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Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses., Experimental Design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals., Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results., Conclusions: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted., (©2024 American Association for Cancer Research.)

Introduction: Diarrhea is a frequent complication after kidney transplantation, however the etiology is often not identified. Multiplex PCR assays may increase the detection of diarrheal pathogens among kidney transplant recipients (KTRs), leading to improved management., Methods: This was a retrospective before-after study, conducted in a high-volume transplant center. In September 2017, multiplex PCR assay was introduced. We reviewed all hospitalized KTRs with diarrhea during 1/2015-8/2017 (pre-GI PCR, n = 111) and 9/2017-12/2021 (GI PCR, n = 159) and followed them for 3 years. We performed univariate and multivariate analysis for predictors of pathogen identification, introducing the study period as an independent variable., Results: Among 270 hospitalized KTRs with diarrhea, 64 (24%) had an identified diarrheal pathogen. The proportion of KTRs with an identified pathogen increased from 20% (13/64) in the pre-GI PCR to 80% (51/64) post GI PCR (p < 0.01). Of 51 KTRs with an identified pathogen in the post GI PCR, 44 (86%) were diagnosed using GI PCR. GI PCR was more likely used in younger KTRs with more recent transplantation and higher creatinine level at admission. The most common non-C. difficile diarrheal pathogens in the post-GI PCR cohort were enteropathogenic Escherichia coli (n = 23, 58%), norovirus (n = 11, 28%), and Campylobacter (n = 11, 28%). Implementing GI PCR significantly increased the detection and identification of GI pathogens (odds ratio [OR] = 21, CI 95% 10-44; p < 0.001)., Conclusions: Infectious etiologies of diarrhea were identified in a higher proportion of KTRs after the implementation of GI PCR. This emphasizes the importance of integrating this diagnostic tool into diarrhea workup in KTRs., (© 2024. The Author(s).)

Objective: To evaluate the risk of recurrent Clostridioides difficile infection (CDI) in solid-organ transplant (SOT) recipients., Methods: Retrospective multicenter study including SOT recipients with a first CDI episode in the year after transplantation (Jan 2017-June 2020). The primary outcome measure was recurrence, defined as a new CDI ≤56 days from the first episode. A competing risk analysis was performed using the sub-distribution hazard model multivariable analysis., Results: 191 SOT recipients were included: 101 (52.9%) were kidney, 66 (34.6%) liver, 11 (5.8%) lung, 8 (4.2%) simultaneous pancreas-kidney, 4 (2.1%) heart and 1 (0.5%) pancreas alone recipients. Treatment for the first CDI were: vancomycin (n = 114,59.7%), vancomycin+metronidazole (n = 39,20.4%), metronidazole (n = 26,13.6%), fidaxomicin (n = 9,4.7%), 3 patients did not receive any therapy. After the first CDI, 17/191 (8.9%) patients died within 56-day mortality without having a recurrence, while 23/191 (12%) patients had a recurrence. Among patients with recurrent CDI, 56-day mortality rate was 30.4% (7/23 patients). On multivariable analysis, severe CDI (sHR4.01, 95% CI 1.77-9.08, p < .001) and metronidazole monotherapy (sHR 3.65, 95% CI 1.64-8.14, p = .001) were factors independently associated with recurrence., Conclusions: Metronidazole monotherapy is associated with increased risk of recurrent CDI in SOT recipients. Therapeutic strategies aimed to reduce the risk of recurrence should be implemented in this setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GT received honoraria for educational meetings by Shionogi and participated to scientific board for MSD. MF received unconditional grants from MSD, Gilead and speaker honoraria from Shionogi, Pfizer, Menarini, MSD, Gilead, GSK, MundiPharma and TermoFisher. Declared conflicts of interest are outside the submitted work and did not affect the scientific objectivity of this study. The other authors have none to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Clostridioides difficile (CDI) is a common cause of infectious diarrhea. The current recommendation is to initiate empirical antibiotic treatment for suspected CDI who have an anticipated delay of confirmatory results or fulminant colitis. This is based on limited clinical trials. The study aims to examine the impact of early treatment on mortality and clinical outcomes., Methods: This retrospective cohort study included adult patients with CDI. Early treatment was defined as the initiation of an anti-Clostridioides medication within the first 24 h following stool sampling. Outcomes were 30 and 90 day mortality, length of hospital stay (LOS), recurrence, and colectomy rate. To address potential bias, propensity score matching followed by logistic regression was performed, P value less than 5% was considered statistically significant., Results: Study cohort consisted of 796 patients; clinical characteristics were balanced following matching. There was no difference, in favor of early treatment, between the groups regarding 30 day mortality and 90 day mortality with HR of 0.91 (95% CI 0.56-1.47) and 0.7 (95% CI 0.45-1.08), respectively. No statistically significant difference in recurrence rate, ICU admission or colectomy rate was observed. The LOS was shorter in the early-treatment group with 6 days vs. 8 days., Conclusion: Early treatment for CDI had shortened hospital stay. However, it did not affect clinical outcomes in adult patients., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Prolactin deficiency is rare. It generally occurs when pituitary disorders, such as large pituitary tumors, pituitary apoplexy, and other conditions associated with sellar mass effect lead to global failure of pituitary function and hypopituitarism. In these situiations, prolactin is commonly the last pituitary hormone affected, after growth hormone and gonadotropins are lost and thyroid-stimulating hormone and adrenocorticotopic hormone secretion is impaired. Prolactin deficiency accompanies several congenital syndromes due to mutations in PROP1 and Pit1/ POU1F and in X-linked IGSF1 deficiency syndrome, and several aqcuired conditions including Sheehan syndrome, IgG4-related hypophysitis, and immune checkpoint-inhibitor-induced hypophysitis. In women, prolactin deficiency prevents lactation following childbirth among other symptoms associated with hypopituitarism. Human prolactin is not available commercially as replacement therapy. However, recombinant human prolactin administered daily to women with hypoprolactinemia and alactogenesis was found to lead to the production of significant milk volume sufficient for lactation., (© 2024. The Author(s).)

Objective: Uterine-sparing surgery for pelvic organ prolapse (POP) repair has shown good results, but the potential negative implications of leaving the uterus in place are yet to be fully defined. We aimed to assess the risk of unanticipated abnormal gynecological pathology at the time of reconstructive pelvic surgery. Methods: A retrospective consecutive case series including women who underwent vaginal hysterectomy for POP repair at a tertiary medical center in 2006-2020. All patients were offered a free Pap smear test at the age of 65 years as part of a national screening program. Transvaginal ultrasound was routinely performed preoperatively. Standard 3 pedicle hysterectomy was performed with/without bilateral salpingo-oophorectomy (BSO). Results: The study comprised 462 women of mean age 63 ± 9.3 years without previous known malignant or premalignant pathology. Benign pathology was observed in 286 patients (61.9%). Endometrial malignancy was found in three patients (0.7%) and significant premalignant pathology in 15 patients (3.2%), including cervical intraepithelial neoplasia stage 2-3 in seven patients (1.5%) and complex hyperplasia with atypia in eight patients (1.7%). All these pathologies were found in postmenopausal women. None had preoperative clinical symptoms or endometrial thickness of ≥5 mm on preoperative ultrasound. In the 35 patients after BSO, adnexal findings were normal (77.2%) or benign (22.8%). Conclusions: Premenopausal women with uterovaginal prolapse and normal preoperative evaluation have a minimal risk of significant abnormal uterine pathology. In postmenopausal women, the risk of unanticipated malignant uterine pathology is 0.7% and 3.2% for significant premalignancy.

