Burnout Prevention in Primary Care Providers

Burnout is a pervasive problem in primary healthcare. Mindfulness training has been shown in decrease symptoms associated with burnout and improve overall patient care. This project attempts to evaluate the rates of both burnout and mindfulness in healthcare workers within Rutland County, Vermont. A survey was distributed to both administrative and primary healthcare workers within the Community Health Centers of the Rutland Region system to determine if employees suffer from symptoms of burnout as well as their willingness to participate in mindfulness training.https://scholarworks.uvm.edu/fmclerk/1103/thumbnail.jp

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort

Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment

Prevalence and architecture of de novo mutations in developmental disorders

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Prior exercise alters the difference between arterialised and venous glycaemia:implications for blood sampling procedures

Oral glucose tolerance and insulin sensitivity are common measures, but are determined using various blood sampling methods, employed under many different experimental conditions. This study established whether measures of oral glucose tolerance and oral glucose-derived insulin sensitivity (ISI) differ when calculated from venous versus arterialised blood. Critically, we also established whether any differences between sampling methods are consistent across distinct metabolic conditions (after rest versus after exercise). Ten healthy men completed two trials in a randomised order, each consisting of a 120-minute oral glucose tolerance test (OGTT), either at rest or post-exercise. Blood was sampled simultaneously from a heated hand (arterialised) and an antecubital vein of the contralateral arm (venous). Under both conditions, glucose time-averaged area under the curve was greater from arterialised compared to venous plasma but importantly, this difference was larger after rest relative to after exercise (0.99 ± 0.46 versus 0.56 ± 0.24 mmolL-1 respectively; p < 0.01). OGTT-derived ISIMatsuda and ISICederholm were lower when calculated from arterialised relative to venous plasma and the arterialised-venous difference was greater after rest versus after exercise (ISIMatsuda: 1.97 ± 0.81 versus 1.35 ± 0.57 au, respectively; ISICederholm : 14.76 ± 7.83 versus 8.70 ± 3.95 au, respectively; both p < 0.01). Venous blood provides lower postprandial glucose concentrations and higher estimates of insulin sensitivity, compared to arterialised blood. Most importantly, these differences between blood sampling methods are not consistent after rest versus post-exercise, preventing standardised venous-to-arterialised corrections from being readily applied. Registered under ClinicalTrials.gov Identifier no. NCT02852044

COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience

Background As of November 2020, severe acute respiratory syndrome coronavirus 2 has resulted in 55 million infections worldwide and more than 1.3 million deaths from coronavirus disease 2019 (COVID-19). Outcomes following severe acute respiratory syndrome coronavirus 2 infection in individuals with primary immunodeficiency (PID) or symptomatic secondary immunodeficiency (SID) remain uncertain. Objectives We sought to document the outcomes of individuals with PID or symptomatic SID following COVID-19 in the United Kingdom. Methods At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. Results A total of 100 patients had been enrolled by July 1, 2020, 60 with PID, 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency, and 33 with symptomatic SID. In individuals with PID, 53.3% (32 of 60) were hospitalized, the infection-fatality ratio was 20.0% (12 of 60), the case-fatality ratio was 31.6% (12 of 38), and the inpatient mortality was 37.5% (12 of 32). Individuals with SID had worse outcomes than those with PID; 75.8% (25 of 33) were hospitalized, the infection-fatality ratio was 33.3% (11 of 33), the case-fatality ratio was 39.2% (11 of 28), and inpatient mortality was 44.0% (11 of 25). Conclusions In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus