniae ATCC 700603 (National Center for Clinical Laboratories, Beijing, China).

    Statistical Analysis

    Statistical analyses were performed using SPSS version 25.0. Count data were reported as percentages, and group comparisons were performed using χ2 tests or Fisher’s exact test for categorical variables. Variables that showed significance (p<0.10) in the univariate analysis, including extremely low birth weight, very premature infants, anemia, hypoalbuminemia, CRKP, mechanical ventilation, and central venous catheterization, were selected for inclusion in a logistic regression model to evaluate their association with poor Prognosis. Statistical significance was considered at p-values less than 0.05.

    Results

    Baseline Characteristics of 139 Neonates with Escherichia coli and Klebsiella pneumoniae Bloodstream Infections

    During the study period, a total of 139 unique cases of neonatal BSIs caused by E. coli and K. pneumoniae were identified. Of these, 29 BSIs were caused by ESBL-EC (20.8%), 13 by ESBL KP (9.3%), 87 by non-ESBL strains, and 10 by CRKP (7.1%). Among the participants, 74 (53.2%) were male. The majority of neonates included in the study were term infants (50.4%) and normal birth weights (48.9%). Most of them developed late-Onset infections (66.2%) and breast-fed (70.5%). The most underlying diseases was hypoalbuminemia (35.9%), while the invasive procedures and devices was mechanical ventilation (53.2%), respectively. The predominant antibiotic exposures was β-lactam-β-lactamase inhibitors (31.6%). 26 (18.7%) neonates with poor prognosis were hospitalized after the onset of E. coli and K. pneumoniae bloodstream infections (Supplementary Table 1).

    Microbiological Characteristics of Escherichia coli and Klebsiella pneumoniae Isolates

    Among the 139 isolates, 95 were E. coli and 44 were K. pneumoniae. All strains have completed antimicrobial susceptibility testing, and the drug resistance profiles are shown in Table 1. Among Escherichia coli strains, the three antimicrobial agents with the highest resistance rates were ampicillin (82.1%), sulfamethoxazole (65.2%), and cefazolin (44.2%). Notably, no strains exhibited resistance to carbapenems. In comparison, the resistance rates of ampicillin (P=0.003), ceftazidime (P=0.015), ceftriaxone (P=0.000), cefepime (P=0.000), cefuroxime (P=0.000), cefazolin (P=0.000), ciprofloxacin (P=0.000), levofloxacin (P=0.01) and minocycline (P=0.031) were significantly higher in the ESBL-EC strains than non- ESBL-EC strains.

    Table 1 Antibiotic Susceptibility Profiles for Escherichia coli and Klebsiella pneumoniae Isolates

    Meanwhile, the resistance rates of K. pneumoniae to ampicillin, cefuroxime, cefazolin, and ceftriaxone are alarmingly high, standing at 100.00%, 54.5%, 54.5%, and 50.00%, respectively. Furthermore, the resistance rates for imipenem and meropenem exceed 20%, specifically standing at 22.7%. In contrast to non-ESBL-KP, ESBL-KP exhibited an elevated level of resistance towards ampicillin-sulbactam (P=0.000), ceftriaxone (P=0.000), cefepime (P=0.000), cefuroxime (P=0.000), cefazolin (P=0.000), ciprofloxacin (P=0.000), chloramphenicol (P=0.000), gentamicin (P=0.001), levofloxacin (P=0.001), sulfamethoxazole (P=0.000), and ticarcillin-clavulanic acid (P=0.000).

    Risk Factors Associated with Bloodstream Infections Caused by ESBL-Producing Strains

    Among 139 patients analyzed, 42 (30.2%) BSIs were attributed to ESBL strains, while 87 (62.6%) were caused by non-ESBL strains. Notably, 10 cases (7.2%) involved CRKP strains. Comparative analysis of demographic, and clinical parameters between patients with ESBL-producing and non-ESBL BSIs is presented in Table 2. The factors most significantly associated with ESBL strains bloodstream infections in neonates were late premature infant (P=0.037), very low birth weight (p=0.001), cesarean section (p=0.003), pneumonia (P=0.037), mechanical ventilation (p=0.000), and length of hospital stay >30 days (p=0.001). In contrast, term infants (p=0.010) and normal birth weight infants (P=0.021) were more prevalent in the non-ESBL strains group than in the ESBL strains group.

    Table 2 Comparison of Neonatal Variables Between Those with BSIs Caused by ESBL and Non-ESBL Strains

    Additionally, the comparison of patient variables between individuals with BSIs due to ESBL E. coli and those with BSIs due to non-ESBL E. coli showed that cesarean section (p=0.031), pneumonia (P=0.041), mechanical ventilation (p=0.014), indwelling catheters (p=0.048) and length of hospital stay >30 days (p=0.012) were more associated with ESBL E. coli BSIs (Table 3).

    Table 3 Comparison of Neonatal Variables Between BSIs ESBL-EC and Non-ESBL-EC

    Furthermore, the analysis of patient characteristics in individuals suffering from BSIs caused by ESBL-producing K. pneumoniae compared to those with infections caused by non-ESBL-producing K. pneumoniae revealed that late premature infants (p=0.031), very low birth weight (p=0.004), and mechanical ventilation (p=0.011) were more commonly linked to ESBL K. pneumoniae BSIs (Table 4).

    Table 4 Comparison of Neonatal Variables Between BSIs ESBL-KP and Non-ESBL-KP

    Risk Factors for Poor Prognosis in Neonates with Escherichia coli and Klebsiella pneumoniae Bloodstream Infections

    The results of the univariate and multivariate analysis were depicted in Table 5. The percentages of favorable and poor prognosis in neonates afflicted with bloodstream infections caused by E. coli and K. pneumoniae stood at 81.29% (113 out of 139) and 18.71% (26 out of 139), respectively. Univariate analysis indicated that very premature infants (p=0.000), extremely low birth weight (p=0.000), hypoalbuminemia (p=0.000), anemia (p=0.015), and isolation of CRKP (p=0.000) were significantly correlated with poor prognosis. In the multivariate analysis, hypoalbuminemia (OR: 3.922, 95% CI: 1.189–12.937, p=0.025), and isolation of CRKP (OR: 11.548, 95% CI: 1.785–74.708, p=0.010) were identified as significant predictors of poor prognosis in neonates afflicted with bloodstream infections caused by E. coli and K. pneumonia.

    Table 5 Logistic Regression Analysis for Variables Associated with Poor Prognosis of Neonates BSIs with E. coli and K. pneumonia

    Discussion

    Bloodstream infections in newborns caused by E. coli and K. pneumoniae present a formidable challenge, given the rising prevalence of ESBL and CR strains, especially in healthcare facilities, and they are two of the drivers of nosocomial and community infections globally.17,18 Between 2017 and 2023, at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region in Southwest China, we found that approximately one-third of the 139 BSIs caused by E. coli and K. pneumoniae were due to ESBL strains and 7.2% were due to CRKP. Among these strains, 20.8% were ESBL-EC, whereas only 9.3% were ESBL-KP. This finding was almost similar to the frequencies of ESBL producers among the neonates in the previous two studies, which reported ESBL-EC at 30.4% and ESBL-KP at 8.2%.19,20 However, a previous study about neonatal sepsis in low- and middle-income countries revealed a much higher prevalence of ESBL-EC (38%) and ESBL-KP (83%) compared to the findings in this study.21 Furthermore, previous studies conducted in china have reported even higher percentages.22,23 Consistent findings have been documented in the literature from various regions, such as Iran,24 South Africa,25 Ghana,26 and India.27 These findings could potentially be attributed to variations in phenotypic detection methods for ESBL production and differences within the study populations.

    Genes encoding ESBL are predominantly located on transposons or insertion sequences within plasmids in conjunction with other resistance genes.8 Consequently, they have the potential to disseminate quickly, leading to resistance against multiple antimicrobials including aminoglycosides, cephalosporins, trimethoprim, sulfonamides, tetracyclines, chloramphenicol, and fluoroquinolones.28 The antibiotic resistance profiles from our study also showed that ESBL-EC exhibited a higher resistance rate to cephalosporins, fluoroquinolones, tetracyclines compared to non-ESBL strains. Meanwhile, ESBL-KP demonstrated elevated resistance rates to aminoglycosides, β-lactam-β-lactamase inhibitors, cephalosporins, sulfonamides, chloramphenicol, and fluoroquinolones. According to the guidelines from the Infectious Diseases Society of America, carbapenems, fluoroquinolones, and cotrimoxazole are recommended for the treatment of infections outside of the urinary tract caused by ESBL-E.29 However, high resistance to fluoroquinolones and cotrimoxazole has been found in our study, consistent with prior research.18 In contrast, no ESBL-E strains exhibited resistance to carbapenems, and ESBL-KP strains showed a resistance rate of 22.7% to imipenem and meropenem, which agrees with earlier studies in Zambia and México.30,31 Therefore, it is crucial to monitor the resistance profiles of commonly used antibiotics in the local area. Of utmost importance is the monitoring of the resistance patterns displayed by ESBL isolates and understanding their impact on patient management, particularly among neonates.

    The clinical characteristics associated with neonatal BSIs caused by ESBL isolates are vital for the prevention of these infections and the effective administration. Co-morbidities like cesarean section, prematurity, very low birth weight, pulmonary disease, malnutrition, malignancy, gastroenteritis, mechanical ventilation, indwelling catheters, central venous catheterization were investigated as risk factors for neonatal BSIs due to ESBL-E isolates.32–35 In our study, patients with late premature infant, very low birth weight, cesarean section, pneumonia, and mechanical ventilation also had a higher risk of ESBL isolates bloodstream infection. Furthermore, we conducted a detailed analysis of the risk factors associated with ESBL-EC and ESBL-KP neonatal BSI. Our investigation revealed a distinct correlation between ESBL-EC infections with cesarean section, pneumonia, mechanical ventilation, and indwelling catheters, whereas ESBL-KP infections showed a notably association with the presence of late premature infants, very low birth weight, and mechanical ventilation. This finding indicates that different subtypes of Enterobacteriaceae bacteria carrying ESBL may demonstrate variations in their pathogenicity and impact on host resistance. E. coli and K. pneumoniae are the most prevalent hosts of ESBL.8 The ST131 clone is predominant in ESBL-producing E. coli, while ST11 is dominant in ESBL-producing K. pneumoniae.11,36 These strains harbor distinctive biological traits or pathogenic mechanisms that enhance their propensity to serve as risk factors for bloodstream infections. Nevertheless, studies on the virulence and molecular epidemiological characteristics have not been undertaken. Subsequent research should prioritize whole-genome sequencing and functional assessments to elucidate the molecular mechanisms that underlie these adaptations and pathogenicity, thereby informing targeted interventions.

