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Background: Few reports describe the yield of postmortem genetic testing from medical examiners' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort., Objectives: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States' largest medical examiner office., Methods: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated., Results: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel., Conclusions: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prenylated quinones are membrane-associated metabolites that serve as vital electron carriers for respiration and photosynthesis. The UbiE (EC 2.1.1.201)/MenG (EC 2.1.1.163) C-methyltransferases catalyze pivotal ring methylations in the biosynthetic pathways of many of these quinones. In a puzzling evolutionary pattern, prokaryotic and eukaryotic UbiE/MenG homologs segregate into 2 clades. Clade 1 members occur universally in prokaryotes and eukaryotes, excluding cyanobacteria, and include mitochondrial COQ5 enzymes required for ubiquinone biosynthesis; Clade 2 members are specific to cyanobacteria and plastids. Functional complementation of an Escherichia coli ubiE/menG mutant indicated that Clade 1 members display activity with both demethylbenzoquinols and demethylnaphthoquinols, independently of the quinone profile of their original taxa, while Clade 2 members have evolved strict substrate specificity for demethylnaphthoquinols. Expression of the gene-encoding bifunctional Arabidopsis (Arabidopsis thaliana) COQ5 in the cyanobacterium Synechocystis or its retargeting to Arabidopsis plastids resulted in synthesis of a methylated variant of plastoquinone-9 that does not occur in nature. Accumulation of methylplastoquinone-9 was acutely cytotoxic, leading to the emergence of suppressor mutations in Synechocystis and seedling lethality in Arabidopsis. These data demonstrate that in cyanobacteria and plastids, co-occurrence of phylloquinone and plastoquinone-9 has driven the evolution of monofunctional demethylnaphthoquinol methyltransferases and explains why plants cannot capture the intrinsic bifunctionality of UbiE/MenG to simultaneously synthesize their respiratory and photosynthetic quinones., Competing Interests: Conflict of interest statement. None declared., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sudden deaths due to thoracic aortic dissection or rupture (TADR) are often investigated by forensic pathologists in the United States. Up to a quarter of reported TADR result from a highly penetrant autosomal dominant single gene variant. Testing genes associated with familial TADR provides an underlying etiology for the cause of death and informs effective sudden death prevention for at-risk family members. At the New York City Office of Chief Medical Examiner (NYC-OCME), TADR cases are routinely tested by the in-house, CAP-accredited Molecular Genetics Laboratory. In this retrospective study, TADR and cardiovascular cases were reviewed to understand the burden of TADR in sudden deaths, value of molecular diagnostic testing in TADR, and genotype-phenotype correlations in a demographically diverse TADR cohort., Methods: Between July 2019 and June 2022, cases with in-house cardiovascular genetic testing at NYC-OCME were retrospectively reviewed. Twenty genes associated with familial TADR were analyzed using high throughput massive parallel sequencing on postmortem tissues or bloodspot cards. Variant interpretation was conducted according to ACMG/AMP guidelines., Results: A total of 1078 cases were tested for cardiovascular genetic conditions, of which 34 (3%) had TADR. Eight of those TADR cases had a pathogenic or likely pathogenic variant (P/LPV), 4 had a variant of uncertain significance (VUS), and 22 cases were negative for variants in TADR genes. The molecular diagnostic yield using the TADR subpanel was 23.5%. The genes with the greatest prevalence of P/LPV were FBN1 (6), followed by TGFBR2 (2), TGFBR1 (1), and MYLK (1). Highly penetrant P/LPV in TGFBR2, FBN1, and TGFBR1 were found in TADR individuals who died younger than 34 years old. Two P/LPV in FBN1 were secondary findings unrelated to cause of death. P/LPV in FBN1 included five truncating variants located in the N-terminal domains and one missense variant involved in the disulfide bonds of the EGF-like domain. All P/LPV in TGFBR1 and TGFBR2 were missense or in-frame deletion variants located in the protein kinase catalytic domain. Three variants were first reported in this study., Conclusions: Molecular testing of familial TADR-associated genes is a highly effective tool to identify the genetic cause of TADR sudden deaths and benefits surviving at-risk families., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition with an estimated prevalence rate of 0.3 per 100,000 people. Patient perspectives on healthcare experiences and quality of life have not yet been studied in depth. This novel study aimed to explore one person's lived experience of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, taking into consideration healthcare experiences in relation to diagnosis and treatment., Method: A mixed-method design was used; one participant completed a semi-structured interview and three self-report measures: Hospital Anxiety and Depression Scale; World Health Organisation Quality of Life Scale (brief); Brief Illness Perception Questionnaire., Results: Three qualitative themes appeared to influence the participant's healthcare experiences and quality of life: (1) Diagnosis and treatment, (2) identity and adjustment, and (3) recovery. Diagnosis and treatment summarised the patient's journey to receiving her diagnosis and the difficulties with treatment for this condition. Identity and adjustment included pre and post-diagnosis identity, frustrations and coping strategies. Recovery included experiences of progression and decline and service provision., Conclusion: All Multidisciplinary Team (MDT) interventions for Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome should be person-centred and focus on identity and personal strengths. Further research and service development should be completed to increase awareness and understanding of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, promote patient wellbeing, reduce psychological distress, and facilitate engagement in neurorehabilitation.Implications for rehabilitationPolyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition and incorrect diagnoses and treatment have a significant impact on patients' physical and psychological wellbeing.Patients and families require support through person-centred care and good communication and continuity of care between multiple services.Multi-disciplinary interventions which focus on identity and strengths were beneficial for the participant in this case study.Further research and education are needed to increase knowledge on patient experiences of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome and continue to improve service provision.

