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This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

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ETHNOPHARMACOLOGICAL RELEVANCE: Mouthwashes based on medicinal plants have demonstrated benefits in controlling plaque and inflammation, acting positively on the oral hygiene of patients with gingivitis. In traditional medicine, Punica granatum L. has been used to treat oral diseases in countries in Europe, Asia, North America, and Africa. AIM OF THE STUDY: The present study aimed to conduct a comprehensive review on the dental applications of Punica granatum L. for the treatment of gingivitis, including ethnomedicinal uses, analysis of randomized clinical trials, antibacterial activity against Porphyromonas gingivalis, mechanisms of action of phytochemicals isolated from this plant, and preclinical toxicity. MATERIALS AND METHODS: The literature was retrieved from Google Scholar, PubMed®, SciELO, and ScienceDirect®, since the first report published on the topic in 2001 until March 2024. RESULTS: Several clinical trials have demonstrated that mouthwashes containing P. granatum have equal or better efficacy than chlorhexidine in treating patients with gingivitis, confirming the indications for use of this plant by traditional communities. However, reports on the in vitro antibacterial activity of extracts from the fruits of this plant have not shown clinical relevance against the pathogen P. gingivalis. The ellagitannin punicalagin isolated from P. granatum has shown potential against several strains of Gram-positive and Gram-negative bacteria, but, to date, this compound has not yet been tested against P. gingivalis. It is likely that the mechanisms of action of flavonoids, such as quercetin, are involved in the inhibition of the activities of the RgpA, RgpB, and Kgp proteases of P. gingivalis. CONCLUSIONS: In summary, natural products obtained from P. granatum do not present toxic side effects and can be considered as possible substitutes of commercial products recommended for the treatment of gingivitis and other oral diseases.

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INTRODUCTION: The head and neck comprise vital organs and are apparent human body parts. Tumours here impair physical and sensory functions as well as appearance and social interactions, leading to body image distress (BID) and threatening mental health and quality of life. Acceptance and commitment therapy has shown effectiveness in improving BID in groups such as breast cancer patients. This study aims to apply this therapy to intervene in head and neck cancer (HNC) patients, aiming to improve BID and promote better psychological well-being. METHODS AND ANALYSIS: This study is a prospective, parallel-group, randomised controlled trial. A total of 64 HNC patients will be allocated to either an intervention group or a control group. The intervention group will engage in a 3 week, six-session group-based acceptance and commitment therapy programme, while the control group will receive standard treatment. The primary outcome is cancer-related BID, and secondary outcomes are HNC-related BID, psychological flexibility, coping style and psychological distress. These indicators will be measured at baseline, postintervention and 1 month following the intervention's completion. ETHICS AND DISSEMINATION: The trial has received approval from the Institutional Review Board of Shanghai Proton and Heavy Ion Hospital (2308-67-02). The study results will be shared through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300077863.

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Normobaric hyperoxia (NBO) is a potentially promising stroke treatment strategy that could protect the ischemic penumbra and could be administered as an adjunct before vascular recanalization. However, the efficacy and safety of NBO have not been confirmed by randomized controlled trials. The study aims to assess the efficacy and safety of NBO for ischemic stroke due to large artery occlusion (LVO) of acute anterior circulation among patients who had endovascular treatment (EVT) and were randomized within 6 h from symptom onset. Based on the data of the modified Rankin Scale (mRS) score at 90 days from the normobaric hyperoxia combined with EVT for acute ischemic stroke (OPENS: NCT03620370) trial, 284 patients will be included to achieve a 90% power by using Wilcoxon-Mann-Whitney test and the proportional odds model to calculate the sample size. The study is a prospective, multicenter, blinded, randomized controlled trial. The NBO group is administered with mask oxygen therapy of 10 L/min, while the sham NBO group is with that of 1 L/min. The primary outcome is the mRS score at 90 days. Secondary endpoints include cerebral infarct volume at 24-48 h, functional independence (mRS ≤2) at 90 days, and improvement in neurological function at 24 h. Safety outcomes include 90-day mortality, oxygen-related adverse events, and serious adverse events. This study will indicate whether NBO combined with EVT is superior to EVT alone for acute ischemic stroke caused by LVO in subjects randomized within 6 h from symptom onset and will provide some evidence for NBO intervention as an adjunct to thrombectomy for acute stroke.

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INTRODUCTION: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH. METHODS: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20-30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events. CONCLUSION: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH.

