Met Consensus Criteria Research Articles

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Moving towards a core measures set for patient safety in perioperative care: An e-Delphi consensus study.

A Core Measures Set (CMS) is an agreed standardized group of measures that should be assessed and reported in research for a specific condition or clinical area. This study undertook the development of a CMS for Patient Safety through a two-round, web-based Delphi consensus approach, in the context of the "Improving quality and patient SAFEty in surgical care through STandardisation and harmonization of perioperative care in Europe" (SAFEST) project-a collaborative, patient-centered and evidence-based European Union-funded project that aims to generate action-oriented evidence in perioperative care. We developed an Initial List of Measures via an umbrella review following the deployment of an e-Delphi method with an inclusive panel of experts to prioritize measures towards a consensualized Final List of Measures. All measures were rigorously assessed for both importance and feasibility. After the two rounds of the e-Delphi consensus method we observed 13 preoperative measures (40.6% of the initial number), 24 intraoperative measures (66.7%), 25 postoperative measures (20.3%) and 23 mixed period measures (41.1%) met consensus criteria for both importance and feasibility. Higher scores were detected in importance ratings compared to feasibility across all groups of measures. Importantly, numeric averages regarding pain-related measures differed in the assessment of patients when compared to that of Healthcare Professionals (HCPs). This work not only informs future SAFEST iterations but also sets a precedent for research into valid, patient-centered, and action-oriented perioperative safety measures.

Acute and persistent post-operative pain following mastectomy: a descriptive study in a tertiary hospital cohort.

Post mastectomy pain syndrome (PMPS) can have significant negative effects on patients' quality of life after mastectomy. The estimated prevalence of PMPS varies widely and there is little data from a New Zealand population. This limits clinicians' ability to meaningfully describe and discuss pain-related complications of mastectomy peri-operatively. We designed a single-centre, retrospective study to describe acute post-operative analgesic requirements after mastectomy, to describe the prevalence of PMPS at least 1 year after surgery, and to identify associated risk factors for this complication. One hundred and thirty mastectomy patients met inclusion criteria and 59 were willing and able to participate in 12-month follow-up. Acute post-operative pain was generally well managed with modest doses of oral analgesics. Sixty-six percent (n=39) of women reported some form of persistent pain symptoms post-mastectomy; this was associated with younger age, axillary surgery and chemotherapy. Only 5% of patients (n=3) met consensus criteria for PMPS, which limited identification of risk factors for this more severe complication. Despite PMPS occurring infrequently, post-operative pain of a less severe nature after mastectomy occurs commonly. Clinicians should remain vigilant to possible risk factors for this post-operative complication and counsel patients appropriately.

Data-driven retrieval of population-level EEG features and their role in neurodegenerative diseases.

Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer's disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10-20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer's disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer's Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59-0.91) and Alzheimer's disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer's subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment.

Measuring Quality-weighted Hospital-Free Days in Acute Respiratory Failure: A Modified Delphi Study.

Rationale: Hospital-free days (HFDs), a measure of the number of days alive spent outside the hospital, is increasingly used as an endpoint in studies of patients with acute respiratory failure (ARF) or other critical and serious illnesses. Current approaches to measuring HFDs do not account for decrements in functional status or quality of life that ARF survivors and family members value. Objectives: To develop an acceptable approach to measure quality-weighted HFDs using patient-reported outcomes. Methods: We conducted a four-round modified Delphi process among ARF experts: those with lived or professional experience. Experts rated survivorship domains, instrument and data collection characteristics, and methods to translate responses into quality-weighted HFDs. The consensus threshold was that ⩾70% of respondents rated an item "totally acceptable" or "acceptable" and ⩽15% of respondents rated the item "totally unacceptable," "unacceptable," or "slightly unacceptable." Results: Fifty-seven experts participated in round 1. Response rates were 82-93% for subsequent rounds. Priority survivorship domains were physical function and health-related quality of life. Participants reached a consensus that data collection during ARF recovery should take less than 15 minutes per assessment, allow surrogate completion when patients are unable, and continue for at least 24 months of follow-up. Using the EuroQol-5 Dimensions (EQ-5D) questionnaire to quality weight HFDs met consensus criteria for acceptability. A majority of panelists preferred quality-weighted HFDs to unweighted HFDs or survival for use in future ARF studies. Conclusions: Quality-weighting HFDs using patient and/or surrogate responses to the EQ-5D captured stakeholder priorities and was acceptable to this Delphi panel.

