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Background: Ambulatory ECG (AECG) monitoring is pivotal to the diagnosis of arrhythmias and can be performed with near "real-time" notification of abnormalities. There are limited data on the relative benefit of real-time monitoring compared with traditional Holter monitoring., Methods and Results: This is a retrospective observational analysis of University of Utah Health patients who underwent ambulatory ECG studies from 2010 to 2022. The study cohort was stratified by patients with an ambulatory ECG that provides real-time event notification (non-Holter) versus those who do not (Holter). The outcomes were cardiac implantable electronic device procedure, ablation procedure, emergency department/hospitalization visit, and initiation of anticoagulation out to 6 months. We identified 20 259 patients, 16 650 with non-Holter studies and 3609 with Holter studies. Holter patients were younger (mean 52 versus 55, P <0.001), more often women (60.2% versus 57%, P <0.001), and had lower mean CHADS 2 -VA 2 Sc scores (1.7 versus 2.1, P <0.001). The median time to ablation procedure was 74 versus 72 ( P =0.5), for Holter versus non-Holter, respectively. Median days to new cardiac implantable electronic device implantation was 54 days versus 52 ( P =0.6); initiation of anticoagulation among patients not already treated was 42 versus 31 days ( P =0.03). Time to first emergency department visit or hospitalization was 63 versus 57 ( P =0.6). In multivariable models, there were no significant differences in time to intervention between Holter and non-Holter for each outcome., Conclusions: Real-time monitoring demonstrates mixed results in terms of reducing time to intervention, with the significant benefit limited to oral anticoagulation initiation. It is time to revisit clinical scenarios where real-time ambulatory monitoring may not improve health care efficiency.

No risk factors have been identified for vaccine-induced immune thrombotic thrombocytopenia (VITT) so far. The aim of this study was to identify human leucocyte antigen (HLA) alleles potentially associated with VITT susceptibility. Specific HLA class II alleles were detected with significantly higher frequency in VITT patients compared with Italian controls: DPB1*17:01, DQA1*05:01, and DRB1*11:04. In silico analysis revealed increased affinity of DRB1*11:04 for a platelet factor 4 (PF4)-derived peptide, ITSLEVIKA, that contains two amino acids present in the specific binding site of anti-PF4 antibodies from VITT patients. Our findings show for the first time a genetic predisposition to developing anti-PF4 antibodies in response to Ad-vector vaccines., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Trisomy 18 syndrome, also known as Edwards syndrome, is the second most common autosomal chromosome syndrome after Down syndrome. Trisomy 18 is a serious medical disorder due to the increased occurrence of structural defects, the high neonatal and infant mortality, and the disabilities observed in older children. Interventions, including cardiac surgery, remain controversial, and the traditional approach is to pursue pure comfort care. While the medical challenges have been well-characterized, there are scant data on the parental views and perspective of the lived experience of rearing a child with trisomy 18. Knowledge of the parental viewpoints can help clinicians guide families through decision-making. Our aim was to identify parents' perspectives by analyzing a series of narratives. In this qualitative study, we collected 46 parent narratives at the 2015 and 2016 conferences of the Support Organization for Trisomy 18 & 13 (SOFT). The participants were asked to "Tell us a story about your experience." Inductive content analysis and close reading were used to identify themes from the stories. Dedoose, a web-based application to analyze qualitative data, was used to code themes more systematically. Of the identified themes, the most common included Impact of trisomy 18 diagnosis and Surpassing expectations. Other themes included Support from professionals, A child, not a diagnosis, and Trust/lack of trust. We examined the voice and the perspectives of the parents in their challenges in caring for their children with this life-limiting condition. The exploration of the themes can ideally guide clinicians in their approach to the counseling and care of the child in a shared decision-making approach., (© 2024 The Author(s). American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Background: Type 2 diabetes is prevalent in cardiovascular disease and contributes to excess morbidity and mortality. We sought to investigate the effect of glycemia on functional cardiac improvement, morbidity, and mortality in durable left ventricular assist device (LVAD) recipients., Methods and Results: Consecutive patients with an LVAD were prospectively evaluated (n=531). After excluding patients missing pre-LVAD glycated hemoglobin (HbA1c) measurements or having inadequate post-LVAD follow-up, 375 patients were studied. To assess functional cardiac improvement, we used absolute left ventricular ejection fraction change (ΔLVEF: LVEF post-LVAD-LVEF pre-LVAD). We quantified the association of pre-LVAD HbA1c with ΔLVEF as the primary outcome, and all-cause mortality and LVAD-related adverse event rates (ischemic stroke/transient ischemic attack, intracerebral hemorrhage, gastrointestinal bleeding, LVAD-related infection, device thrombosis) as secondary outcomes. Last, we assessed HbA1c differences pre- and post-LVAD. Patients with type 2 diabetes were older, more likely men suffering ischemic cardiomyopathy, and had longer heart failure duration. Pre-LVAD HbA1c was inversely associated with ΔLVEF in patients with nonischemic cardiomyopathy but not in those with ischemic cardiomyopathy, after adjusting for age, sex, heart failure duration, and left ventricular end-diastolic diameter. Pre-LVAD HbA1c was not associated with all-cause mortality, but higher pre-LVAD HbA1c was shown to increase the risk of intracerebral hemorrhage, LVAD-related infection, and device thrombosis by 3 years on LVAD support ( P <0.05 for all). HbA1c decreased from 6.68±1.52% pre-LVAD to 6.11±1.33% post-LVAD ( P <0.001)., Conclusions: Type 2 diabetes and pre-LVAD glycemia modify the potential for functional cardiac improvement and the risk for adverse events on LVAD support. The degree and duration of pre-LVAD glycemic control optimization to favorably affect these outcomes warrants further investigation.

