Search

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.)

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.)

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage., (© 2024 British Society for Haematology and 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.)

Objectives: Secretory Carcinoma is a malignant salivary gland tumor, initially described in 2010. This rare tumor is associated with the translocation t(12;15) (p13;q25), resulting in the fusion gene ETV6-NTRK3. Since this tumor is quite rare, most publications describe only small cohorts of patients. We aimed to investigate the clinical, pathological, and prognostic features of this newly defined malignant entity., Data Sources: Pubmed, Google Scholar, and Web of Science databases., Review Methods: All published articles between 2010 and 2023 were reviewed. Search terms included the terms "Mammary Analogue Secretory Carcinoma" and "Secretory Carcinoma". All articles published in English reporting on Secretory Carcinoma of salivary glands were retrieved., Results: One-hundred and 12 retrospective articles reporting a total of 674 patients were included, with 52% males and a mean age of 44.9 ± 18.9. The event rate for patients with advanced-stage disease (Stage 3/4) at presentation was 24.1% (95% CI 17.6%-31.9%, I 2  = 9.2%), 14.6% for regional metastases (95% CI 10.5%-20%, I 2  = 12%), and the event rate of distant metastasis was 8.4% (95% CI 5.5%-12.7%, I 2  = 4.2%). Adjuvant radiotherapy was administered for 30.3% of patients (95% CI 24.1%-37.2%, I 2  = 21.5%). The recurrence rate was 19% (95% CI 15.1%-23.8%, I 2  = 5%). Survival outcomes showed a 17.2% death of disease rate for Secretory Carcinoma patients (95% CI 13.5%-21.8%, I 2  = 7.3%)., Conclusions: Secretory Carcinoma is a rare and relatively newly defined entity arising in the parotid gland most commonly. Characterized as a low-grade tumor, the majority of patients are diagnosed at an early stage, without regional or distant disease, and the prognosis is relatively good., Level of Evidence: NA Laryngoscope, 134:1716-1724, 2024., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Banking of frozen spermatozoa by single men opens the possibility of procreation long after their death. Requests for posthumous reproduction by the families of the deceased are growing, raising an ethical debate, especially when written instructions were not left by the patients and in cases of unplanned perimortem collection. The issue of the progenitors' intention to procreate after death is the key to ethically based decision-making in these cases., Objectives: To evaluate the attitude of single men cryopreserving spermatozoa before life-threatening medical situations towards post-mortem usage of their cryopreserved spermatozoa., Materials & Methods: Adult single men prior to sperm cryopreservation before cytotoxic therapy were asked to sign a structured form declaring their will and instructions for the usage of their cryopreserved spermatozoa in case of their demise., Results: Four hundred fifty-two men of diverse ethnicity, religious and cultural backgrounds signed the form providing instructions for the use of their cryopreserved spermatozoa in case of mortality. Their age was 27.4 ± 8.06 years. Seven (1.5%) patients willed their spermatozoa for posthumous reproduction to a sibling, 22 (4.9%) to parents, and 26 (5.7%) to their informal female partners. The significant majority (n = 397; 87.8 %) of the single men were ordered to destroy their cryopreserved spermatozoa in case of their expiry. Note that, 26-39 years old men were less likely (81.8% vs. >90% in other ages) to order sperm destruction, as well as men with a poorer prognosis (83% vs. 90%)., Discussion: In this study group, most single men cryopreserving spermatozoa in the face of future life-threatening morbidity do so for their own future live parenthood, and are not interested in posthumous reproduction., Conclusion: Our results doubt the claim that single men who had an unplanned perimortem sperm collection can be universally presumed to have wished to father a child posthumously. Any claimed assumed consent in these cases should be considered for each case individually based on its specific circumstances., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: The long-term impact of rhinitis and chronic rhinosinusitis (CRS) on general health and medical services utilization in young adults have been limitedly studied., Methods: A case-control study in the Israeli Defense Forces, between the years 2005 and 2019, of all individuals with either rhinitis or CRS and a matched cohort of healthy individuals with a minimum of 5 years of consecutive follow-up., Results: The study groups included 617 patients with rhinitis and 296 patients with CRS and 2739 healthy controls with an average age of 28 years. During a mean follow-up of 8 years, a significant fraction of patients in both study groups were diagnosed with asthma compared to the control group, (26.1% and 23.3% vs. 3.7%, respectively; CI 95%: 12.1%-14.9%, p < 0.0001). 7.6% of patients with rhinitis developed CRS. Significantly increased loss of productivity and medical system utilization were noted in the study groups compared to controls (p < 0.0001). Moreover, deterioration in general health, manifested as loss of physical fitness for combative service was observed in a third of patients during follow-up., Conclusions: Rhinitis and CRS significantly impact productivity and medical service utilization in young adults, as well as general health associated with development of asthma and impairment of physical fitness. A minority of rhinitis patients develop CRS overtime, further affecting this patient group. These patients should be followed up and managed to improve disease control and associated outcomes., Level of Evidence: 3 Laryngoscope, 133:3299-3303, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Aims: To investigate the potential association of chronic use of omeprazole with the occurrence of osteoporotic fractures (OF) in community-dwelling elderly subjects., Methods: The cohort consisted of community-dwelling residents aged >65 years registered with a large health maintenance organization in Israel between January 2002 and December 2016. Data were retrospectively collected from the electronic medical files on demographics, parameters known to be associated with OF, diagnoses of osteoporotic hip, wrist, and vertebral fractures, and chronic use of omeprazole (>11 prescriptions/year). Time to OF/death/end of study was calculated from the beginning of the study (2002). The risk of fractures in the chronic users of omeprazole was analyzed by multivariate Cox proportional hazard regression model., Results: In total, 46 805 subjects were included (41% men), mean age 83.4±6.4 years, of whom 10 272 (21.9%) were chronic users of omeprazole. During 14 years of follow-up, OF were diagnosed in 414 (4.0%) omeprazole users and 1007 (2.8%) omeprazole nonusers (p < 0.001). In a Cox regression model adjusted for age and gender only, chronic use of omeprazole was associated with a 16% excess of OF. However, when parameters known to be associated with OF were entered into the multivariate Cox regression model, chronic use of omeprazole was not found to be an independent risk factor for OF, either overall (adjusted hazard ratio = 0.965, 95% confidence interval 0.86-1.08, P = .55) or specifically, in the ≥85 years age group (adjusted hazard ration = 0.780, 95% confidence interval 0.635-0.958, P < .05) in which an inverse correlation between omeprazole use and OF, was demonstrated., Conclusions: Chronic use of omeprazole was not associated with the occurrence of OF in elders., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