The neuropathology of intimate partner violence

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd–8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd–9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.

ThTP3.7 Video-Based Coaching for Surgeons in the UK: Consensus on Essential Elements

Abstract Aims To determine consensus on essential elements of a video-based surgical coaching program for general surgeons in the United Kingdom. Methods A modified e-Delphi study was designed with three sequential rounds utilising cross-sectional survey design, distributed using REDCAP software. A purposeful sample of international experts from affiliated disciplines were invited to participate. Survey statements were rated on level of importance for inclusion in a coaching program using a 7-point Likert scale (1=extremely unimportant, 7=extremely important). Consensus criteria was defined as 70% of participants rating a given statement at 6 or 7. Results Fifty-nine experts participated. Round 1 consisted of 8 open questions developed from a systematic review of audiovisual coaching. Analysis of responses generated 92 novel statements regarding surgical coaching, categorised within 8 domains: infrastructure (9), coaching session components (9), audio-visual technology (22), program (20), formation of coaching pairs (11), coaches (8), coaches (4), and outcome criteria (9). In round 2, participants rated each statement, with a total of 22 statements reaching consensus criteria, 32 statements for reconsideration, and 38 statements rejected. Currently in round 3, a further 4 statements have met consensus criteria. Overall, the highest rated statements were: Clear and formal training for coaches prior to participation (90.6%) and Coaches should be good communicators (90.6%). Conclusions Prior surgical coaching work has predominantly been implemented in North America. This consensus study has established 26 essential elements for a video-based surgical coaching program in the UK. These results will inform a user-centered design of a video-based coaching pilot.

Development of an Orthopedic Surgery Anatomy Curricular Model for Fourth Year Medical Students Using a Modified Delphi Method

The purpose of this study was to develop anatomy-focused learning outcomes that can be used to design a fourth-year elective for students matriculating into orthopedic surgery residencies. A series of proposed learning outcomes (N=72) was developed using the ACGME Orthopedic Milestones 2.0 as a framework. In 2021, these were converted into a survey asking participants to rate the importance of each outcome on a 5-point Likert scale. The modified Delphi Method was used to refine the list of outcomes until group consensus was achieved. The consensus was defined using a conservative 3-tier approach. Eighteen academic centers with an associated orthopedic surgery residency. Twenty-six orthopedic surgeons (ranging from 1 to 42 years in practice). Of the 72 learning outcomes from the first-round survey, 25 met consensus criteria. Of the 62 learning outcomes from the second-round survey, 45 met consensus criteria. All learning outcomes that met consensus criteria after the second-round survey were stratified into low-yield (n = 8), intermediate-yield (n = 34), and high-yield (n = 28) categories. Using a modified Delphi Method, this study elicited feedback from experts in the field of orthopedic surgery to develop a framework for a fourth-year elective focused on anatomical concepts important for students applying to residencies in orthopedic surgery. The product of this process affords a great deal of flexibility when utilizing the results of this study in institution-specific curricular development.

The core outcomes for open lower limb fracture study.