    Although we have conducted a statistical analysis on the risk factors associated with ESBL strains infections, the total number of ESBL infection cases is insufficient for a multivariate analysis. Consequently, we undertook a study analyzing the prognosis of 139 cases of neonatal bloodstream infections to identify the risk factors contributing to poor prognosis. Our study indicated that very premature infants, extremely low birth weight, hypoalbuminemia, anemia, and isolation of CRKP were significantly correlated with a poor prognosis. In the management of neonates, invasive procedures and devices such as mechanical ventilation and central venous catheterization, although crucial for life support, heighten the vulnerability to infections in newborns, especially premature infants and those with low birth weight.37 Research has confirmed that prematurity, low birth weight, hypoalbuminemia, anemia, CRKP, and invasive procedures such as mechanical ventilation are associated with a poor prognosis for neonatal BSI.38–41 Consistent with our research results, further studies are needed to explore the specific mechanisms. Importantly, isolation of CRKP and hypoalbuminemia were identified as significant predictors of poor prognosis in neonates afflicted with bloodstream infections caused by E. coli and K. pneumonia. In line with the findings of Dilan et al39 and Yasemin et al42 recent research has consistently demonstrated that the presence of carbapenem-resistant gram-negative bacteria, specifically isolation of CRKP serves as a significant predictor of unfavorable outcomes in neonatal bloodstream infections. According to the results of our search in the PubMed database, we did not retrieve any relevant literature indicating that hypoalbuminemia is an independent risk factor for poor prognosis in neonatal BSI. Proteins play vital roles in the body, contributing to immune function, nutrient metabolism, and cell structure. Newborns have an immature immune system at birth, and hypoalbuminemia could potentially compromise immune function, elevating the susceptibility to infections. In the context of neonatal BSI, hypoalbuminemia might worsen the disease severity, impacting treatment efficacy and prognosis.

    Our study was subject to certain limitations. The predominant limitation pertained to its retrospective study and single-center design, encompassing a cohort of 139 neonatal patients, thereby rendering it susceptible to selection bias. Further prospective, multicenter studies are warranted. Secondly, our research exclusively targeted bloodstream infections caused by E. coli and K. pneumoniae, without encompassing other gram-negative bacteria. Furthermore, our research has focused solely on drug resistance phenotypes rather than delving into the molecular aspects such as drug resistance mechanisms, virulence, and molecular epidemiology studies. Exploring the correlation between strain molecular characteristics and clinical traits is crucial for infection prevention and control, which will be the primary focus of our future investigations. Lastly, the study design did not include a preset long-term follow-up, resulting in a lack of data on mortality within 28 days, which limits the completeness of the research conclusions and the evaluation of long-term patient outcomes. In future studies, we will consider incorporating a long-term follow-up plan to more comprehensively assess treatment efficacy and patient prognosis.

    Conclusion

    The predominant children’s hospital in this autonomous region exhibits a relatively low incidence of ESBL-EC and ESBL-KP. Compared to non-ESBL strains, ESBL strains demonstrated a higher resistance rate to cephalosporins, fluoroquinolones, and tetracyclines. Late-preterm infants, very low birth weight, cesarean section history, pneumonia, and mechanical ventilation were found to be associated with bloodstream infections caused by ESBL strains. The isolation of CRKP and hypoalbuminemia were identified as significant predictors of poor prognosis in neonates afflicted with bloodstream infections caused by E. coli and K. pneumonia. The implementation of infection control initiatives and antimicrobial stewardship programs is critical for controlling healthcare expenditures, reducing antimicrobial resistance rates, enhancing patient outcomes, and mitigating the adverse ecological impacts of antimicrobial overuse.

    Data Sharing Statement

    The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

    Ethics Approval and Consent to Participate

    This research adhered to the ethical principles outlined in the Declaration of Helsinki and followed applicable guidelines. Ethical approval was obtained from the Institutional Review Board of the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region (Approval No. 2023-3-42). Since the study involved a retrospective analysis of de-identified medical records, participant privacy was safeguarded, and no additional risks were introduced. Due to the use of anonymized data and the study’s retrospective design, the ethics committee granted an exemption from obtaining informed consent.

    Acknowledgments

    We extend our sincere appreciation to the Clinical Laboratory Department of the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region for their invaluable support. Special thanks go to the management and microbiology team for enabling efficient bacterial identification and automated susceptibility testing. We also recognize the dedicated efforts of all clinical and laboratory personnel involved in this study. Lastly, we are deeply grateful to all participants for their contribution.

    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 work was supported by a self-funded project by the Health Commission of Guangxi Zhuang Autonomous Region (Z-A20240291 and Z-A20220288).

    Disclosure

    The authors declare that they have no conflict of interest.

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    41. Sahu P, Srinivasan M, Thunga G, Lewis LE, Kunhikatta V. Identification of potential risk factors for the poor prognosis of neonatal sepsis. Med Pharm Rep. 2022;95(3):282–289. doi:10.15386/mpr-2331

    42. Ozsurekci Y, Aykac K, Cengiz AB, et al. Bloodstream infections in children caused by carbapenem-resistant versus carbapenem-susceptible gram-negative microorganisms: risk factors and outcome. Diagn Microbiol Infect Dis. 2017;87(4):359–364. doi:10.1016/j.diagmicrobio.2016.12.013

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  • Airway Management Following Head and Neck Microvascular Reconstruction

    Airway Management Following Head and Neck Microvascular Reconstruction

    Introduction

    Head and neck oncologic resections with microvascular free flap reconstruction present unique airway management challenges. Extensive resections and bulky flap reconstructions can cause significant postoperative upper airway edema, bleeding, or anatomic distortion, risking airway obstruction. Traditionally, many centers performed prophylactic tracheostomy for all major head and neck free flap cases to secure the airway.1 However, accumulating evidence indicates that routine elective tracheostomy may not be necessary in every case.1,2 Avoiding unnecessary tracheostomies can reduce patient morbidity, improve recovery, and lower health-care costs.3 On the other hand, inappropriately withholding a needed airway can lead to life-threatening obstruction. This review synthesizes recent studies on perioperative airway management in this context, focusing on predictors for requiring tracheostomy, timing and criteria for decannulation, airway assessment tools, and airway-related complications.

    Airway Management Strategies and Evolving Practices

    Prophylactic Tracheostomy vs Alternative Strategies

    In the past, an “elective” tracheostomy was often performed at the end of the primary tumor resection and flap reconstruction to preempt airway compromise. Many institutions have moved away from one-size-fits-all tracheostomy toward selective strategies. Two common alternatives are delayed extubation, keeping the patient intubated overnight in intensive care for observation, and immediate extubation in the operating room for low-risk cases. Recent multi-center experiences demonstrate that both alternatives can be safe in appropriately chosen patients.3,4

    A large prospective study of 720 patients involving all types of major oral surgery revealed that avoiding upfront tracheostomy and instead using overnight intubation followed by extubation led to significantly shorter hospital stays (mean ~7.2 vs 11.5 days) and quicker return to oral diet (5.1 vs 7.2 days) compared to routine tracheostomy.5 In that series, over 90% of patients managed with delayed extubation never required a tracheostomy. Similarly, a 2024 cohort study (193 patients) from a United States cancer center that extubated most patients immediately after surgery reported that only 2.1% needed an unplanned “rescue” tracheostomy, with no airway-related mortalities.4 These data suggest that for appropriately selected head and neck patients with free flap repair, a well-planned extubation strategy may obviate tracheostomy without compromising safety.

    Global Trends

    There is a worldwide trend toward tracheostomy avoidance in suitable patients. A decade ago, a United Kingdom survey found nearly one-third of centers still did a tracheostomy for every free flap case.6 Now, many high-volume centers in North America, Europe, and Asia have moved toward a selective tracheostomy approach, meaning they intubate and observe overnight, reserving tracheostomy only for patients with certain risk factors. Recent series from Taiwan,7 India,5 and Portugal8 have all concluded that routine tracheostomy is unnecessary and often over-utilized. Enhanced Recovery After Surgery (ERAS) protocols for head and neck reconstruction also encourage minimizing invasive interventions and expediting recovery, which aligns with avoiding unnecessary tracheostomies.9–11 Nevertheless, practice is not uniform globally; some centers still err on the side of prophylactic tracheostomy, especially where intensive care unit (ICU) resources for overnight observation are limited or where prior institutional culture favors tracheostomy. The COVID-19 pandemic further influenced practices.12 Overall, the contemporary approach is to individualize airway management, performing a tracheostomy only when specific risk factors dictate its necessity. The common risk factors for requiring tracheostomy after head and neck microvascular repair are listed in Table 1. Notably, more than 90% of head and neck cancer patients might have one or more of these factors, so the presence of a single risk factor does not automatically mandate a tracheostomy. A holistic, case-by-case assessment is needed.

    Table 1 Risk Factors for Requiring Tracheostomy After Head and Neck Microvascular Reconstruction

    Intraoperative Decision-Making

    The decision on airway management is typically made intraoperatively towards the end of the free flap reconstruction. The surgical and anesthesia teams jointly assess factors such as airway swelling, bleeding, and patient physiology. If the airway appears sufficiently patent and the patient is stable, an attempt at extubation is often favored.2 However, if there is any doubt about airway safety—for example, significant tongue/base-of-tongue swelling, extensive pharyngeal edema, difficult anatomy, or the patient remains obtunded—a tracheostomy is performed for definitive airway security.2,13

    Many institutions have developed internal algorithms or guidelines. As an example, Singh et al3 proposed that patients with bilateral neck dissection or oropharyngeal resections requiring additional exposure procedures should receive a primary tracheostomy, whereas patients with unilateral neck dissection and no other high-risk features can be safely managed with delayed extubation. Newer protocols favor a “wait-and-see” extubation trial for most patients, with the capability to perform an urgent tracheostomy if the extubation fails. This selective approach has been validated by multiple studies showing low rates of reintubation or emergency tracheostomy when careful criteria are applied.5,14–16 In summary, the contemporary strategy is tailored: routine prophylactic tracheostomy is no longer standard, and each case is managed according to its risk profile and intraoperative findings.