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Research on the benefits of non-invasive brain stimulation in stroke patients to improve executive functions is scarce. The objective of this study was to investigate the effectiveness of transcranial direct current stimulation (tDCS) in combination with cognitive training for the rehabilitation of executive functions in acute and subacute stroke patients as well as to explore the underlying physiological mechanisms. A triple-blinded, randomized-controlled clinical trial will be conducted involving 60 stroke patients with frontal or basal ganglia lesions and a Montreal Cognitive Assessment (MoCA) score less than 26. Participants will be randomly assigned to receive active tDCS (anode over the left dorsolateral prefrontal cortex, cathode at the right supraorbital region, 20 min at 2 mA) or sham tDCS in a 1:1 ratio for 10 sessions, followed by targeted executive function training. The primary efficacy outcome will be the MoCA score, while secondary outcomes will include the five-digit test (inhibitory control), the Digit Span Task (working memory), the abbreviated version of the Wisconsin Card Sorting test (cognitive flexibility), modified Rankin scale (functional state), Beck-II depression inventory, apathy evaluation scale, and the WHOQOL-BREF (quality of life), assessed immediately after the intervention and at 1, 3, 6, and 12 months post-intervention. Additionally, resting-state functional connectivity and blood biomarkers, such as neurotrophins, growth factors, and inflammatory molecules, will be evaluated before and after the intervention. This study will contribute to the investigation of the efficacy of tDCS in rehabilitating executive functions in acute and subacute stroke patients. The multidimensional approach utilized in this study, which includes analysis of resting-state connectivity and neuroplasticity-related blood biomarkers, is expected to provide insights into the underlying brain mechanisms involved in the rehabilitation of dysexecutive syndrome.

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This article reviews the design of a recently published randomized controlled trial (RCT) on immediate vs delayed access to gender-affirming hormones for transgender and gender-diverse (TGD) people and outlines key learning points that clinicians should know about how RCTs can and cannot contribute to advancing health equity for TGD people.

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BACKGROUND: Cognitive-behavioral intervention techniques are increasingly demonstrating their efficacy in preventing relapses and managing problems in patients with schizophrenia. There is still variation in its effectiveness for negative symptoms, such as mood-related symptoms and motivation to engage socially. METHODS: A systematic search was conducted in PubMed, Web of Science for English literature on cognitive-behavioral therapy (CBT) interventions in patients with schizophrenia. The search included randomized controlled trials and nonrandomized controlled trials. The search period extended from the inception of the databases to September 30, 2022. Two researchers independently performed quality assessment and data extraction based on predefined inclusion and exclusion criteria. RESULTS: Discrepancies were resolved through discussion or consultation with a third researcher. Initially, 169 articles were retrieved through database searches and other means. After applying the inclusion and exclusion criteria, 10 randomized controlled studies were included in the final analysis. The intervention group comprised a total of 680 patients with schizophrenia, while the control group included 686 patients with schizophrenia. Meta-analysis results demonstrated a statistically significant difference in negative symptom reduction between the CBT intervention group (WMD = -1.19, 95% CI [-1.73, -0.66], P < .0001) and the control group. CONCLUSION: We have analyzed the effectiveness of CBT based on our previous research, CBT was found to effectively improve negative symptoms in individuals diagnosed with schizophrenia.

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BACKGROUND: Comparing causal effect estimates obtained using observational data to those obtained from the gold standard (i.e., randomized controlled trials [RCTs]) helps assess the validity of these estimates. However, comparisons are challenging due to differences between observational data and RCT generated data. The unknown treatment assignment mechanism in the observational data and varying sampling mechanisms between the RCT and the observational data can lead to confounding and sampling bias, respectively. AIMS: The objective of this study is to propose a two-step framework to validate causal effect estimates obtained from observational data by adjusting for both mechanisms. MATERIALS AND METHODS: An estimator of causal effects related to the two mechanisms is constructed. A two-step framework for comparing causal effect estimates is derived from the estimator. An R package RCTrep is developed to implement the framework in practice. RESULTS: A simulation study is conducted to show that using our framework observational data can produce causal effect estimates similar to those of an RCT. A real-world application of the framework to validate treatment effects of adjuvant chemotherapy obtained from registry data is demonstrated. CONCLUSION: This  study constructs a framework for comparing causal effect estimates between observational data and RCT data, facilitating the assessment of the validity of causal effect estimates obtained from observational data.