A core outcome set for adult, open lower limb fracture has been established consisting of 'Walking, gait and mobility', 'Being able to return to life roles', 'Pain or discomfort', and 'Quality of life'. This study aims to identify which outcome measurement instruments (OMIs) should be recommended to measure each core outcome. A systematic review and quality assessment were conducted to identify existing instruments with evidence of good measurement properties in the open lower limb fracture population for each core outcome. Additionally, shortlisting criteria were developed to identify suitable instruments not validated in the target population. Candidate instruments were presented, discussed, and voted on at a consensus meeting of key stakeholders. The Wales Lower Limb Trauma Recovery scale was identified, demonstrating validation evidence in the target population. In addition, ten candidate OMIs met the shortlisting criteria. Six patients, eight healthcare professionals, and 11 research methodologists attended the consensus meeting. Consensus was achieved for the EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and the Lower Extremity Functional Scale (LEFS) to measure 'Quality of life' and 'Walking, gait and mobility' in future research trials, audit, and clinical assessment, respectively. No instrument met consensus criteria to measure 'Being able to return to life roles' and 'Pain or discomfort'. However, the EQ-5D-5L was found to demonstrate good face validity and could also be used pragmatically to measure these two outcomes, accepting limitations in sensitivity. This study recommends the LEFS and EQ-5D-5L to measure the core outcome set for adult open lower limb fracture.

Changes in motor activity level in individuals with frontotemporal dementia.

Changes in motor activity are common in individuals with Frontotemporal dementia (FTD). Yet, it remains unclear why some individuals become motorically hyperactive, while others hypoactive even in early stages of the disease. This study aimed to examine the relationship between motor activity level and (1) FTD clinical subtype, and (2) cortical thickness and subcortical volumes. Eighty-two charts were retrospectively reviewed from patients meeting consensus criteria for one of the three main clinical subtypes of FTD: probable bvFTD, semantic variant Primary Progressive Aphasia (PPA), or non-fluent variant PPA. Participants were assigned to one of three groups: (1) hyperactive, (2) hypoactive, or (3) no record of change. Hyperactivity was prevalent among bvFTD (58.5%) and semantic PPA (68.8%) subtypes while hypoactivity was less common in both subtypes (29.3% and 18.8%, respectively). The majority of patients with non-fluent PPA showed no record of change in motor activity (66.7%). The analysis of cortical thickness and subcortical volumes did not identify significant associations with motor activity levels. In conclusion, increased motor activity is highly prevalent among individuals with FTD, especially bvFTD and svPPA subtypes. These findings may inform prognosis and prediction of changes in motor activity, and allow planning for appropriate environmental and behavioural interventions. Future studies with prospective, standardized longitudinal collection of information regarding the type and level of change in motor activity, including wearable measures of actigraphy, may help to further delineate the onset and progression of abnormal motor behaviours and determine neuroanatomic associations in FTD.

Lymphoid Interstitial Pneumonia (LIP) Revisited: A Critical Reappraisal of the Histologic Spectrum of "Radiologic" and "Pathologic" LIP in the Context of Diffuse Benign Lymphoid Proliferations of the Lung.

The use of lymphoid interstitial pneumonia (LIP) as a diagnostic term has changed considerably since its introduction. Utilizing a multi-institutional collection of 201 cases from the last 20 years that demonstrate features associated with the LIP rubric, we compared cases meeting strict histologic criteria of LIP per American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus ("pathologic LIP"; n=62) with cystic cases fulfilling radiologic ATS/ERS criteria ("radiologic LIP"; n=33) and with other diffuse benign lymphoid proliferations. "Pathologic LIP" was associated with immune dysregulation including autoimmune disorders and immune deficiency, whereas "radiologic LIP" was only seen with autoimmune disorders. No case of idiopathic LIP was found. On histology, "pathologic LIP" represented a subgroup of 70% (62/88) of cases with the distinctive pattern of diffuse expansile lymphoid infiltrates. In contrast, "radiologic LIP" demonstrated a broad spectrum of inflammatory patterns, airway-centered inflammation being most common (52%; 17/33). Only 5 cases with radiologic cysts also met consensus ATS/ERS criteria for "pathologic LIP." Overall, broad overlap was observed with the remaining study cases that failed to meet consensus criteria for "radiologic LIP" and/or "pathologic LIP." These data raise concerns about the practical use of the term LIP as currently defined. What radiologists and pathologist encounter as LIP differs remarkably, but neither "radiologic LIP" nor "pathologic LIP" present with sufficiently distinct findings to delineate such cases from other patterns of diffuse benign lymphoid proliferations. As a result of this study, we believe LIP should be abandoned as a pathologic and radiologic diagnosis.