Background: Recent data in nonpregnant individuals suggest a protective effect of influenza vaccination against SARS-CoV-2 infection and its severity., Objectives: Our primary objective was to evaluate whether influenza vaccination was associated with COVID-19 severity and pregnancy and neonatal outcomes among those infected with SARS-CoV-2. The secondary objective was to examine the association between influenza vaccination and SARS-CoV-2 infection., Study Design: Secondary analysis of a multicenter retrospective cohort of pregnant people who tested positive for SARS-CoV-2 between March and August 2020, and a cohort of random deliveries during the same time period. The associations between 2019 influenza vaccination and the primary outcome of moderate-to-critical COVID-19 as well as maternal and perinatal outcomes were examined among all people who tested positive for SARS-CoV-2 between March and August 2020. The association between 2019 influenza vaccination and having a positive SARS-CoV-2 test was examined among a cohort of individuals who delivered on randomly selected dates between March and August 2020. Univariable and multivariable analyses were performed., Results: Of 2325 people who tested positive for SARS-CoV-2, 1068 (45.9%) were vaccinated against influenza in 2019. Those who received the influenza vaccine were older, leaner, more likely to have private insurance, and identify as White or Hispanic. They were less likely to smoke tobacco and identify as Black. Overall, 419 (18.0%) had moderate, 193 (8.3%) severe, and 52 (2.2%) critical COVID-19. There was no association between influenza vaccination and moderate-to-critical COVID-19 (29.2% vs. 28.0%, adjusted OR 1.10, 95% CI 0.90-1.34) or adverse maternal and perinatal outcomes among those who tested positive. Of 8152 people who delivered in 2020, 4658 (57.1%) received the influenza vaccine. Prior vaccination was not associated with a difference in the odds of SARS-CoV-2 infection (3.8% vs. 4.2%, adjusted OR 0.94, 95% CI 0.74-1.19)., Conclusion: Prior influenza vaccination was not associated with decreased severity of COVID-19 or lower odds of SARS-CoV-2 infection in pregnancy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking., Methods and Results: We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death., Conclusions: The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.

Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature., (© 2024 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Study Objective: The objective of the study was to assess clinical outcomes (composite of any venous thromboembolism [VTE], any bleeding, and mortality) associated with anti-Xa monitoring in the 30 days following enoxaparin initiation for VTE prophylaxis., Design: Retrospective cohort study., Setting: Hospital within an academic healthcare system., Patients: Propensity score-matched hospitalized adults receiving enoxaparin for VTE prophylaxis., Intervention: Low-molecular-weight heparin anti-Xa monitoring., Measurements and Main Results: During the 13-month study period, a total of 6611 patients received enoxaparin for VTE prophylaxis, 301 in the anti-Xa monitored group and 6310 in the unmonitored group (4.6% received monitoring). The mean age was 52.9 years and 52% of patients were male. The mean body mass index was 31 kg/m 2 and the mean creatinine clearance was 109 mL/min. Twenty percent of patients had active cancer. The most common indication for enoxaparin prophylaxis was hospitalization for medical illness (52%) followed by nonorthopedic surgery (37%). The adjusted odds ratio for the primary outcome comparing monitored to unmonitored patients was 1.26 (95% confidence interval, 0.75-2.11). None of the between-group differences in the individual components of the composite outcome were statistically significant., Conclusions: Thirty-day clinical outcomes in patients receiving enoxaparin for VTE prophylaxis were not improved by anti-Xa monitoring. Our results support current evidence-based guideline recommendations against anti-Xa monitoring for patients receiving enoxaparin for VTE prophylaxis., (© 2023 Pharmacotherapy Publications, Inc.)

Background and Aims: Patient navigation (PN) may benefit pregnant individuals with opioid use disorder (OUD) by improving treatment adherence. We examined participant enrollment, session delivery and assessment feasibility for a PN intervention among pregnant participants and compared PN preliminary effectiveness for OUD treatment engagement with participants in usual care (UC)., Design: This study was a pilot single-blinded multi-site randomized trial., Setting: Two academic medical centers in Pennsylvania (n = 57) and Utah (n = 45), United States participated., Participants: One hundred and two pregnant adult participants unestablished (fewer than 6 weeks) on medication for OUD (MOUD) were randomized to PN (n = 53) or UC (n = 49)., Intervention: PN was composed of 10 prenatal sessions (delivered after baseline but before the prenatal assessments) and four postnatal sessions (delivered before the 2- and 6-month postpartum assessments) focused upon OUD treatment and physical/mental health needs. UC involved brief case management., Measurements: Feasibility assessments included consent, session delivery and assessment rates. Mixed-effect models for intent-to-treat (ITT) and per protocol (PP, received six or more sessions) populations were estimated to compare outcomes of MOUD use, secondary outcomes of substance use disorder (SUD) treatment attendance and non-prescribed opioid use, and exploratory outcome of overdose at baseline, predelivery and 2 and 6 months postpartum., Findings: We consented 87% (106 of 122) of the proposed target, delivered ~60% of sessions delivered and completed ≥ 75% assessments. PN ITT and PP had better MOUD adherence, SUD treatment attendance, non-prescribed opioid use and overdose outcomes than UC. Notable changes included good evidence for greater percentage change in days for PN PP MOUD use from baseline to 2 months postpartum [PN = 28.0 versus UC = -10.9, 95% confidence interval (CI) = 9.7, 62.1] and some evidence for baseline to 6 months postpartum (PN = 45.4 versus UC = 23.4, 95% CI = -0.7, 48.2). PN PP percentage change in days for SUD treatment attendance also showed good evidence for improvements from baseline to prenatal assessment (PN = 7.4 versus UC = -21.3, 95% CI = 3.3, 53.5). PN compared to UC participants reported fewer overdoses at 2 months (PN = 11.9%/UC = 16.1%) and at 6 months postpartum (PN = 3.8%/UC = 6.2%)., Conclusions: Patient navigation appears to be associated with improvements in opioid use disorder treatment engagement and overdoses during pregnancy. This pilot trial shows the feasibility of the intervention and a future large-scale trial., (© 2023 Society for the Study of Addiction.)