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Background: We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost-utility analysis. Methods: We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost-utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results: The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations: We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions: In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work: More randomised controlled trials are necessary. Study registration: This study is registered as PROSPERO CRD42019130504. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Cancers of the bowel, ovary or stomach can spread to the lining of the abdomen ('peritoneal metastases'). Chemotherapy (the use of drugs that aim to kill cancer cells) given by injection or tablets ('systemic chemotherapy') is one of the main treatment options. There is uncertainty about whether adding cytoreductive surgery (cytoreductive surgery; an operation to remove the cancer) and 'hyperthermic intraoperative peritoneal chemotherapy' (warm chemotherapy delivered into the lining of the abdomen during cytoreductive surgery) are beneficial. We reviewed all the information from medical literature published until 14 April 2022, to answer the above uncertainty. We found the following from eight trials, including about 1000 participants. In people with peritoneal metastases from bowel cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably does not provide any benefits and increases harm compared to cytoreductive surgery + systemic chemotherapy, while cytoreductive surgery + systemic chemotherapy appears to increase survival compared to systemic chemotherapy alone. There is uncertainty about the best treatment for people with peritoneal metastases from stomach cancer. In women with peritoneal metastases from ovarian cancer who require systemic chemotherapy before cytoreductive surgery to shrink the cancer to allow surgery ('advanced ovarian cancer'), hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably increases survival compared to cytoreductive surgery + systemic chemotherapy. In people who can withstand a major operation and in whom cancer can be removed, cytoreductive surgery + systemic chemotherapy should be offered to people with peritoneal metastases from bowel cancer, while hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered to women with peritoneal metastases from 'advanced ovarian cancer'. Uncertainty in treatment continues for gastric cancer. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

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INTRODUCTION: Physical frailty is associated with increased mortality and poor quality of life (QoL) before and after liver transplantation (LT). Evidence is lacking on how to tailor exercise and behavioural techniques in this patient population. METHODS AND ANALYSIS: Home-based EXercise and motivAtional programme before and after Liver Transplantation (EXALT) is a phase 2b, open-label, two-centre randomised controlled clinical trial designed to investigate whether a remotely monitored 'home-based exercise and theory-based motivation support programme (HBEP)' before and after LT improves QoL in LT recipients. Adult patients awaiting a primary LT will be assessed for eligibility at two LT centres (Birmingham, Royal Free London). Participants will be randomly assigned (1:1) to receive either an HBEP while on the LT waiting list through to 24 weeks after LT (Intervention) or a patient exercise advice leaflet (Control). Using a standard method of difference in means (two-sided significance level 0.05; power 0.90) and accounting for a 35% attrition/withdrawal rate, a minimum of 133 patients will be randomised to each treatment group. The primary outcome measure will be assessed using intention-to-treat analysis of the difference in the Physical Component Score of Short form-36 version 2.0 health-related QoL questionnaire between the groups at 24 weeks post-LT. ETHICS AND DISSEMINATION: The protocol was approved by the South Central-Hampshire A National Research Ethics Committee. Recruitment into the EXALT trial started in May 2022 and is due to end in June 2024, with 217/266 patients randomised to date. The intervention follow-up is due to finish in May 2026. The findings of this trial will be disseminated through peer-reviewed publications, conferences and social media. TRIAL REGISTRATION NUMBER: ISRCTN13476586.

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INTRODUCTION: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings. METHODS AND ANALYSIS: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives. ETHICS AND DISSEMINATION: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT06455384.

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This document reports a brief update to the previously published protocol of the MinDial study.Trial registration German Clinical Trials Register DRKS00029691. Registered on 12 Sept. 2022, https://drks.de/search/en/trial/DRKS00029691 .