    Predictors of Tracheostomy Requirement

    Not all head and neck free flap patients carry equal risk for airway compromise. Extensive research has identified specific predictors for which patients are likely to require a tracheostomy versus those who can be safely extubated. These predictors can be broadly categorized into surgical factors and patient factors.

    Defect Location and Extent

    Perhaps, the strongest predictors are related to the location and size of the resection. Large defects involving the tongue base, floor of mouth, or oropharynx are well known to cause significant postoperative edema in critical airway structures. A 2019 analysis of 533 cases by Cai et al found that defects of the tongue, floor of mouth, or oropharynx were significantly associated with needing a tracheostomy.1 Essentially, resections that cross the midline or involve the tongue base/oropharynx leave patients at higher risk of obstructing their airway from swelling or hemorrhage.

    Ledderhof et al (2020) similarly reported that composite resections involving the floor of mouth had a high incidence of airway complications (15.4%) and thus often warranted prophylactic tracheostomy.17 In contrast, more “lateral” or anterior oral cavity tumors (eg confined to the buccal mucosa, lateral tongue, or mandibular alveolus) have a lower risk of airway compromise. A recent Portuguese study (116 cases in 2019–2020) concluded that patients with lateral oral cavity tumors and smaller T-stage (T1–T2) could frequently avoid elective tracheostomy.8

    Reconstruction Type and Flap Bulk

    The choice of flap and its bulkiness also influence airway risk. Heavier, thicker flaps such as the anterolateral thigh or bulky rectus abdominis flaps can cause more mass effect in the oral cavity or oropharynx, as well as increased edema due to larger tissue volume transplanted. In Cai et al’s study, a “bulky soft-tissue flap reconstruction” was a significant risk factor for tracheostomy.1 On the other hand, thin fasciocutaneous flaps like the radial forearm free flap contribute less to airway narrowing. The Myatra study’s results underscore that favorable factors for delayed extubation included limited surgical extent (eg primary closure) or use of a thin fasciocutaneous free flap.5 These conditions differ from more extensive composite resections (eg those requiring bulky myocutaneous flaps or bone-containing flaps), which inherently carry higher risk of airway compromise. Indeed, one 2024 study found that use of a forearm flap was associated with tracheostomy avoidance, an odds ratio (OR) = 0.15, indicating patients with radial forearm free flap were much less likely to need tracheostomy).4

    Similarly, if no flap or only a local flap is needed for very limited defects, the airway risk is inherently lower. Composite bony reconstructions (eg fibula flap for mandible) can be double-edged: they involve large surgeries but also by removing the mandible they may open up the airway space. In fact, the Nebraska cohort noted that “mandibulectomy” as a variable was associated with a lower likelihood of tracheostomy with an OR = 0.04 on multivariate analysis.4 However, extensive segmental mandibulectomies crossing the midline still pose risk due to floor-of-mouth involvement. Tsai et al (2024) identified that cross-midline segmental mandibulectomy was an independent predictor of post-extubation airway failure in oral cancer patients managed without prophylactic tracheostomy.7

    Neck Dissection

    Neck dissection contributes to postoperative neck swelling and can reduce lymphatic drainage. A bilateral neck dissection is a well-established risk factor for difficult airway in the recovery period. Removing lymphatic tissue on both sides of the neck leads to more diffuse edema and can also weaken neck support for the upper airway structures. Multiple studies have found bilateral neck dissection to significantly increase the need for tracheostomy.3,4,18 For example, multivariate analysis by Holcomb et al (2024) showed bilateral neck dissection tripled the odds of requiring tracheostomy (OR ~3.13).

    Even a unilateral neck dissection adds some risk, though generally manageable. Singh’s data from the United Kingdom suggested that free flap patients with only unilateral neck dissection could usually be extubated safely without tracheostomy,3 whereas bilateral dissection often warranted one. The combination of floor-of-mouth or tongue base resection plus bilateral neck dissection is particularly high risk—this scenario in Ledderhof’s series is where airway events were most frequent.17 In contrast, if no neck dissection is needed, the airway risk is markedly lower.

    Prior Radiation or Chemotherapy

    Patients who have received prior radiation to the head-neck region have fibrotic, less compliant tissues that may respond to surgery with more swelling and inflammation. Scarred neck skin can also make reintubation or emergent surgical airways more challenging. Cai et al found a history of radiotherapy significantly correlated with needing tracheostomy (OR ~3.4).1 Prior chemoradiation often implies more advanced disease and more extensive surgery as well, compounding the risk. In the same study, a history of chemotherapy trended toward increased tracheostomy need, though not reaching significance. These patients may benefit from a lower threshold for elective tracheostomy, given the unpredictable nature of tissue edema in previously irradiated fields.

    Patient Factors

    Patient-specific factors are sometimes overlooked but can be important. Poor baseline pulmonary function or obstructive sleep apnea (often associated with higher BMI) could impair the patient’s ability to protect their airway or handle secretions after extubation.3,4 Interestingly, some recent findings are counterintuitive regarding age and BMI. Tsai et al noted older age was a risk factor for post-op airway events in extubated patients, which fits the intuition that elderly patients have less physiological reserve.7 However, the Nebraska study found age >70 years was actually associated with lower odds of tracheostomy (OR 0.33), possibly reflecting a tendency to avoid invasive procedures in the very old or that surgeons selected smaller, less risky surgeries for older patients.4

    In addition to tumor-related factors, patient comorbidities and physiologic reserves, such as chronic pulmonary disease, obesity or obstructive sleep apnea, and overall frailty,19 can impact the risk of airway compromise and thus must be considered in airway planning. Low body mass index (BMI < 20, possibly a marker of frailty or malnutrition) was associated with increased tracheostomy need in that same study (OR ~3.8).4 Comorbidities such as cardiovascular and cerebrovascular disease, chronic lung disease, and diabetes were flagged by Tsai et al as more prevalent in patients who suffered airway complications.7 These conditions might not directly cause obstruction, but they can slow recovery or affect breathing and coughing strength. Smoking status is another factor: heavy smokers may have reactive airways and coughing that could either demand a secure airway or conversely complicate tracheostomy care. The smokers in Cai’s cohort had higher tracheostomy rates, OR ~2.36.1 Moreover, perioperative support resources (eg intensive care monitoring capabilities and experienced staffing levels overnight) can sway the decision towards a safer course.

    Collectively, the need for tracheostomy is multi-factorial. Patients with advanced tumors (T3–T4), midline or base-of-tongue involvement, bilateral neck dissection, and bulky flap reconstructions are prime candidates for a prophylactic tracheostomy. By contrast, those with small lateral defects, minimal or thin flaps, and limited neck dissection often do well without a tracheostomy. These predictors are being used to guide more selective airway management.

    Preoperative Airway Assessment and Planning

    Proper airway management starts before the surgery, with a thorough preoperative assessment. The goals are twofold: (1) to plan a safe anesthesia strategy for intubation and intraoperative airway management and (2) to predict postoperative airway risks to guide the need for tracheostomy or other interventions.

    Anatomic Airway Evaluation

    The anesthesiology team evaluates standard airway parameters such as mouth opening, Mallampati score, thyromental distance, and cervical spine mobility preoperatively.20–22 Patients with large intraoral or pharyngeal tumors may pose a difficult intubation, sometimes necessitating an awake fiberoptic intubation or video laryngoscopy-assisted intubation at the start of the case. Fiberoptic examination of the upper airway can be performed in clinic or immediately prior to induction to assess how much the tumor is encroaching on the airway lumen.23 If severe obstruction is present (eg a near-total supraglottic obstruction by tumor), a prophylactic awake tracheostomy before resection might even be considered.24 However, in most cases, tumors that require free flap reconstruction are still intubatable with careful technique. The key is anticipation—for instance, a patient with a large tongue tumor and trismus should prompt an awake nasendoscopy and a well-planned awake intubation to avoid losing the airway during induction.

    Risk Stratification Tools

    Beyond the technical intubation, surgeons and anesthesiologists collaborate to stratify the risk of postoperative airway compromise. In recent years, several predictive scoring systems have been proposed. These include: the Kruse -Lösler score (2005)25 based on tumor location and size, the Cameron score (2010)26 which factors in tumor site (cutaneous, mouth, oropharynx) and neck dissection, the “TRACHY” score (published 2018),27 and more recently the scoring model by Cai et al (2019)1 which incorporates defect, neck dissection, flap type, and comorbidities.

    The common aim is to create an objective tool to guide whether a patient “needs” a tracheostomy. For example, the TRACHY score assigns points for factors like tumor crossing midline, size of tongue resection, etc., and a threshold score ≥5 was recommended to perform a tracheostomy. Similarly, Cai’s model assigns weights based on OR of risk factors such as bilateral mandible defect (score 4), bilateral neck dissection (score 3), radiotherapy history (score 2), oropharynx defect (score 2), etc., and suggests tracheostomy if total score ≥3 (with <2 suggesting safe extubation, and 2–3 intermediate).

    These systems are valuable educational tools, but none has been universally adopted into routine practice. One issue is that many scoring systems were derived in single institutions with specific patient populations, and they sometimes give discordant recommendations for the same patient. For instance, the study applying Cameron and TRACHY scores to 116 patients found the two systems only agreed ~54% of the time on whether a tracheostomy was indicated.8 This underscores that clinical judgment still prevails. Nevertheless, using such tools in the preoperative planning meeting can highlight risk factors that might be overlooked and provide a checklist-like approach to airway planning.

    Multidisciplinary Planning

    Ideally, the decision-making for airway management is done as a team. Many centers hold a preoperative huddle involving the surgeon, anesthesiologist, and nursing team to discuss the case complexity. Important considerations include: “Given the planned resection and flap, do we expect significant swelling? Does this patient have any unique risk? What is our plan A and plan B for extubation?” If the team anticipates borderline airway status post-op, they might elect to consent the patient for a possible tracheostomy and have equipment ready. Conversely, if they anticipate no tracheostomy, they plan for postoperative monitoring accordingly. Part of pre-op planning is also patient counseling—explaining to the patient and family whether a temporary tracheostomy is expected or if the aim is to avoid it. Therefore, preoperative assessment combines standard airway evaluation with risk stratification for post-op obstruction. Tools like scoring systems and thorough airway exams help inform the plan, but they augment rather than replace clinical judgment. The outcome of this planning is an initial strategy (extubation vs tracheostomy) that will be confirmed or revised based on intraoperative findings.