Germline de novo mutations (DNMs) refer to spontaneous mutations arising during gametogenesis, resulting in genetic changes within germ cells that are subsequently transmitted to the next generation. While the impact of maternal exposures on germline DNMs has been extensively studied, more recent studies have begun to highlight the increasing importance of the effects of paternal factors. In this review, we have summarized the existing literature on how various exposures experienced by fathers affect the germline DNM burden in their spermatozoa, as well as their consequences for semen analysis parameters, pregnancy outcomes, and offspring health. A growing body of literature supports the conclusion that advanced paternal age (APA) correlates with a higher germline DNM rate in offspring. Furthermore, lifestyle choices, environmental toxins, assisted reproductive techniques (ART), and chemotherapy are associated with the accumulation of paternal DNMs in spermatozoa, with deleterious consequences for pregnancy outcomes and offspring health. Ultimately, our review highlights the clear importance of the germline DNM mode of inheritance, and the current understanding of how this is affected by various paternal factors. In addition, we explore conflicting reports or gaps of knowledge that should be addressed in future research., (© 2024 American Society of Andrology and European Academy of Andrology.)

Objective: To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses., Design: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study., Setting: Multicenter, 59 hospitals in five geographic regions in the USA., Population: 388 stillbirth cases of the SCRN study (2006-2008)., Methods: Fetal structural malformations were grouped by anatomic system and specific malformation type (e.g. central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNVs >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance., Main Outcome Measures: The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-square test., Results: The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs than among those with normal CNVs (47.5 versus 19.1%; P-value <0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by hydrops, craniofacial defects and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g. CHD1L) and a duplication of 21q22.13 involving four genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively., Conclusion: Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counselling and care surrounding pregnancies affected by FSMs at risk for stillbirth., (© 2023 John Wiley & Sons Ltd.)

Introduction: Vancomycin is frequently used for prolonged courses in treating osteoarticular infections despite a high rate of adverse drug events (ADE). The objective of this study was to evaluate the safety and effectiveness of transitioning to oral therapy compared to continuing parenteral vancomycin in patients with orthopedic infections., Methods: We conducted a single-center, retrospective cohort study of patients with orthopedic infections discharged on parenteral vancomycin with a planned duration of at least 4 weeks. We compared rates of ADE while on vancomycin to rates of ADE after switching to an oral regimen. As a secondary analysis, we compared unplanned hospital readmission within 60 days and treatment failure at 1 year between patients who were transitioned to oral antibiotics within 4 weeks of vancomycin initiation and those that were not., Results: Two hundred twenty-eight patients met the inclusion criteria. Vancomycin was associated with significantly greater toxicity compared to oral regimens. Fifty-one patients had an adverse event while on vancomycin (5.87 ADE per 1000 patient-days) while 9 patients had an adverse event on oral therapy (1.49 ADE per 1000 patient-days) (Rate difference 4.39 per 1000 patient days, 95% CI: 2.52 to 6.26 events per 1000 patient-days). In proportional hazards analysis, transition to an oral antibiotic regimen was independently associated with a lower rate of ADE (aHR 0.12, 95% CI: 0.02-0.86). Forty-one patients (18%) were transitioned to oral therapy within 4 weeks; these patients did not have an increased rate of unplanned readmission (12.2% vs 17.1%) or treatment failure (17.1% vs 21.9%)., Conclusions: Patients transitioned to oral therapy within 4 weeks of discharge had significantly fewer adverse events and similar incidences of 1-year treatment failure compared to patients maintained on parenteral vancomycin. Substituting oral antibiotics for parenteral vancomycin is a potential strategy to minimize vancomycin toxicity during the treatment of orthopedic infections., (© 2023 Pharmacotherapy Publications, Inc.)

Objective: To determine whether women with spontaneous preterm birth (PTB) have increased risks for long-term mortality., Design: Retrospective cohort., Setting: Births in Utah between 1939 and 1977., Population: We included women with a singleton live birth ≥20 weeks who survived at least 1 year following delivery. We excluded those who had never lived in Utah, had improbable birthweight/gestational age combinations, underwent induction (except for preterm membrane rupture) or had another diagnosis likely to cause PTB., Methods: Exposed women had ≥1 spontaneous PTB between 20 +0  weeks and 37 +0  weeks. Women with >1 spontaneous PTB were included only once. Unexposed women had all deliveries at or beyond 38 +0  weeks. Exposed women were matched to unexposed women by birth year, infant sex, maternal age group and infant birth order. Included women were followed up to 39 years after index delivery., Main Outcome Measures: Overall and cause-specific mortality risks were compared using Cox regression., Results: We included 29 048 exposed and 57 992 matched unexposed women. There were 3551 deaths among exposed (12.2%) and 6013 deaths among unexposed women (10.4%). Spontaneous PTB was associated with all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.21-1.31), death from neoplasms (aHR 1.10, 95% CI 1.02-1.18), circulatory disease (aHR 1.35, 95% CI 1.25-1.46), respiratory disease (aHR 1.73, 95% CI 1.46-2.06), digestive disease (aHR 1.33, 95% CI 1.12-1.58), genito-urinary disease (aHR 1.60, 95% CI 1.15-2.23) and external causes (aHR 1.39, 95% CI 1.22-1.58)., Conclusions: Spontaneous PTB is associated with modestly increased risks for all-cause and some cause-specific mortality., (© 2023 John Wiley & Sons Ltd.)

