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Aim: This retrospective study aimed to assess the efficacy of prophylactic antibiotics in preventing ascending cholangitis following Kasai portoenterostomy (KPE). Data from 72 patients treated across four tertiary centres in Israel from 2008 to 2018 were analysed., Methods: Clinical and laboratory data were collected from biliary atresia (BA) diagnosis until liver transplantation (LT) or study completion., Results: Median age at KPE was 58.5 days. Successful KPE was achieved in 23 (32%) patients. Ascending cholangitis occurred in 6/23 (26%) successful KPE cases and 15/45 (33%) unsuccessful cases. Primary antibiotic prophylaxis (49% of patients) was associated with earlier onset of cholangitis (median 77 vs 239 days, p = 0.016). During follow-up, 39% underwent LT, with a 5-year survival with native liver (SNL) of 54%., Conclusion: Prophylactic antibiotics did not reduce cholangitis rates post-KPE in our cohort. Further research is essential to optimise management strategies for infants with BA., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose: To assess the risk for pseudophakic cystoid macular oedema (PCME) and posterior capsular opacification (PCO) associated with combined cataract surgery and trabeculectomy compared to cataract surgery alone., Methods: Data analysis of subjects who underwent routine cataract surgery without and with concomitant trabeculectomy at the Department of Ophthalmology, Bristol Eye Hospital, the UK, between January 2008 and December 2017. Odds ratios (ORs) for PCME between the types of surgeries were calculated using univariate and multivariate regression analysis. Multivariate Cox regression controlling for age and gender was used to estimate the hazard ratio (HR) for neodymium-doped yttrium aluminium garnet (Nd:YAG) laser capsulotomies., Results: This study included 56 973 cataract surgeries without and 288 with concomitant trabeculectomy (phaco-trab) with a mean follow-up time of 6.9 ± 4.2 years. Baseline variables (age and gender, diabetes, pseudoexfoliation, use of pupil expansion device and postoperative follow-up time) were comparable between the groups. Postoperative rates of PCME remained non-significant between the cataract surgery and phaco-trabe groups both in uni- and multi-variate analysis (OR 0.347, 95%CI 0.049-2.477, p = 0.291). Furthermore, in Cox regression analysis adjusted for the patients' age and gender, Nd:YAG laser capsulotomy rates remained non-significant between the cataract surgery and phaco-trabe groups (HR 1.250, 95%CI 0.883-1.769, p = 0.209)., Conclusions: In our large cohort study, combining trabeculectomy with cataract surgery did not predispose to an increased PCME or Nd:YAG laser capsulotomy rates., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: A significant percentage of patients with congenital heart disease surviving into adulthood will develop arrhythmias. These arrhythmias are associated with an increased risk of adverse events and death. We aimed to assess arrhythmia prevalence, risk factors, and associated health care usage in a large national cohort of patients with adult congenital heart disease., Methods and Results: Adults with a documented diagnosis of congenital heart disease, insured by Clalit and Maccabi health services between January 2007 and December 2011, were included. We assessed the associations between arrhythmia and subsequent hospitalization rates and death with mixed negative binomial and Cox proportional hazard models, respectively. Among 11 653 patients with adult congenital heart disease (median age, 47 years [interquartile range, 31-62]), 8.7% had a tachyarrhythmia at baseline, 1.5% had a conduction disturbance, and 0.5% had both. Among those without a baseline arrhythmia, 9.2% developed tachyarrhythmias, 0.9% developed a conduction disturbance, and 0.3% developed both during the study period. Compared with no arrhythmia (reference group), arrhythmia in the previous 6 months was associated with a higher multivariable adjusted hospitalization rate, 1.33-fold higher than the rate of the reference group (95% CI, 1.00-1.76) for ventricular arrhythmia, 1.27-fold higher (95% CI, 1.17-1.38) for atrial arrhythmias, and 1.33-fold higher (95% CI, 1.04-1.71) for atrioventricular block. Atrial tachyarrhythmias were associated with an adjusted mortality hazard ratio (HR) of 1.65 (95% CI, 1.44-2.94), and ventricular tachyarrhythmias with a >2-fold increase in mortality risk (HR, 2.06 [95% CI, 1.44-2.94])., Conclusions: Arrhythmias are significant comorbidities in the adult congenital heart disease population and have a significant impact on health care usage and survival.

Background: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited., Aims: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity., Methods: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE., Results: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01)., Conclusion: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing., (© 2024 John Wiley & Sons Ltd.)