    Postoperative Airway Management and Monitoring

    Whether a patient is extubated or has a tracheostomy, vigilant postoperative monitoring is critical in the first 24–48 hours after head and neck free flap surgery. This period carries the highest risk for airway events due to swelling peaking, potential bleeding, and effects of anesthesia wear-off on airway reflexes.

    If Patient is Intubated (Delayed Extubation Strategy)

    For delayed extubation strategy, the focus is on controlling factors that could worsen airway edema—adequate sedation/analgesia to prevent agitation, head elevation to promote venous drainage, and possibly steroids. The ICU team assesses the patient’s readiness for extubation the next day. Key assessments include a cuff leak test and direct airway visualization. The cuff leak test involves deflating the endotracheal tube cuff and checking for an audible air leak or a drop in ventilator peak pressure, indicating that air can pass around the tube—a surrogate for adequate airway caliber.28 A positive cuff leak (good air leak) suggests less severe laryngeal/tracheal edema, whereas the absence of a cuff leak raises concern for significant swelling.29 It is important to note that while a cuff leak test is a helpful screening tool, it is not foolproof; patients with no cuff leak can sometimes still be extubated successfully, so results are interpreted in context.

    Therefore, many anesthesiologists will also perform a flexible fiberoptic laryngoscopy through the endotracheal tube to directly inspect the glottis and tongue base before extubation. This allows visualization of flap position, hematoma, or edema. If the airway looks patent and the patient is starting to wake, they will proceed with extubation. Some protocols call for exchanging the endotracheal tube for a hollow airway exchange catheter prior to extubation, which can serve as a guide for rapid reintubation if the patient fails extubation. In a prospective Indian study of 720 patients, using such a “staged extubation” approach, none of the delayed extubation patients who met extubation criteria experienced an irreversible airway loss—any who did show signs of compromise could be quickly reintubated or given a tracheostomy without adverse outcome.5

    If Patient Has a Tracheostomy

    In cases where a prophylactic tracheostomy is done, immediate post-op management revolves around tracheostomy care and monitoring for tracheostomy-related complications. The team should ensure the tracheostomy ties are secure—this is especially important in free flap patients who often have bulky dressings or flaps in the neck that could dislodge a poorly secured tracheostomy tube. One nursing article highlighted innovative ways to secure tracheostomy collars in these patients to prevent displacement, given the critical nature of a fresh tracheostomy in a swollen airway. The patient is typically kept sedated or at least not fully awake immediately after surgery even with a tracheostomy, to prevent coughing/bucking that might stress fresh microvascular anastomoses. However, over-sedation is avoided to allow neurological monitoring and because a benefit of tracheostomy is that the patient can be awake and breathing comfortably. Within the first 24 hours, the cuff may be switched from inflated to deflated intermittently to assess airflow around the tracheostomy and begin weaning if appropriate.

    Observation for Complications

    The team must watch for signs of airway compromise. Warning signs include: increased work of breathing, use of accessory muscles, stridor if extubated, or high peak airway pressures and agitation if intubated. In tracheostomy patients, indicators are diminished airflow through the tracheostomy, the patient “bucking” or attempting to breathe around it, or oxygen desaturation. Nursing staff in the ICU or step-down unit are trained to call rapid response or the surgical team at the first sign of airway trouble, as these events can escalate quickly.

    In extubated patients, one must also monitor for bleeding into the airway. Any expanding neck hematoma in a recent free flap patient can threaten both the flap and airway patency and often necessitates urgent bedside opening of sutures or return to the OR—potentially including securing the airway first if not already secured. In the Portuguese series of 116 tracheostomy cases, no airway emergencies were reported, possibly due to having the tracheostomy in place, whereas in primarily extubated cohorts, approximately 2–8% of patients required emergent reintubation or tracheostomy for airway compromise.8 These statistics highlight that with proper monitoring, even those few patients who do develop airway obstruction can be rescued in a controlled manner.

    Multidisciplinary Approach

    Early postoperative airway management is often a collaboration among surgeons, intensivists, anesthesiologists, and specialized nursing such as tracheostomy nurses or respiratory therapists. Many institutions have airway emergency protocols in place for head and neck post-op patients—for instance, a difficult airway cart at the bedside, and surgeons on standby especially the first night. Having an otolaryngology or anesthesia team member experienced in fiberoptic intubation on call is advisable.

    In summary, the postoperative phase requires constant vigilance. For delayed extubation strategies, tools like the cuff leak test and fiberoptic exam guide the timing of extubation, usually on postoperative day 1 if all is well. If extubation fails or appears too risky, a tracheostomy is performed—some centers will do it bedside in the ICU if needed emergently, while others bring the patient to the OR. The overall objective is to ensure a secure airway at all times, either via a tube or a tracheostomy, until the patient demonstrably can maintain their own airway.

    Tracheostomy Decannulation: Timing and Criteria

    Once a tracheostomy has been placed, the next consideration is how long to keep it and when it can be safely removed. In the context of temporary tracheostomies for head and neck free flap patients, the goal is to decannulate as soon as the patient’s airway is stable to minimize tracheostomy-related morbidity and hasten recovery. Criteria for safe tracheostomy decannulation is listed in Table 2.

    Table 2 Criteria for Safe Tracheostomy Decannulation

    Typical Timing

    For most patients who receive a prophylactic tracheostomy after head and neck reconstruction, decannulation usually occurs about one week post-surgery, once the peak edema has resolved. Reported averages range from 5–10 days post-op. In a 2019 series from Peking University, the mean decannulation time was ~7.9 ± 1.8 days after surgery. Similarly, a single-institution audit found a median decannulation day of 5 (interquartile range 4–10 days) for temporary tracheostomies in free flap patients.30

    Decannulation tends to be delayed beyond one week in patients who had more extensive surgery or any postoperative complications like flap issues or pulmonary infections. For example, Cai et al noted one outlier patient with a flap necrosis who was decannulated on day 22 and only discharged on day 33, illustrating that surgical complications can prolong the need for airway protection.1 On the other hand, some institutions practicing very early decannulation have reported success; an Israeli team described a “one-stage decannulation” protocol in which they removed the tracheostomy in ICU as early as postoperative day 5–6 on average, with monitoring for 24 hours, achieving decannulation by day 7 in all 24 patients studied.31 None of those patients required reintubation, suggesting that with strict criteria, decannulation before the one-week mark is feasible.31 However, this aggressive approach has not been widely adopted, and most surgeons are more comfortable waiting about a week.

    Decannulation Criteria

    The fundamental requirement for decannulation is that the patient no longer needs the tracheostomy for airway patency or toileting. Specific criteria commonly include:

    • Resolution of Hazardous Edema: The swelling of the tongue, floor of mouth, and neck should be significantly reduced. Often clinical examination or nasendoscopy is used to confirm that airway structures are no longer edematous enough to obstruct breathing.
    • Protective Airway Reflexes and Consciousness: The patient should be awake, alert, and able to manage their secretions. They need an effective cough and gag reflex to clear mucus and protect against aspiration.
    • Cuff Down Trials: Many protocols perform a trial where the tracheostomy cuff is deflated and the tracheostomy tube is corked or covered for a period (eg 12–24 hours) to see if the patient breathes comfortably around the tracheostomy tube. During this trial, oxygen saturation and respiratory rate are monitored. Successful completion indicates the patient can handle breathing through the natural upper airway.
    • Absence of High Oxygen/ventilation needs: The patient should not be requiring high levels of respiratory support. If they are still needing frequent suctioning or have copious secretions (eg due to pneumonia), it might be safer to keep the tracheostomy until that resolves.
    • Swallowing Assessment: This is somewhat controversial in timing—some surgeons prefer to ensure the patient can swallow safely before removing the tracheostomy, especially if a cuffed tracheostomy was serving as a safeguard against aspiration. Others decannulate earlier and then do swallow evaluations with the natural airway.
    • Pulmonary Reserve: The patient’s lungs should be in good condition. If they remain on ventilator support or have significant pulmonary edema/atelectasis, decannulation is delayed.
    • No Immediate Need for Reoperation: If a patient needs a second-look surgery or neck re-exploration in the first week, the team often keeps the tracheostomy in until after that procedure, to avoid having to re-intubate through a normal airway in a swollen field.

    When these criteria are met, the actual decannulation is usually performed in a stepwise manner: downsizing the tracheostomy tube to a smaller diameter for a day or two, capping it to ensure the patient tolerates full airflow through the upper airway, and then removing it if all goes well. Some teams expedite this by skipping the downsizing and doing a “one-stage” removal after a successful capping trial, as described by Wasserzug et al.31 After decannulation, the stoma is covered with a dressing and the patient is observed for ~24 hours to ensure they do not develop respiratory distress. The stoma usually closes on its own within days.

    Delayed or Failed Decannulation

    Early decannulation is beneficial—it allows the patient to speak, improves coughing and mobilization, and often shortens hospital stay.32 Recent evidence suggests no increase in complications with earlier decannulation when proper criteria are met. However, despite meeting initial criteria, a subset of patients experience delayed decannulation, meaning they require the tracheostomy for longer than the typical period, or failed decannulation, where an attempt to remove the tracheostomy results in respiratory compromise and the tracheostomy has to be reinserted. An analysis by Isaac et al indicated about 15% of tracheostomy patients had delayed decannulation and around 14% had decannulation failure, often related to factors like total glossectomy or complications.33

    In more recent practice, these rates may be lower with better protocols. Predictors of delayed decannulation align with those needing a tracheostomy in the first place: larger or bulky flaps, postoperative complications, and advanced age could all prolong the need for a secure airway. A recent study recommended that in head and neck free flap patients, efforts should be made to decannulate by 10 days if possible, as prolonged tracheostomy beyond 10 days increases risk of tracheal stenosis and infection.34 They advocated that if a patient is still not meeting criteria by 10 days, a thorough evaluation is needed to identify why (eg unresolved edema, silent aspiration, etc.) and address those issues.

    Airway-Related Complications in Head & Neck Free Flap Patients

    Airway management in the context of head and neck free flap surgery must balance preventing one set of complications (those due to airway obstruction) against causing another set of complications (those due to the airway intervention itself).