Background Little is known about the impact of transcatheter mitral valve edge-to-edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge-to-edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge-to-edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all-cause mortality, major adverse cardiac event (composite end point of all-cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P <0.001) and had higher mean LVEF (54.8±14.0% versus 32.7±10.4%; P <0.001) at baseline. After 6 to 12 months (median, 9.9 months; interquartile range, 7.8-11.9 months), LVEF was significantly lower in patients with PMR (53.0% versus 56.0%; P <0.001) but not in patients with SMR. The 1-year mortality was higher in patients with PMR with LVEFR (16.9% versus 9.7%; P <0.001) but not in those with SMR ( P =0.236). LVEF at baseline (odds ratio, 1.03 [95% CI, 1.01-1.05]; P =0.002) was predictive of LVEFR for patients with PMR, but not those with SMR ( P =0.092). Conclusions Reduction in LVEF is not uncommon after transcatheter mitral valve edge-to-edge repair and is correlated with worsened prognosis in patients with PMR but not patients with SMR. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05311163.

Objective: Chronic sialadenitis is the most common complication of radioactive iodine (RAI) treatment. The aim of the study was to ascertain sonographic features of the major salivary glands in patients with papillary thyroid cancer (PTC) treated with RAI., Methods: The database of a tertiary medical center was retrospectively searched for consecutive patients who underwent total thyroidectomy for PTC in 2011-2020 with ultrasound follow-up after 1 year. Changes in ultrasound features of the major salivary glands were compared between patients treated or not treated with RAI postoperatively., Results: The cohort included 158 patients, of whom 109 (69%) were treated postoperatively with RAI (mean dose, 131 mCi) and 49 were not (control group). Sonographic changes were observed in the major salivary glands in 43% of the study group and 18% of the control group (p = 0.002), including coarse echotexture, decreased echogenicity, fibrosis, and atrophy. Higher RAI doses were significantly correlated with the prevalence and severity of glandular changes (p < 0.0001)., Conclusion: RAI treatment following thyroidectomy is associated with a dose-response effect and adverse changes in the major salivary glands and should be prescribed carefully., Level of Evidence: 4 Laryngoscope, 133:1271-1275, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking., Objectives: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate., Methods: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment., Results: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition., Conclusions: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters., (© 2023 European Academy of Dermatology and Venereology.)

Melanoma is widely treated with programmed cell death-1 (PD-1) inhibitors. As part of their anti-tumor immunity effect, they increase the susceptibility to cutaneous immune-related adverse events (cIRAE) among other autoimmune effects. To characterize the manifestations of cIRAE in melanoma patients treated with PD-1 inhibitors, and evaluate the correlation with tumor response. A retrospective study of 95 metastatic malignant melanoma patients treated with PD-1 inhibitors at the Hadassah Medical Center during 2013-2016. The most common cIRAE was pruritus reported by 39 (41%) patients. All other cIRAE were noted in 34 patients (35.8%), of which the most common cutaneous manifestation was vitiligo, demonstrated in 17 patients (17.9%) followed by various rashes (7.4%, including erythema multiforme, oral lichen planus, photosensitive rash, insect bite-like reaction, and urticaria), psoriasiform rash (3.2%), bullous pemphigoid (3.2%), and eczema (1%). Interestingly, higher response rates to immunotherapy were demonstrated in patients who developed pruritus (85%) and cIRAE (88%), with lower mortality rates in the cIRAE group (38.2%) versus the non-cIRAE group (70.5%, p = 0.002). cIRAE are common among malignant melanoma patients treated with PD-1 inhibitors and may be a marker for favorable prognosis., (© 2022 The Authors. Dermatologic Therapy published by Wiley Periodicals LLC.)

Treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered standard of care (SOC) second-line treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, outcomes remain suboptimal. A systematic review and meta-analysis of randomised controlled trials comparing efficacy and safety of SOC versus chimeric antigen receptor T-cell (CAR-T) therapy as second-line for patients with LBCL refractory or relapsing within 12 months. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR) and safety. Three trials published in 2021 (involving 865 participants) fulfilled the eligibility criteria. EFS as well as OS were significantly improved with CAR-T therapy as compared to SOC, hazard ratio (HR) 0.57 (95% confidence interval [CI] 0.49-0.68) and HR 0.77 (95% CI 0.60-0.98) respectively. CAR-T therapy was associated with significantly better ORR, relative risk (RR) 1.55 (95% CI 1.12-2.13, p = 0.001). The risk of Grade III/IV adverse event was comparable between the two arms, RR 1.03 (95% CI 0.93-1.14). In summary, CAR-T therapy has superior outcomes as compared to SOC in patients with LBCL refractory or relapsing within 12 months, without excess of toxicity. Longer follow-up is needed to confirm these results and determine the optimal sequencing of CAR-T therapy in the management of LBCL., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive nonmelanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs, a retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (p = 0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs., (© 2022 Wiley Periodicals LLC.)