Background: The leading causes of maternal mortality include respiratory failure, cardiovascular events, infections, and hemorrhages. The use of extracorporeal membrane oxygenation (ECMO) as rescue therapy in the peripartum period for cardiopulmonary failure is expanding in critical care medicine., Methods: This retrospective observational study was conducted on a nationwide cohort in Israel. During the 3-year period, between September 1, 2019, and August 31, 2022, all women in the peripartum period who had been supported by ECMO for respiratory or circulatory failure at 10 large Israeli hospitals were identified. Indications for ECMO, maternal and neonatal outcomes, details of ECMO support, and complications were collected., Results: During the 3-year study period, in Israel, there were 540 234 live births, and 28 obstetric patients were supported by ECMO, with an incidence of 5.2 cases per 100 000 or 1 case per 19 000 births (when excluding patients with COVID-19, the incidence will be 2.5 cases per 100 000 births). Of these, 25 were during the postpartum period, of which 16 (64%) were connected in the PPD1, and 3 were during pregnancy. Eighteen patients (64.3%) were supported by V-V ECMO, 9 (32.1%) by V-A ECMO, and one (3.6%) by a VV-A configuration. Hypoxic respiratory failure (ARDS) was the most common indication for ECMO, observed in 21 patients (75%). COVID-19 was the cause of ARDS in 15 (53.7%) patients. The indications for the V-A configuration were cardiomyopathy (3 patients), amniotic fluid embolism (2 patients), sepsis, and pulmonary hypertension. The maternal and fetal survival rates were 89.3% (n = 25) and 100% (n = 28). The average ECMO duration was 17.6 ± 18.6 days and the ICU stay was 29.8 ± 23.8 days. Major bleeding complications requiring surgical intervention were observed in one patient., Conclusions: The incidence of using ECMO in the peripartum period is low. The maternal and neonatal survival rates in patients treated with ECMO are high. These results show that ECMO remains an important treatment option for obstetric patients with respiratory and/or cardiopulmonary failure., (© 2023 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m 2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Curcumin and QingDai (QD, Indigo) have been shown to be effective for treating active ulcerative colitis (UC)., Aim: To evaluate the real-world experience with the Curcumin-QingDai (CurQD) herbal combination to induce remission in active UC., Methods: A retrospec-tive multicentre adult cohort study from five tertiary academic centres (2018-2022). Active UC was defined as a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3. Patients were induced by CurQD. The primary outcome was clinical remission at weeks 8-12, defined as SCCAI ≤2 and a decrease ≥3 points from baseline. Secondary outcomes were clinical response (SCCAI decrease ≥3 points), corticosteroid-free remission, faecal calprotectin (FC) response (reduction ≥50%), FC normalisation (FC ≤100 μg/g for patients with FC ≥300 μg/g at baseline), and safety. All outcomes were analysed for patients who were maintaining stable treatment., Results: Eighty-eight patients were included; 50% were biologics/small molecules experienced, and 36.5% received ≥2 biologics/small molecules. Clinical remission was achieved in 41 (46.5%), and clinical response in 53 (60.2%). Median SCCAI decreased from 7 (IQR:5-9) to 2 (IQR:1-3); p < 0.0001. Of the 26 patients on corticosteroids at baseline, seven achieved corticosteroid-free remission. Among 43 biologics/small molecules experienced patients, clinical remission was achieved in 39.5% and clinical response in 58.1%. FC normalisation and response were achieved in 17/29 and 27/33, respectively. Median FC decreased from 1000 μg/g (IQR:392-2772) at baseline to 75 μg/g (IQR:12-136) at the end of inductions (n = 30 patients with paired samples); p < 0.0001. No overt safety signals emerged., Conclusion: In this real-world cohort, CurQD effectively induced clinical and biomarker remission in patients with active UC, including patients who were biologics/small molecules experienced., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aim: To investigate the potential benefits of medical clowns (MCs) in reducing anxiety and pain during paediatric urinary catheter insertion., Methods: In this prospective pilot study, 51 children who required urinary catheter insertion were randomised into two groups; the first group (n = 29) underwent the procedure in the presence of a MCs, and the second control group (n = 22) underwent the procedure using sedation. Pain and anxiety levels as well as procedural duration were recorded. All procedures were filmed and evaluated for anxiety level by a paediatric psychiatrist. General satisfaction questionnaires were filled by the medical team and parents in the clown group., Results: There were no differences in pain scores or anxiety levels between the two groups. Procedure duration and total hospital stay were significantly shorter in the MC group (p < 0.001). One hundred percent of the parents and the medical team were in favour of incorporating MCs during urinary catheter insertion., Conclusion: MCs are as good as sedation in lowering anxiety and pain levels in children undergoing urinary catheter insertion. In addition, MCs reduce the duration of the procedure and elicit a high degree of overall satisfaction from the parents and medical team., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Since the early 1970s, the treatment of acute myeloid leukaemia (AML) has undergone a major transformation. Initially based on only two drugs, an anthracycline and cytosine arabinoside, the aim of therapy was to achieve a haematological response allowing patients to recover and go home. Back in those early days, cure was not a realistic expectation. Treatment was analogous to a heart attack; upon recovery and a short respite, recurrence and death inevitably followed. Over the subsequent decades, slow but remarkable progress was made such that a subgroup of young adults could become long-term survivors. This astonishing feat was achieved initially without the use of new drugs. Supportive care played a major role with the widespread availability of platelet transfusions and improved antimicrobial therapy, particularly antifungal. No less important was the better use of existing drugs and the development of allogeneic haematopoietic cell transplantation. While initially the focus was on maximal tolerated therapy, an understanding of the immunologic role of allogeneic transplantation, better genetic characterization of the biology of the disease, advanced tools for detection of minimal disease as well as the recent development of new drugs changed the focus to a more refined approach targeting patients who are more likely to respond. Clearly, the historical paradigm where the term AML was generic and applicable to all patients requires a rethinking from the traditional therapeutic demarcations of therapy into phases of induction, consolidation and maintenance. These evolving new concepts and paradigm will be herein considered., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Belantamab mafodotin, an immuno-conjugate targeting B-cell maturation antigen, showed single-agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real-world data and long-term follow-up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One-hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2-11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow-up time was 11.9 [95% confidence interval (CI) 10.0-13.8] months. Overall response rate was 45.5%. Median progression-free survival was 4.7 (95% CI 3.5-5.9) months in the entire cohort and 8.8 (95% CI 6.6-10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5-19.6) months, and not reached for responders. To conclude, in a real-world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Women with inflammatory bowel diseases (IBD) often receive biologics to maintain remission during pregnancy., Aims: To assess maternal and neonatal outcomes in patients with IBD treated with ustekinumab (UST) during pregnancy METHODS: In a multicentre, prospective cohort study, we recruited women with IBD treated with UST during pregnancy between 2019 and 2021. Outcomes were compared among patients treated with UST, anti-tumour necrosis factor α, (anti-TNF) and non-UST, non-anti-TNF therapies. UST-treated patients were matched 1:2 to controls according to age, body mass index and parity. Newborns were followed up to 12 months., Results: We recruited 129 pregnant patients: UST 27; anti-TNF 52; non-UST, non-anti-TNF 50 (thiopurine or mesalazine 30, no therapy 20); Crohn's disease 25 (96.9%). Overall, pregnancy, neonatal and newborn outcomes were satisfactory, with no significant differences among patients treated with UST, anti-TNF and non-UST non-anti-TNF agents for obstetrical maternal complications [UST 3 (11.5%), anti TNF 12 (23.1%), non UST, non-anti-TNF 4 (8.2%), p = 0.095], pre-term delivery [1 (4.3%), 9 (18.4%), 4 (5.7%), p = 0.133], low birth weight [1 (4.2%), 5 (10.2%), 4 (8.3%), p = 0.679], or first year newborn hospitalisation [2 (9.1%), 4 (8.2%), 3 (6.1%), p = 0.885]., Conclusion: Pregnant patients with IBD treated with UST demonstrated favourable pregnancy and neonatal outcomes that were comparable with those in patients treated with anti-TNF or other therapy. Data are reassuring for patients with IBD and their physicians when considering UST during pregnancy., (© 2022 John Wiley & Sons Ltd.)