    Tracheostomy-Related Complications

    Temporary tracheostomies, while generally safe, carry complication rates of 5–15% in head and neck surgery patients. Early complications include bleeding from the stoma or thyroid vessels, infection, subcutaneous emphysema, pneumothorax, and tube blockage or displacement. In Singh’s 2016 study, 12% of patients experienced serious complications, including one cardiorespiratory arrest from tube obstruction.3 Other risks include pneumonia (1.55–4%),1 hemorrhage from tracheal erosion (0.7–2%),35 and accidental decannulation (0.5–1%).3

    Beyond physical complications, tracheostomies impact quality of life by delaying speech and oral feeding while increasing hospital stays by approximately 2.2 days.36 Long-term tracheostomies (over 10 days) elevate the risk of subglottic stenosis and granulation tissue formation, leading to stenosis and scar formation at the stoma site. Though fatal complications are rare with no deaths reported in recent large cohorts, these potential issues underscore why avoiding tracheostomy when possible is advantageous.

    Complications of Prolonged Intubation/Delayed Extubation

    For patients receiving overnight intubation rather than immediate tracheostomy, the main risks include extubation failure and prolonged intubation effects. Extubation failure rates in head and neck free flap patients are relatively low—Tsai reported 7.6% experiencing adverse airway events requiring reintubation or secondary tracheostomy,7 while Myatra’s study found only about 6% in the delayed extubation group ultimately needed tracheostomy.5 These events, when they occur, can be managed if they happen in ICU under monitoring—usually by reintubation fiberoptically or doing a tracheostomy at bedside. The goal is to avoid a “crash” scenario where the patient obstructs unexpectedly. That is why careful adherence to extubation criteria and having trained staff present is essential.

    Extended intubation poses risks of laryngeal injury and post-extubation edema, which may cause stridor. While the cuff leak test helps predict these complications, it is not completely reliable.37 Treatment for post-extubation laryngeal edema typically involves nebulized epinephrine and possible reintubation if respiratory distress occurs.

    Impact on the Flap and Surgical Outcome

    Airway issues can indirectly impact the success of the microvascular reconstruction. Episodes of severe coughing or bucking on the tube can precipitate hematoma formation under the flap or cause venous pressure spikes that threaten the anastomosis. That is one reason to keep patients adequately sedated while intubated and, if a tracheostomy is in place, to ensure the tracheostomy tube is secured to prevent excessive movement or cough.

    Conversely, performing a tracheostomy introduces another incision in an already operated neck, which theoretically could increase the risk of wound infection or flap exposure if not placed carefully. Most surgeons place the tracheostomy away from the flap pedicle, often on the contralateral side or a lower tracheal ring, to avoid interfering with the microvascular pedicle in the neck. In rare cases, stoma infection could track to the neck and endanger the flap or cause carotid exposure.38 Fortunately, reported infection rates are low with temporary tracheostomies in this setting, especially with prophylactic antibiotics often given as part of head-neck surgery protocols.39–41

    From a swallowing and voice perspective, tracheostomy and prolonged intubation both can cause temporary dysfunction. An endotracheal tube passing through the glottis can lead to vocal cord edema or ulceration, and a tracheostomy with cuff inflated prevents subglottic air passage needed for speech and can reduce airflow for an effective cough. A study on quality of life after free flap surgery noted that patients with prolonged tracheostomy had delayed return of normal speech and felt socially isolated during that period.42 These issues typically resolve after decannulation, but they contribute to patient dissatisfaction in the early recovery.

    Comparison of Approaches

    To contextualize complications, it helps to compare outcomes between those who get tracheostomy and those who do not. Comparison of airway management approaches is listed in Table 3.

    Table 3 Comparison of Airway Management Approaches

    • Hospital Stay and Recovery: Multiple studies confirm tracheostomy tends to prolong hospital stay. As noted, one large study showed a 2.2-day longer stay with tracheostomy, and the United Kingdom study by Singh showed tracheostomy patients stayed ~27 days vs ~20 days without tracheostomy (p = 0.03).3 Earlier ability to speak and eat in the no-tracheostomy group likely facilitates faster recovery milestones.
    • Return to OR: Unplanned OR returns for airway or bleeding complications occur more frequently in tracheostomy patients according to some analyses. This might stem from larger disease burden in these patients or challenges managing both tracheostomy and flap. Notably, the Nebraska 2024 study8 demonstrated significantly fewer unplanned reoperations in tracheostomy-avoidance patients, suggesting this approach correlates with smoother recovery without increasing airway emergency interventions.
    • Mortality: The airway-related mortality in modern free flap series is very low. Studies focusing on tracheostomy vs no tracheostomy have not shown differences in 30-day mortality.4,5,14 In other words, avoiding a tracheostomy when appropriate does not appear to increase the risk of death; no mortalities were attributed to failed airways in the recent literature reviewed. This suggests that as long as backup plans are in place, patients are not being lost to sudden obstruction.

    Complications Summary

    Evidence suggests tracheostomy-related complications including infection, bleeding, blockage, and extended ICU stays typically outweigh extubation failure risks in appropriate candidates, supporting more selective tracheostomy use. However, prophylactic tracheostomy remains necessary for highest-risk patients who would face greater complications without it.

    The complication profile necessitates individualized care. Best practice involves patient stratification to provide tracheostomy only to those truly needing it while avoiding unnecessary morbidity in others. Regular outcome monitoring is essential—frequent early decannulation suggests criteria should be tightened to reduce overuse, while excessive extubation failures indicate need for stricter guidelines or more prophylactic tracheostomies.

    Conclusion

    Growing evidence supports a shift from routine prophylactic tracheostomy toward a selective, risk-stratified approach for head and neck free flap reconstruction. Large prospective and cohort studies show that when clear criteria guide immediate or delayed extubation, more than 90% of patients avoid tracheostomy without airway-related mortality, while achieving shorter hospitalization and faster return to oral intake. Objective tools such as the TRACHY score and the Cai scoring model highlight tumor extent, bilateral neck dissection, bulky flap size and comorbidity burden as dominant predictors of airway compromise, yet they complement rather than replace multidisciplinary judgement.

    For high-risk scenarios—extensive tongue or base-of-tongue resection, cross-midline mandibulectomy, bilateral neck dissection or thick soft-tissue flaps—a primary tracheostomy remains prudent to pre-empt obstruction and facilitate pulmonary toileting. Conversely, patients with lateral oral cavity defects, thin radial forearm flaps or unilateral neck dissection can usually be extubated safely in theatre or after brief intensive-care observation. Should clinical doubt arise, a “wait-and-see” strategy with overnight intubation offers a reversible safeguard and is associated with low re-intubation rates.

    Once a temporary tracheostomy is placed, timely decannulation—ideally within ten days—infection, stenosis and speech delay. Successful removal hinges on resolution of hazardous oedema, intact airway reflexes, effective cough, stable flap and the patient’s ability to maintain oxygenation during capping trials. Centers employing structured decannulation protocols report failure rates below fifteen percent and no increase in adverse events with earlier removal.

    Current literature also underscores the broader recovery benefits of tracheostomy avoidance: reduced ICU utilization, fewer unplanned returns to theatre and improved early quality-of-life metrics including voice and swallowing. Nevertheless, fatal airway loss remains rare across all strategies, provided that rigorous monitoring and rapid rescue pathways are in place.

    In summary, the safest and most efficient airway management paradigm is tailored rather than routine. Therefore, airway management in head and neck free flap surgery should be individualized, summarizing risk factors, decision tools, and patient-centered benefits of avoiding unnecessary tracheostomy.

    Abbreviations

    BMI, body mass index; COVID-19, coronavirus disease 2019; ERAS, Enhanced Recovery After Surgery; ICU, intensive care unit; OR, odds ratio; TRACHY, tracheostomy risk scoring system (predictive score for need of tracheostomy); pre-op, preoperative; post-op, postoperative; T1, tumor stage 1 (small primary tumor); T2, tumor stage 2; T3, tumor stage 3; T4, tumor stage 4 (advanced primary tumor).

    Funding

    This research was supported by a grant from CDRPG8M0022.

    Disclosure

    The authors affirm that they do not have any competing interests.

    References

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  • The duration of prophylactic antibiotic use for esophageal cancer pati

    The duration of prophylactic antibiotic use for esophageal cancer pati

    Introduction

    Esophageal cancer (EC) is a common malignant tumor, and the preferred treatment is surgery. However, due to the complex anatomy of the esophagus, EC surgery is difficult, and the incidence of postoperative complications is high. During the surgical process, bacteria in the esophageal cavity may seriously contaminate the surgical field and become important endogenous bacteria for postoperative infections.1 Postoperative infection not only prolongs the hospital stay of patients and increases medical expenses, but also affects the prognosis of patients.2 The rational use of antibiotics is the key to preventing infections, according to the Global Guidelines for the Prevention of Surgical Site Infections released by the World Health Organization (WHO) and current standard documents guiding the cautious use of antibiotic substances. The long-term prophylactic use of antibiotics after EC surgery is not recommended. Excessive prolongation of medication time does not improve the preventive effect, but may instead increase the chance of drug-resistant bacterial infections.3,4 However, in clinical practice, the problem of prolonged prophylactic use of antibiotics during the perioperative period still exists, especially in departments with high surgical difficulty and postoperative infection risk. Due to their own diseases and surgical trauma, patients with EC often suffer from malnutrition to varying degrees. Malnutrition can damage the immune system of patients, affect postoperative recovery, and increase the chance of infection.5 Among them, serum albumin (ALB) is the main protein synthesized by the liver, which can reflect the protein nutritional status of the body and the synthetic function of the liver. Prealbumin (PA) has a short half-life and can sensitively reflect the changes in recent nutritional intake and consumption. Hemoglobin (Hb) is related to the body’s oxygen-carrying capacity and anemia status.6,7 The dynamic changes of these three indicators (ALB, PA, Hb) can directly reflect the recovery process of the postoperative nutritional status of patients and are closely related to the risk of infection and prognosis. Therefore, nutritional support plays a crucial role in the postoperative recovery of EC. Enteral nutrition is a simple, safe, effective, and economical clinical nutritional support method. It not only promotes the recovery of gastrointestinal motility and protects the intestinal mucosal barrier, but also reduces the incidence of intestinal infections, facilitates nutrient absorption, and promotes early recovery of patients. Early postoperative enteral nutrition support can quickly correct patients’ immune dysfunction and reduce the incidence of postoperative complications.8

    Given the high incidence of postoperative infections in EC and the controversy surrounding the timing of antibiotic use, as well as the impact of malnutrition on postoperative recovery, based on the WHO guidelines for the prevention of surgical site infections and the current situation of overly long antibiotic courses in clinical practice, this study set testable goals: ① Compare the differences in the incidence of infection among the three groups of patients with postoperative antibiotic use time < 24 hours, 24–48 hours, and > 48 hours; ② Analyze the correlation between the medication duration and the nutritional indicators 10 days after the operation; ③ Independent risk factors for infection were identified through multivariate Logistic regression. The study adopted a retrospective design to provide relevant evidence for evidence-based drug use.