Aim: Following the Hamas terror attack on Israeli towns on October 2023, 250 individuals were taken into captivity. On November-December 2023, during the cease-fire deal, 26 women and children were released. This study is the first to describe the physical and behavioural findings in children and their mothers in the immediate phase of returning home from captivity., Methods: This is a retrospective study describing the clinical characteristics of the returnees after 49-53 days in captivity. Patients were admitted to a designated unit in the Schnieder Children's Medical Center of Israel on November-December 2023. The hospitalisation duration was 1-9 days. All patients were evaluated according to a detailed protocol and were treated respectively., Results: Patient population included 19 children (ranged 2-18 years old) and 7 women (ranged 34-78 years old). The most common clinical findings upon return included significant weight loss, psychological trauma, complications of poor hygiene and complications of recent shrapnel injuries. Microbiology tests were positive for multiple gastrointestinal pathogens. Serologic screening tests were positive for various infectious diseases., Conclusion: Clinical findings in this time period were diverse and required the attention of a multidisciplinary team. Long term clinical and psychological effects are yet to be known., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Evidence is growing that the individual adjustment of energy targets guided by indirect calorimetry (IC) can improve outcome. With the development of a new generation of devices that are easier to use and rapid, it appears important to share knowledge and expertise that may be used to individualize nutrition care. Despite the focus of this tutorial being on one contemporary device, the principles of IC apply across existing devices and can assist tailoring the nutrition prescription and in assessing response to nutrition therapy. The present tutorial addresses its clinical application in intubated mechanically ventilated and spontaneously breathing adult patients (canopy), i.e. it covers the range from critical illness to outpatients. The cases that are presented show how the measured energy expenditure (mEE), and the respiratory quotient (RQ), i.e. the ratio of expired CO 2 to consumed O 2 , should be applied in different cases, to adapt and individualize nutrition prescription, as it is a good marker of over- or underfeeding at the different stages of disease. The RQ also informs about the patient's body's capacity to use different substrates: the variations of RQ indicating the metabolic changes revealing insufficient or excessive feeding. The different cases reflect the use of a new generation device as a metabolic monitor that should be combined with other clinical observations and laboratory biomarkers. The tutorial also points to some shortcomings of the method, proposing alternatives., Competing Interests: Declaration of competing interest None of the authors declares any conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Neonatal clavicular fractures represent the most common fracture during delivery. We aimed to define risk factors associated with these fractures in a large population-based database., Methods: Data were extracted from Clalit Health Services' electronic health records from 2000 to 2020. Newborns with clavicular fractures were compared with a healthy control group. The following parameters were compared-for the newborns: sex, birth weight, birth height, and head circumference; for the delivery process: assisted delivery, cesarean section, use of epidural, birth week, and number of fetuses; and for the mother: age at delivery, socioeconomic status, height, weight, and body mass index (BMI)., Results: We found a rate of 0.28% for neonatal clavicular fractures (5015 clavicular fractures/1 755 660 deliveries). Male gender and heavier birth weight were found to be significantly associated with clavicular fractures (P < .001). Increased risk was also associated with lower socioeconomic status, baseline weight, and maternal BMI (P < .001 for all). Assisted delivery increased the risk of clavicular fracture (OR = 2.274; 95% CI, 1.661-3.115; P < .0001), while cesarean section and use of epidural were found to be protective (OR = 0.149; 95% CI, 0.086-0.26; P < .0001; and OR = 0.687; 95% CI, 0.0531-0.89; P < .004, respectively)., Conclusions: This study provides insight into the risk factors associated with neonatal clavicular fractures on the largest group of patients reported to date., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: While the number of female medical graduates continues to increase, only a few pursue an orthopaedic career. This is related to challenges regarding pregnancy and the peripartum period during orthopaedic training., Aims: To evaluate fertility, pregnancy-related complications and attitudes towards female orthopaedic surgeons in Israel., Methods: An electronic anonymous 34-question electronic web-based survey was sent to all Israeli female orthopaedic surgeons. Participation was voluntary. Questions were formulated to determine demographics, obstetrics medical history, teratogenic exposure, medical leave and breastfeeding parameters along with attitude towards pregnancy., Results: Twenty-six orthopaedic surgeons complied with the survey, 68% of all registered female orthopaedic surgeons. Participants age was 39.5 (±8.8). The average number of children for a female orthopaedic surgeon was 2.2 (±1.4), with an average of 1.3 (±1.1) deliveries during residency. The average age for a first child was 31.1 (±3.7) years. Four surgeons required fertility treatments and six had abortions. Thirty-eight per cent experienced pregnancy complications. Most surgeons were exposed to radiation and bone cement during pregnancy. The average duration of maternity leave was 19.4 (±9.9) weeks and return to work was associated with cessation of breastfeeding. Seventy-six per cent of surgeons felt that pregnancy had negatively influenced their training, and 12% reported negative attitudes from colleagues and supervisors., Conclusions: Orthopaedic surgeons in Israel experience a delay in childbirth and higher rates of pregnancy complications. Most feel that their training is harmed by pregnancy. Programme directors should design a personalized support programme for female surgeons during pregnancy and the peripartum period., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Foreign bodies that migrate into the heart may include medical devices dislodged from their original location or, rarely, external particles (shrapnel and other foreign bodies) that penetrate the vein, remain intraluminal, and migrate via the venous blood flow to the right heart. Most reported entry sites of these external foreign bodies were in the torso, thigh, or neck; none of them penetrated through a distal extremity of the body. We report a case where shrapnel was found in the right ventricle (RV) following penetrating injury to the hand., Case Summary: An otherwise healthy 24-year-old man presented with an isolated shrapnel injury to his right hand and forearm from an explosion trauma. Computed tomography demonstrated multiple small metal objects in the forearm, hand, and wrist. Additionally, a 3 × 3.5 mm metal object was found in the RV, consistent with a metal shrapnel embolus from the forearm. Echocardiography indicated the fragment to be in a fixed position within the RV, without any additional pathology., Discussion: Even shrapnel that penetrates through the hand or forearm may migrate to the heart. In this case, following a multidisciplinary discussion, a conservative approach was recommended based on the following condition: lack of symptoms, small size of the foreign body, no obstruction of venous effluent, low risk of significant embolization to the pulmonary vasculature, absence of fever or endocarditis, no current evidence or risk of valve dysfunction, and no myocardial irritation indicated by arrhythmia. The patient was instructed to avoid magnetic resonance imaging scans., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome., Methods: We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first., Findings: The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%., Interpretation: Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) has shown promise in achieving pathologic complete response (pCR) and enabling organ preservation through watch-and-wait (WW) strategies. However, implementation of WW protocols in diverse patient populations and safety-net hospitals faces unique challenges. The objective of this study is to evaluate TNT outcomes and identify barriers to WW implementation in a predominantly Hispanic safety-net hospital in South Texas., Methods: A retrospective review was conducted of 40 LARC patients treated with TNT at an academic tertiary referral center in South Texas between 2018 and 2023. Patient demographics, disease characteristics, and pCR rates were analyzed. A survey of multidisciplinary providers assessed perceived institutional and patient-related barriers to WW implementation., Results: The cohort was 70% Hispanic, with a median age of 54 years. Most patients had advanced disease at diagnosis (57.5% T4, 65% N2). The pCR rate was 18.5% (5/27) among patients undergoing surgery. Re-review of MRIs for pCR patients revealed that 2/5 had minimal residual disease. The provider survey identified MRI quality variability, lack of dedicated treatment coordinators, and concerns about patient compliance and financial barriers as key obstacles to WW implementation., Conclusions: Despite advanced disease presentation in a predominantly Hispanic population, TNT achieved pCR rates comparable to international trials. Institutional and patient-level barriers to WW were identified, informing the development of a tailored WW protocol for this unique patient population., (© 2024 Wiley Periodicals LLC.)