Interstitial deletions of 16q24.1-q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema-Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1-q24.2. This report extends the phenotype of both 16q24.1-q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3'-UTR part of FOXC2., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: The literature on paediatric mycosis fungoides (MF) and especially its folliculotropic variant (FMF) is sparse., Objectives: To describe the clinical manifestations, treatments, outcomes and long-term course of paediatric MF, including FMF., Methods: A retrospective analysis was conducted of all consecutive MF patients diagnosed at ≤18 years attending two medical centres in 1995-2015., Results: The cohort included 71 patients, all but two of whom had early-stage disease: hypopigmented (55%), folliculotropic (42%) and classical MF (39%), alone or in combination. The head and neck area were involved in 43% of patients with early-stage FMF compared to 12% of the non-FMF group (P = 0.004). There was no difference in the involvement of other body areas between the groups. Pruritus, although mild, was more often recorded among patients with early-stage FMF compared to non-FMF (58% vs. 29%, respectively, P = 0.02). Complete response (CR) was achieved in 60 of the 69 patients with early-stage MF (87%) after an average of 1.8 treatment modalities. NBUVB was the most administered treatment to non-FMF patients with CR rates of 63% vs. 29% of FMF patients (P = 0.04). Systemic/bath PUVA and UVA+NBUVB were the most administered treatments to FMF patients with CR rates of 60% vs. 81% for non-FMF patients (P = 0.17). During a mean follow-up of 9.2 years (range 1-24), stage progression was observed in four (6%) of the patients with early-stage disease, two of whom (all FMF) to advanced stage., Conclusions: Paediatric MF presents as an early-stage disease with over-representation of hypopigmented and FMF variants. NBUVB and UVA-based therapies yield good response rates in non-FMF and FMF patients, respectively. Disease course is indolent, and even on relatively long follow-up, it has a very low progression rate from early to advanced-stage disease, occurring in patients with FMF. We propose a treatment algorithm for paediatric MF., (© 2022 European Academy of Dermatology and Venereology.)

Background: In view of inconsistencies in threshold values of severe aortic stenosis (AS) hemodynamic indices, it is unclear what is the relative contribution of each variable in a binary classification of AS based on aortic valve replacement (AVR) indication. We aimed to assess relative discriminative value and optimal threshold of each constituent hemodynamic parameter for this classification and confirm additional prognostic value., Methods: Echocardiography studies of 168 patients with ≥ moderate AS were included. AS types were dichotomized into Group-A, comprising moderate and Normal-Flow Low-Gradient (NFLG), and Group-B, comprising High-Gradient(HG), Low Ejection Fraction Low-Flow Low-Gradient(Low EF-LFLG), and Paradoxical Low-Flow Low-Gradient(PLFLG) AS. Aortic valve area (AVA), Doppler velocity index (DVI), peak aortic velocity, mean gradient, stroke volume index and transaortic flow rate(TFR) were assessed for A/B Group discrimination value and optimal thresholds were determined. Dichotomized values were assessed for predictive value for AVR or death., Results: C-statistic values for binary AS classification was .74-.9 for the tested variables. AVA and DVI featured the highest score, and SVI the lowest one. AVA≤.81 cm 2 and DVI≤.249 had 87.6% and 86% respective sensitivity for Group B patients, and a similar specificity of 80.9%. During a mean follow-up of 9.1±10.1 months, each of the tested dichotomized variables except for SVI predicted AVR or death on multivariate analysis., Conclusion: An AVA value ≤.81 cm 2 or a DVI ≤ .249 threshold carry the highest discriminative value for severe AS in patients with aortic stenosis, translating into an independent prognostic value, and can be helpful in making clinical decisions., (© 2021 Wiley Periodicals LLC.)

Background: Intra-uterine insemination is an essential component in the treatment of infertility. Success rates are dependent on clinical factors of the female partner, sperm quality, and preparation technique. The effect of the time interval between the end of sperm preparation in the lab, and its injection into the uterine cavity (lab-to-uterus time) is yet to be determined., Aim: To investigate the association between the lab-to-uterus time and the pregnancy rate., Materials and Methods: Partner and donor spermatozoa intra-uterine insemination cycles were included. Preparation for intra-uterine insemination of partners' fresh ejaculate or donor thawed spermatozoa was identical. The time interval from the completion of this stage to the actual intra-uterine injection was recorded. The lab-to-uterus intervals were divided into groups A (0-29 min), B (30-59 min), C (60-89 min), and D (90-180 min). Pregnancy was defined as two adequate consecutive doubling levels of hCG and the pregnancy rates were compared between the groups., Results: A total of 267 female patients (138 partner spermatozoa, 129 donors) who had 470 intra-uterine insemination cycles (218 partner spermatozoa, 252 donors) were included. No significant differences in pregnancy rates per treatment cycle were found between the four lab-to-uterus interval groups: A (n = 96 cycles; 16.7%), B (n = 217; 19.4%), C (n = 121; 16.5%), and D (n = 36; 36.1%). No difference was found in the pregnancy rates between partner and donor spermatozoa. In the case of fresh partner spermatozoa, the pregnancy rates for groups were as follows: A (n = 40 cycles, 20%); B (n = 94; 14.9%), C (n = 70; 17.1%), and D (n = 14; 35.7%) (NS). In the case of thawed donor spermatozoa, the pregnancy rates (per cycle) for groups were as follows: A (n = 56; 14.3%), B (n = 123; 22.8%), C (n = 51; 15.7%), and D (n = 22; 36.4)% (NS)., Conclusions: The intra-uterine insemination outcome was not affected by the lab-to-uterus time interval. Extended waiting up to 3 h for insemination did not have any detrimental effect on pregnancy rates, regardless if partner or donor spermatozoa was used., (© 2021 American Society of Andrology and European Academy of Andrology.)