Objective: Ashkenazi-Jewish (AJ) population-based BRCA testing is acceptable, cost-effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long-term results of population-based BRCA testing on lifestyle behaviour and cancer risk perception., Design: Two-arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population-screening (PS); (b) family history (FH)/clinical criteria testing., Setting: North London AJ-population., Population/sample: AJ women/men >18 years., Exclusions: prior BRCA testing or first-degree relatives of BRCA-carriers., Methods: Participants were recruited through self-referral. All participants received informed pre-test genetic counselling. The intervention included genetic testing for three AJ BRCA-mutations: 185delAG(c.68&#95;69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1-year/2-year/3-year follow-ups. Generalised linear-mixed models adjusted for covariates and appropriate contrast tests were used for between-group/within-group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P < 0.0039 considered significant., Outcome Measures: Lifestyle/behavioural outcomes at baseline/1-year/2-year/3-year follow-ups., Results: 1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS- and FH-based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA-negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P < 0.001)., Conclusion: Population-based and FH-based AJ BRCA testing have similar long-term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria., Aim: To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug., Methods: We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery., Results: We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups., Conclusion: Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Infantile Krabbe disease (OMIM 245200) is a severe, fatal autosomal recessive neurodegenerative disorder that is relatively frequent in two Muslims villages within Jerusalem. After the characterization of the founder mutation, a population carrier screening for Krabbe disease became a component of the Israeli program for the detection and the prevention of birth defects. Between 2010 and 2018, 3366 individuals were tested and among them 247 carriers for Krabbe disease were identified (7.3%). Most of the 21 carrier couples identified that had pregnancies after being informed that they were at risk used preventive measures including termination of pregnancies of affected fetuses. During the study period, eight children affected with Krabbe disease were born in the villages, four to couples not detected though the program. Twenty years after the beginning of the carrier screening program, Krabbe disease remained relatively frequent in the villages. The establishment of a genetic clinic in the villages may allow to improve the carrier screening program while giving individual counseling for the risk to the other genetic diseases existing in the villages., (© 2022 Wiley Periodicals LLC.)