Objective: To assess the relationship between allostatic load, a measure of cumulative chronic stress in early pregnancy and cardiovascular disease risk, 2-7 years postpartum, and pathways contributing to racial disparities in cardiovascular disease risk., Design: Secondary analysis of a prospective cohort study., Setting Multicenter Population: Pregnant women., Methods: Our primary exposure was high allostatic load in the first trimester, defined as at least 4 of 12 biomarkers (systolic blood pressure, diastolic blood pressure, body mass index, cholesterol, low-density lipoprotein, high-density lipoprotein, high-sensitivity C-reactive protein, triglycerides, insulin, glucose, creatinine and albumin) in the unfavourable quartile. Logistic regression was used to test the association between high allostatic load and main outcome adjusted for confounders: time from index pregnancy and follow up, age, education, smoking, gravidity, bleeding in the first trimester, index adverse pregnancy outcomes, and health insurance. Each main outcome component and allostatic load were analysed secondarily. Mediation and moderation analyses assessed the role of high allostatic load in racial disparities of cardiovascular disease risk., Main Outcome Measure: Incident cardiovascular disease risk: hypertension, or metabolic disorders., Results: Cardiovascular disease risk was identified in 1462/4022 individuals (hypertension: 36.6%, metabolic disorder: 15.4%). After adjustment, allostatic load was associated with cardiovascular disease risk (adjusted odds ratio [aOR] 2.0, 95% CI 1.8-2.3), hypertension (aOR 2.1, 95% CI 1.8-2.4) and metabolic disorder (aOR 1.7, 95% CI 1.5-2.1). Allostatic load was a partial mediator between race and cardiovascular disease risk. Race did not significantly moderate this relationship., Conclusions: High allostatic load during pregnancy is associated with cardiovascular disease risk. The relationships between stress, subsequent cardiovascular risk and race warrant further study., (© 2023 John Wiley & Sons Ltd.)

Background: Administration of vancomycin as a continuous infusion has been associated with reduced nephrotoxicity. Given limited published experience with continuous infusion vancomycin in outpatient parenteral antimicrobial therapy (OPAT) programs, we reviewed outcomes from our center., Methods: This was a retrospective, single-center study of adult patients receiving vancomycin OPAT as continuous or intermittent infusion for an intended treatment duration of at least 7 days. The primary outcome was time to nephrotoxicity with continuous versus intermittent infusion vancomycin while on OPAT; additional outcomes included time to any vancomycin-associated adverse event, time to 60-day death or readmission, and time to 60-day emergency department encounter. Proportional hazards modeling was used to identify variables independently associated with outcomes, as well as assess the strength of association of continuous infusion with each outcome., Results: Four-hundred ninety-two patients were included: 118 treated with continuous and 374 with intermittent vancomycin infusion. Continuous infusion was not associated with lower rates of nephrotoxicity compared to intermittent infusion (adjusted hazard ratio (aHR) 0.72, 95% CI: 0.35-1.50). There were no advantages of continuous over intermittent infusion in the rates of any adverse event (aHR 0.93, 95% CI: 0.56-1.53), 60-day death or readmission (aHR 1.04, 95% CI: 0.68-1.61), or 60-day emergency department encounter (aHR 1.17, 95% CI: 0.68-1.99). Vancomycin area under the concentration-time curve (AUC) at discharge was the only modifiable factor identified that was independently associated with patient safety outcomes., Conclusion: There was no appreciable benefit of continuous infusion vancomycin on outpatient safety outcomes. AUC-centered dosing approaches warrant further investigation as strategies to improve vancomycin safety in OPAT programs., (© 2023 Pharmacotherapy Publications, Inc.)

Several studies have suggested a possible relationship between exfoliation syndrome (XFS) and abdominal aortic aneurysm (AAA). A systematic literature review was undertaken to investigate this potential association. The systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clear definitions of XFS and AAA were used to identify eligible studies via an unrestricted search of the PubMed interface from 1979 to October 31st, 2021. After review, 876 citations were gathered and evaluated for inclusion, from which 22 articles were included. Of these 22, 16 were excluded because they did not assess the relationship between AAA and XFS or provide primary data. Ultimately, six studies were included in this literature review. Half of the studies explored AAA prevalence in a population with or without XFS, and the other half explored the opposite. Three studies supported XFS as a risk factor for the development of AAA, and the other three found this relationship to be inconclusive. This systematic review revealed inconsistent results regarding an association between AAA and XFS. A large database study including XFS and AAA patients would be useful in further determining if an association does in fact exist., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined., Methods: EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA., Results: In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR = 0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR = 0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%)., Conclusion: Our findings do not support an association between AAA and XFS/XFG., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Treatment of diabetic ketoacidosis with intravenous insulin is effective but resource intensive. Treatment guidelines recommend transitioning to subcutaneous insulin when the anion gap closes, but transition failures due to recrudescent ketoacidosis are common despite adherence to treatment protocols following such guidance., Study Objective: The primary objective of our study was to evaluate the ability of serum bicarbonate levels of ≤16 mEq/L to predict intravenous to subcutaneous transition failures among those with a normal anion gap at the time of transition., Design and Setting: This retrospective cohort study evaluated critically ill adult patients with a primary diagnosis of diabetic ketoacidosis. Historical patient data were obtained by manual chart review. The primary outcome was transition failure, defined as the re-initiation of intravenous insulin within 24 h of transitioning to subcutaneous insulin. Odds ratios were calculated using generalized estimating equations with a logit link and weighted by standardized inverse probability weights to assess the predictive value of serum bicarbonate levels., Main Results: The primary analysis included 93 patients with a total of 118 distinct transitions. In the adjusted analysis, patients whose anion gap had normalized but had a serum bicarbonate of ≤16 mEq/L were significantly more likely to experience a transition failure (odds ratio = 4.74, 95% confidence interval: 1.24-18.1, p = 0.02). The results of the unadjusted analysis were similar., Conclusions: In patients with a normal anion gap at the time of insulin transition, serum bicarbonate levels of ≤16 mEq/L were associated with significantly increased odds of transition failure., (© 2023 Pharmacotherapy Publications, Inc.)