Obesity and Eligibility for Obesity Treatments Among Adults With Disabilities in the U.S.

Obesity has been associated with disability; yet, the proportion who meet clinical criteria for obesity treatment among adults with disabilities remains poorly defined. Characterization of obesity and treatment eligibility by disability type may prioritize high-need groups. This study assessed the prevalence of obesity and eligibility for antiobesity pharmacotherapy and/or bariatric surgery in adults with disability. This cross-sectional weighted analysis of the 2019 National Health Interview Survey, including self-reported health and sociodemographic information, was conducted in 2021. Burden of obesity defined by BMI and odds of meeting consensus criteria for antiobesity pharmacotherapy and/or surgery were calculated by functional disability type: vision, hearing, cognition, communication, mobility, and self-care. From 29,170 community-dwelling adult respondents (59.1% response), the overall prevalence of disability was 10%. The prevalence of obesity among adults with a disability was 40.1% vs 30.5% for U.S. adults overall (p<0.0001). An estimated 17.1% with disability met the criteria for both bariatric surgery and antiobesity pharmacotherapy; another 39.8% were eligible for pharmacotherapy alone (vs 7.9% and 33.2%, respectively, for adults overall; p<0.0001). In fully adjusted models, disability was associated with greater ORs for mild obesity (OR=1.2; 95% CI=1.1, 1.4), moderate‒severe obesity (OR=2.1; 95% CI=1.8, 2.3), and criteria for bariatric surgery (OR=2.4; 95% CI=2.1, 2.7) and pharmacotherapy (OR=1.3; 95% CI=1.2, 1.4). Mobility, self-care, and cognition disabilities were associated with eligibility for bariatric surgery and antiobesity pharmacotherapy. Individuals with disabilities have higher odds of obesity and eligibility for antiobesity treatments. Comorbidities should be considered, accommodations should be provided, and insurance coverage should be expanded to ensure access to antiobesity treatments for adults with disabilities.

Risk of adverse outcomes for small fetuses not meeting consensus criteria for fetal growth restriction

To assess whether an independent association exists between an estimated fetal weight (EFW) and/or abdominal circumference (AC) < 10th centile and adverse outcomes when Delphi consensus criteria [Gordijn S et al Ultrasound Obstet Gynecol 2016;48(3):333-9] for fetal growth restriction (FGR) are not met.

Principles to guide spinal cord injury research partnerships: a Delphi consensus study

Purpose To establish consensus regarding principles that should be used to guide spinal cord injury (SCI) research partnerships between researchers and research users. Materials and methods A three-round Delphi consensus exercise was carried out with researchers and/or research users involved in one or more SCI research partnerships. Participants considered a list of 125 partnership principles. In rounds 1 and 2, participants rated their agreement that a principle should guide SCI research partnerships on an 11-point Likert scale. After each round, principles that received a mean score of ≥8.0 or 70% of participants rated the principle ≥8.0 were retained. In round 3, participants categorized principles as essential, desirable, irrelevant, or unsure. Results At least 20 individuals participated in each round. In round 1, 103 principles met consensus criteria and eight principles were added. In round 2, 93 principles met the criteria. In round 3, 29 principles were categorized as essential and eight as desirable. Recommended principles focused on the interpersonal, relational, and logistical aspects of partnerships. Principles that did not reach consensus related to social justice and actionable impact. Conclusions Findings provide insight into 37 principles that could be used to combat tokenism and inform future guidance to meaningfully engage partners in SCI research. Implications for Rehabilitation Consensus-based research partnership principles (i.e., norms or beliefs) were identified and could be prioritized to help support spinal cord injury (SCI) researchers and research users combat tokenism and meaningfully engage research users as partners in the co-creation of knowledge. The resulting list of recommended research partnership principles was used to inform the development of guidance to support quality partnerships between SCI researchers and research users within and outside the rehabilitation context (www.IKTprinciples.com). Guidance supporting meaningful research partnerships may accelerate the time between discovery and use of research in practice.