Introduction: High-dose therapy with melphalan followed by autologous stem cell transplant in the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, the role of upfront ASCT approach has been called into question. Several prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (triplet-alone) could result in comparable outcomes., Methods: This was a systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT versus triplet-alone approach among myeloma patients treated with triplet therapy, which included two novel agents and a corticosteroid, as induction. Cochrane Library, PubMed and conference proceedings were searched. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), safety, and second primary malignancies (SPM). Subgroup analysis was conducted for high-risk cytogenetics., Results: Our search yielded three trials, conducted between 2010-2018, including 1,737 patients. Two trials evaluated bortezomib plus lenalidomide (VRd) induction and the third study tested carfilzomib plus lenalidomide (KRd) induction. Maintenance was given in all trials to both arms. There was no difference in OS between the arms; the pooled OS in all patients and those with high-risk cytogenetics was hazard ratio (HR) 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials) and 0.85 (95% CI, 0.59-1.23; I2 = 0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT versus triplet-alone was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 (95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials) and HR 0.59 (95% CI: 0.44-0.7; I2 = 0%; 306 patients, 3 trials), respectively. The risk of any grade 3-4 adverse events was higher in the upfront ASCT arm versus triplet-alone approach (relative risk = 1.17 [95% CI, 1.12-1.23; 1,737 patients]). The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm versus triplet-alone approach, OR 9.7 (1.8-52.25, I2 = 0%, 1,422 patients)., Conclusion: Although upfront ASCT approach, in the era of triplet therapy, resulted in a significantly longer PFS among all patients, this did not translate into a survival benefit, regardless of cytogenetic risk. Upfront ASCT was associated with an increased rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable., (© 2024 S. Karger AG, Basel.)

Hyperuricemia is a known predictor of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension), but its role in excluding PH secondary to chronic lung diseases (WHO Group 3) remains unclear. We retrospectively analyzed data from 323 patients with severe chronic pulmonary diseases who underwent evaluation for lung transplantation at a tertiary medical center between June 2017 and February 2023. We examined the association between hyperuricemia (serum uric acid > 6 mg/dL or > 0.357 mmol/L) and PH [mean pulmonary arterial pressure (MPAP) > 20 mmHg]. Compared to the normouricemia group (n = 211), hyperuricemic patients (n = 112) were more likely to be younger (P = 0.02), male (P < 0.001), and present with PH (P = 0.001) and severe PH (MPAP > 35 mmHg; P < 0.001). These patients also had a higher body mass index (P = 0.004), plasma N-terminal pro-B-type natriuretic peptide (P < 0.001), serum creatinine (P < 0.001), and C-reactive protein levels (P = 0.03). Significant associations with PH included higher body mass index (P = 0.005), uric acid levels (P < 0.001), total lung capacity (P = 0.02), and residual volume (P = 0.01); shorter 6-min walk test distance (P = 0.005); and lower forced expiratory volume in one second (P = 0.006) and diffusing capacity for carbon monoxide (P < 0.001). Multivariate analysis showed elevated uric acid levels remained significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, P = 0.01). In conclusion, normal serum uric acid levels serve as a significant predictor for excluding pulmonary hypertension in patients with severe chronic lung diseases., (© 2024. The Author(s).)

Objectives: Evaluating the effectiveness and safety of repeated high-dose intradetrusor abobotulinumtoxin A (Dysport®) injections for the treatment of pediatric neurogenic bladders refractory to medications., Design: Retrospective interventional study., Participants: The cohort included 37 children (22 boys and 15 girls) of median age 9.2 years. Inclusion criteria were diagnosis of neurogenic bladder and failure to respond to medical treatment. Exclusion criteria were augmented bladder, insufficient data, and interval of > 11 months between video-urodynamic study and Dysport injection., Interventions: All participants were treated with an intra-detrusor injection of Dysport 30 IU/kg (up to 1000 IU) under general anesthesia. Repeated (second and third) injections were scheduled (6-12 months) in patients who demonstrated an improvement in cystometric parameters. All participants underwent video urodynamic testing before onset of treatment and 4-5 months after subsequent injection., Main Outcome Measures: Success of treatment was defined as a decrease in end filling pressure (EFP) to < 40 cm H 2 O and/or a 20% increase in maximal cystometric capacity (MCC). These parameters along with initial bladder features were evaluated for ability to predict treatment success., Results: No side effects of Dysport were observed or reported. The overall success rate was 62%. MCC increased by a median of 30% (IQR 200-300, p < 0.001), 37% (IQR 197-310, p = 0.001) and 45% (IQR 245-300, p = 0.025) after the first, second and third injections, respectively. Median EFP decreased from 45 cm H 2 O to 34 cm H 2 O (IQR 20-45, p = 0.029), 23 cm H 2 O (IQR 20-37, p = 0.004), and 20 cm H 2 O (IQR 12-32, p = 0.049) after the first, second, and third injections, respectively. No predicting factor of success of treatment were found; However, three of five cases of "end stage" bladder showed improvement., Conclusions: High-dose Dysport injection is safe and effective for the treatment of neurogenic bladder. Studies with larger cohort and a control group would further elucidate which bladders would benefit most. At present, we recommend treating also bladders with "end stage" features with botulinum toxin before considering augmentation., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Objective: To investigate how many novel pathogenic (P) and likely pathogenic (LP) nonprotein-truncating or noncanonical splicing variants would be classified as variants of unknown significance (VUS) if they were detected in fetuses without abnormalities., Methods: The study included 156 patients with neurodevelopmental disorders diagnosed through postnatal exome sequencing. Causative P/LP nonprotein-truncating and noncanonical splicing variants were retrospectively reclassified in cases without specific prenatal manifestations, disregarding postnatal symptoms., Results: Of the 156 patients, 72 had a nontruncating or noncanonical splicing variant. Six patients were excluded for having more than one possible causative variant. Twelve patients had prenatal malformations known to be associated with the diagnosed disorder; therefore, variant interpretation remained unchanged. In 33 of the 54 remaining cases, the variant had been previously reported as P/LP. Reclassification of the other 21 LP/P variants revealed that 16 would have been classified as VUS if detected prenatally., Conclusion: In our cohort, ∼24% (16/66) of causative nonprotein-truncating/noncanonical splicing variants would have been classified as VUS if sequencing had been conducted during pregnancy. The potential for false-negative results, stemming from limitations in the phenotypic information available prenatally, should be discussed with prospective parents. The criteria for classifying and reporting variants in the prenatal setting may require adjustment., (© 2024 John Wiley & Sons Ltd.)