Background and Aims: While biopsy is the gold standard for liver fibrosis staging, it poses significant risks. Noninvasive assessment of liver fibrosis is a growing field. Recently, deep learning (DL) technology has revolutionized medical image analysis. This technology has the potential to enhance noninvasive fibrosis assessment. We systematically examined the application of DL in noninvasive liver fibrosis imaging., Methods: Embase, MEDLINE, Web of Science, and IEEE Xplore databases were used to identify studies that reported on the accuracy of DL for classification of liver fibrosis on noninvasive imaging. The search keywords were "liver or hepatic," "fibrosis or cirrhosis," and "neural or DL networks." Risk of bias and applicability were evaluated using the QUADAS-2 tool., Results: Sixteen studies were retrieved. Imaging modalities included ultrasound (n = 10), computed tomography (n = 3), and magnetic resonance imaging (n = 3). The studies analyzed a total of 40 405 radiological images from 15 853 patients. All but two of the studies were retrospective. In most studies the "ground truth" reference was the METAVIR score for pathological staging (n = 9.56%). The majority of the studies reported an accuracy >85% when compared to histopathology. Fourteen studies (87.5%) had a high risk of bias and concerns regarding applicability., Conclusions: Deep learning has the potential to play an emerging role in liver fibrosis classification. Yet, it is still limited by a relatively small number of retrospective studies. Clinicians should facilitate the use of this technology by sharing databases and standardized reports. This may optimize the noninvasive evaluation of liver fibrosis on a large scale., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Diabetic ketoacidosis (DKA) is an acute metabolic complication characterized by hyperglycaemia, ketones in blood or urine, and acidosis., Objective: The aim of this study was to characterize features of patients hospitalized for DKA, to identify triggers for DKA and to evaluate the long-term effects of DKA on glycaemic control, complications of diabetes, re-hospitalizations, and mortality., Methods: Historical prospectively collected data of patients hospitalized to medical wards for DKA between 2011 and 2017. Data regarding comorbidities, mortality, triggers, and re-hospitalizations for DKA were also collected., Results: The cohort consisted of 160 patients (mean age 38 ± 18 years, 43% male). One fifth of the patients (34 patients, 21%) were newly diagnosed with diabetes, and DKA was their first presentation of the disease. Among the 126 patients with pre-existing diabetes, the common identified triggers for DKA were poor compliance to treatment (22%) and infectious diseases (18%). During over 7 years of follow-up, mortality rate was 9% (15 patients), and re-hospitalization for DKA rate was 31% (50 patients). Risk factors for re-hospitalization for DKA included young age (OR = 1.02, 95% CI, 1.00-1.04), pre-existing diabetes compared to DKA as the first presentation (OR = 5.4, 95% CI, 1.7-18), and poorer glycaemic control before initial hospitalization (10.5 ± 2.5% vs. 9.4 ± 2.2%; OR = 0.8, 95% CI [0.68-0.96]) and after discharge (10.3 ± 2.4% vs. 9.0 ± 1.9%; OR = 0.73, 95% CI [0.61-0.87]). Laboratory tests during the initial hospitalization, smoking, alcohol, or comorbidities did not increase the risk for re-hospitalization for DKA., Conclusions: The risk for readmission for DKA is higher for young patients with long duration of diabetes, poor compliance of insulin treatment and poorly controlled diabetes., (© 2020 John Wiley & Sons Ltd.)

Background: We set out to examine incidence of chronic headache and back pain in women with PDPH after accidental dural puncture during labor., Methods: Chronic headache, backache, and disability were assessed 18-24 months postpartum. Women with PDPH treated with epidural blood patch (PDPH-EBP) were identified and matched with women who had a PDPH without epidural blood patch (PDPH-no EBP), with women with uncomplicated epidural analgesia and with women without epidural analgesia. Our primary outcome was incidence of chronic headache and backache. Secondary outcome was the effect of epidural blood patch on chronic pain development. We used Chi-square or Fisher's exact test to calculate odds ratios., Results: There was no statistically significant difference in demographic characteristics between groups. In the no epidural group, no women reported chronic headache and 2/116 (1.7%) reported chronic backache. In the uncomplicated epidural group, no women reported chronic headache and 7/116 (6.0%) reported chronic backache. In the PDPH-no EBP group, 9/56 (16.1%) women reported chronic headache and 10/56 (17.9%) reported chronic backache. In the PDPH-EBP group, 12/59 (20.3%) had chronic headache and 14/59 (23.7%) had chronic backache. No women in the no epidural or uncomplicated epidural group reported disability (chronic pain score of 3 or 4). High disability was reported by 8.9% of women in the PDPH-no EBP group and by 8.4% in the PDPH-EBP group., Conclusion: Women with PDPH had a high incidence of chronic headache, back pain, and disability. We did not find a statistically significant difference in chronic pain development between conservatively treated and EBP-treated patients., (© 2021 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Metamizole is commonly used as analgesic and antipyretic drug. The use of metamizole is prohibited in several countries due to its rare side effect of neutropenia and even agranulocytosis. Among the many symptoms of COVID-19, fever and diffuse pain predominant and therefore it can be assumed that metamizole may be widely used in the current epidemic period. So far, there have been no reports on the safety of metamizole in COVID-19 patients. We describe a series of 3 patients who developed severe neutropenia under metamizole treatment, raising a concern of a possible increased risk of this side effect among COVID-19 patients., (© 2020 British Pharmacological Society.)

Background: Endocrine and metabolic associations have been recently reported in patients with hidradenitis suppurativa (HS); however, fertility was only rarely investigated in women and not at all in men., Objective: To evaluate the association of HS with male and female infertility., Methods: A cross-sectional, matched controlled, population-based study was designed. The association between HS and male and female infertility was evaluated in patients with HS (n = 4191) and age- and gender-matched controls (n = 20 941), while utilising the Clalit Health Services databases, the largest community-based health maintenance organisation in Israel., Results: Hidradenitis suppurativa was associated with infertility in males and females over all reproductive-age groups, especially among individuals aged 36-45 years (OR 4.50, 95%CI 2.55-7.93, P < 0.001), and in female patients (OR 3.10, 95%CI 2.57-3.74, P < 0.001). After adjustment for demographic and clinical factors, the association remained significant only in females (OR 1.26 95%CI 1.04-1.55, P < 0.05)., Conclusion: Patients with HS are at increased risk of infertility, particularly females and patients in the 36- to 45-year age group. Physicians should take the additional physiological and psychological burden of infertility among HS patients into account, primarily among female patients at procreative age., (© 2021 The Australasian College of Dermatologists.)