Background: The association between COVID-19 infection and the cardiovascular system necessitates the use of an echocardiogram in this setting. Information on the utilization, safety, and quality of point-of-care cardiac and lung ultrasound using a hand-held device in these patients is scarce., Aims: To investigate the safety, technical aspects, quality indices, and interpretive accuracy of a hand-held echocardiogram in patients with COVID-19., Methods: From April-28 through July-27, 2020, consecutive patients with COVID-19 underwent hand-held echocardiogram and lung ultrasound evaluation (Vscan Extend™; GE Healthcare) within 48-h of admission. The operators recorded a series of technical parameters and graded individual experiences. The examinations were further analyzed by a blinded fellowship-trained echocardiographer for general quality, proper acquisition, and right ventricular (RV) demonstration., Results: Among 103 patients, 66 (64.1%) were male. Twenty-nine (28.2%) patients could not turn on their left side and 23 (22.3%) could not maintain effective communication. The mean length of each echocardiogram study was 8.5 ± 2.9 min, battery usage was 14 ± 5%, and mean operator-to-patient proximity was 59 ± 11 cm. Ninety-five (92.2%) examinations were graded as fair/good quality. A fair agreement was demonstrated between the operator and the echocardiographer for general ultrasound quality (Kappa = 0.329, p < 0.001). A fair-good correlation (r = 0.679, p < 0.001) and substantial agreement (Kappa = 0.612, p < 0.001) were demonstrated between the operator and echocardiographer for left ventricular ejection fraction (LVEF), whereas a fair agreement was demonstrated for RV systolic function (Kappa = 0.308, p = 0.002). LVEF agreement was also assessed using the Bland-Altman analysis revealing a mean bias of -0.96 (95% limits of agreement 9.43 to -11.35; p = 0.075)., Conclusions: Among patients with COVID-19, echocardiography with a hand-held ultrasound is a safe and reasonable alternative for a complete formal study (<10% poor-quality indices). Echocardiogram assessment by the operators during the exam acquisition is reliable for LVEF, while RV systolic function should be subsequently offline reassessed., (© 2022 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Introduction: Cardiac output (CO) assessment in neonates is commonly done by echocardiography. It is unclear which is the best site to measure the left ventricular (LV) outflow tract for CO assessment (the aortic valve [AV] aortic sinus [AS] or the sinotubular junction [STJ]). In the normal heart, the blood flow entering the LV equals the blood ejected from it. Therefore, measuring the blood flow into the LV through the mitral valve (MV) is an alternative way to measure CO., Methods: In stable preterm infants the MV CO was compared with the right ventricular (RV) CO and the three ways to measure LV CO, in 30 stable preterm neonates. Interobserver variability for MV CO was established., Results: In the 30 neonates studied, MV CO was best correlated and had a minimal bias to the RV CO and LV CO measured at the STJ. Left ventricular CO measured at the AV and AS had significant bias relative to RV CO and MV CO. MV CO inter-observer variability was similar to other echocardiographic CO assessment methods., Conclusion: MV CO may be used as an alternative way to assess CO. The STJ may be the optimal site to measure LV outflow tract., (© 2022 Wiley Periodicals LLC.)

Objective: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing., Design: Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115)., Setting: London Ashkenazi-Jewish (AJ) population., Population or Sample: AJ men and women, >18 years., Methods: Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing., Main Outcome Measures: Interest, intention, uptake of BRCA testing., Results: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation., Conclusions: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations., Tweetable Abstract: Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations., (© 2021 John Wiley & Sons Ltd.)

Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS)/small patella syndrome (SPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three-generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung-specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651-C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans noncoding hypomorphic variants in the lung-specific enhancer of TBX4 contribute to LLDD., (© 2022 Wiley Periodicals LLC.)

Aim: We evaluated the prevalence of paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using antibody testing and characterised antibody titres by time from exposure., Methods: This was a single-centre, prospective, cross-sectional cohort study. Patients under 18 years old were eligible to participate if they attended the paediatric emergency department at the tertiary Shaare Zedek Medical Center, Jerusalem, Israel, from 18 October 2020 to 12 January 2021 and required blood tests or intravenous access. SARS-CoV-2 seropositivity and antibody levels were tested by a dual-assay model., Results: The study comprised 1138 patients (56% male) with a mean age of 4.4 years (interquartile range 1.3-11.3). Anti-SARS-CoV-2 antibodies were found in 10% of the patients. Seropositivity increased with age and 41% of seropositive patients had no known exposure. Children under 6 years of age had higher initial antibody levels than older children, followed by a steeper decline. The seropositivity rate did not vary during the study, despite schools re-opening. The findings suggest that children's immunity may start falling 4 months after the initial infection., Conclusion: Immunity started falling after just 4 months, and re-opening schools did not affect infection rates. These findings could aid decisions about vaccinating paediatric populations and school closures., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Combinations of the BCL-2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event-free survival (EFS) of 11.7 months (95% CI, 10.09-13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42-13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo-SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de-novo AML patients, and allo-SCT could be offered to selected patients achieving CR/CRi., (© 2021 Wiley Periodicals LLC.)

The emergence of the genetic counseling profession has allowed laypeople to understand and benefit from biological advances, and to make critical decisions about their application. The discipline of genetic counseling has been criticized from its very beginning, in particular because of its early association with the eugenics movement. This paper presents a critical and reflective overview of how genetic counseling is implicitly embedded in the history of eugenics but also counteracts past eugenic practices and ideas. After World War II, attempts were made to distance genetic counseling from eugenics. The first definition of genetic counseling did not position this field as a medical encounter but "as a kind of genetic social work aimed primarily to provide people with an understanding of their family's genetics problems." This approach was a reaction to the genetic and social evolutionary ideas that informed eugenic theories during the first half of the 20th century. Professionals engaged in genetic counseling during the 1940s and1950s rejected eugenic practices, but there was still support for eugenics' goals of improving heredity and eliminating disease. From the 1960s, genetic counseling underwent professionalization alongside feminization and a definition of core values. Among these values were nondirectiveness counseling and the autonomy of the counselee. The dark shadow of Nazi ideology and other eugenic practices, attempts to employ the historical responsibility of geneticists, and the dynamic medical, social, political, and educational changes of the 1960s and 1970s helped to frame approaches and delineate the goals and limits of the new profession of "genetic counseling.", (© 2021 John Wiley & Sons Ltd.)

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol., (© 2021 Wiley Periodicals LLC.)

Aim: We aimed at assessing the frequency of Community-acquired Methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, identifying its risk factors and evaluating resistance patterns of Staphylococcus aureus to various antibiotics in order to recommend the optimal empirical treatment for suspected Staphylococcus aureus infections., Methods: We reviewed the medical records of children who were treated at Shaare Zedek medical centre, located in Jerusalem, Israel, over the years 2008-2019 and had a positive culture for Staphylococcus aureus. Patients with CA-MRSA infections were compared with Methicillin-susceptible Staphylococcus aureus (CA-MSSA) infections., Results: In this study, 620 paediatric patients were included. The number of children in the CA-MRSA study group was 124, while the MSSA control group consisted of 496 children. Risk factors for CA-MRSA infections included young age (1-5 years), female sex, Arab ethnicity and residence in East Jerusalem. The incidence of CA-MRSA increased over the past decade, with an average of 11.2%. An increase in MSSA resistance to clindamycin was noted while Trimethoprim-Sulphamethoxazole resistance remained low., Conclusion: The incidence of CA-MRSA in Jerusalem was rising, along with changes in resistance patterns of both MSSA and MRSA to various antibiotic agents. In order to optimise empirical treatment for suspected staphylococcal infection, continued monitoring of CA-MRSA prevalence and resistance rates is essential., (©2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Physiological selection of spermatozoa for ICSI (PICSI) is a sperm selection method based on sperm binding to hyaluronic acid. Previous studies on the effect of hyaluronic acid binding assays on fertilization and embryo quality have shown inconsistent results. Previous sibling oocyte studies have not found a significant improvement in fertilization or embryo development with hyaluronic acid binding assays., Objective: To compare fertilization and embryo development between standard intracytoplasmic sperm injection (ICSI) and PICSI in sibling oocytes., Materials and Methods: This is a retrospective analysis of all in vitro fertilization (IVF) cycles between January 2017 and April 2020 in which sibling oocytes were randomly fertilized by both ICSI and PICSI. Fertilization rate and the rate of embryos eligible for transfer were compared., Results: Forty-five IVF cycles, in which 257 oocytes were fertilized with PICSI and 294 with standard ICSI, were compared. Most of the patients included in the study had previous failures of fertilization, poor embryonic development, implantation failure, or miscarriage. All but two of the patients had at least one previous unsuccessful IVF cycle. Both fertilization rates (71% vs. 83%) and transfer eligible embryo rates (38% vs. 51%) were significantly higher in PICSI fertilized oocytes (p = 0.008 and p = 0.01 respectively)., Discussion: Our study is the largest sibling oocyte study comparing ICSI and PICSI, and the first to find a significant improvement in fertilization and embryo quality with PICSI using sibling oocytes. The fact our cohort included almost exclusively couples with previous unsuccessful IVF cycles might suggest that PICSI should be used in selected cases., Conclusion: PICSI improves fertilization rates and transfer eligible embryo rates in sibling oocytes in a selected study group., (© 2021 American Society of Andrology and European Academy of Andrology.)