Objective: The traditional categorical division of surgical margins using a 5 mm cutoff in oral cavity squamous cell carcinoma (OCSCC) is controversial. The primary aim of this study was to investigate the presence of an optimal cutoff point or, alternatively, assess the potential improvement in predictive value by considering the surgical margins as a continuum., Methods: Retrospective analysis of OCSCC patients at a tertiary medical center in 1995-2020. Clinical, pathological, and surgical data were evaluated for effect on survivability by regression analyses., Results: The cohort included 266 patients (48.1% male, mean age 65.4 ± 17.7). Patient stratification by categorical margin status yielded no significant between-group differences in survival (p = 0.54). Significance was achieved when margin distance was reevaluated as a continuous variable (p = 0.0018). Similar results were shown in local control (categorical p = 0.59 vs. continuous p = 0.06). Multivariate model excluded possible confounders. A predictive model was created to provide a more accurate prediction of survival., Conclusions: The continuum spectrum of margin distance better predicts survival outcomes and locoregional control in OCSCC., Level of Evidence: 3 Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Genome-wide sequencing, which includes exome sequencing and genome sequencing, has revolutionized the diagnostics of genetic disorders in both postnatal and prenatal settings. Compared to exome sequencing, genome sequencing enables the detection of many additional types of genomic variants, although this depends on the bioinformatics pipelines used. Variant classification might vary among laboratories. In the prenatal setting, variant classification may change if new fetal phenotypic features emerge as the pregnancy progresses. There is still a need to evaluate the incremental diagnostic yield of genome sequencing compared to exome sequencing in the prenatal setting. This article reviews the advantages and limitations of genome sequencing, with an emphasis on fetal diagnostics., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background & Aims: Accurately estimating resting energy requirements is crucial for optimizing energy intake, particularly in the context of patients with varying energy needs, such as individuals with cancer. We sought to evaluate the agreement between resting energy expenditure (REE) predicted by 40 equations and that measured by reference methods in women undergoing active breast cancer treatment stage (I-IV) and post-completion (i.e., survivors)., Methods: Data from 4 studies were combined. REE values estimated from 40 predictive equations identified by a systematic search were compared with REE assessed by indirect calorimetry (IC) using a metabolic cart (MC-REE N = 46) or a whole-room indirect calorimeter (WRIC-REE N = 44). Agreement between methods was evaluated using Bland-Altman and Lin's concordance coefficient correlation (Lin's CCC)., Results: Ninety participants (24 % survivors, 61.1% had early-stage breast cancer I or II, mean age: 56.8 ± 11 years; body mass index: 28.7 ± 6.4 kg/m 2 ) were included in this analysis. Mean MC-REE and WRIC-REE values were 1389 ± 199 kcal/day and 1506 ± 247 kcal/day, respectively. Limits of agreement were wide for all equations compared to both MC and WRIC (∼300 kcal for both methods), including the most commonly used ones, such as Harris-Benedict and Mifflin ST. Jeor equations; none had a bias within ±10% of measured REE, and all had low agreement per Lin's CCC analysis (<0.90). The Korth equation exhibited the best performance against WRIC and the Lvingston-Kohlstadt equation against MC. Similar patterns of bias were observed between survivors and patients and between patients with stages I-III versus IV cancer., Conclusion: Most equations failed to accurately predict REE at the group level, and none were effective at the individual level. This inaccuracy has significant implications for women with or surviving breast cancer, who may experience weight gain, maintenance, or loss due to inaccurate energy needs estimations. Therefore, our research underscores the need for further efforts to improve REE estimation., Competing Interests: Conflict of interest C.M.P. reports receiving unrelated honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestle Health Science, Pfizer, and AMRA Medical. B.R.S, A.P.P, A.A.K, M.C.G, M.J.H, A.A.J, P.S, E.C, I.P, E.P and R.T. declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of the present study was to evaluate the impact of late third-trimester sonographic estimation of large for gestational age fetuses on pregnancy management and selected fetal and maternal adverse outcomes., Methods: A retrospective cohort study was conducted in a tertiary, university-affiliated medical center between 2015 and 2019. All singleton large-for-gestational-age neonates born during this period were included. The cohort was divided into two groups: neonates for whom fetal weight was estimated on late third trimester (<14 days before delivery) sonography and neonates with no recent fetal weight estimation. The groups were compared for pregnancy management strategies, rates of labor induction, cesarean deliveries, and maternal and neonatal outcomes., Results: A total of 1712 neonates were included in the study, among whom 791 (46.2%) had a late third-trimester fetal weight estimation (study group) and 921 (53.8%) did not (control group). Compared to the control group, the study group was characterized by higher rates of maternal primiparity (24.20% vs 19.20%, P = 0.013), higher maternal body mass index (26.0 ± 6.2 kg/m 2 vs 24.7 ± 4.5 kg/m 2 , P = 0.002), more inductions of labor (29.84% vs 16.40%, P < 0.001) and cesarean deliveries (31.0% vs 19.97%, P < 0.001). There were no clinical differences in neonatal birth weight (4041 ± 256 g vs 3984 264 g, P < 0.001) and no significant differences between other neonatal outcomes, as rates of admission to the neonatal intensive care unit, jaundice, hypoglycemia, and shoulder dystocia., Conclusion: Late third-trimester sonographic fetal weight estimation is associated with a higher rate of labor induction and planned and intrapartum cesarean deliveries. In this retrospective cohort study, those interventions did not lead to reduction in maternal or neonatal adverse outcomes., (© 2024 International Federation of Gynecology and Obstetrics.)

Although chimeric antigen receptor (CAR) T cell therapy represents a transformative immunotherapy, it is also associated with distinct toxicities that contribute to morbidity and mortality. In this systematic review and meta-analysis, we searched MEDLINE, Embase and CINAHL (Cochrane) for reports of nonrelapse mortality (NRM) after CAR T cell therapy in lymphoma and multiple myeloma up to March 2024. After extraction of causes and numbers of death, we analyzed NRM point estimates using random-effect models. We identified 7,604 patients across 18 clinical trials and 28 real-world studies. NRM point estimates varied across disease entities and were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%) and indolent lymphoma (5.7%). Entity-specific meta-regression models for large B cell lymphoma and multiple myeloma revealed that axicabtagene ciloleucel and ciltacabtagene autoleucel were independently associated with increased NRM point estimates, respectively. Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%). Conversely, the CAR T cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome and hemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths (cumulatively 11.5%). Our findings underline the critical importance of infectious complications after CAR T cell therapy and support the comprehensive reporting of NRM, including specific causes and long-term outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Tefillin are a religious article worn by Jewish men during daily prayer. Tefillin dermatitis secondary to potassium dichromate sensitivity is recognised, but data remain sparse., Objective: To investigate the prevalence and clinical characteristics of tefillin dermatitis., Methods: Patients who underwent patch testing with the European baseline series in a tertiary dermatology clinic in 2009-2023 and were diagnosed with tefillin dermatitis were identified by file review and their clinical data recorded., Results: Of 1679 consecutive male patients tested, 25 (1.49%) were diagnosed with tefillin dermatitis, accounting for 15.34% of all potassium-dichromate-positive patients (163/1679). Mean pre-symptomatic duration of tefillin use was 38 ± 16.9 years, and mean follow-up time, 3.1 ± 2.9 years. Patients presented with an eczematous rash on body areas in direct contact with the leather box or straps of the tefillin. An id reaction was noted in 32%, and sensitivity to other leather accessories, in 44%. Fourteen patients (56%) switched to chromate-free tefillin: symptoms resolved completely in 11 (79%) and partially in 2., Limitations: Retrospective cohort design., Conclusion: This is the largest study to date of tefillin dermatitis caused by sensitivity to potassium dichromate used in leather production. Prognosis after switching to chromate-free tefillin was good-to-excellent. Tefillin dermatitis may be more prevalent than previously thought., (© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.)