Objectives/hypothesis: Recent evidence indicates an increased prevalence of intravenous opioid drug abusers (IVDAs) among supraglottic squamous cell carcinoma (SG-SCC) patients. This study investigates whether the clinical course of SG-SCC in IVDA differs from SG-SCC in non-IVDA., Study Design: A retrospective case-control study conducted in a in two tertiary referral centers., Methods: This case-control study compares IVDA with non-IVDA patients diagnosed and treated for SG-SCC in between 2005 and 2018. Disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator. Adjusted odds ratios (ORs) for mortality were calculated using multivariant analyses., Results: A total of 124 patients were included; 21% (26) were IVDA, and 79% (98) were non-IVDA. Age at diagnosis in the IVDA group versus the non-IVDA group was 53 and 66 years, respectively (P = .001). Nevertheless, the age hazard ratio for OS was calculated and found to have minimal to no effect, 1.05 (95% Cl: 1.025-1.076). Otherwise, the two groups were comparable regarding demographics, other risk factors (i.e., gender, smoking, and alcohol), and comorbidities status, as well as the comparable stage at diagnosis, histologic grading, and treatment modalities. Although the DFS was comparable in both groups, the 5-year OS was 55% in the IVDA group compared with 34% among the non-IVDA patients (P = .04). In multivariant analyses for mortality, positive IVDA history was found to be protective, adjusted OR: 0.263 (95% CI: 0.081-0.854). Similarly, within the subgroup of 100 patients with advanced-stage disease (III and IV), the adjusted OR was 0.118 (95% CI: 0.028-0.495)., Conclusions: SG-SCC in IVDA patients has a distinct clinical course, presenting at a younger age, and may have improved prognosis., Level of Evidence: NA Laryngoscope, 131:E1190-E1197, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

A male patient with a de novo mutation in the YWHAG gene and mild phenotype is presented. He had normal delivery and normal development, with normal speech and social milestones. At the age of 9 months, myoclonic seizures started, with generalized epileptiform discharges. The child responded well to levetiracetam monotherapy with complete seizure resolution. Levetiracetam was stopped and he remained seizure-free for 10 months. His development was appropriate for age according to psychological evaluation and he attended a regular kindergarten. At the age of approximately 4 years, the seizures reappeared with different semiology of staring with eye blinking. Electroencephalogram (EEG) showed multifocal spikes. Brain magnetic resonance imaging did not reveal any structural abnormality. Genetic analysis revealed a de novo likely pathogenic missense variant in the YWHAG gene (c.619G>A p.Glu207Lys). We compared our case to the other cases published in the literature. Our case is unique in its seizure semiology and evolution of EEG. Moreover, in contrast to our case, the majority of cases described in the literature have dysmorphism and intellectual disability or autistic spectrum disorder. This report emphasizes the phenotypic heterogeneity of YWHAG mutation as is the case in other developmental encephalopathies., (© 2021 Wiley Periodicals LLC.)

Background: There are cases where epidural analgesia is initially effective but subsequently fails and needs to be resited. We evaluated the rate of normal vaginal delivery and operative delivery among parturients who had resited epidurals compared to parturients with epidurals that were not resited., Methods: A retrospective electronic medical review of parturients with a singleton gestation attempting normal vaginal delivery under epidural analgesia between the years 2012-2016 was conducted. Resited epidurals were defined as epidurals that were considered effective but subsequently removed and reinserted. For each resited epidural, two previous and two consecutive deliveries of parturients with normally functioning epidural catheter inserted by the same anesthesiologist were matched controls (non-resited epidurals)., Results: There were 35,984 attempted vaginal deliveries with 118 resited epidurals and 472 non-resited epidurals. When adjusted for nulliparity, oxytocin administration, sex and weight of the baby, and maternal BMI, labor epidural catheter replacement was not associated with need for instrumental or caesarean delivery, (OR 1.5, 95% CI 0.91-2.49, P = .11)., Conclusions: Need for labor epidural catheter replacement does not appear to be associated with need for operative delivery based on this single-centre cohort analysis., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: We performed an open controlled one-arm clinical trial to assess whether preoperative anxiety influences phenylephrine dosage required to maintain normotension during cesarean section under spinal anesthesia., Methods: Ninety-four parturients undergoing elective cesarean delivery under spinal anesthesia were included. Anxiety levels were measured using a verbal numerical scale anxiety score (0-10). Phenylephrine infusion to prevent hypotension was adjusted by a standard algorithm. The primary outcome was total phenylephrine dose. Linear uni- and multivariate regressions were performed to assess the relationship between preoperative anxiety and the outcome. P < .05 was considered statistically significant., Results: We found no association between preoperative anxiety and phenylephrine dosage (R 2  = 0.05). Taking the number of attempts for spinal anesthesia and surgical time into account did not lead to a significant improvement of the regression model., Conclusion: In conclusion, we did not find a large independent effect of preoperative anxiety on phenylephrine dose required to maintain normotension in our cohort. We believe that spinal hypotension and phenylephrine dose requirement are multifactorial and anxiety is only one of the factors in this complex interaction., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

High levels of efficacy were demonstrated in randomized controlled trials assessing the efficacy of guselkumab; however, real-life data are lacking. In this retrospective cohort study, we assessed the efficacy and safety of guselkumab in a cohort of psoriasis patients heavily pretreated with biologic agents. Primary efficacy endpoint was the percentage of patients achieving ≥psoriasis area and severity index (PASI) 90 response at week 24. The cohort included 33 patients of mean age 60 ± 13 years. Guselkumab was initiated after a mean of 4.0 ± 1.0 prior biologics failed over a mean period of 7. 4 ± 3.8 years. The mean duration of guselkumab treatment was 9.5 ± 3.7 months; 29 patients completed at least 24 weeks of treatment. At week 24, 22 patients (76%) achieved response of PASI 75 or higher, 18 (62%) achieved PASI 90 or higher, five (17%) PASI 100, and seven (24%) ≤PASI 50. No adverse effects were observed. This study confirms the efficacy and safety of guselkumab in real-world clinical practice, although for a lesser degree compared with clinical trials., (© 2020 Wiley Periodicals LLC.)