    Materials and Methods

    General Materials

    A retrospective analysis was conducted on 566 patients who underwent EC surgery at the Affiliated Hospital of North Sichuan Medical College in Shunqing District, Nanchong City, Sichuan Province, from January 2020 to October 2022. The inclusion process was shown in Figure 1. Inclusion criteria: (1) Patients who met the clinical diagnostic criteria for EC9 and had been pathologically diagnosed as malignant tumors of the esophagus; (2) The patients had indications for radical surgery for EC (patients with clinical stages T1b-N0-M0 to T3-N1-M0, without obvious invasion or surgical contraindications; patients with lesions exceeding 5cm or distant metastasis or lymph node metastasis), and they were all first-time recipients of surgical treatment; (3) The Eastern Cooperative Oncology Group (ECGO) score ranged from 0 to 2 points;10 (4) The patient’s expected survival period was ≥ 6 months; (5) Patients with complete clinical data. Exclusion criteria: (1) Patients with infection at admission; (2) Patients with symptomatic central nervous system metastases; (3) Patients with concomitant thrombotic diseases or those receiving anticoagulant therapy; (4) Patients merged with other types of malignant tumors; (5) Patients with distant metastasis; (6) Patients with combined acute and chronic infections, hematological diseases, and autoimmune diseases.

    Figure 1 The inclusion process of patients.

    Surgery Methods

    All patients underwent thoracoscopic radical EC. The surgical operations followed the standard surgical procedures, and the specific details of the surgical methods did not affect the analysis of the antibiotic use time in this study.

    Grouping and Treatment Methods

    Referring to the WHO guidelines for the prevention of surgical site infections,3 three time points were set according to the duration of postoperative antibiotic use, among which there were 228 cases in Group A (< 24 hours), 180 cases in Group B (24–48 hours), and 158 cases in group C (>48 hours). Antibiotic treatment plan: Cephalosporins or penicillins were administered intravenously. Cephalosporins: Cefuroxime (Fujian Fukang Pharmaceutical Co., Ltd., approval number: H20063900), 1.5–3g each time, dissolved in 100 mL of 0.9% sodium chloride injection, intravenous drip, once every 12 hours. Penicillins: Ampicillin Sodium and Sulbactam Sodium (Sichuan Pharmaceutical Preparation Co., Ltd., National Medical Products Approval No. H20053497, 0.75g), 1.5g each time, added to 250 mL of 0.9% sodium chloride injection, intravenous drip, every 6 hours.

    Use principle: if the patient had no significant infection risk factors (such as old age, weak body, low immune function, diabetes, etc)., the prophylactic use of antibiotics after surgery could be shortened, generally not more than 24 hours. For patients with high infection risk factors, including old age, infirmity, immune dysfunction, diabetes, etc., or with contaminated wounds during surgery, the prophylactic use of antibiotics after surgery is needed more than 48 hours.11 If the surgery time was long (more than 3 hours), the blood loss was large (more than 300 mL), or there were mild risk factors for infection in the patient, the prophylactic use of antibiotics after surgery might need to be extended to 24–48 hours.12

    Outcome Measures

    (1) The incidence of postoperative infection in groups A, B, and C was recorded with the following criteria:13 peripheral white blood cell count (WBC)>15×109/L, body temperature ≥ 38°C, worsening symptoms such as cough and sputum after surgery, rales in the lungs, and infiltrative lesions on chest X-rays. Infection diagnosis was based on clinical symptoms and laboratory tests, but bacterial culture and inflammatory marker detection were not routinely carried out. Because this operation was not a necessary step in the decision-making of the antibiotic treatment course after EC, and only a few patients retained relevant records in the retrospective data.

    (2) A total of 5mL of elbow venous blood was drawn from the patients in the early morning on 7 days and 10 days after the operation, respectively. Among them, 3mL was injected into an anticoagulant tube containing heparin sodium anticoagulant, and 2mL was injected into a common tube without anticoagulant. The tubes were centrifuged at 3000r/min for 10 minutes to separate the plasma from the anticoagulant tube samples and the serum from the ordinary tube samples. The upper layer of serum was taken for testing. The levels of serum albumin (ALB), prealbumin (PA), and hemoglobin (Hb) were measured using a high-performance liquid-phase electrochemical method (the kits were purchased from Shenzhen Zike Biotechnology Co., Ltd).

    (3) A retrospective research method was adopted to collect and analyze the clinical data of patients through the Hospital Infection Prevention and Control Information Platform (HAISS), including demographic characteristics (age and gender, etc)., medical history (smoking history, drinking history, chemotherapy history), preoperative lung ventilation test results, surgical duration, American Society of Anesthesiologists (ASA) score, intraoperative blood loss, length of hospital stay and the duration of postoperative antibiotic prophylaxis, preoperative nutritional status, and other data. Criteria for determining malnutrition: BMI<18.5 kg/m2; For patients aged ≥ 70 years, a BMI<22 kg/2 indicated malnutrition and/or recent involuntary weight loss exceeding 10%, or involuntary weight loss exceeding 5% within 3 months.

    Determination of antibiotic treatment course: The time of the first use of antibiotics after the operation is recorded as 0 points. The time of drug withdrawal is based on the end time of the last intravenous infusion, which is independently verified by two attending physicians through the electronic medical order system for confirmation.

    Nutritional index detection quality control: ALB and PA were detected using the Beckman Coulter AU5800 fully automatic biochemical analyzer (USA). The intra-batch CV of the kit was less than 5%, and the inter-batch CV was less than 8%. Hb detection was carried out using the Sysmex XN-9000 blood analyzer, and the calibration of the matching calibrators was conducted before the daily startup.

    Data collection norms: Data were extracted by three trained researchers through the hospital’s electronic medical record system (EMR). A double-person double-entry method was adopted, and logical verification was conducted using Epidata 3.1 software. Inconsistent data were confirmed through the review of the original medical records.

    Statistical Analysis

    SPSS 22.0 software was used for statistical data analysis in this study. The enumeration data were represented as [cases (%)] and subjected to a χ2 test. The measurement data were subjected to normality and homogeneity of variance tests. Measurement data that conformed to a normal distribution or approximately followed a normal distribution were presented in the form of (x±s). Analysis of variance was used for inter group comparisons, and the LSD test was used for pairwise comparisons. Univariate and multivariate logistic regression analysis were used to identify risk factors for postoperative infection in patients with EC. In this study, a statistical result of P<0.05 was considered statistically significant.

    Results

    Comparison of General Information Among the Three Groups

    There was no statistically significant difference in age, gender, and ECGO scores among the three groups of patients (P>0.05, Table 1).

    Table 1 Comparison of General Information Among the Three Groups

    Comparison of Postoperative Infection Rates Among the Three Groups

    Group A had a lower incidence of postoperative infection than Group B and Group C, and Group B had a lower incidence than Group C. However, there was no statistically significant difference among the three groups (P>0.05, Table 2).

    Table 2 Comparison of Postoperative Infection Rates Among the Three Groups

    Comparison of Nutritional Indicators Among the Three Groups

    Before surgery, there was no statistically significant difference in the levels of ALB, PA, and Hb among the three groups of patients (P>0.05). On day 10 after surgery, the ALB, PA, and Hb levels of patients in group A were much higher than those in group B and group C (P<0.05). There was no statistically significant difference in the levels of ALB, PA, and Hb between Group B and Group C (P>0.05, Table 3).

    Table 3 Comparison of Nutritional Indicators Among the Three Groups

    Univariate Analysis of Influencing Factors on Postoperative Infection in EC Patients

    Univariate analysis exhibited that the infected group had a much higher proportion of patients with age ≥ 65 years, moderate pulmonary ventilation impairment, intraoperative blood loss ≥ 200mL, postoperative respiratory support with a tube, hospitalization days ≥ 25 days, and malnutrition than the uninfected group (P<0.05, Table 4).

    Table 4 Univariate Analysis of Influencing Factors on Postoperative Infection in EC Patients

    Multivariate Logistic Regression Analysis of Risk Factors for Postoperative Infection in Patients with EC

    Using variables with P<0.05 in the univariate analysis as independent variables (age: ≥ 65 years=1, <65 years=0; pulmonary ventilation: moderate impairment=1, normal=0; intraoperative blood loss: ≥ 200mL=1, <200mL=0; postoperative respiratory support with tube: yes=1, no=0; length of hospital stay: ≥ 25d=1, <25d=0), and postoperative infection in EC patients as the dependent variable (infection=1, non infection=0), a multivariate logistic regression analysis was performed. The analysis showed that age, lung ventilation, hospitalization days, and preoperative malnutrition were all risk factors for postoperative infection in EC patients (P<0.05, Table 5 and Figure 2). By adjusting for confounding variables such as age, pulmonary ventilation, and malnutrition through multivariate Logistic regression (Table 5), the results showed that the duration of antibiotic use was still independently associated with the infection trend (P=0.029).

    Table 5 Multivariate Logistic Regression Analysis of Risk Factors for Postoperative Infection in Patients with EC

    Figure 2 Forest plot analysis of risk factors for postoperative infection in EC patients.

    Notes: A: Age; B: Pulmonary ventilation; C: Intraoperative blood loss; D: Postoperative respiratory support with a tube; E: Hospitalization days; F: Malnutrition.