Purpose of Review: This review explores characterizing candidates for obesity treatments including pharmacotherapy, endoscopic bariatric therapies, and metabolic bariatric surgery (MBS), focusing on established clinical parameters for diagnosing obesity beyond body mass index alone., Recent Findings: Existing literature primarily provides rates for fat mass percentage (i.e., a marker for adiposity quantity), waist circumference (i.e., a marker for adiposity distribution), and C-reactive protein levels (i.e., a marker for adiposity functionality) among obesity treatment candidates. Limited data on abnormal values and sex-based differentiation exist. The literature indicates high central-tendency measures for fat mass percentage and waist circumference, while C-reactive protein levels vary. Data on the Edmonton Obesity Staging System (i.e., a marker for adiposity-related disease severity) is predominantly available for MBS candidates. Future studies in obesity interventions should improve screening and diagnosis of obesity by incorporating sex-specific considerations and providing abnormal value rates for measurements to enhance understanding of patients' characteristics., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cutaneous fungal infections are one of the most common skin conditions, hence, the burden of determining fungal elements upon microscopic examination with periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) stains, is very time consuming. Despite some morphological variability posing challenges to training artificial intelligence (AI)-based solutions, these structures are favored potential targets, enabling the recruitment of promising AI-based technologies. Herein, we present a novel AI solution for identifying skin fungal infections, potentially providing a decision support system for pathologists. Skin biopsies of patients diagnosed with a cutaneous fungal infection at the Sheba Medical Center, Israel between 2014 and 2023, were used. Samples were stained with PAS and GMS and digitized by the Philips IntelliSite scanner. DeePathology® STUDIO fungal elements were annotated and deemed as ground truth data after an overall revision by two specialist pathologists. Subsequently, they were used to create an AI-based solution, which has been further validated in other regions of interests. The study participants were divided into two cohorts. In the first cohort, the overall sensitivity of the algorithm was 0.8, specificity 0.97, F1 score 0.78; in the second, the overall sensitivity of the algorithm was 0.93, specificity 0.99, F1 score 0.95. The results obtained are encouraging as proof of concept for an AI-based fungi detection algorithm. DeePathology® STUDIO can be employed as a decision support system for pathologists when diagnosing a cutaneous fungal infection using PAS and GMS stains, thereby, saving time and money., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Purpose: The purpose of this study was to identify early indicators of keratoconus progression in Pentacam data using machine learning (ML) techniques., Methods: A retrospective Pentacam tabular data set was created by retrieving 11,760 tomography tests performed in patients with keratoconus. Data for eyes labeled unstable based on their referral for cross-linking were differentiated from data for eyes labeled stable and not referred for follow-up procedures. A boosted decision tree was trained on the final data set using a cross-validation method., Results: The final labeled data set included 1218 tomography tests. Training a ML model on a single test for each eye did not accurately predict disease progression, as indicated by the mean receiver-operating characteristic area under the curve of 0.59 ± 0.1, with precision of 0.27, recall of 0.3, and F1 score of 0.28. Training on serial tests for each eye included 819 tomography scans and yielded good prognostic abilities: a receiver-operating characteristic area under the curve of 0.75 ± 0.07, precision of 0.32, recall of 0.67, and F1 score of 0.43. In addition, 4 of the 55 Pentacam raw data parameters predominantly used the algorithm decision: age, central keratoconus index, Rs B, and D10 mm pachy., Conclusions: This study revealed specific dominant parameters attributing to the classification of stability, which are not routinely assessed in determining progression in common practice. Using ML techniques, keratoconus deterioration was evaluated algorithmically with training on multiple tests, yet was not predicted by a single tomography test. Hence, our study highlights novel factors to the current consideration of cross-linking referral and may serve as a supportive tool for clinicians., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The prognostic significance of pretransplant N-terminal pro-brain (B)-type natriuretic peptide (NT-proBNP) level has not been investigated in lung transplant recipients. The electronic files of 173 patients with chronic lung disease who underwent lung transplantation in 2018-2022 at a tertiary medical center were retrospectively reviewed. Right heart catheterization (RHC) and NT-proBNP determination were performed preoperatively in all cases. Pretransplant demographic, clinical, and laboratory data were compared between posttransplant survivors and nonsurvivors. Correlations of NT-proBNP values with lung function and RHC parameters and all-cause mortality were analyzed. NT-proBNP level correlated positively with mean pulmonary artery pressure ( R  = 0.51, p  < 0.001) and pulmonary vascular resistance (PVR) ( R  = 0.45, p  = 0.0013), and negatively with diffusing lung capacity for carbon monoxide ( R  = -0.25, p  = 0.0017), cardiac index ( R  = -0.26, p  = 0.001), and cardiac output ( R  = -0.23, p  = 0.004). Over a median follow-up time of 23.22 months, 74 patients died. On univariate analysis, mortality was significantly associated with higher log-NT-proBNP (hazard ratio [HR] = 0.54, 95% confidence interval [CI] 1.15-2.05, p  = 0.016), older age at transplant registration (HR = 1.033, 95% CI 1.009-1.058, p  = 0.0068), higher PVR (HR 1.15, 95% CI 1.07-1.23, p  = 0.015), and lower cardiac output (HR = 0.62, 95% CI 0.42-0.92, p  = 0.045). On multivariate analysis adjusted for age, sex, and body mass index, mortality significance was maintained only for higher log-NT-proBNP (HR = 1.54, 95% CI 1.12-2.11, p  = 0.007). Among lung transplant recipients, pretransplant NT-proBNP levels correlated well with RHC parameters and were strongly associated with posttransplantation mortality. Assessment of NT-proBNP may improve risk stratification of lung transplant candidates., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS., Objectives: To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting., Methods: We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS., Results: In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression., Conclusions: PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR., Competing Interests: Conflicts of interest E.H. has received honoraria for consulting and/or lectures from Helsinn, Takeda, Vidac, Recordati and Rafa; and support for travel/meeting participation from Rafa. C.J. has received honoraria for consulting and/or lectures and support for travel/meeting participation from Takeda, Kyowa Kirin and Recordati. J.N. has received honoraria for consulting and/or lectures from Kyowa Kirin, Takeda, Recordati/Helsinn and Mallinckrodt/Therakos; and research funding from Kyowa Kirin. P.Q. has received honoraria for consulting and/or lectures from Takeda, Kyowa Kirin, Recordati/Helsinn, Mallinckrodt and 4SC. J.C.