Purpose: To evaluate and correlate levels of various proteins involved in coagulation, inflammation and angiogenesis processes in the vitreous of patients with different vitreoretinal pathologies., Methods: Vitreous samples were collected from patients scheduled for pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment (RRD), vitreous haemorrhage or tractional retinal detachment associated with proliferative diabetic retinopathy (PDR). Macular hole and epiretinal membrane served as controls. Levels of vascular endothelial growth factor, thrombin-antithrombin III complex, interleukin-8, tissue factor, thrombomodulin, P-selectin, D-dimer and tissue factor pathway inhibitor were compared among the vitreoretinal pathology groups., Results: Compared to controls, patients with PDR had significantly higher levels of thrombin-antithrombin III complex (p < 0.001), vascular endothelial growth factor (p < 0.001), D-dimer (p = 0.038) and interleukin-8 (p = 0.04), and patients with RRD group had significantly higher levels only of thrombin-antithrombin III complex (p < 0.001). There was a significant linear correlation between levels of P-selectin and D-dimer (p = 0.003), P-selectin and interleukin-8 (p < 0.001), and D-dimer and IL-8 (p = 0.007). These correlations were particularly strong in the PDR group compared to the other groups., Conclusion: Patients with PDR manifest high coagulative and angiogenic activity in the vitreous. These pathways are highly correlated with the inflammatory cascade., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Drug survival rates in patients with psoriasis had been described extensively. Different survival rates of TNF-α inhibitors (TNFIs), ustekinumab and secukinumab were reported., Objectives: To investigate drug survival rates of TNFIs, ustekinumab and secukinumab, with particular emphasis on the difference between ustekinumab and secukinumab., Methods: Survival analysis was performed in patients with moderate-to-severe psoriasis who received adalimumab, infliximab, etanercept, ustekinumab and secukinumab treatment in 2002-2018, using the Clalit Health Services database. Stratified analysis was performed according to biologic treatment lines. Multivariate analysis was performed adjusting for demographic variables, calendar year, metabolic syndrome, psoriatic arthritis, biologic treatment line, biologic naivety, co-administration of oral treatments and previous oral systemic treatment exposure., Results: Among 1459 patients treated with 3070 biologic medication courses, ustekinumab had a significantly higher crude survival as compared with TNFIs and secukinumab. The mean drug survival of ustekinumab, adalimumab, etanercept, infliximab and secukinumab was 43.5 (CI: 39.7-47.2), 38.2 (CI: 34.8-41), 33.9 (CI: 30.8-37.1), 28.2 (CI: 22.5-33.8) and 17.1 (CI: 15.6-18.6) months, respectively, with significant statistical differences for all comparisons (P < 0.001). The differences between ustekinumab and secukinumab were not significant following adjustment to factors that included treatment line (hazard rate 1.16, CI: 0.93-1.43)., Conclusion: Different drug survival rates between ustekinumab and secukinumab are determined by the treatment line and calendar year, reflecting the availability of biologic medications, and not only by the biologic attributes of each medication., (© 2020 European Academy of Dermatology and Venereology.)

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.)

Introduction: Various biopsychosocial factors affect women's preferences with respect to mode of birth, but they are usually not examined simultaneously and prospectively. In the current study, we assessed the contribution of personal characteristics of first-time mothers, their prior prenatal perceptions, events during birth, and subjective birth experiences, on their preference about mode of second birth., Methods: This was a secondary analysis of two prospective birth cohort studies. Participants included 832 primiparous women recruited mostly from women's health centers in Israel, and through natural birth communities and cesarean birth websites. Women completed questionnaires prenatally and were followed up at 6-8 weeks postpartum to understand their preferences for a second birth., Results: Regression models indicated that after vaginal first birth, being less religious, believing that birth is a medical process, and having a negative experience increased the odds of preferring primary cesarean for the second birth. After cesarean birth, being more religious, having higher education, conceiving spontaneously, having a more negative birth experience, and perceiving better treatment from the staff during birth contributed to preferring vaginal birth for the second birth., Conclusions: Religiosity is central to women's preferences, probably because of its association with the desire to have many children. Modifiable factors, such as women's beliefs about the nature of birth, their overall birth experience, and their perceived treatment from the staff, could influence the uptake of having vaginal births. Intrapartum care that is empathic and encouraging, along with education about modes of birth, could help decrease cesarean birth rates., (© 2020 Wiley Periodicals, Inc.)

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: From a dermatologist's perspective, there are four major types of cutaneous porphyrias (CPs): porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Scarce data are available regarding the epidemiology of CPs., Objectives: To describe the epidemiology of CPs in Israel, including distribution, incidence and prevalence rates of major types., Methods: This retrospective study includes all patients who were diagnosed with CPs between the years 1988-2018. It is based on data from Israel's National Service for the Biochemical Diagnoses of Porphyrias, and Israeli patients' nationwide electronic medical charts. Incidence and prevalence rates were calculated., Results: Of 173 patients with CPs diagnosed during a 30-year period, 65 (38%) had VP, 62 (36%) had PCT, 31 (18%) had HCP and 15 (9%) had EPP; with incidence rates of 0.29, 0.30, 0.17, 0.07, and prevalence rates of 6.3, 4.8, 2.9, 1.6, respectively, per million population. Characteristics of patients with PCT differed from those with other CPs with regard to lack of family history, older mean age at diagnosis [51 vs. 36 (VP), 35 (HCP) and 25 (EPP) years] and male predominance (81% vs. similar distribution). All patients with PCT were diagnosed at adulthood, while 20%, 19% and 15% of patients with VP, HCP and EPP, respectively, were diagnosed during childhood or adolescence., Conclusions: Variegate porphyria and PCT were found to be the most prevalent in Israel; however, CPs might be underdiagnosed, thus dermatologists' awareness of these rare disorders is highly important., (© 2019 European Academy of Dermatology and Venereology.)

MYH7-related disease (MRD) is the most common hereditary primary cardiomyopathy (CM), with pathogenic MYH7 variants accounting for approximately 40% of familial hypertrophic CMs. MRDs may also present as skeletal myopathies, with or without CM. Since pathogenic MYH7 variants result in highly variable clinical phenotypes, from mild to fatal forms of cardiac and skeletal myopathies, genotype-phenotype correlations are not always apparent, and translation of the genetic findings to clinical practice can be complicated. Data on genotype-phenotype correlations can help facilitate more specific and personalized decisions on treatment strategies, surveillance, and genetic counseling. We present a series of six MRD pedigrees with rare genotypes, encompassing various clinical presentations and inheritance patterns. This study provides new insights into the spectrum of MRD that is directly translatable to clinical practice., (© 2018 Wiley Periodicals, Inc.)

Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Objectives/hypothesis: To assess the differences between patients with laryngeal squamous cell carcinoma under 40 years old and those 40 years old or older. A secondary objective was to compare survival outcome between these cohorts., Study Design: Retrospective chart review., Methods: We reviewed the medical charts of all patients treated in our tertiary referral center for laryngeal squamous cell carcinoma from 2005 to 2014. Patients aged < 40 years at diagnosis were compared to older patients., Results: The study group comprised 160 patients. Of them, 13 were aged < 40 years at diagnosis. Mean age was 35 ± 3.9 years and 64.4 ± 11 years for the two groups. Among the younger patients, 38% were smokers (mean pack/day, 2.2) versus 71% in the older group (mean pack/day, 3). The younger group typically had a more advanced stage than the older group at presentation; eight young patients (62%) had stage III or IV versus 49 (33%) in the older group (P = .042). Mean overall survival was 6.7 ± 1 years for those under 40 years old and 7.7 ± 0.2 years for the older patients (P = .2). The 5-year survival rate was 69% for young patients and 90% for the older group (P = .04). However, there was no significant between-group difference in overall survival or 5-year survival rate when stratified for early- and late-stage disease., Conclusions: There is a lower prevalence of classic risk factors in younger patient with laryngeal carcinoma in this study, suggesting a different etiology compared to our older cohort. The under-40 cohort presented with more advanced disease and had a worse 5-year survival; however, when stratified for early- versus late-stage disease, there was no significant difference in overall or 5-year survival between the groups. This may suggest that, despite a different etiology, laryngeal cancer behaves similarly in older and younger patients., Level of Evidence: 4. Laryngoscope, 128:1602-1605, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Investigate the association between body mass index (BMI), length of stay (LOS), and mortality in hospitalized patients with and without diabetes mellitus (DM)., Methods: Historical prospectively collected data of adult patients hospitalized between 2011 and 2013. Body mass index was calculated according to measurement or self-report on admission and classified as follows: underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9), obese (30-34.9), and severely obese (≥35). The main outcomes were LOS, in-hospital, and end-of-follow-up mortality., Results: Cohort included 24 233 patients (53% male; mean age ± SD, 65 ± 18), including 7397 patients with DM (31%). Among patients with normal BMI, LOS was shorter compared with underweight patients, but it was longer compared with overweight and obese patients. Following multivariate adjustment, this difference remained significant only for patients with DM. There was a significant interaction between DM status and BMI group, in the models for in-hospital and end-of-follow-up mortality. Compared with normal BMI, in-hospital mortality risk was increased by 80% and 100% for the underweight with and without DM, respectively. For patients with and without DM, in-hospital mortality risk was 30% to 40% lower among overweight and obese patients, and there was no difference between severely obese and normal weight patients. At the end-of-follow-up, mortality risk was 1.6-fold and 1.7-fold higher among underweight patients with and without DM, respectively. For overweight, obese, and severely obese patients, mortality risk was decreased by 30% to 40% in those with DM and by 20% to 30% in those without DM., Conclusions: In hospitalized patients with and without DM, there was an inverse association between BMI and mortality., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Women perceive what birth is even before they are pregnant for the first time. Part of this conceptualization is the basic belief about birth as a medical and natural process. These two separate beliefs are pivotal in the decision-making process about labor and birth. Adapting Engel's biopsychosocial framework, we explored the importance of a wide range of factors which may contribute to these beliefs among first-time mothers., Method: This observational study included 413 primiparae ≥24 weeks' gestation, recruited in medical centers and in natural birth communities in Israel. The women completed a questionnaire which included the Birth Beliefs Scale and a variety of biopsychosocial characteristics such as obstetric history, birth environment, optimism, health-related anxiety, and maternal expectations., Results: Psychological dispositions were more related to the birth beliefs than the social or biomedical factors. Sociodemographic characteristics and birth environment were only marginally related to the birth beliefs. The basic belief that birth is a natural process was positively related to optimism and to conceiving spontaneously. Beliefs that birth is a medical process were related to pessimism, health-related anxiety, and to expectations that an infant's behavior reflects mothering. Expectations about motherhood as being naturally fulfilling were positively related to both beliefs., Conclusion: Psychological factors seem to be most influential in the conceptualization of the beliefs. It is important to recognize how women interpret the messages they receive about birth which, together with their obstetric experience, shape their beliefs. Future studies are recommended to understand the evolution of these beliefs, especially within diverse cultures., (© 2017 Wiley Periodicals, Inc.)