Systems-Level Opportunities in the Management of Primary Hyperparathyroidism: An Informatics-based Assessment.

Primary hyperparathyroidism (PHPT), a leading cause of hypercalcemia and secondary osteoporosis, is underdiagnosed. This work aims to establish a foundation for an electronic medical record-based intervention that would prompt serum parathyroid hormone (PTH) assessment in patients with persistent hypercalcemia and identify care gaps in their management. A retrospective cohort study was conducted in a tertiary academic health system of outpatients with persistent hypercalcemia, who were categorized as having classic or normohormonal PHPT. Main outcome measures included the frequencies of serum PTH measurement in patients with persistent hypercalcemia, and their subsequent workup with bone mineral density (BMD) assessment, and ultimately, medical therapy or parathyroidectomy. Among 3151 patients with persistent hypercalcemia, 1526 (48%) had PTH measured, of whom 1377 (90%) were confirmed to have classic (49%) or normohormonal (41%) PHPT. PTH was measured in 65% of hypercalcemic patients with osteopenia or osteoporosis (P < .001). At median 2-year follow-up, bone density was assessed in 275 (20%) patients with either variant of PHPT (P = .003). Of women aged 50 years or older with classic PHPT, 95 (19%) underwent BMD assessment. Of patients with classic or normohormonal PHPT, 919 patients (67%) met consensus criteria for surgical intervention, though only 143 (15%) underwent parathyroidectomy. Within a large academic health system, more than half of patients with confirmed hypercalcemia were not assessed for PHPT, including many patients with preexisting bone disease. Care gaps in BMD assessment and medical or surgical therapy represent missed opportunities to avoid skeletal and other complications of PHPT.

Influence of Autoimmune Antibody Testing on the Use of Immunotherapy on an Inpatient Neurology Service.

To determine the frequency of autoimmune antibody testing in an inpatient neurology setting and its influence on immunotherapy use on an inpatient neurology service. A retrospective descriptive cohort study of patients admitted to the neurology inpatient service at a large tertiary academic medical center who had autoimmune and/or paraneoplastic antibody testing performed between 10/1/2017 and 10/1/2018. Characteristics of patients' initial clinical presentation, antibody testing results, test timing in relation to initiating immunotherapy, and final diagnosis using consensus criteria were extracted and analyzed. Case reports of patients with positive antibody panels are presented. Of 1,604 patients, 50 patients (3.1%) had an antibody panel sent. Tests resulted after an average of 17 days (range 7-27). The most common clinical presenting symptom in those with a panel sent was encephalopathy. There were 5 (10%) positive serum panels and no positive CSF panels. Only one of these 5 patients had autoimmune encephalitis and was treated with immunotherapy. Of those with negative serum and CSF panels, 15 were treated acutely with empiric immunotherapy and the remainder with supportive care. Of those treated with immunotherapy, 14/15 (93%) were treated before the panel tests resulted. Four patients who had negative panels but were empirically treated met consensus criteria for an autoimmune-mediated neurologic process. Our study suggests that the results of antibody testing did not influence inpatient neurologists' decision to treat with immunotherapy as most treatments began prior to final results being available.

Self-Report Fatigue Management for Instrumental Musicians: A Delphi Survey.