Hyperphagia leading to severe obesity with increased morbidity and mortality is the major manifestation of Prader-Willi syndrome. Caring for these individuals in a home environment is challenging and stressful for caregivers and families. Residential hostels specifically for PWS adults offer programs of diet, exercise, and vocational opportunities, but long-term effects of PWS hostel living have not been reported. We studied long-term changes in body mass index (BMI) for PWS adults living in residential hostels compared with age-matched controls living with families at home. The study included all 34 individuals (18 men) aged >17 years with genetically confirmed PWS living in residential hostels. BMI was recorded at the time of yearly clinic visits and compared to 23 PWS adults (10 men) living at home. BMI on entering the hostel was 36.3 ± 11.0 kg/m 2 and decreased to 27.0 ± 5.6 kg/m 2 (p < 0.001) after 6.9 ± 3.9 years. For 21 residents, a slight rise of BMI to 28.8 kg/m 2 was observed 5.1 ± 2.5 years after the lowest value was achieved. BMI of 23 PWS adults at home was 36.8 ± 12.7 kg/m 2 versus 27.9 ± 7.1 kg/m 2 for hostel residents in the same age range (p = 0.008). From 2008 to 2019, there were five deaths among PWS individuals aged 18-40 years living at home, compared with one death (a 43-year-old man) among hostel residents. Adults with PWS living in hostels lose weight, maintain BMI values in a normal to mildly overweight range, and have lower mortality in contrast to individuals in a family home environment., (© 2021 Wiley Periodicals LLC.)

Aim: To measure the prognostic value of C-reactive protein (CRP) and its ability to predict pneumonia-associated complications., Methods: A 3.75-years retrospective cohort analysis of all paediatric emergency department visits with a discharge diagnosis of pneumonia. Visits where CRP was not measured or with a discharge diagnosis of viral pneumonia were excluded. The following five outcomes were studied: hospitalisation, presence of parapneumonic effusion (PPE), placement of a chest drain, admission to paediatric intensive care unit (PICU) and bacteremia. A multivariate model was constructed and validated using k-fold cross-validation., Results: During the study time period, there were 2561 visits for pneumonia, of which 810 were included in our analysis. The median age of included children was 3.2 years (range 0.2-17.7). Overall, 38.8% visits ended in hospitalisation, 2.2% required admission to PICU, 15.2% were complicated by a PPE of which 28% required the placement of a chest drain. Statistically significant association was found between CRP levels and each of these outcomes (P < .001). Incorporating CRP within a multivariate prediction model provided an area under the curve of up to 0.96., Conclusion: CRP can be a useful prognostic marker when evaluating a patient with suspected bacterial pneumonia and could help the paediatrician in identifying patients needing closer follow-up., (© 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background Several studies have examined hospitalizations among patients with adult congenital heart disease (ACHD). Few investigated other services or utilization patterns. Our aim was to study service utilization patterns and predictors among patients with ACHD. Methods and Results We identified 11 653 patients with ACHD aged ≥18 years (median, 47 years), through electronic records of 2 large Israeli healthcare providers (2007-2011). The association between patient, disease, and sociogeographic characteristics and healthcare resource utilization were modeled as recurrent events accounting for the competing death risk. Patients with ACHD had high healthcare utilization rates compared with the general population. The highest standardized service utilization ratios (SSRs) were found among patients with complex congenital heart disease including primary care visits (SSR, 1.53; 95% CI, 1.47-1.58), cardiology outpatient visits (SSR, 5.17; 95% CI, 4.69-5.64), hospitalizations (SSR, 6.68; 95% CI, 5.82-7.54), and days in hospital (SSR, 15.37; 95% CI, 14.61-16.12). Adjusted resource utilization hazard increased with increasing lesion complexity. Hazard ratios (HRs) for complex versus simple disease were: primary care (HR, 1.14; 95% CI, 1.06-1.23); cardiology outpatient visits (HR, 1.40; 95% CI, 1.24-1.59); emergency department visits (HR, 1.19; 95% CI, 1.02-1.39); and hospitalizations (HR, 1.75; 95% CI, 1.49-2.05). Effects attenuated with age for cardiology outpatient visits and hospitalizations and increased for emergency department visits. Female sex, geographic periphery, and ethnic minority were associated with more primary care visits, and female sex (HR versus men, 0.89 [95% CI, 0.84-0.94]) and periphery (HR, 0.72 [95% CI, 0.58-0.90] for very peripheral versus very central) were associated with fewer cardiology visits. Arab minority patients also had high hospitalization rates compared with the majority group of Jewish or other patients. Conclusions Healthcare utilization rates were high among patients with ACHD. Female sex, geographic periphery, and ethnicity were associated with less optimal service utilization patterns. Further research should examine strategies to optimize service utilization in these groups.