Background: Evidence on the economic burden of stillbirth is limited. In this systematic review, we aimed to identify studies focusing on the economic burden of stillbirth, describe the methods used, and summarize the findings., Method: We performed a systematic search in Medline, EMBASE, Cochrane library, and EconLit from inception to July 2021. Original studies reporting the cost of illness, economic burden, or health care expenditures related to stillbirth were included. Two reviewers independently extracted data and evaluated study quality using the Larg and Moss checklist. A narrative synthesis was performed. Costs were presented in US dollars (US$) in 2020., Results: From the 602 records identified, a total of four studies were included. Eligible studies were from high-income countries. Only one study estimated both direct and indirect costs. Among three cost-of-illness studies, two studies undertook a prevalence-based approach. The quality of these studies varied and was substantially under-reported. Four studies describing direct costs ranged from $6934 to $9220 per stillbirth. Indirect costs account for around 97% of overall costs. No studies have incorporated intangible cost components., Conclusions: The economic burden of stillbirth has been underestimated and not extensively studied. There are no data on the cost of stillbirth from countries that bear a higher burden of stillbirth. Extensive variation in methodologies and cost components was observed in the studies reviewed. Future research should incorporate all costs, including intangible costs, to provide a comprehensive picture of the true economic impact of stillbirth on society., (© 2023 Wiley Periodicals LLC.)

The lack of United States population-based data on Turner syndrome limits assessments of prevalence and associated characteristics for this sex chromosome abnormality. Therefore, we collated 2000-2017 data from seven birth defects surveillance programs within the National Birth Defects Prevention Network. We estimated the prevalence of karyotype-confirmed Turner syndrome diagnosed within the first year of life. We also calculated the proportion of cases with commonly ascertained birth defects, assessed associations with maternal and infant characteristics using prevalence ratios (PR) with 95% confidence intervals (CI), and estimated survival probability. The prevalence of Turner syndrome of any pregnancy outcome was 3.2 per 10,000 female live births (95% CI = 3.0-3.3, program range: 1.0-10.4), and 1.9 for live birth and stillbirth (≥20 weeks gestation) cases (95% CI = 1.8-2.1, program range: 0.2-3.9). Prevalence was lowest among cases born to non-Hispanic Black women compared to non-Hispanic White women (PR = 0.5, 95% CI = 0.4-0.6). Coarctation of the aorta was the most common defect (11.6% of cases), and across the cohort, individuals without hypoplastic left heart had a five-year survival probability of 94.6%. The findings from this population-based study may inform surveillance practices, prenatal counseling, and diagnosis. We also identified racial and ethnic disparities in prevalence, an observation that warrants further investigation., (© 2023 Wiley Periodicals LLC.)

Background Diagnosis of shockable rhythms leading to defibrillation remains integral to improving out-of-hospital cardiac arrest outcomes. New machine learning techniques have emerged to diagnose arrhythmias on ECGs. In out-of-hospital cardiac arrest, an algorithm within an automated external defibrillator is the major determinant to deliver defibrillation. This study developed and validated the performance of a convolution neural network (CNN) to diagnose shockable arrhythmias within a novel, miniaturized automated external defibrillator. Methods and Results There were 26 464 single-lead ECGs that comprised the study data set. ECGs of 7-s duration were retrospectively adjudicated by 3 physician readers (N=18 total readers). After exclusions (N=1582), ECGs were divided into training (N=23 156), validation (N=721), and test data sets (N=1005). CNN performance to diagnose shockable and nonshockable rhythms was reported with area under the receiver operating characteristic curve analysis, F1, and sensitivity and specificity calculations. The duration for the CNN to output was reported with the algorithm running within the automated external defibrillator. Internal and external validation analyses included CNN performance among arrhythmias, often mistaken for shockable rhythms, and performance among ECGs modified with noise to mimic artifacts. The CNN algorithm achieved an area under the receiver operating characteristic curve of 0.995 (95% CI, 0.990-1.0), sensitivity of 98%, and specificity of 100% to diagnose shockable rhythms. The F1 scores were 0.990 and 0.995 for shockable and nonshockable rhythms, respectively. After input of a 7-s ECG, the CNN generated an output in 383±29 ms (total time of 7.383 s). The CNN outperformed adjudicators in classifying atrial arrhythmias as nonshockable (specificity of 99.3%-98.1%) and was robust against noise artifacts (area under the receiver operating characteristic curve range, 0.871-0.999). Conclusions We demonstrate high diagnostic performance of a CNN algorithm for shockable and nonshockable rhythm arrhythmia classifications within a digitally connected automated external defibrillator. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03662802; Unique identifier: NCT03662802.

Changes in medical intervention over the last decade have improved outcomes for individuals with trisomy 18, the second most common human aneuploidy syndrome at birth. As children with trisomy 18 live longer, a shared concern of medical experts and parents is the occurrence and treatment of seizures. Previously published surveillance guidelines for this condition have not addressed seizure management. Using parent-reported data collected as part of the Tracking Rare Incidence Syndromes project, we report on the prevalence, course, and management of seizures in individuals with trisomy 18. Twenty-eight percent (52/186) of individuals diagnosed with trisomy 18 in our retrospective cohort experienced generalized, focal, or mixed seizures at some point in their lifetime. For many individuals, seizures were effectively managed by broad-spectrum anti-seizure medications. Correlation analysis showed that focal and generalized seizures were more likely to occur in individuals who had previously experienced infantile spasms or central apnea. Electroencephalogram testing should be considered as part of a standard screening approach in individuals with trisomy 18 to enable early diagnosis and treatment of seizures. An international registry that incorporates parent-reported and clinical data for patients with trisomy 18 may facilitate ongoing research and recruitment into clinical trials for seizure management., (© 2023 Wiley Periodicals LLC.)