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Background: Osteonecrosis of the femoral head (ONFH) is acknowledged as a prevalent, challenging orthopedic condition for patients. Purpose: This study aimed to evaluate the efficacy of various interventions for non-traumatic ONFH and provide guidance for clinical decision-makers. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to February 2023 for relevant randomized controlled trials evaluating treatments for femoral head necrosis, without language restrictions. Quality evaluation was performed using the Cochrane risk-of-bias assessment tool, and analysis was performed using Stata 15.1. Results: Eleven randomized controlled trials were included in this study. The meta-analysis results revealed that CellTherapy [MD= -3.46, 95%CI= (-5.06, -1.85)], InjectableMed [MD= -3.68, 95%CI= (-6.11, -1.21)], ESWT [MD= -2.84, 95%CI= (-4.23, -1.45)], ESWT+InjectableMed [MD= -3.86, 95%CI= (-6.22, -1.53)] were significantly more effective in improving VAS pain score than CD+PTRI, as well as CD+BG+CellTherapy, and CD+BG. Furthermore, CD+BG+CellTherapy was better than CD+BG [MD= -0.97, 95%CI= (-1.71, -0.19)]. The SUCRA ranking for HHS score indicated that CellTherapy (77%) has the best effectiveness rate, followed by ESWT+InjectableMed (72.2%), ESWT (58.3%), InjectableMed (50%), CD+PTRI (31.4%), and CD+BG (11%). In terms of WOMAC and Lequesne scores, the meta-analysis showed no statistically significant differences between the experimental group CD+BG+CellTherapy and the control group CD+BG. Conclusion: CellTherapy and non-surgical ESWT combined with medication or CellTherapy have the best effect on ONFH. Surgical CD+BG combined with CellTherapy is more effective than CD+BG alone. ESWT+InjectableMed is recommended for short-term or acute onset patients, while ESWT is recommended for long-term patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024540122.

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OBJECTIVE: To evaluate the effects of different intervention measures on duration of mechanical ventilation and the length of intensive care unit (ICU) stay in critically ill patients using network Meta-analysis. METHODS: Randomized controlled trial (RCT) on the effects of different intervention measures on duration of mechanical ventilation and the length of ICU stay in critically ill patients were systematically searched in PubMed, Embase, China Biomedical Literature Database, CNKI, and other databases. The search time limit was from the establishment of the database to November 2023. Literature screening, quality assessment, and data extraction were independently conducted by two researchers. Network Meta-analysis was employed to assess the effects of each intervention on duration of mechanical ventilation and the length of ICU stay, and funnel plots were generated. RESULTS: A total of 37 RCTs were included, involving 3 977 severe patients, 2 041 in the intervention group and 1 936 in the control group. Thirteen types of interventions were analyzed, including usual care (UC), early activity (EA), early comprehensive rehabilitation (ECR), early pulmonary rehabilitation (EPR), cluster intervention strategy (CS), sedation, analgesia and cluster nursing (SACN), music therapy (MT), neuromuscular electrical stimulation (NMES), modified education and visitation (MV), virtual reality (VR), auricular point sticking (APS), acupoint acupuncture (AA), and concerted intervention (COR). Network Meta-analysis showed that MV significantly better than COR [standardized mean difference (SMD) = -2.35, 95% confidence interval (95%CI) was -4.30 to -0.39], EPR (SMD = -2.59, 95%CI was -4.81 to -0.37), and UC (SMD = -4.10, 95%CI was -5.71 to -2.49) in improving duration of mechanical ventilation in critically ill patients. COR was significantly better than UC in shortened length of ICU stay (SMD = -5.72, 95%CI was -10.07 to -1.37). The efficacy ranking results showed that for duration of mechanical ventilation, the surface under the cumulative ranking curve (SUCRA) was highest for MV (85.4%) and EA (85.4%), followed by AA (74.9%), NMES (63.1%), ECR (51.7%), CS (48.8%), SACN (34.3%), COR (29.4%), EPR (26.1%), and UC (0.7%). For the length of ICU stay, COR had the highest SUCRA (82.3%), followed by APS (79.7%), MV (77.7%), EPR (68.0%), NMES (57.6%), CS (54.4%), ECR (51.1%), SACN (41.9%), MT (39.8%), EA (39.3%), AA (33.0%), VR (15.4%), and UC (9.8%). The funnel plot results of ICU stay showed that the publication bias between studies were relatively small. CONCLUSIONS: MV and COR appear to be effective interventions for reducing mechanical ventilation time and ICU stay in critically ill patients. However, due to the number and quality of included studies, these findings require confirmation through additional high-quality research.

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During patient follow-up in a randomized trial, some deaths may occur. Where death (or noncardiovascular death) is not part of an outcome of interest it is termed a competing risk. Conventional analyses (eg, Cox proportional hazards model) handle death similarly to other censored follow-up. Patients still alive are unrealistically assumed to be representative of those who died. The Fine and Gray model has been used to handle competing risks, but is often used inappropriately and can be misleading. We propose an alternative multiple imputation approach that plausibly accounts for the fact that patients who die tend also to be at high risk for the (unobserved) outcome of interest. This provides a logical framework for exploring the impact of a competing risk, recognizing that there is no unique solution. We illustrate these issues in 3 cardiovascular trials and in simulation studies. We conclude with practical recommendations for handling competing risks in future trials.