Retrognathia (recessed chin) and prognathism (prominent chin) often present as signs of an underlying condition. Accurate clinical definitions are important. Yet their definitions were according to "clinical impression", or to seldom used X-ray criteria. We propose a statistical and anthropometric definition of retrognathia and prognathism based upon the ratio between the goniomaxillar length (distance between the gonion at the mandible angle and the subnasale and the goniomandibular length (distance between the mandible angle and the most anterior point of the bony chin). We assumed that an increase in the ratio indicates retrognathia and a decrease reflects prognathism. We conducted a prospective, observational, anthropometric study in 204 consecutive healthy term infants. Measurements took place on the second day of life, using sliding calipers. Mean ± SD of goniomandibular length (5.1 ± 0.3 cm), goniomaxillar length (5.4 ± 0.3 cm), were calculated. All measurements correlated significantly with gestational age, and with infant birthweight. The mean ± SD goniomaxillar length/goniomandibular length ratio was 1.06 ± 0.05. We defined a normal ratio as being within 2 SD of the mean, that is, between 0.96 and and 1.16. This ratio correlated with neither gestational age nor with birthweight. We conclude that the goniomaxillar length/goniomandibular length ratio can be calculated whenever retro - or prognathism is suspected. A ratio outside of the 95% confidence interval should help in making this diagnosis. An increase in this ratio beyond 2 SD above the mean (1.16) could be interpreted as retrognathia and a decrease beyond 2 SD below the mean (0.96) as prognathism., (© 2020 Wiley Periodicals LLC.)

After decades when intensive chemotherapy remained the only effective anti-acute myeloid leukaemia (AML) treatment, a torrent of novel, less toxic agents are about to revolutionise AML therapy. Prolonged remissions with good quality of life become achievable for many patients previously considered only for palliative care because they could not tolerate intensive therapy. As treatment options multiply, the importance of genetic profile is recognised, even for advanced-age patients for whom cure is unlikely. With lack of randomised comparative trials for most treatment regimens, one can only extrapolate data from existing studies to make evidence-based decisions. We herein present seven common clinical scenarios illustrating the complexity of treating older AML patients and describe our approach to their management. In each case, up-to-date data on relevant agents to be offered to a particular patient are discussed. The current review is limited to the drugs, available and approved in the Western world and many promising agents, still under investigation, are not discussed., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Aim: To assess the association of seasonal and perinatal parameters with early age of type 1 diabetes (T1D) onset., Methods: A cross-sectional review of all medical records of T1D patients born between the years 1990 and 2005, and diagnosed before/by the age of 10 years, from 13 university-affiliated paediatric medical centres in Israel, was performed. Data included: gender, ethnicity, seasons of birth and disease onset, birth gestational age and weight, and autoimmune diseases of the probands and their first-degree family members. Statistical analysis included the Chi-square test or Mann-Whitney test, as appropriate and multivariate regression analysis., Results: Enrolled were 1571 T1D patients at a median age of T1D onset 6.9 years (IQR 4.4,8.4); 336 of them presented before 4 years of age. The median age of this group was 2.5 years (IQR 1.7,3.2), and of the 1235 patients who presented after 4 years of age, median presentation age was 7.5 years (IQR 6.1,8.8). Multivariate regression analysis demonstrated that a more recent birth year; OR = 1.06, 95% CI 1.02-1.1, P = 0.003, and birth during the moderate weather months (September, October, March, and April) were significantly associated with younger age at T1D onset; OR = 1.68, 95% CI 1.17-2.4, P = 0.005., Conclusions: Our novel finding demonstrates the association between younger than 4 years old age at presentation and birth during moderate weather months. The results also support previous reports, that there is a slight increase in the annual incidence of T1D in the youngest age groups., (© 2020 John Wiley & Sons Ltd.)

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease., (© 2020 Wiley Periodicals, Inc.)

We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity., (© 2020 Wiley Periodicals, Inc.)

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure, hypotonia, decreased muscle mass, and cognitive impairment make exercise challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may mediate beneficial metabolic effects. We aimed to determine if young PWS adults can perform a resistance exercise program and to measure myokine responses in PWS versus age- and BMI-matched controls. Each group included 11 participants (7M/4F). Ages and BMI for PWS and controls were 30.7 ± 4.6 versus 30.1 ± 4.3 years and 28.3 ± 4.3 versus 28.2 ± 4.2 kg/m 2 , respectively. Glucose, creatine kinase (CK), lactate, and myokines were measured before, after, 30, and 60 min after completing eight resistance exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). CK was lower in PWS versus controls (62 ± 16 vs.322 ± 100 U/L, p < .04). Peak lactate was 3.7 ± 0.7 in PWS versus 7.3 ± 0.7 mmol/Lin controls (p < .001). The increase in interleukin-6 was similar in PWS and controls (41 ± 16% and 35 ± 10%, respectively). Pre- and post-exercise levels of the six myokines assayed showed no consistent differences between the PWS and control participants. PWS young adults are capable of performing resistance/strength-building exercise. The lower CK and peak lactate levels in PWS may reflect decreased muscle mass in this population. Further studies are needed to determine optimal exercise regimens and assess the role of myokines incontributing to the metabolic phenotype of PWS., (© 2019 Wiley Periodicals, Inc.)