Objective: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees., Design: State-wide matched case-control study., Setting: Utah, United States., Population: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019., Methods: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models., Main Outcome Measures: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models., Results: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively., Conclusions: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth., (© 2022 John Wiley & Sons Ltd.)

STUDY OBJECTIVE: Aspirin (ASA) has demonstrated inconsistent results in primary prevention of cardiovascular disease (CVD). Guidelines are also inconsistent in the recommendation of routine ASA use for primary prevention of CVD, but advocate dosing as a "one-size-fits-all" approach., Design: An intention-to-treat, double-blind, randomized, controlled, clinical trial comparing three treatment arms of ASA 81, 325, and 500 mg daily dosed for 14 days were evenly randomized across the dosing categories to measure the impact of dosing by body mass index (BMI) (20-24.9, 25-29.9, ≥30 kg/m 2 ) on ASA anti-platelet effects., Setting: University Ambulatory Clinic., Patients: Healthy volunteers defined as individuals who were medication free without acute or chronic significant health problems., Intervention: Change in ASA reactivity unit (ARU), salicylate levels, and thromboxane B2 (TxB2) levels were measured across BMI dosing categories and time. MAIN RESULTS: Fifty-four participants with a mean (±SD) age of 34.4 ± 10.9 years (M:F; 23:31) completed the study. Baseline ARU and TxB2 levels were not significantly different between obese and non-obese individuals. BMI was not a predictor of platelet inhibition. There was no interaction between gender and platelet activation at baseline or following ASA treatment. ASA 81 mg was associated with a lower ARU response (approximate 50% lower response) than either the 325-mg or the 500-mg doses of ASA. TxB2 and salicylate levels exhibited lower trends at 81 mg compared with higher doses., Conclusions: In healthy male and female participants administered ASA for 14 days, obesity is not associated with increased basal platelet activation or ASA resistance. ASA 81 mg was significantly less effective in reducing platelet aggregation compared with ASA 325 and 500 mg, independent of BMI., (© 2023 Pharmacotherapy Publications, Inc.)

Platelets are uniquely positioned as mediators of not only hemostasis but also innate immunity. However, how age and geriatric conditions such as frailty influence platelet function during an immune response remains unclear. We assessed the platelet transcriptome at baseline and following influenza vaccination in Younger (age 21-35) and Older (age ≥65) adults (including community-dwelling individuals who were largely non-frail and skilled nursing facility (SNF)-resident adults who nearly all met criteria for frailty). Prior to vaccination, we observed an age-associated increase in the expression of platelet activation and mitochondrial RNAs and decrease in RNAs encoding proteins mediating translation. Age-associated differences were also identified in post-vaccination response trajectories over 28 days. Using tensor decomposition analysis, we found increasing RNA expression of genes in platelet activation pathways in young participants, but decreasing levels in (SNF)-resident adults. Translation RNA trajectories were inversely correlated with these activation pathways. Enhanced platelet activation was found in community-dwelling older adults at the protein level, compared to young individuals both prior to and post-vaccination; whereas SNF residents showed decreased platelet activation compared to community-dwelling older adults that could reflect the influence of decreased translation RNA expression. Our results reveal alterations in the platelet transcriptome and activation responses that may contribute to age-associated chronic inflammation and the increased incidence of thrombotic and pro-inflammatory diseases in older adults., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: To examine the association of fetal/placental DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in pregnancies complicated by stillbirth., Design: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study., Setting: Multicenter, 59 hospitals in five geographical regions in the USA., Population: 387 stillbirth cases (2006-2008)., Methods: Using standard definitions, PPLs were categorised by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNV >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance., Main Outcome Measures: The proportions of abnormal CNVs and normal CNVs compared between stillbirth cases with and without PPLs using the Wald Chi-square test., Results: Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs than in those with normal CNVs (81.7% versus 64.2%; P = 0.008). The proportions of fetal vascular, maternal/fetal inflammatory and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs and those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several known genes., Conclusions: Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillbirth cases. The findings may provide insight into the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth., (© 2022 John Wiley & Sons Ltd.)

Background: Risk factors for bleeding complications during extracorporeal life support (ECLS) indicated for cardiac support remain poorly investigated. The aim is to develop and internally validate a prediction model to calculate the risk for bleeding complications in adult patients receiving veno-arterial (V-A) ECLS., Methods: Data of the Extracorporeal Life Support Organization registry of adult patients undergoing V-A ECLS between 2010 and 2020 were analyzed. The primary outcome was bleeding complications recorded during V-A ECLS. Multivariable logistic regression with backward stepwise elimination was used to develop the prediction model. Performance of the model was tested by discriminative ability and calibration with receiver operator characteristic, area under the curve, and visual inspection of the calibration plot. Internal validation was performed to detect overfitting of the model., Results: In total 28 767 adult patients were included, of which 29.0% developed bleeding complications. Sex, body mass index, surgical cannulation, pre-ECLS respiratory and hemodynamic variables, pre-ECLS support and interventions, and different type of diagnosis were included in the prediction model. This prediction model showed a predictive capability with an AUC of 0.66., Conclusion: The model is based on the largest cohort of V-A ECLS patients and is the best available predictive model for bleeding events given the predictors that are available in V-A ECLS compared to current literature. The model can help in identifying patients at high risk for bleeding complications and will help in developing further research and decision-making in terms of anticoagulation management. External validation is warranted to extrapolate this model in the clinical setting., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Additional discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the trunk and limbs and define and illustrate the terms that describe the major characteristics of these body regions., (© 2022 Wiley Periodicals LLC.)

