Decreasing Cerebral Oxygen Consumption During Upright Tilt in Vasovagal Syncope

We measured changes in transcranial Doppler ultrasound (TCD) and near infrared spectroscopy (NIRS) during 70 degrees upright tilt in patients with recurrent vasovagal syncope (VVS, N = 20), postural tachycardia syndrome (POTS, N = 20), and healthy controls (N = 12) aged 15-27 years old. VVS was included if they fainted during testing within 5-15 min of upright tilt. We combined TCD and NIRS to obtain estimates of percent change in the cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow velocity (CBFv), and oxygen extraction fraction (OEF). Over the course of 10 min of upright tilt, CBFv decreased from a baseline of 70 +/- 5 to 63 +/- 5 cm/sec in controls and 74 +/- 3 to 64 +/- 3 cm/sec in POTS while decreasing from 74 +/- 4 to 44 +/- 3 cm/sec in VVS CMRO2 was unchanged in POTS and controls during tilt while OEF increased by 19 +/- 3% and 15 +/- 3%, respectively. CMRO2 decreased by 31 +/- 3% in VVS during tilt while OEF only increased by 7 +/- 3%. Oxyhemoglobin decreased by 1.1 +/- 1.3 mumol/kg brain tissue in controls, by 1.1 +/- 1.3 mumol/kg in POTS, and 11.1 +/- 1.3 mumol/kg in VVS CBFv and CMRO2 fell steadily in VVS during upright tilt. The deficit in CMRO2 in VVS results from inadequate OEF in the face of greatly reduced CBF

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Third-Party Fecal Microbiota Transplantation for High-Risk Treatment-Naïve Acute GVHD of the Lower Gi Tract

Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders, and clinical responses were durable without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased after FMT. Although recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT04139577

Whole-Genome Sequencing Uncovers Two Loci for Coronary Artery Calcification and Identifies Arse as a Regulator of Vascular Calcification

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Editors\u27 Introduction: Toward Transitional Justice in Ireland? Addressing Legacies of Harm

The testimony above comes from the CLANN report, an evidence gathering and advocacy project that facilitated survivor participation in the Republic of Ireland’s ongoing Commission of Investigation into Mother and Baby Homes and Certain Related Matters. We open this special issue of Éire-Ireland, entitled Toward Transitional Justice in Ireland? Addressing Legacies of Harm, with survivors’ voices in order to acknowledge that the volume is concerned with the experience of hundreds of thousands of individuals who were born or grew up in Ireland, and of their families across multiple generations, who have been too frequently ignored. As academics and members of the Justice for Magdalenes Research (JFMR) advocacy group, for the past decade we have endeavored to place the motto of survivors, “nothing about us, without us,” at the center of our research and activism on the subject of Ireland’s class, race, disability, and gender-based abuses, so evident in Irish carceral institutions.2021-01-27 JG: PDF replaced with published version at publisher\u27s reques

Advances in DNA diagnostics.

The key advances in DNA diagnostics during the past year are techniques which will lead to advanced throughput without sacrificing sensitivity: miniaturization of samples to reduce material cost and preparation time, and parallelization through use of measurement arrays. The most promising gains have come in the areas of DNA arrays and mass spectrometry, where differential sequencing measurements are now possible

Postural Heart Rate Changes in Young Patients With Vasovagal Syncope

BACKGROUND AND OBJECTIVES: Recurrent postural vasovagal syncope (VVS) is caused by transient cerebral hypoperfusion from episodic hypotension and bradycardia; diagnosis is made by medical history. VVS contrasts with postural tachycardia syndrome (POTS), defined by chronic daily symptoms of orthostatic intolerance with excessive upright tachycardia without hypotension. POTS has recently been conflated with VVS when excessive tachycardia is succeeded by hypotension during tilt testing. We hypothesize that excessive tachycardia preceding hypotension and bradycardia is part of the vasovagal response during tilt testing of patients with VVS. METHODS: We prospectively performed head-up tilt (HUT) testing on patients with recurrent VVS (n = 47, 17.9 +/- 1.1 y), who fainted at least 3 times within the last year, and control subjects (n = 15, 17.1 +/- 1.0 y), from age and BMI-matched volunteers and measured blood pressure, heart rate (HR), cardiac output, total peripheral resistance, and end tidal carbon dioxide. RESULTS: Baseline parameters were the same in both groups. HR (supine versus 5 and 10 minutes HUT) significantly increased in control (65 +/- 2.6 vs 83 +/- 3.6 vs 85 +/- 3.7, P /=40 beats per minute by 5 and 10 minutes or before faint with HUT, occurred in 26% and 44% of patients with VVS, respectively, but not in controls. CONCLUSIONS: Orthostasis in VVS is accompanied by large increases in HR that should not be construed as POTS

The Preponderance of Initial Orthostatic Hypotension in Postural Tachycardia Syndrome

Reduced systolic/diastolic blood pressure (BP) by \u3e40/20 mmHg defines initial orthostatic hypotension (IOH). Rapid resolution of hypotension and lightheadedness follows, but tachycardia may be prolonged. We aimed to examine IOH in controls and patients with postural tachycardia syndrome (POTS) using indices of spontaneous fluctuations of heart rate (HR) and systolic BP as measures of cardiac baroreflex differences. We recruited otherwise healthy IOH patients without POTS (n = 20, 16 ± 3 yr), healthy volunteers (n = 32, 17 ± 3 yr), and POTS patients (n = 39, 17 ± 4 yr). Subjects were instrumented for electrocardiography and beat-to-beat BP. After 10 min supine, subjects stood for 5 min. Following supine recovery, subjects underwent 70° head-up tilt for 10 min to test for POTS. BP, HR, and time, referenced to standing, were measured at events during standing: minimum BP, BP recovery, peak HR, HR minimum, and steady state. Baseline HR and BP were higher in POTS compared with healthy groups. IOH occurred in 13% of controls and 51% of POTS patients. The BP minimum was lower in POTS. Parasympathetic modulation of cardiac baroreflex was decreased in all POTS and control-IOH subjects. Sympathetic indices were increased. Events following BP minimum occurred progressively later in all POTS and control-IOH subjects compared with non-IOH controls. IOH is more frequent in POTS than in controls with a lower minimum BP. POTS has markedly reduced heart rate variability and baroreflex, indicating reduced HR buffering of BP. POTS-IOH and control-IOH subjects had similar peak HR despite decreased minimum BP in POTS. IOH data indicate modest parasympathetic and cardiovagal baroreflex deficits in control-IOH subjects. Parasympathetic deficits are more severe in all POTS patients.NEW & NOTEWORTHY Significant initial orthostatic hypotension (IOH) occurs in ~50% of postural tachycardia syndrome (POTS) patients and 13% of controls. Heart rate and blood pressure recovery are prolonged in IOH sustaining lightheadedness; IOH is more prevalent and severe in POTS. Altered cerebral blood flow and cardiorespiratory regulation are more prevalent in POTS. Altered heart rate variability and baroreflex gain may cause nearly instantaneous lightheadedness in POTS. IOH alone fails to confer a strong probability of POTS