Aims: The present study evaluates the effect of antenatal lamotrigine exposure, on short- and long-term paediatric outcome., Methods: The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004-2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. In addition, the parents completed a questionnaire regarding their child's development and health up to the age of 12 years., Results: No major malformations were found in the newborns. None of the newborns had significant withdrawal symptoms by Finnegan score. The children were followed-up to the age of 12 years (56.6% were 6-12 years at the time of evaluation). There were no significant findings in the incidence of neurodevelopmental disorders., Conclusions: According to our experience, lamotrigine is generally safe for pregnancy use, associated with minimal short-term complications with no long-term effects on the outcome., (© 2017 The British Pharmacological Society.)

Background: Packing of the middle meatus and ethmoid cavities is a common practice in endoscopic sinus surgery (ESS), but its necessity recently has been challenged. The aim of this study was to formulate a decision-analysis model to determine the need for packing in ESS and identify variables affecting the decision., Methods: A systematic review of the literature was conducted for all randomized control trials comparing packing to no packing in ESS, and a decision-analysis model was generated. Probabilities and utilities were derived from the literature. Sensitivity analysis was used to determine which variables most affected the model., Results: No packing was associated with better expected utilities than packing. On sensitivity analysis, packing was preferred when the disutility of no packing outweighed the disutility of packing, and when the probability for synechiae was greater than 35% without packing or lower than 2% with packing. When the component of packing removal was subtracted from the overall disutility simulating absorbable packing, the results favored packing., Conclusion: Our decision-analysis model indicates that middle meatal packing is not advantageous for patients undergoing ESS. Absorbable packing materials have a less adverse effect on quality of life than nonabsorbable materials., Level of Evidence: 1a. Laryngoscope, 127:1506-1512, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: During robot-assisted transaxillary thyroidectomy, the patient's arm is maintained in an overhead flexed position for a prolonged time, which poses a risk of postoperative brachial plexopathy. The aim of the study was to identify the causes of brachial plexopathy and to assess the benefit of intraoperative neurophysiological monitoring (IONM) in preventing positional brachial plexopathy in this setting., Study Design: Retrospective case series., Methods: The computerized database of a tertiary medical center was searched for all consecutive patients who underwent robot-assisted transaxillary thyroidectomy between 2012 and 2014. Clinical, operative, and outcome parameters were collected from the medical files. Findings were compared between patients operated with and without IONM., Results: The cohort included 30 patients, 14 operated with IONM and 16 without. Three events of impending brachial plexopathy were detected in the monitored group. The monitored group had significantly better shoulder movement (P = .003), a lower rate of hypoesthesia (P = .011), less pain (P = .001) in the early postoperative period than the nonmonitored group and higher quality of life in the early postoperative period (P = .012). The monitored group was significantly younger than the nonmonitored one (P = .02) and had a significantly larger diameter of thyroid nodule than the nonmonitored group (P = .043)., Conclusions: IONM during robot-assisted transaxillary thyroidectomy may improve short-term postoperative pain and shoulder movement and longer-term quality of life., Level of Evidence: 4 Laryngoscope, 126:2187-2193, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Extracorporeal photopheresis (ECP) is recommended for the erythrodermic mycosis fungoides (MF) and Sezary syndrome (SS) alone or in combination with other therapies. The possibility of a differential response in the blood and skin has hardly been addressed in the literature., Objectives: To evaluate the clinical response rate of patients with erythrodermic MF and SS to ECP as part of a multimodality approach and to compare the kinetics of the blood and skin responses in the presence of leukaemic involvement., Methods: Twenty patients were treated with ECP and other modalities at a tertiary medical centre in 2003-2013. Ten patients had SS, 1 CD8-positive patch-stage MF with leukaemic involvement and nine erythrodermic MF. Clinical and outcome data were collected retrospectively from the medical files. Response was evaluated overall and for blood and skin separately., Results: Adjunctive therapies were interferon-α, narrow-band ultraviolet B, psoralen and ultraviolet A, isotretinoin, acitretin, methotrexate, prednisone, topical nitrogen mustard and total skin or localized hands/feet electron beam radiotherapy. Overall response was documented in 13 patients (65%)--complete 30%, partial 35%--and maintained for >2 years in 38.5%. In patients with leukaemic involvement (n = 11), the blood response occurred earlier than skin response (P = 0.008) and was maintained longer (P = 0.03). In three of the patients with a complete blood response, the skin response was partial (n = 2) or absent (n = 1)., Conclusion: Extracorporeal photopheresis as part of a multimodality approach yields a high durable clinical response in patients with erythrodremic MF and SS. The kinetics of the response differ between the blood and skin. The blood response occurs earlier and lasts longer; it does not necessarily predict the clinical skin response. Further studies are needed to determine if there is a survival advantage to a blood response in the absence of a skin response., (© 2015 European Academy of Dermatology and Venereology.)

Aim: This study investigated the relationship between lenticulostriated vasculopathy (LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV) infection., Methods: We included all infants with cCMV infection who were followed in our clinic for more than a year with only LSV signs of brain involvement on initial brain ultrasound. Group one comprised 13 infants with no hearing impairment at birth who were not treated with gan/valganciclovir during 2006-2009. Group two was 51 infants with LSV and no hearing impairment who had been treated since mid-2009. Group three was 25 infants born with LSV and hearing loss, who had been treated from birth. Group four was 52 control infants born during the same period with asymptomatic cCMV. Hearing tests were performed during the neonatal period and every four to six months until four years of age., Results: Hearing deterioration was more extensive in group one (85%) than in group two (0%, p < 0.001) and the asymptomatic group (10%, p < 0.001) and occurred more often in group four (10%) than in group two (0%, p = 0.008)., Conclusion: Lenticulostriated vasculopathy was common in infants with cCMV infection and may serve as a sign of central nervous system involvement and further hearing deterioration. Antiviral treatment may be prudent in such infants., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)