Objective: To evaluate whether hypertensive disorders of pregnancy (HDP) among low-risk nulliparous women expectantly managed at or after 39 weeks of gestation are associated with adverse outcomes., Design: Secondary analysis of a randomised trial., Setting: Multicentre, USA., Population: Individuals in the expectantly managed group who delivered on or after 39 weeks., Methods: Multivariable analysis to estimate adjusted relative risks (aRR) for binomial outcomes, adjusted odds ratios (aOR) for multinomial outcomes and 95% CI., Main Outcome Measures: Composite adverse maternal outcome including placental abruption, pulmonary oedema, postpartum haemorrhage, postpartum infection, venous thromboembolism or intensive care unit admission. Secondary outcomes included a composite of perinatal death or severe neonatal complications, mode of delivery, small and large for gestational age and neonatal intermediate or intensive unit length of stay., Results: Of the 3044 women randomised to expectant management in the original trial, 2718 (89.3%) were eligible for this analysis, of whom 373 (13.7%) developed HDP. Compared with participants who remained normotensive, those who developed HDP were more likely to experience the maternal composite (12% versus 6%, aRR 1.84, 95% CI 1.33-2.54) and caesarean delivery (29% versus 23%, aOR 1.32, 95% CI 1.01-1.71). Differences between the two groups were not significantly different for the adverse perinatal composite (7% versus 5%, aRR 1.38, 95% CI 0.92-2.07) or for other secondary outcomes., Conclusion: Almost 14% of low-risk nulliparous individuals expectantly managed at 39 weeks developed HDP, and were more likely to experience adverse maternal outcomes compared with those who did not develop HDP., Tweetable Abstract: Almost 14% of low-risk nulliparous individuals expectantly managed at 39 weeks developed hypertensive disorders of pregnancy, and were more likely to experience adverse maternal outcomes compared with those who did not develop hypertensive disorders., (© 2021 John Wiley & Sons Ltd.)

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Extracorporeal membrane oxygenation (ECMO) use in the United States occurs often in cardiothoracic ICUs (CTICU). It is unknown how it varies across ICU types., Methods: We identified 10 893 ECMO runs from the Extracorporeal Life Support Organization (ELSO) Registry across 2018 and 2019. Primary outcome was ECMO case volume by ICU type (CTICU vs. non-CTICU). Adjusting for pre-ECMO characteristics and case mix, secondary outcomes were on-ECMO physiologic variables by ICU location stratified by support type., Results: CTICU ECMO occurred in 65.1% and 55.1% (2018 and 2019) of total runs. A minority of total runs related to cardiac surgery procedures (CTICU: 21.7% [2018], 18% [2019]; non-CTICU: 11.2% [2018], 13% [2019]). After multivariate adjustment, non-CTICU ECMO for cardiac support associated with lower 4- and 24-h circuit flow (3.9 liters per minute [LPM] vs. 4.1 LPM, p < 0.0001; 4.1 LPM vs. 4.3 LPM, p < 0.0001); for respiratory support, lower on-ECMO mean fraction of inspired oxygen ([F i O 2 ], 67% vs. 69%, p = 0.02) and lower respiratory rate (14 vs. 15, p < 0.0001); and, for extracorporeal cardiopulmonary resuscitation (ECPR), lower ECMO flow rates at 24 h (3.5 LPM vs. 3.7 LPM, p = 0.01)., Conclusions: ECMO mostly remains in CTICUs though a minority is associated with cardiac surgery. Statistically significant but clinically minor differences in on-ECMO metrics were observed across ICU types., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

As growth of the elderly population continues to increase alongside improvements in percutaneous and minimally invasive interventions, cardiac surgeons question the role of high-risk surgery in treating these patients. TAVR has transformed the management of symptomatic severe aortic stenosis in elderly patients and has become standard therapy for patients greater than 80 years of age. With improvements in procedural risks and technical complications for both transcatheter valves and percutaneous interventions, should we rethink the operative strategies for octogenarians and nonagenarians, particularly as they apply to concurrent high-risk operations?, (© 2022 Wiley Periodicals LLC.)

Rare cases of COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S-associated VITT patients are uniformly strongly positive in PF4-polyanion enzyme-linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4-dependent p-selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150 x 10 3 /µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4-polyanion ELISAs and functional assay are non-specific and detect all three conditions. Here, we report that a novel un-complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV-19, from both spontaneous HIT, HIT and commonly-encountered HIT-suspected patients who are PF4/polyanion ELISA-positive but negative in functional assays. In summary, Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis., (© 2022 Wiley Periodicals LLC.)