    Discussion

    EC is a common malignant tumor of the digestive tract that poses a serious threat to human health. Surgical treatment is one of the important means of comprehensive treatment for EC, but postoperative complications are more common, among which infection is a prominent problem.14 Postoperative infection can lead to prolonged hospitalization, increased medical expenses, and in severe cases, even endanger the patient’s life. Common infection sites include the lungs, incisions, chest cavity, etc. Infection can cause a series of symptoms such as fever, pain, and respiratory dysfunction, which can affect the patient’s recovery process.15 According to research, the incidence of postoperative infection in EC is relatively high. A study16 showed that among 97 patients undergoing EC surgery, 37 of them developed hospital-acquired infections, with an infection rate of 38.14%. Preventive measures are crucial for postoperative infections, and early prophylactic escalation of antibiotic use is also considered an effective strategy to reduce postoperative lung infections.17 However, the excessive use of antibiotics may hurt nutritional status, such as causing dysbiosis of the gut microbiota, affecting the absorption and utilization of nutrients, etc.18 Therefore, reasonable control of antibiotic use time is also one of the important measures to protect the nutritional status of patients.

    In surgical procedures, prophylactic use of antibiotics is an effective measure to prevent postoperative infections, increase surgical safety, and improve cure rates. The application of antibiotics can achieve effective bactericidal concentrations in blood and tissue, and maintain them during the risk period of surgical infection, thereby significantly reducing postoperative infections.19 The duration of postoperative prophylactic use of antibiotics varies depending on the type of surgery and patient condition. However, studies have shown20 that extending the duration of antibiotic prophylaxis does not further reduce the risk of postoperative infection, but may instead increase the risk of adverse drug reactions and emergency visits. A study by American scholars21 showed that the benefits of prophylactic use of antibiotics after surgery are limited to 24 hours after surgery. For most surgeries, antibiotics should be discontinued within 24 hours after the surgical incision. Bratzler et al22 found that only 55.7% of the patients received single-dose antibiotic prophylaxis within one hour before the operation. Besides, 92.6% of the patients’ medication types were in line with the guideline recommendations. The drug withdrawal rate was only 40.7% within 24 hours after the operation. Hartmann et al23 found that 877 out of 4304 patients who underwent general surgery and trauma surgery received inappropriate antibiotic prophylaxis. Gorecki et al24 reported that 71% of patients who underwent elective surgery received unreasonable antibiotic treatment. The main reasons for unreasonable use of antibiotics included prolonged treatment time (61%), followed by inappropriate timing of medication (29%) and improper selection of antibiotic types (28%). At present, relevant guidelines in China mainly refer to foreign data, suggesting that the postoperative antibiotic prophylaxis time should be 24 hours, and it can be extended to 48 hours after surgery for high-risk infected populations. This study showed that the incidence of postoperative infection increased sequentially in Group A, Group B, and Group C, but there was no statistically significant difference among the three groups. The use of antibiotics within 24 hours after surgery might reduce the incidence of postoperative infections. The reason for this might be that the use of antibiotics within 24 hours after surgery could quickly reach effective drug concentrations in the surgical site and blood, thereby inhibiting or killing possible bacteria and reducing the risk of infection. In surgical operations, the prophylactic use of antibiotics is the core measure to prevent postoperative infections. Multiple studies have confirmed that the excessive use of antibiotics after EC surgery is positively correlated with the risk of colonization by drug-resistant bacteria. For example, Suehiro et al25 found that the use of antibiotics for more than 24 hours during gastric cancer and colorectal surgery did not reduce the infection rate. Instead, it increased the risk of Clostridium difficile infection. Chareancholvanich et al26 pointed out in the knee replacement study that extending the medication to more than 24 hours increased the prosthesis infection rate from 0.5% to 1.2%. Research by American scholars27 has shown that the benefits of postoperative antibiotics are limited to within 24 hours, which is consistent with the 24-hour drug withdrawal principle recommended by the international consensus on joint replacement infections.28 Furthermore, specific studies on EC have shown that the risk of postoperative infection in patients with preoperative malnutrition increases by 2.1 times,29 which echoes the conclusion in this study that malnutrition is an independent risk factor.

    The results of this study showed that on postoperative day 14, the levels of ALB, PA, and Hb in group A were higher than those in group B and group C, suggesting that the use time of antibiotics ≤24 hours may facilitate nutritional recovery by reducing inflammatory consumption. The possible reason for this might be that antibiotics could effectively inhibit the growth of pathogenic bacteria in the surgical site and the whole body, thereby reducing postoperative infections and inflammatory reactions, and ultimately reducing the consumption of nutrients by inflammation in the body. In addition, after infection, the body will produce a series of inflammatory reactions that consume a large amount of nutrients such as protein, vitamins, etc. The application of antibiotics can alleviate inflammatory reactions, thereby reducing the consumption of nutrients and helping to improve the nutritional status of patients.30 In clinical practice, the specific situation of patients should be comprehensively considered to reasonably control the duration of antibiotic prophylaxis after EC surgery, in order to reduce the risk of postoperative infection, improve the nutritional status of patients, and promote their recovery. The trend change in the incidence of infection in this study might mainly reflect the preventive effect of incision site infection, while the influence of the duration of antibiotic use on complex complications such as anastomotic fistula needs to be further subdivided and studied in combination with surgical techniques.

    In this study, we corrected confounding variables such as age, lung ventilation, and malnutrition through multivariate Logistic regression analysis. The results showed that the duration of antibiotic use was still correlated with the infection trend, weakening the influence of selective bias to a certain extent. As age increases, the immune system function of the human body gradually weakens, which reduces the resistance of elderly patients to infections. The wound healing and overall recovery speed of elderly patients after surgery is slow, which increases the risk of infection.31 In addition, elderly patients may be accompanied by a variety of chronic diseases, such as diabetes, hypertension, etc, which will increase the risk of infection.32 EC radical surgery often involves incision of the chest cavity and traction of lung tissue, which may lead to inflammation and increased secretion in the lungs. Due to pain, weakness, and other reasons, postoperative patients have limited ability to expel phlegm, and respiratory secretions are prone to accumulate in the lungs. When lung ventilation increases, the airflow velocity accelerates, but secretion discharge may still be obstructed, providing an environment for bacteria to grow and reproduce. Too many or complex types of bacteria in respiratory secretions may further lead to the occurrence of lung infections.33,34 The extension of hospitalization time means that patients are more exposed to the hospital environment, which is a high-density gathering place for various pathogens. Prolonged hospitalization may also lead to further decline in patients’ physical function and sustained weakening of the immune system, thereby increasing the risk of infection.35 Meanwhile, cross-infection within hospitals is also one of the important reasons for the increased risk of infection in long-term hospitalized patients. To reduce the risk of postoperative infection caused by these risk factors, the following measures can be taken to conduct a comprehensive preoperative evaluation of elderly patients: (1) Develop personalized surgical and postoperative care plans based on the patient’s physical condition and chronic disease situation. (2) Strengthen infection control measures within hospitals, such as regular disinfection, strict aseptic procedures, and rational use of antibiotics. (3) For patients who require postoperative respiratory support, the use time and frequency of the tubing should be minimized as much as possible, and the cleaning and disinfection of the tubing should be strengthened. (4) Encourage patients to get out of bed and move around as early as possible to promote physical recovery and improve immune function. (5) Shorten hospitalization time and reduce the exposure time of patients in the hospital, thereby reducing the risk of infection. Preoperative malnutrition can lead to a lack of nutrients such as protein and vitamins in the patient’s body, slowing down the healing process of the wound and even potentially causing poor healing. Once the wound does not heal properly, it is susceptible to invasion by external pathogens, thereby increasing the risk of postoperative infection.36 In addition, malnutrition can weaken the patient’s immune system, leading to a decrease in the number and function of immune cells, thereby reducing the patient’s resistance to external pathogens.37 After EC surgery, patients themselves have a lower immune system, and if malnutrition occurs, they are more susceptible to infection by pathogens. The results of this study only reflected the statistical association between the duration of antibiotic use and infection/nutritional indicators, rather than a causal relationship. The use of antibiotics might indirectly affect nutritional consumption by inhibiting bacterial colonization at the surgical site, but this requires verification through prospective studies.

    In summary, the prophylactic use of antibiotics for 24 to 48 hours balanced infection prevention and control with nutritional protection. Age ≥65 years old, pulmonary ventilation disorder, hospitalization ≥25 days, and preoperative malnutrition were independent risk factors for postoperative infection. Comprehensive interventions such as preoperative pulmonary function assessment and nutritional support reduced the risk of infection. In the future, we need to expand the sample size and incorporate the research on the deepening mechanism of microbiological detection. This study was a single-center retrospective design. Bacterial culture and detection of inflammatory factors (such as PCT and CRP) before and after antibiotic treatment were not conducted. Therefore, the direct association between the duration of antibiotic use and the clearance efficiency of pathogenic bacteria or the intensity of the inflammatory response could not be clearly defined. Judging infection solely based on clinical symptoms (such as body temperature and white blood cell count) lacks microbiological evidence support, which might lead to false positives or false negatives in the diagnosis of infection. Subsequent studies need to combine etiological detection and dynamic monitoring of inflammatory markers to improve the mechanism analysis. In the future, multicenter prospective cohort studies still need to be carried out to control confounding factors through randomized grouping, to clarify the causal relationship between the duration of antibiotic use and infection.

    Conclusion

    The prophylactic use of antibiotics after EC surgery was advisable for 24 to 48 hours. This course of treatment reduced the risk of infection and improved nutritional indicators (ALB, PA, Hb). Age, pulmonary ventilation function, length of hospital stay, and preoperative malnutrition were the main risk factors for postoperative infection. In clinical practice, preoperative nutritional assessment, respiratory management, and precise use of antibiotics should be combined to improve the surgical efficacy.

    Data Sharing Statement

    The figures used to support the findings of this study are included in the article.

    Ethical Approval

    The Ethics Committee of Affiliated Hospital of North Sichuan Medical College authorized the study (Approval number. 2022ER555-1). Written informed consent was obtained from all individual participants included in the study. Our study complies with the Declaration of Helsinki.

    Consent to Participate

    The patients participating in the study all agree to publish the research results.

    Funding

    This study was supported by the grants: The 14th Five-Year Plan project of Nanchong Social Science Federation in 2023 (No. NC23C131).

    Disclosure

    Dong Ning and Lin Zhou are co-first authors for this study. The authors declare that they have no competing interests in this work.