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Background: There is limited evidence on the effectiveness of the existing rehabilitation interventions for old adults with long coronavirus disease (COVID), which is of particular concern among old adults. Methods: We systematically searched studies published in PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases from their inception to 15 November 2023. Randomised controlled trials (RCTs) compared rehabilitation interventions with other controls in old adults (mean/median age of 60 or older) with long COVID were included. We performed a meta-analysis to compare the effects of the rehabilitation interventions with the common control group. Mean difference (MD) or standardised mean difference (SMD) with its 95% confidence intervals (CI) were used as summary statistics. Moreover, subgroup analyses based on the intervention programmes, the severity of acute infection, and the age of participants were carried out. Results: A total of 11 RCTs involving 832 participants (64.37 ± 7.94 years, 52.2% were men) were included in the analysis. Compared with the control groups, rehabilitation interventions significantly improved 6-minute walking test (6 MWT; MD = 15.77 metres (m), 95% CI = 5.40, 26.13, P < 0.01), 30-second sit-to-stand test (MD = 4.11 number of stands (n), 95% CI = 2.46, 5.76, P < 0.001), all aspects of quality of life, independence in activities of daily living (SMD = 0.31, 95% CI = 0.14, 0.48, P < 0.001), and relieved fatigue (SMD = -0.66, 95% CI = -1.13, -0.19, P < 0.01), depression (SMD = -0.89, 95% CI = -1.76, -0.02, P < 0.05) and anxiety (SMD = -0.81, 95% CI = -1.58, -0.05, P < 0.05). However, the improvement of hand grip strength and pulmonary function was not statistically significant (P > 0.05). Subgroup analyses showed that improvements in 6 MWT, fatigue, anxiety, and depression were more pronounced in old patients who received exercise training, while those who received respiratory rehabilitation had more pronounced improvements in pulmonary function and quality of life. Conclusions: Old adults with long COVID who underwent rehabilitation interventions experienced significant improvement in functional capacity, fatigue, quality of life, independence in activities of daily living, and mental health outcomes compared with usual/standard care. These findings suggest that screening, management, and rehabilitation interventions for long COVID in older adults should be strengthened to improve their complete health status and functional status, thereby reducing the long-term disease burden caused by long COVID and fostering healthy aging during the post-pandemic era.

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Introduction: Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol: Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion: This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

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BACKGROUND: When sufficient maternal milk is not available, donor human milk or formula are the alternative forms of enteral nutrition for very preterm or very low-birthweight (VLBW) infants. Donor human milk may retain the non-nutritive benefits of maternal milk and has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To assess the effectiveness of donor human milk compared with formula for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants when sufficient maternal milk is not available. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care (MIC) database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to February 2024. We searched clinical trials registries and examined the reference lists of included studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing feeding with donor human milk versus formula in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. DATA COLLECTION AND ANALYSIS: Two review authors evaluated the risk of bias in the trials, extracted data, and synthesised effect estimates using risk ratio, risk difference, and mean difference, with associated 95% confidence intervals. The primary outcomes were NEC, late-onset invasive infection, and all-cause mortality before hospital discharge. The secondary outcomes were growth parameters and neurodevelopment. We used the GRADE approach to assess the certainty of the evidence for our primary outcomes. MAIN RESULTS: Twelve trials with a total of 2296 infants fulfilled the inclusion criteria. Most trials were small (average sample size was 191 infants). All trials were performed in neonatal units in Europe or North America. Five trials were conducted more than 40 years ago; the remaining seven trials were conducted in the year 2000 or later. Some trials had methodological weaknesses, including concerns regarding masking of investigators and selective reporting. Meta-analysis showed that donor human milk reduces the risk of NEC (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.37 to 0.76; I² = 4%; risk difference (RD) -0.03, 95% CI -0.05 to -0.01; 11 trials, 2261 infants; high certainty evidence). Donor human milk probably has little or no effect on late-onset invasive infection (RR 1.12, 0.95 to 1.31; I² = 27%; RD 0.03, 95% CI -0.01 to -0.07; 7 trials, 1611 infants; moderate certainty evidence) or all-cause mortality (RR 1.00, 95% CI 0.76 to 1.31; I² = 0%; RD -0.00, 95% CI -0.02 to 0.02; 9 trials, 2116 infants; moderate certainty evidence). AUTHORS' CONCLUSIONS: The evidence shows that donor human milk reduces the risk of NEC by about half in very preterm or VLBW infants. There is probably little or no effect on late-onset invasive infection or all-cause mortality before hospital discharge.

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