Background: During extracorporeal life support (ECLS), bleeding is one of the most frequent complications, associated with high morbidity and increased mortality, despite continuous improvements in devices and patient care. Risk factors for bleeding complications in veno-venous (V-V) ECLS applied for respiratory support have been poorly investigated. We aim to develop and internally validate a prediction model to calculate the risk for bleeding complications in adult patients receiving V-V ECLS support., Methods: Data from adult patients reported to the extracorporeal life support organization (ELSO) registry between the years 2010 and 2020 were analyzed. The primary outcome was bleeding complications recorded during V-V ECLS. Multivariable logistic regression with backward stepwise elimination was used to develop the predictive model. The performance of the model was tested by discriminative ability and calibration with receiver operating characteristic curves and visual inspection of the calibration plot., Results: In total, 18 658 adult patients were included, of which 3 933 (21.1%) developed bleeding complications. The prediction model showed a prediction of bleeding complications with an AUC of 0.63. Pre-ECLS arrest, surgical cannulation, lactate, pO 2 , HCO 3 , ventilation rate, mean airway pressure, pre-ECLS cardiopulmonary bypass or renal replacement therapy, pre-ECLS surgical interventions, and different types of diagnosis were included in the prediction model., Conclusions: The model is based on the largest cohort of V-V ECLS patients and reveals the most favorable predictive value addressing bleeding events given the predictors that are feasible and when compared to the current literature. This model will help identify patients at risk of bleeding complications, and decision making in terms of anticoagulation and hemostatic management., (© 2021 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Objective: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth., Design: Secondary analysis of a case-control study., Setting: Multicentre study of five geographic catchment areas in the USA., Population: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls., Main Outcome Measures: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth., Results: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 μmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 μmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 μmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes., Conclusions: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth., Tweetable Abstract: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: To estimate during pregnancy correlations between frequency of self-reported use of marijuana and quantified marijuana metabolite in biospecimens including urine, sera and umbilical cord homogenate., Design: Prospective cohort., Setting: Two urban hospitals in Colorado with legal recreational and medicinal marijuana., Participants: Pregnant women (<16 weeks gestation) self-reporting marijuana use., Measurements: Participants completed a written self-report survey and provided biospecimens at <16 weeks gestation (n = 46), 18 to 22 weeks gestation (n = 43), 32 to 36 weeks gestation (n = 39), and delivery (n = 37). Self-reported marijuana use frequency was calculated based on past-month days of use multiplied by number of daily uses. Maternal urine and sera were tested for presence (>5 ng/mL) of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Liquid chromatography tandem mass spectrometry quantified THC-COOH in umbilical cord homogenate (ng/g). Last marijuana use by any measure was recorded to evaluate the time frame over which THC-COOH remains detectable (>0.10 ng/g) in cord., Findings: From December 2017 through May 2019, 51 pregnant women enrolled, and 46 were included in analyses (2 withdrew and 3 had a spontaneous abortion). The majority were normal weight, White or Black race, and insured by Medicaid. At the time of enrollment between 7 to 15 weeks' gestation, 87% had ongoing use by self-report, or positive urine or serum. The majority (33 [66%]) stopped using before delivery. Sera and urine results were strongly correlated with self-reported use frequency (Spearman correlation coefficient [r] range 0.70-0.87 across visits, P < 0.001), and with each other. There was only one positive cord result when use stopped before 22 weeks. Frequency of self-reported marijuana use at delivery had strong correlation with quantified cord THC-COOH (r = 0.80, 95% CI = 0.62-0.89)., Conclusions: Quantified umbilical cord THC-COOH appears to strongly correlate with frequency of maternal marijuana use in the last month of pregnancy. Earlier use can be measured by either quantitative urine or serum assay., (© 2021 Society for the Study of Addiction.)

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication., (© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Background Recent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD-mediated cardiac improvement to guide patient selection, treatment, and monitoring. Methods and Results Ninety-three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-6, IL-7, IL-13, and interferon gamma were lower in responders, compared with nonresponders ( P <0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription-3, an inflammatory response regulator, was less activated in responders ( P =0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01-0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00-0.43), independently predict cardiac improvement, creating a 2-cytokine model effectively predicting responders (area under the curve, 0.903; P <0.0001). Conclusions Baseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2-cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD-mediated cardiac improvement and device weaning.

Background Cardiogenic shock from most causes has unfavorable prognosis. Hypertrophic cardiomyopathy (HCM) can uncommonly present with apical ballooning and shock in association with sudden development of severe and unrelenting left ventricular (LV) outflow obstruction. Typical HCM phenotypic features of mild septal thickening, outflow gradients, and distinctive mitral abnormalities differentiate these patients from others with Takotsubo syndrome, who have normal mitral valves and no outflow obstruction. Methods and Results We analyzed 8 patients from our 4 HCM centers with obstructive HCM and abrupt presentation of cardiogenic shock with LV ballooning, and 6 cases reported in literature. Of 14 patients, 10 (71%) were women, aged 66±9 years, presenting with acute symptoms: LV ballooning; depressed ejection fraction (25±5%); refractory systemic hypotension; marked LV outflow tract obstruction (peak gradient, 94±28 mm Hg); and elevated troponin, but absence of atherosclerotic coronary disease. Shock was managed with intravenous administration of phenylephrine (n=6), norepinephrine (n=6), β-blocker (n=7), and vasopressin (n=1). Mechanical circulatory support was required in 8, including intra-aortic balloon pump (n=4), venoarterial extracorporeal membrane oxygenation (n=3), and Impella and Tandem Heart in 1 each. In refractory shock, urgent relief of obstruction by myectomy was performed in 5, and alcohol ablation in 1. All patients survived their critical illness, with full recovery of systolic function. Conclusions When cardiogenic shock and LV ballooning occur in obstructive HCM, they are marked by distinctive anatomic and physiologic features. Relief of obstruction with targeted pharmacotherapy, mechanical circulatory support, and myectomy, when necessary for refractory shock, may lead to survival and normalization of systolic function.

Healthcare professionals, including practitioners of medical genetics and genetic counseling, have much to learn about the experiences of parents who are raising and caring for a child with a rare disease or developmental disability. Knowledge and understanding of the challenges in the care of a child with conditions such as Down syndrome and Wolf-Hirschhorn syndrome are at the core of the practice of genetic medicine. Insights into this experience can come from active listening to stories and from deep reading of memoirs and narratives authored by parents of children having these challenges. A recent book, Raising a rare girl: A memoir, by writer, poet, and teacher, Heather Lanier, represents a relevant and prototypic example of this genre. Spending the effort in the contemplation of the parental stories provides a valuable lesson in narrative medicine and the experience of empathy for the plight of the family., (© 2021 Wiley Periodicals LLC.)