Citations

ABSTRACTUniparental Disomy (UPD) occurs when both copies of a chromosome or chromosomal segment originate from only one parent. Mosaic genome‐wide UPD (mos gwUPD) is typically identified in cases of fetal demise and placental dysplasia or in prenatal cases, where imprinting effects are associated with abnormal ultrasound findings. Children with mos gwUPD and clinical features due to UPD‐associated imprinting effects (especially Beckwith‐Wiedemann syndrome) have been reported; however, reports of adults with mos gwUPD are rare. Here we describe mos gwUPD in two apparently healthy pregnant adult women. Carrier testing noted variants with skewed allelic ratios outside of the normal heterozygous range, prompting further testing. Single nucleotide polymorphism (SNP) microarray identified mosaicism for gwUPD in both individuals, present at 85% and 90%, respectively, in blood, with varying percentages in other tissues. Neither woman displayed clinical features that would be expected with gwUPD at the time of testing, although retrospective careful personal history was consistent. Both women had uneventful pregnancies and delivered full‐term healthy infants. These two cases demonstrate that mos gwUPD can be an incidental finding identified in apparently healthy adult women. Clinical follow‐up is important for tumor monitoring, genetic counseling, and monitoring of future pregnancies due to mos gwUPD in the maternal endometrial tissue.

Introduction: High-power short-duration (HPSD) ablation has emerged as a promising alternative to conventional power delivery (CPD) for pulmonary vein isolation (PVI) among patients with atrial fibrillation (AF). However, its efficacy, procedural efficiency, and safety profile remain uncertain. Methods: PubMed, Embase, Cochrane Library and ClinicalTrials.Gov databases were systematically searched for randomized controlled trials (RCTs) comparing HPSD with CPD ablation for PVI in patients with AF. Random-effects models were used to pool hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI). R version 4.4.2 was used for statistical analysis. Results: Seven RCTs with 1,006 patients (514 HPSD, 489 CPD) were included. No significant differences were found in freedom from arrhythmia during the follow-up period (HR 0.77; 95% CI 0.41–1.45; p=0.424). AF recurrence did not differ (RR 0.94; 95% CI 0.65–1.36; p=0.733) between groups. HPSD had a significantly shorter procedural (MD -22.61 min; 95% CI -33.18, -12.04; p<0.001) and RF ablation times (MD -15.70 min; 95% CI -20.86, -10.55; p<0.001). No differences were observed in fluoroscopy time and first-pass isolation for right and left pulmonary veins. There was no difference in esophageal lesion rates, pericardial, or neurological complications, but there was a higher incidence of steam pops in HPSD (RR 3.42; 95% CI 1.45–8.09; p=0.005). Conclusion: In patients with AF undergoing PVI, HPSD did not increase freedom from arrhythmia as compared with CPD ablation, however it was associated with shorter procedure and RF ablation times with a similar safety profile.

Abstract Background Professional medical societies recommend that carrier screening for 113 different genetic disorders be offered during pregnancy or preconception to all individuals, regardless of ancestry, in order to provide more equitable opportunities for patients to ascertain their reproductive risks. In our clinical laboratory experience, however, the vast majority of healthcare providers continue to order carrier screening for only cystic fibrosis (CF), which is disproportionately common in white individuals of Northern European descent. Our highest volume CF screening test is performed on &gt;10,500 diverse patients per year and utilizes a targeted genotyping array that detects &gt;500 variants in CFTR and &gt;1200 variants in &gt;150 other pertinent genes. Here we report the inequities in diagnostic yield among our first 8,000 patients for whom only limited testing was ordered and examine the barriers to widespread adoption of more inclusive carrier screening. Methods Three carrier screening options (CF, CF+spinal muscular atrophy [SMA], CF+SMA+fragile X syndrome [FXS]+hemoglobinopathies) were ordered clinically and performed on DNA extracted from 8,000 whole blood samples from unique individuals utilizing a custom SNP array (Thermo Fisher GeneTitanTM platform) designed to detect &gt;1700 pathogenic variants in 218 different genes. Data was retrospectively reviewed to determine overall detection rates for carriers of all recommended conditions vs. only the condition(s) included in the originally ordered service. Finally, reproductive health providers at nine different ordering sites across the U.S. were interviewed regarding their current carrier screening practices. Results Patients were referred for testing by 119 different clinical facilities. 98.1% (7847/8000) had CF-only testing ordered, 1.2% (99/8000) had CF+SMA testing ordered, and 0.68% (54/8000) had testing for CF+SMA+FXS+hemoglobinopathies ordered. 7.1% (568/8000) of patients had reportable variants in CFTR. Had CF+SMA testing been ordered on all 8,000 patients, however, the diagnostic yield would have been 8.9%. Of the patients who had CF-only or CF+SMA testing ordered, 11.9% (943/7946) were found to be carriers of hemoglobinopathies. Finally, had all 8000 patients had testing for all currently recommended targets on the panel, the diagnostic yield would have increased to 55% (4396/8000). Ordering providers at 9/50 different contacted sites agreed to interview requests. 100% (9/9) of respondents indicated that their patients experience significant disparities in access to carrier screening, and that the primary cause of these inequities was insufficient insurance reimbursement. 67% (6/9) of respondents indicated that &gt;50% of their patient population identified as non-white and would have “very strongly” benefitted from “testing for other disorders beyond CF.” Conclusions Despite clinical practice guidelines urging for more population-neutral carrier screening, major gaps exist between what is recommended versus ultimately ordered. This significantly limits the clinical utility of testing, especially in patients from underrepresented backgrounds. Improved insurance coverage for more inclusive carrier screening is needed to help reduce such disparities.