Objective: To determine influence of age and HIV infection on influenza vaccine responses., Design: Evaluate serologic response to seasonal trivalent influenza vaccine (TIV) as the immunologic outcome in HIV-infected (HIV⁺) and age-matched HIV negative (HIV⁻) adults., Methods: During 2013-2016, 151 virologically controlled HIV⁺ individuals on antiretroviral therapy and 164 HIV⁻ volunteers grouped by age as young (<40 years), middle aged (40-59 years) and old (≥60 years) were administered TIV and investigated for serum antibody response to vaccine antigens., Results: At prevaccination (T0) titers were in seroprotective range in more than 90% of participants. Antibody titers increased in all participants postvaccination but frequency of classified vaccine responders to individual or all three vaccine antigens at 3-4 weeks was higher in HIV⁻ than HIV⁺ adults with the greatest differences manifesting in the young age group. Of the three vaccine strains in TIV, antibody responses at T2 were weakest against H3N2 with those to H1N1 and B antigens dominating. Among the age groups, the titers for H1N1 and B were lowest in old age, with evidence of an age-associated interaction in HIV⁺ persons with antibody to B antigen., Conclusion: Greater frequencies of vaccine nonresponders are seen in HIV⁺ young compared with HIV⁻ adults and the observed age-associated interaction for B antigen in HIV⁺ persons are supportive of the concept of premature immune senescence in controlled HIV infection. High-potency influenza vaccination recommended for healthy aging could be considered for HIV⁺ adults of all ages.

Introduction: In June 2012, the federal government made cuts to the Interim Federal Health (IFH) Program that reduced or eliminated health insurance for refugee claimants in Canada. The purpose of this study was to examine the effect of the cuts on emergency department (ED) use among patients claiming IFH benefits., Methods: We conducted a health records review at two tertiary care EDs in Ottawa. We reviewed all ED visits where an IFH claim was made at triage, for 18 months before and 18 months after the changes to the program on June 30, 2012 (2011-2013). Claims made before and after the cuts were compared in terms of basic demographics, chief presenting complaints, acuity, diagnosis, presence of primary care, and financial status of the claim. Bivariate or multivariate logistic regression analysis was performed to yield odds ratios (OR) with 95% confidence intervals., Results: There were a total of 612 IFH claims made in the ED from 2011-2013. The demographic characteristics, acuity of presentation and discharge diagnoses were similar during both the before and after periods. Overall, 28.6% fewer claims were made under the IFH program after the cuts. Of the claims made, significantly more were rejected after the cuts than before (13.7% after vs. 3.9% before, adjusted OR 4.28, 95% CI: 2.18-8.40; p<0.05). The majority (75.0%) of rejected claims have not been paid by patients. Fewer patients after the cuts indicated that they had a family physician (20.4% after vs. 30% before, unadjusted OR 1.67, 95% CI: 1.14-2.44; p<0.05) yet a higher proportion of patients without a family physician were still advised to follow up with their family doctor during the after period (67.2% after vs. 41.8% before, unadjusted OR 2.85, 95% CI: 1.45-5.62; p<0.05)., Conclusion: A higher proportion of both rejected and subsequently unpaid claims after the IFH cuts in June 2012, as demonstrated in the logistic regression analysis in this health records review, represents a potential barrier to emergency medical care, as well as a new financial burden to be shouldered by patients and hospitals. A reduction in IFH claims in the ED and a reduction in the number of patients with access to a family physician also suggests inadequate primary care for this population, yet this was not reflected in the follow-up advice offered by ED physicians to patients.

Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old ( > 60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Though substantial work has been done on the usability of health information technology, improvements in electronic health record system (EHR) usability have been slow, creating frustration, distrust of EHRs and the use of potentially unsafe work-arounds. Usability standards could be part of the solution for improving EHR usability. EHR system functional requirements and standards have been used successfully in the past to specify system behavior, the criteria of which have been gradually implemented in EHR systems through certification programs and other national health IT strategies. Similarly, functional requirements and standards for usability can help address the multitude of sequelae associated with poor usability. This paper describes the evidence-based functional requirements for usability contained in the Health Level Seven (HL7) EHR System Functional Model, and the benefits of open and voluntary EHR system usability standards., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To develop a population physiologically-based pharmacokinetic (PBPK) model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that allows extrapolation and prediction of their concentration profiles in liver (efficacy) and muscle (toxicity)., Methods: SV/SVA plasma concentrations (34 healthy volunteers) were simultaneously analysed with NONMEM 7.2. The implemented mechanistic model has a complex compartmental structure allowing inter-conversion between SV and SVA in different tissues. Prior information for model parameters was extracted from different sources to construct appropriate prior distributions that support parameter estimation. The model was employed to provide predictions regarding the effects of a range of clinically important conditions on the SV and SVA disposition., Results: The developed model offered a very good description of the available plasma SV/SVA data. It was also able to describe previously observed effects of an OATP1B1 polymorphism (c.521 T > C) and a range of drug-drug interactions (CYP inhibition) on SV/SVA plasma concentrations. The predicted SV/SVA liver and muscle tissue concentrations were in agreement with the clinically observed efficacy and toxicity outcomes of the investigated conditions., Conclusions: A mechanistically sound SV/SVA population model with clinical applications (e.g., assessment of drug-drug interaction and myopathy risk) was developed, illustrating the advantages of an integrated population PBPK approach.

Background: There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line., Methods: A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses., Results: Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention., Interpretation: We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)