-M. has received honoraria for lectures from Takeda and Janssen. P.O. has received honoraria for lectures from Kyowa, Helsinn, Recordati, Mallinkrodt and 4SC; and support for travel/meeting participation from Kyowa, Almirall and LEO Pharma., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To describe the placement of a silicone shield to protect the optical cylinder following osteo-keratoprosthesis or osteo-odonto-keratoprosthesis (O/OKP) procedures in four patients., Methods: In this retrospective observational study, we reviewed all patients who underwent O/OKP in our tertiary medical centre. We found four patients in whom a protective cellphone silicone shield (VisionGuard + , Zagg, Utah, USA) was cut with a 3 mm dermal punch and placed on the polymethyl methacrylate (PMMA) optical cylinder of an O/OKP 3-4 months after implantation to either correct or prevent abrasions., Results: The first patient presented with a severely abraded OOKP optic that reduced BCVA from 6/6 to 6/20. The shield smoothed the optical surface and filled minor scratches, leading to BCVA improvement to 6/9. In the subsequent three patients, the optic was relatively clear, and the shield was used as a preventive measure. In two patients, the shield fell off after a few weeks and was replaced., Conclusions: Placing a protective silicone shield on the optical cylinder of an O/OKP can prevent permanent abrasions and, in an already scratched polymethyl methacrylate (PMMA) optic cylinder, improve vision by smoothing the surface. This intervention can be clinically significant, considering that the optical cylinder cannot be removed after implantation., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Laryngeal chondroradionecrosis (LCRN) is a rare but severe complication of radiation therapy. The study aimed to review the management of LCRN and evaluate the clinical benefit of hyperbaric oxygen therapy (HBOT)., Methods: We retrospectively analyzed all radiation-induced LCRN patients between 2006 and 2019 at a tertiary medical center. Diagnosis was based on signs and symptoms of Chandler's classification, imaging, and/or histopathology report. The primary outcome was improvement in Chandler's grade after HBOT., Results: Of 678 irradiated laryngeal cancer patients, 29 (4.3%) were diagnosed with LCRN. The most common primary management was tracheostomy with intravenous steroids and antibiotics (59%). Ten patients received HBOT (34.5%), and six underwent total laryngectomy (21%). In HBOT-treated patients, Chandler's grade significantly improved from a median of 4 (range 2-4) to 2.5 (range 1-4; p = 0.005)., Conclusions: HBOT may benefit in the management of patients with persistence and unresponsive symptoms of LCRN following radiation therapy for laryngeal SCC., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Objective: Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls., Design: A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel., Methods: Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event., Results: A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9-20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44-2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies., Conclusion: Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population., Competing Interests: Conflict of Interest: Yaron Rudman, Laura Dery, Hiba Masr-Iraqi, Liat Sasson, Tzipora Shochat, and Shiri Kushnir do not have any financial or personal relationships with other people or organizations to disclose. Amit Akirov has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm. Maria Fleseriu has been a PI with research funding from the university and has received occasional scientific fee for scientific consulting and advisory boards from Crinetics, Recordati, Sparrow, and Xeris. Ilan Shimon has been an investigator for Xeris Biopharma and has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The third stage of labor is a pivotal phase in obstetric care. Management may be physiological or active. Although the use of prophylactic placental cord drainage has been assessed in prior data, there is still no clear-cut evidence supporting its effectiveness in improving key obstetric outcomes., Objective: The aim of the study was to investigate the impact of placental cord drainage during the third stage of labor on the amount of maternal bleeding, duration of the third stage, and incidence of postpartum hemorrhage., Study Design: A randomized controlled trial was conducted at a high-volume tertiary obstetric center between May 2021 and December 2022. A total of 212 pregnant women with a singleton uncomplicated pregnancy were randomly assigned to undergo placental cord drainage or standard care without drainage. The randomization was manual, using premarked cards drawn by the participants. The power calculation determined a sample size of 92 participants per group to achieve 80% power at a 5% significance level, aiming to detect 20% difference in bleeding amount between the groups. In practice, we included more than 100 women in each group. The primary outcome was the amount of bleeding during the third stage of labor, while secondary outcomes included the duration of the third stage and incidence of postpartum hemorrhage. After delivery, all participants received 10 units of oxytocin via intravenous drip, and delayed cord clamping was performed. In the study group, the maternal umbilical cord was then unclamped. Blood was allowed to drain into a plastic bag placed under the women's buttocks. If an episiotomy or perineal tear was observed, pressure packing was applied to reduce bleeding. The collected blood was measured in milliliters after placental expulsion., Results: A total of 212 women were recruited of whom 104 underwent placental cord drainage and 108 received standard care without drainage. No significant differences were observed between the intervention and control groups in mean duration of the third stage of labor (10.56±6.12 vs 10.95±6.33 minutes, P=.65), incidence of postpartum hemorrhage (3.84% vs 7.41%, P=.38), or mean amount of bleeding during the third stage of labor (292±200 vs 300±242 mL, P=.79). Furthermore, there were no significant between-group differences in the mean amount of bleeding on separate analysis of nulliparous women (356±246 vs 330±240 mL, P=.68), multiparous women (265±171 vs 289±244 mL, P=.50), women who were not exposed to external oxytocin during labor (287±204 vs 317±250 mL, P=.59), and women who were exposed to external oxytocin (296±198 vs 289±238 mL, P=.39)., Conclusion: Placental cord drainage during the third stage of labor showed no statistically significant impact on bleeding amount, third-stage length, or postpartum hemorrhage rate. The findings suggest that placental cord drainage may not offer additional benefits in preventing postpartum hemorrhage in women with uncomplicated pregnancies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The study aimed to identify factors affecting the management and prognosis of iatrogenic cervical oesophageal and hypopharyngeal perforations (iCEHPs)., Methods: We retrospectively analysed 24 patients treated for iCEHP between 2004 and 2021 at a tertiary university medical centre. Data on demographics, clinical features, imaging, management and outcomes were collected. Factors associated with primary management and patient outcome were assessed., Results: The most common management approach was surgical neck exploration (15 patients, 62.5%). Surgical management was used in 93% of uncontained perforations compared to 11% of contained perforations (p < 0.001). Surgically-treated patients had higher levels of C-reactive protein (CRP) than conservatively-treated patients (median, 18.3 vs 4.8 mg/dL; p = 0.001). Delayed diagnosis (≥ 24 hours) was associated with increased mortality (100 vs 5%; p = 0.011). The mortality rate was significantly higher in patients who had a history of neck irradiation than in patients who did not (67 vs 5%; p = 0.032)., Conclusions: Early diagnosis of iCEHP improves outcomes. The appropriate management should be carefully selected on the basis of CRP level and imaging findings. Prior neck radiation is a poor prognostic factor., (Copyright © 2024 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: COVID-19 infection and immunizations have been implicated in developing a range of thyroid diseases, including subacute thyroiditis (SAT). This study aimed to evaluate the association between COVID-19 infection and/or COVID-19 vaccination with SAT., Methods: A population of 3 million adults insured by Clalit Health Services was evaluated from March 2020 to September 2022. Patients with a new diagnosis of SAT were identified and matched in a 1:10 ratio to a control group. Each control was assigned an index date that was identical to that of their matched case, defined as the date of SAT diagnosis. Multivariate conditional logistic regression models were used to evaluate the association between COVID-19 infection, vaccine, and thyroiditis., Results: A total of 3221 patients with SAT were matched with 32 210 controls. Rates of COVID-19 vaccination (first, second, or third dose) and COVID-19 infection were evaluated prior to the date of SAT diagnosis (disease group) or index date (control group) to detect a possible association. No difference was detected between the groups in relation to vaccinations at the 30 days, 60 days, and 90 days of time points (P = .880/0.335/0.174, respectively). No difference was found between groups in relation to COVID-19 infection at these time points (P = .735/0.362/0.956, respectively). There was higher use of medications for the treatment of thyroiditis, including nonsteroidal anti-inflammatory drugs (28.6% vs 7.9%, P < .01), steroids (10.3% vs 1.8%, P < .01), and beta-blockers (18.3% vs 5.4%, P < .01)., Conclusion: Based on this large population study, no association was found between COVID-19 infection and/or the COVID-19 vaccine and SAT., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction: Kidney perfusion on CT is an encouraging surrogate for renal scintigraphy in assessing renal function. However, data on dynamic volumetric CT in patients with kidney