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    35. Li N, Wei S, Qi Y, Wei W. The effects of enhanced recovery after surgery on wound infection, complications, and postoperative hospital stay in patients undergoing colorectal surgery: a systematic review and meta-analysis. Int Wound J. 2023;20(10):3990–3998. doi:10.1111/iwj.14287

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    37. Chen N, Yu Y, Shen W, Xu X, Fan Y. Nutritional status as prognostic factor of advanced oesophageal cancer patients treated with immune checkpoint inhibitors. Clin Nutr. 2024;43(1):142–153. doi:10.1016/j.clnu.2023.11.030

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  • Protecting the environment and human health from persistent, mobile, and toxic substances

    Protecting the environment and human health from persistent, mobile, and toxic substances

    PMT substances pose a worrying impact to human health and the environment. This article highlights why it’s crucial to recognize the need for integrated prevention and remediation strategies to effectively combat the challenges these pollutants present

    Safe drinking water

    Safe and clean drinking water is essential for human life. However, a new generation of pollutants has been increasing in concentration in the sources of drinking water as well as being found more commonly in human blood. These pollutants are called persistent, mobile, and toxic (PMT) substances and very persistent and very mobile (vPvM) substances. By nature, these substances do not break down in the environment over appreciable timescales (persistent). They can travel long distances with water (mobile) and, in some cases, cause negative effects on the ecosystem and humans (toxic).

    A well-known example of a group of PMT/vPvM substances is per- and polyfluoroalkyl substances (PFAS), which are typically used in non-stick pans and Gore-Tex jackets. These substances are now found globally and have coined the name ‘forever chemicals’ owing to their intergenerational presence in the environment.

    Daily exposure to harmful substances

    Many of us come into contact with PMT/ vPvM substances daily, and the water industry struggles to find remediation methods to remove them from the sources of drinking water. Today, thousands of harmful PMT/vPvM substances are used to produce everyday items, including cosmetics, outdoor garments, and kitchen equipment such as pans and dishware. There is no single current remediation solution that can be used to remove all of the known PMT/vPvM substances from water, let alone those that still remain unknown. One of the most widely used remediation methods is removal via the use of activated carbon; however, this method is not suitable for all PMT/vPvM substances. Reverse osmosis and nanofiltration methods can be used to purify drinking water, but these techniques are energy-intensive and produce a waste concentrate that has to be disposed of or remediated itself.

    The cost of inaction

    Action is urgently needed to mitigate potential harm. In a report entitled “The cost of inaction: A socioeconomic analysis of environmental and health impacts linked to exposure to PFAS”, costs related to identification, screening and remediation of sites contaminated with PFAS across Europe is estimated to be around €10-20 billion per year. This cost covers immediate interventions and does not account for costs related to, for example, increased healthcare demands, ecological damage, property loss, and impacts on the agricultural sector. Including those costs raises the overall cost to the European Economic Area to around €52-84bn per year.

    Currently, European chemicals legislation is developing to be more protective and safeguard clean water, as outlined in the Chemicals Strategy for Sustainability towards a Toxic Free Environment, released in 2020. Importantly, in April 2023, new hazard classes for PMT substances and vPvM substances were introduced into the Classification, Labelling and Packaging regulation (EC) No. 1272/2008, paving the way for a better protection of human health and the environment by identifying and managing chemicals with specific properties.

    ZeroPM: Zero pollution of persistent, mobile substances

    Given the far-reaching effects of PMT/ vPvM substances in the environment, it becomes clear that preventative approaches that proactively address the problem are needed. By preventing the production, use, and release of PMT/vPvM substances, downstream, reactive measures will be needed less. This is the approach taken in the European Horizon 2020 research and innovation action project called ZeroPM, which stands for Zero Pollution of Persistent, Mobile Substances. ZeroPM interlinks and synergizes three strategies to protect the environment and human health from persistent, mobile substances: Prevent, Prioritize, and Remove. To prevent, ZeroPM has developed scientific, policy, and market tools for the substitution and mitigation of prioritized PMT/vPvM substances to safer and sustainable alternatives. To prioritize, ZeroPM has identified the groups of PMT/vPvM substances requiring the most urgency to act upon, considering the sustainability aspects of removal. To remove, ZeroPM has investigated real-world scale remediation solutions and found the limits of their sustainability. The results from ZeroPM can be used to guide policy, technological, and market incentives to minimize the use, emissions, and pollution of entire groups of PMT/vPvM substances.

    The unique feature of ZeroPM is the interdisciplinary team of partners that have been instrumental in advancing the awareness and providing scientific evidence of the human and environmental concerns of PMT/vPvM substances. Regulators and academics who were instrumental in recent policy updates (from The German Environment Agency, the Norwegian Geotechnical Institute and the German Water Centre), work together with leading environmental researchers and toxicologists (from Stockholm University, EMPA, the University of Luxembourg, Fraunhofer ITEM, Vrije Universiteit Amsterdam, Chalmers University of Technology, the University of the Aegean, NIVA, TGER), as well as social scientists (from the University of Vienna), policy analysts (from Milieu Law and Policy Consulting) and a well-known NGO (ChemSec) to tackle the problem of PMT/vPvM substances in the environment.

    The key results and outcomes of ZeroPM, all of which are fully findable, accessible, interoperable, and reproducible, include the following:

    PREVENT

    PRIORITIZE

    REMOVE

    Working in such a holistic manner will support a better protection of the environment and human health from PMT/vPvM substances and allow the goals of the Chemical Strategy for Sustainability to be realised.

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  • Got the flu? Have some chocolate; centenarians age differently; August APA journals are out now – Morning Medical Update

    Got the flu? Have some chocolate; centenarians age differently; August APA journals are out now – Morning Medical Update

    Morning Medical Update © meeboonstudio – stock.adobe.com

    Chocolate-based combo outperforms Tamiflu

    A surprising new drug combo — featuring theobromine, a compound found in chocolate — has outperformed Tamiflu in fighting the flu, including drug-resistant bird and swine strains. Researchers at Hebrew University say the combo blocks a key viral ion channel, cutting off replication in both cell and animal models. Published in PNAS, the study suggests this novel approach could lead to more durable antivirals and even help prepare for future pandemics. Human trials are expected next.

    Centenarians age differently

    New research from Karolinska Institutet shows that centenarians not only live longer but develop fewer diseases, and at a slower pace, than their peers. Published in eClinicalMedicine, the study found that disease burden levels off after age 90 and that cardiovascular and neuropsychiatric conditions are less common in those who live to 100.

    August APA journals out now: genetics, telehealth risks and advocacy in focus

    The latest issues of APA’s American Journal of Psychiatry, Psychiatric Services and Focus are out now, with studies on ADHD genetics, telehealth stimulant prescribing, youth recidivism and gaps in perinatal mental health. A special issue of Focus — guest-edited by The Kennedy Forum — highlights how psychiatrists can drive policy change.

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  • Ketamine’s Antidepressant Action May Depend on Opioid System

    Ketamine’s Antidepressant Action May Depend on Opioid System

    Activation of the body’s opioid system may be required for ketamine’s antidepressant effects, new research hinted.

    In a small study of adults with major depressive disorder, taking the opioid blocker naltrexone before a low-dose ketamine infusion both blunted the surge in glutamate — a key brain chemical linked to mood — and reduced ketamine’s rapid antidepressant benefit the next day.

    “These results suggest that opioid receptors help mediate ketamine’s effects and that blocking opioid receptors may lessen ketamine’s acute mood-lifting action,” lead researcher Luke Jelen, MBBS, clinical lecturer in psychiatry, King’s College London, London, England, told Medscape Medical News.

    “However, this was a small, mechanistic study, not a treatment trial, so there is no immediate indication to change clinical practice or avoid naltrexone. Larger, dedicated clinical studies are required before recommending any alteration to current protocols,” Jelen cautioned.

    The study was published online on July 24 in Nature Medicine.

    New Mechanistic Insights

    Ketamine’s rapid-acting antidepressant effects are thought to work by transiently elevating glutamate in the anterior cingulate cortex and other frontal regions, setting off a cascade of plasticity-related pathways.

    Prior animal and small human studies have suggested that activating mu-opioid receptors might be necessary for ketamine’s mood benefits.

    To investigate, Jelen and colleagues enrolled 26 adults with moderate-to-severe depression in a randomized double-blind crossover trial separated by 3 weeks.

    Participants received either oral placebo or 50 mg naltrexone 1 hour before receiving intravenous ketamine (0.5 mg/kg).

    During the first 30 minutes of each infusion, they measured brain glutamatergic activity in the anterior cingulate cortex using functional magnetic resonance spectroscopy. Depressive symptoms were measured before and 24 hours after infusion, when ketamine’s antidepressant effects peak, using the Montgomery-Åsberg Depression Rating Scale (MADRS).

    Compared with placebo, pretreatment with a single 50-mg dose of oral naltrexone reduced the brain’s glutamatergic response and dampened the average improvement on MADRS measured 24 hours later, the researchers observed.

    Specifically, the glutamate signal climbed significantly during ketamine when participants had taken placebo, but the rise was significantly smaller when they had taken naltrexone (P = .029; Cohen’s d = 0.34).

    “We also identified a sex-related effect: The attenuating effect of naltrexone on glutamate activity appeared more pronounced in males with depression than in females with depression,” Jelen said.

    Alongside the attenuation of ketamine-induced glutamatergic activity, naltrexone pretreatment also led to less marked reductions in clinician-rated MADRS scores 24 hours after infusion — equating to a 28% attenuation in the main effect of ketamine (P = .023), the researchers reported.

    Reductions in self-reported depressive measures were numerically lower in the presence of naltrexone than in the presence of placebo, but the differences were not statistically significant.

    “The possibility of an opioid mechanism underlying the antidepressant mechanisms of ketamine has been a recent subject of considerable debate. Our study provides evidence that opioid system activation may contribute to the acute antidepressant effects of ketamine,” the authors wrote.

    Looking ahead, Jelen told Medscape Medical News, a larger, well-powered study should include a true placebo-infusion arm to disentangle naltrexone’s effects on both ketamine and placebo responses.

    He also noted that adding PET imaging would directly quantify opioid-receptor engagement, and prespecified analyses by sex are essential, given the stronger glutamate-dampening effect observed in men.

    “Understanding more about how ketamine works can lead to treatment being personalized for different people, which is vital for creating safe and effective treatments,” Jelen said.

    The study had no commercial funding. Jelen had no relevant disclosures.

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