Aim: Early-onset neonatal sepsis (EOS) may lead to significant morbidity and mortality, yet the recommended antimicrobials have not changed for many years. We aimed to optimise EOS treatment by examining EOS pathogens, resistance rates and resistance risk factors., Methods: A retrospective, nationwide cohort study analysing 2010-2015 EOS data in Israel., Results: The 21 participating centres constitute 92% of the total birth cohort (around 180 000 live births/year). Of 549 EOS neonates (0.57/1000 live births), 306 (56%) and 243 (44%) were full-term and preterm, respectively (0.35 vs. 2.94 per/1000 live births). Gram-negative pathogens predominated, especially in preterms. Escherichia coli and Streptococcus agalactiae were most common pathogens (0.2 and 0.19 per 1000 live births, respectively). In 277 Gram-negatives, 16%, 14%, 8% and 3% were gentamicin-resistant, extended-spectrum beta-lactamase (ESBL)-positive, gentamicin-resistant and ESBL-positive, and amikacin-resistant, respectively; preterms had higher resistance rates. No risk factors for antimicrobial resistance were identified. Mortality was reported in 21% of Gram-negative EOS versus 7% of Gram-positive EOS [OR 3.4 (95% CI 1.8-6.2), p < 0.01]., Conclusion: In this nationwide study, EOS was caused predominantly by Gram-negatives, with high gentamicin resistance and ESBL phenotype rates, without identifiable resistance risk factors. As EOS is life-threatening, modification of empiric therapy for amikacin-based regimens should be considered, mainly in preterms., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: External cephalic version (ECV) should be offered for patients presenting with a noncephalic pregnancy that are willing to deliver vaginally. Various reports have evaluated predictors for successful ECV. Yet, none have reported a single-operator large cohort experience. We aim to analyze the outcome of referrals for ECV., Methods: We conducted a retrospective cohort study of prospectively collected data. We performed a multivariate analysis of data with respect to ECV procedures performed by a single operator in a 6-year period. Maternal and fetal characteristics were compared between ECV success and failure groups., Results: Six hundred and two women underwent ECV. Of them, ECV was successful in 432 (71.7%). A multivariate binary logistic regression model demonstrated that high liquor volume was a predictor of ECV success (Adj OR 1.17 [95% CI 1.09-1.26]). Failure of ECV was correlated with anterior placenta (0.44 [0.56-0.76]) and nulliparity (0.21 [0.11-0.36]). Adverse events were rare and mostly minor, occurring in 1% of procedures., Conclusions: ECV has a high success rate and a low complication rate, enabling vaginal birth and avoiding cesarean. The role of manipulation of modifiable determinants such as liquor volume should be further assessed in future studies., (© 2019 Wiley Periodicals, Inc.)

Background Mineralocorticoid receptor antagonists (MRAs) have emerged as potential atrial fibrillation (AF) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRAs on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRAs on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta-analyses to compute odds ratios with 95% CIs. Meta-regression was then applied to explore the sources of between-study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow-up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta-analyses showed a significant overall reduction in AF occurrence in the MRA-treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI, 0.44-0.70 [ P <0.00001]), with the greatest benefit regarding recurrent AF episodes (odds ratio, 0.42; 95% CI, 0.31-0.59 [ P <0.00001]) and with significant heterogeneity among the included studies ( I 2 =54%; P =0.0008). Meta-regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRAs seem to be effective in AF prevention, especially regarding recurrent AF episodes.

Objective: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ)., Design: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115)., Setting: North London AJ population., Population or Sample: Ashkenazi Jews women/men >18 years, recruited through self-referral., Methods: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire., Main Outcome Measures: Interest, intention, uptake, attitude towards BRCA testing., Results: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing., Conclusions: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing., Tweetable Abstract: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo-immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single-arm, phase II trial to examine the efficacy and safety of lower-dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD-FCR) in elderly patients with previously untreated CLL. Forty patients received LD-FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression-free survival (PFS) was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment-related neutropenia occurred in 20 (47.6%) patients. During the entire study follow-up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non-neutropenic infections. In conclusion, LD-FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both "time and cost limited" and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high-risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard., (© 2019 John Wiley & Sons, Ltd.)

Aim: We surveyed whether clinicians used the WhatsApp messaging application to view neonatal chest radiographs and asked a sub-sample to compare them with computer screen viewings., Methods: The study was conducted at three university-affiliated medical centres in Israel from June-December 2016. Questionnaires on using smartphones for professional purposes were completed by 68/71 paediatric residents and 20/28 neonatologists. In addition, 11 neonatologists viewed 20 chest radiographs on a computer screen followed by a smartphone and 10 viewed the same radiographs in the opposite order, separated by a washout period of 2 months. After another 2 months, five from each group viewed the same radiographs on a computer screen. Different interpretations between viewing modes were assessed., Results: Most respondents used WhatsApp to send chest radiographs for consultation: 82% of the paediatric residents and 80% of the neonatologists. The mean number of inconsistencies in diagnosis was 3.7/20 between two computer views and 2.9/20 between computer and smartphone views (p = 0.88) and the disease severity means were 3.7/20 and 2.85/20, respectively (p = 0.94). Neonatologists using WhatsApp only determined umbilical line placement in 80% of cases., Conclusion: WhatsApp was reliable for preliminary interpretation of neonatal chest radiographs, but caution was needed when assessing umbilical lines., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)