Abstract Background Given the elevated prevalence and impact of overweight and the potential risk of non-communicable diseases among women of Somali background in high-income countries and recognising the potential positive impact of physical activity (PA) on these health conditions, it becomes imperative to focus on understanding the PA behaviour of this specific population. The objectives of this paper were twofold: firstly, to provide a comprehensive description of both objectively and subjectively measured PA level and sedentary time in a group of overweight women of Somali background in Norway, and secondly, to assess the effectiveness of a tailored, culturally sensitive, and community-based intervention in enhancing PA levels and reducing sedentary time. Methods 169 overweight women of Somali background in Norway were randomised by borough to either a lifestyle programme or a comparison group. The programme consisted of two sessions per week for 12 weeks, combining classroom discussion with graded group-based PA activity led by coaches, followed by monthly sessions over nine months. PA was measured objectively using the ActivPAL monitor and subjectively using the international PA questionnaire short form (IPAQ). Results The women took on average 6804 (SD = 3286) steps per day and were sedentary for 9.1 hours (SD = 3) per day at baseline. There were no differences between groups on any objectively measured PA variable at any timepoint. There were significant differences on vigorous intensity PA and total PA at the 12-month measurement session between the two groups using the IPAQ. Conclusion Despite observing initially low PA levels and high sedentary time at baseline and thus a considerable potential for intervention, the intervention failed in attaining an increase in objectively measured PA or reduction in sedentary time compared to the control condition. However, self-reported measures indicated success in these aspects. The potential threats to the programme's reliability and validity include contamination, low attendance rates, and high drop-out rates possible due to the COVID-19 pandemic. These challenges underscore the complexity of interventions in this demographic, emphasising the need for further exploration and refinement of study methodologies to effectively enhance PA levels and reduce sedentary time in immigrant women living in high-income countries. Trial registration : clinicaltrials.gov NCT04578067. Keywords: Immigrant Somali women, Lifestyle programme, Overweight, Physical activity, Sedentary time, ActivPAL

Introduction: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are the most aggressive group of hematologic malignancies (Pulte et al, 2020) and will be responsible for approximately 12,700 deaths in the U.S. during 2023(Seiger et al,2023). Improved overall survival (OS) has been observed in the past decades in both diseases, but high mortality in the Intensive Care Unit (ICU) persists, which may prevent ICU admission of those patients. We aimed to review the literature on mortality data and survival predictors of patients with acute leukemia (AL) admitted to the ICU. Methods: Embase, Pubmed and Cochrane databases were searched for articles published from January of 2005 to December of 2020. Due to OS improvement of patients with AML, we only included studies published as of 2005 (Percival et al, 2015). Editorials, case reports and small case series were excluded. Results: Initial search revealed 1,015 manuscripts from database and references, 650 were screened and 115 were fully assessed, for which 24 met eligibility criteria (Figure 1). A total of 13,350 patients were included in the review. Median age was 54.8 years and 57.3% of patients were male. AML represented the majority of diagnoses (98.2%).Two studies included only newly diagnosed patients, 1 study only included patients with relapsed disease and the rest (N=21) included subjects regardless of the AL status. Only 0.7% of patients had a history of hematopoietic stem cell transplantation . 81.9% of patients required mechanical ventilation, 25.3% needed renal replacement therapy, and 65.9% used vasopressors in studies data was available. Median SOFA score in the first 24h of ICU admission was 10.85 . Pooled ICU mortality and hospital mortality were 45.0% and 43.1%, respectively; 58.2% of patients were deceased at 90-day mark (Table 1). The 12 months OS was 37.3%. Higher SOFA score, need for mechanical ventilation, sepsis, vasopressor use, and age greater than 60 years were the most common predictors of ICU, hospital and 90-day mortality. Relapsed or refractory status of underlying AL was the most significant risk factor for long-term mortality. Conclusions: Our systemic review showed that ICU mortality in patients with AL was 45.0%, which represents a survival improvement compared to prior studies on patients with hematological malignancies, where ICU mortality could be as high as 69% (Ashkenazi et al, 1986). Predictors of ICU mortality were closely related to the severity of acute illness rather than malignancy status. We acknowledge that our patient population was mostly comprised of AML cases and the majority of the original studies included a small number of patients with AL with exception of one large study (Halpern et al, 2017).

Introduction Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM. Methods Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (&lt;20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety. Results As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population. After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts. After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation. Conclusion Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

Abstract Uniparental disomy (UPD) is the inheritance of both chromosomal homologs from one parent. Depending on the chromosome involved and the parental origin, UPD may result in phenotypic abnormalities due to aberrant methylation patterns or unmasking recessive conditions in isodisomic regions. UPD primarily originates from somatic rescue of a single meiotically‐derived aneuploidy, most commonly a trisomy. Double UPD is exceedingly rare and triple UPD has not been previously described. Here, we report two unrelated clinical cases with UPD of multiple chromosomes; an 8‐month‐old male with maternal isodisomy of chromosome 7 and paternal isodisomy of chromosome 9, and a 4‐week‐old female with mixed paternal UPD for chromosomes 4, 10, and 14. These cases also demonstrate that although extremely rare, the detection of AOH on two or more chromosomes may warrant additional clinical and laboratory investigation such as methylation and STR marker analysis, especially when involving chromosomes known to be associated with imprinting disorders.