obstruction is lacking. Thus, the aim of this study is to determine the feasibility of CT-based renal perfusion using a dynamic volume to assess renal hemodynamics at different degrees and durations of obstruction., Materials and Methods: We included patients with unilateral kidney obstruction in our single-center, prospective study. The patients were divided into three groups. Patients without dilatation of the pelvicalyceal system (PCS) and normal parenchyma thickness were included into Group 1; patients with PCS dilatation and parenchyma thickness 1.8-2.4 cm-into Group 2; and patients with ureteropyelocalicoectasia and parenchyma thickness less than 1.8 cm-into Group 3., Results: Total of 56 patients were enrolled. In Group 1 mean values of cortical and medullar arterial blood flow, blood volume, and extraction fraction were within the normal range. Changes in contralateral kidney were not determined. Patients from Group 2 showed significant differences in blood flow parameters in the cortical and medulla of the obstructed kidney. No changes in perfusion values in the contralateral kidney was observed. In patients from Group 3 there was a marked decrease in perfusion on the side of obstruction compared to Group 2, indicating that the degree of expansion of the PCS directly correlates with the change in blood flow. However, in the contralateral kidney, these indicators exceeded the normal values of perfusion., Conclusion: CT perfusion allows to objectively assess changes in blood flow in the setting of renal obstruction. The degree of obstruction directly affects the measured rate of blood flow., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose of Review: The use of noninvasive techniques [noninvasive ventilation (NIV) or high flow nasal cannula (HFNC) oxygen therapy] to support oxygenation and/or ventilation in patients with respiratory failure has become widespread, even more so since the coronavirus disease 2019 pandemic. The use of these modalities may impair the patient's ability to eat. "To breath or to eat" may become a dilemma. In this review, we identify the patients at risk of malnutrition that require medical nutritional therapy and understand the mechanisms of function of the devices to better give adapted nutritional indications for noninvasive ventilation or high flow nasal cannula., Recent Findings: The Global Leadership Initiative for Malnutrition has been validated in the Intensive Care setting and can be used in patients requiring NIV. Many patients are underfed when receiving noninvasive ventilation therapies. HFNC may impair the swallowing ability and increase dysphagia while NIV may improve the swallowing reflexes. New technology preventing reflux and ensuring enteral feeding efficacy may increase the medical nutrition therapy safety and provide near-target energy and protein provision., Summary: The patient requiring noninvasive ventilation presents one of the most challenging nutritional challenges. The main steps to improve nutrition administration are to assess nutritional status, evaluate the presence of dysphagia, choose the most adequate tool of respiratory support, and adapt nutritional therapy (oral, enteral, or parenteral) accordingly., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Single-nucleotide variants (SNVs) are of great significance in prenatal diagnosis as they are the leading cause of inherited single-gene disorders (SGDs). Identifying SNVs in a non-invasive prenatal screening (NIPS) scenario is particularly challenging for maternally inherited SNVs. We present an improved method to predict inherited SNVs from maternal or paternal origin in a genome-wide manner., Methods: We performed SNV-NIPS based on the combination of fragments of cell free DNA (cfDNA) features, Bayesian inference and a machine-learning (ML) prediction refinement step using random forest (RF) classifiers trained on millions of non-pathogenic variants. We next evaluate the real-world performance of our refined method in a clinical setting by testing our models on 16 families with singleton pregnancies and varying fetal fraction (FF) levels, and validate the results over millions of inherited variants in each fetus., Results: The average area under the ROC curve (AUC) values are 0.996 over all families for paternally inherited variants, 0.81 for the challenging maternally inherited variants, 0.86 for homozygous biallelic variants and 0.95 for compound heterozygous variants. Discriminative AUCs were achieved even in families with a low FF. We further investigate the performance of our method in correctly predicting SNVs in coding regions of clinically relevant genes and demonstrate significantly improved AUCs in these regions. Finally, we focus on the pathogenic variants in our cohort and show that our method correctly predicts if the fetus is unaffected or affected in all (10/10, 100%) of the families containing a pathogenic SNV., Conclusions: Overall, we demonstrate our ability to perform genome-wide NIPS for maternal and homozygous biallelic variants and showcase the utility of our method in a clinical setting., (© 2024 John Wiley & Sons Ltd.)

Mutated skeletal muscle ryanodine receptor-1 (RYR1) gene is associated with a spectrum of autosomal dominant and recessive RyR1-related disorders with a wide phenotype. This report describes a variable phenotype associated with a previously unreported RYR1 frameshift pathogenic variant, (NM&#95;000540.2) c.12815&#95;12825del; p.Ala4272Glyfs*307, common in Libyan Jews. Clinical and genetic features of 14 carriers from 8 unrelated families were collected. There were 12 heterozygotes and 2 compound heterozygotes. Six heterozygotes (median age 49.8) were asymptomatic, and six (median age 24.5) presented with myopathy (n = 3) or severe arthrogryposis-like features, severe scoliosis, pes planus, post-anesthesia malignant hyperthermia, or cystic hygroma (in a fetus) (n = 1 each). None had an abnormal echocardiogram study or elevated creatine phosphokinase (CPK) levels. One bi-allelic carrier had a severe skeletal phenotype and myopathy; the other was a fetus with a cystic hygroma. Assessment of variant frequency in 447 Libyan Jews who underwent exome testing for unrelated reason yielded a prevalence of 1:55. The RYR1 p.Ala4272Glyfs*307 variant is common in Libyan Jews. It is associated with a broad phenotypic spectrum, with possible presentation among heterozygotes. Further genotype-phenotype studies are essential to delineate the clinical significance of the variant in mono- and bi-allelic carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To determine whether equivocal prelabor rupture of membranes (PROM) cases are associated with adverse outcomes., Methods: A retrospective study was conducted in a tertiary medical center between July 2012 and March 2022. The cohort comprised all women diagnosed with term PROM (≥37 gestational weeks), divided into two groups. (1) Certain PROM-suggestive history of a watery vaginal discharge confirmed by visualization of fluid leaking from the cervix or pooling in the vagina on speculum examination. (2) Uncertain PROM-suggestive history of a watery vaginal discharge not supported by speculum examination. All patients were hospitalized and gave birth spontaneously or following either expectant management for up to 24 h from PROM or induction. The primary outcome measure was cesarean delivery (CD) rate. Secondary outcome measures were adverse maternal/neonatal events., Results: Of the 2012 women included in the study, 1750 had certain PROM and 262 uncertain PROM. CD rate was 5.8% in the certain PROM group and 8.8% in the uncertain PROM group; the difference was not statistically significant (P = 0.074). There was a significant between-group difference in the rate of CD due to failed induction on univariate analysis (0.69% vs 2.67%, respectively, P = 0.007), but it was not maintained on multivariate logistic regression (odds ratio 0.37, 95% confidence interval: 0.12-1.17). Other maternal and neonatal outcomes were similar in the two groups., Conclusion: Our findings indicate that following the same management guidelines for equivocal cases of ruptured membranes as for confirmed cases of term PROM did not compromise maternal or fetal outcomes., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: Laryngeal squamous cell carcinoma (SCC) is a predominantly male illness. Although the rate of female patients increased, a knowledge gap exists in the medical literature regarding gender-based differences., Design: Retrospective cohort study., Setting: Adult patients treated for laryngeal SCC in a tertiary medical centre between 2006 and 2020. Data were collected on demographics, clinical presentation, treatment modalities, disease recurrence and survival status., Participants: Two hundred ninety-one patients with laryngeal SCC, 50 (17.2%) females and 241 (82.8%) males., Main Outcome Measures: Disease-specific survival (DSS), overall survival (OS) and disease-free survival (DFS), as well as differences in disease characteristics and treatment modalities., Results: Tumour subsites differed significantly between females and males (36% vs. 19.5% supraglottic, 62% vs. 80.5% glottic and 2% vs. 0% subglottic, respectively; p = 0.006). Females were diagnosed at younger ages (61.7 ± 10.58 vs. 65.87 ± 11.11 years, p = 0.016) and advanced-stage disease (58% vs. 39.4%, p = 0.018). Females were treated with combined modalities at higher rates (36% vs. 54.8% for single modality, p = 0.031). DSS rates did not differ between genders (log-rank p = 0.12). Despite being diagnosed at more advanced disease stages, females demonstrated prolonged median OS compared to males (130.17 vs. 106.17 months, log-rank p = 0.017). No significant differences in DFS were observed (log-rank p = 0.32). In a multivariate Cox proportional hazards model, male gender remained an independent negative OS predictor (HR = 2.08; CI, 1.10-3.96; p = 0.025), along with increasing age (HR = 1.06; CI, 1.04-1.09; p < 0.001) and advanced disease stage (HR = 1.7; CI, 1.08-2.67; p = 0.023)., Conclusions: Our findings suggest the importance of considering gender-specific factors in the management of laryngeal SCC., (© 2024 The Author(s). Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Background: Advances in medicine have enabled more patients with congenital heart disease (CHD) to become pregnant. However, these patients face significant challenges during the peripartum period. Current peripartum anesthesia guidelines for CHD patients mainly rely on case reports and small series., Methods: In this retrospective study at a high-volume tertiary care center, we analyzed peripartum anesthetic approaches, postpartum hemorrhage (PPH) incidence, and maternal outcomes in CHD patients stratified by the modified World Health Organization (mWHO) classification., Results: Among 85 473 deliveries between 2009 and 2023, 409 occurred in 282 patients with CHD. Cesarean deliveries were significantly more frequent in mWHO class III, p=0.005. Labor epidural analgesia was the most common analgesic modality for vaginal deliveries (epidural rate was 71.1% with no differences between mWHO classes). Anesthesia management for cesarean deliveries varied significantly by class p<0.001. While spinal anesthesia was predominant in classes I and II, combined spinal-epidural anesthesia was more common in class III. PPH incidence was 6.4%, with no significant difference across classes, and no association was found between mWHO class severity and PPH risk (OR 0.97; 95% CI; 0.93 to 1.02, p=0.2). Higher mWHO classes correlated with significantly higher intensive care unit (ICU) admission rates, longer hospital stays, and one-year cardiac hospitalizations., Conclusion: In this retrospective study on the peripartum anesthetic management and outcomes of CHD patients stratified by mWHO class, cases with greater mWHO class were more likely to deliver preterm, by cesarean delivery, with a combined spinal-epidural anesthetic and an arterial line placement for that cesarean delivery. They overall had a longer hospital stay and were more likely to be admitted to the ICU. However, the overall risk of PPH did not increase with mWHO class severity., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14-4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07-2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management., (© 2024. The Author(s).)

Most oncology trials define superiority of an experimental therapy compared to a control therapy according to frequentist significance thresholds, which are widely misinterpreted. Posterior probability distributions computed by Bayesian inference may be more intuitive measures of uncertainty, particularly for measures of clinical benefit such as the minimum clinically important difference (MCID). Here, we manually reconstructed 194,129 individual patient-level outcomes across 230 phase III, superiority-design, oncology trials. Posteriors were calculated by Markov Chain Monte Carlo sampling using standard priors. All trials interpreted as positive had probabilities > 90% for marginal benefits (HR < 1). However, 38% of positive trials had ≤ 90% probabilities of achieving the MCID (HR < 0.8), even under an enthusiastic prior. A subgroup analysis of 82 trials that led to regulatory approval showed 30% had ≤ 90% probability for meeting the MCID under an enthusiastic prior. Conversely, 24% of negative trials had > 90% probability of achieving marginal benefits, even under a skeptical prior, including 12 trials with a primary endpoint of overall survival. Lastly, a phase III oncology-specific prior from a previous work, which uses published summary statistics rather than reconstructed data to compute posteriors, validated the individual patient-level data findings. Taken together, these results suggest that Bayesian models add considerable unique interpretative value to phase III oncology trials and provide a robust solution for overcoming the discrepancies between refuting the null hypothesis and obtaining a MCID.

Targeted gene panel sequencing is used to limit the search for causative genetic variants solely to genes with an established association with the phenotype. The design of gene panels is challenging due to the lack of consensus regarding phenotypic associations for some genes, which results in high variation in gene composition for the same panel offered by different laboratories. We developed PANGEN, a platform that provides a centralized resource for gene panel information, with the ability to compare and generate new intelligent diagnostic panels. Gene-phenotype associations were collected from 12 public and commercial sources (Blueprint, Cegat, Centogene, ClinGen, Fulgent, GeneDx, Health in Code, Human Phenotype Ontology, Invitae, PanelApp, Prevention genetics, and Pronto diagnostics). Gene-phenotype associations are categorized into tiers according to categories derived from the original source panel. Pairwise panel similarity was calculated by dividing the number of common genes by the total number of genes in both panels. Regions with extreme guanine-cytosine (GC) content were collected from the Genome in a Bottle stratifications dataset, and putative genomic duplications were retrieved from the University of Santa Cruz database. Overall, 1533 panels, 9759 phenotypes, and 6979 genes were collected. The platform provides an interface to (i) explore and compare collected panels, (ii) find similar panels, (iii) identify genes with high GC content or duplication levels, (iv) generate gene panels by combining panels from various sources, and (v) stratify a generated panel into genes with a strong phenotype association ('core') and those with a weaker association ('extended'). The presented platform represents a unique resource for gene panel exploration and comparison that facilitates the generation of tailored diagnostic panels through a public online web server. Database URL: https://c-gc.shinyapps.io/PANGEN/., (© The Author(s) 2023. Published by Oxford University Press.)

Covid-19 disease is implicated in increased mortality among immunocompromised patients. The JAK inhibitor, baricitinib (bar), or the IL-6 inhibitor, tocilizumab (toc), demonstrated a survival benefit in patients with severe disease.However, evidence supporting their use in immunocompromised patients with severe Covid-19 is scarce.We aimed to assess clinical outcomes of bar/toc treatment in immunocompromised patients. A multi-center registry of consecutive immunocompromised patients hospitalized due to severe Covid-19 during the Omicron variant dominance period. After excluding patients who did not require high oxygen supply, patients treated with bar/toc were compared to patients treated by standard of care (SOC). Primary outcome was in hospital mortality. Secondary outcomes were 30 and 60 day mortality, super-infection and thromboembolic events. Among an overall 228 immunocompromised patients hospitalized in six Israeli hospitals with severe Covid-19, 112 patients required high oxygen support, of whom 48 (43%) were treated with bar/toc. In-hospital mortality rates were exceptionally high and did not significantly differ between bar/toc and SOC treated patients (62.5% vs. 64.1%, p = 1.0). A logistic regression analysis revealed that advanced age and incomplete vaccination were predictors of in-hospital mortality. Patients treated with bar/toc had no excess of suspected super-infection (62.8% vs. 60.7%, p = 0.84) or thromboembolic events (8.3% vs 3.1%, p = 0.39). In immunocompromised patients with severe Covid-19 and a high oxygen demand, bar/toc therapy was not associated with reduced mortality or with a higher rate of associated complications, compared to SOC. Larger prospective studies should better address efficacy and safety., (© 2024. The Author(s).)