Mismanagement of fatigue and playing load have been consistently identified as risk factors for playing-related pain and injuries. Studies in sport demonstrate that fatigue management strategies can predict and prevent overuse syndromes and related injuries through consistent assessment of playing load and physical/psychological stress. Self-report strategies show particular responsiveness to both the short and long-term impacts of training. No equivalent fatigue management strategies exist for musicians. Establish key items and feasibility parameters to inform the development of a self-report fatigue management tool for musicians. A working party of international experts in musicians' medicine was invited to complete a two-phase Delphi survey. In Phase I, working party members rated established items from sport (REST-Q subscales with demonstrated responsiveness to both acute and chronic training stresses) with respect to relevance and prospective utility for musicians. Members could also propose additional items and were asked to indicate a maximum feasible questionnaire length. In Phase II, working party members ranked top performing items from Phase I. Consensus best items were determined based on Phase II rankings. A 28-member working party was assembled (15 clinicians, 13 researchers). Of 20 researcher proposed items and 58 working party proposed items, 5 items met consensus criteria: I had pain; I had to play too much; I felt physically fit; I did not get enough sleep; I recovered well physically. A strong majority (89%) of working party members indicated that regular use of a fatigue questionnaire with up to 10 items is feasible. Key questionnaire items and feasibility parameters for a novel fatigue management tool for musicians are established. Future research in musicians is needed to validate study results and this novel fatigue management tool.

Myocardial Gene Expression Signatures in Human Heart Failure With Preserved Ejection Fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes half of all HF but lacks effective therapy. Understanding of its myocardial biology remains limited because of a paucity of heart tissue molecular analysis. We performed RNA sequencing on right ventricular septal endomyocardial biopsies prospectively obtained from patients meeting consensus criteria for HFpEF (n=41) contrasted with right ventricular septal tissue from patients with HF with reduced ejection fraction (HFrEF, n=30) and donor controls (n=24). Principal component analysis and hierarchical clustering tested for transcriptomic distinctiveness between groups, effect of comorbidities, and differential gene expression with pathway enrichment contrasted HF groups and donor controls. Within HFpEF, non-negative matrix factorization and weighted gene coexpression analysis identified molecular subgroups, and the resulting clusters were correlated with hemodynamic and clinical data. Patients with HFpEF were more often women (59%), African American (68%), obese (median body mass index 41), and hypertensive (98%), with clinical HF characterized by 65% New York Heart Association Class III or IV, nearly all on a loop diuretic, and 70% with a HF hospitalization in the previous year. Principal component analysis separated HFpEF from HFrEF and donor controls with minimal overlap, and this persisted after adjusting for primary comorbidities: body mass index, sex, age, diabetes, and renal function. Hierarchical clustering confirmed group separation. Nearly half the significantly altered genes in HFpEF versus donor controls (1882 up, 2593 down) changed in the same direction in HFrEF; however, 5745 genes were uniquely altered between HF groups. Compared with controls, uniquely upregulated genes in HFpEF were enriched in mitochondrial adenosine triphosphate synthesis/electron transport, pathways downregulated in HFrEF. HFpEF-specific downregulated genes engaged endoplasmic reticulum stress, autophagy, and angiogenesis. Body mass index differences largely accounted for HFpEF upregulated genes, whereas neither this nor broader comorbidity adjustment altered pathways enriched in downregulated genes. Non-negative matrix factorization identified 3 HFpEF transcriptomic subgroups with distinctive pathways and clinical correlates, including a group closest to HFrEF with higher mortality, and a mostly female group with smaller hearts and proinflammatory signaling. These groupings remained after sex adjustment. Weighted gene coexpression analysis yielded analogous gene clusters and clinical groupings. HFpEF exhibits distinctive broad transcriptomic signatures and molecular subgroupings with particular clinical features and outcomes. The data reveal new signaling targets to consider for precision therapeutics.

Coronavirus Disease 2019 and Acute Respiratory Distress Syndrome: Why the Intensivist Is More Important Than Ever.

Coronavirus Disease 2019 and Acute Respiratory Distress Syndrome: Why the Intensivist Is More Important Than Ever.

Risk of Neuroleptic Malignant Syndrome with Vesicular Monoamine Transporter Inhibitors.

ObjectiveVesicular monoamine transporter-2 (VMAT2) inhibitors have been proven to be effective for the treatment of tardive dyskinesia and their use is likely to increase. The evidence base of published clinical reports was reviewed to evaluate the possible risk of neuroleptic malignant syndrome (NMS) with these drugs.MethodsPubmed, Embase, Web of Science and PsycINFO databases were queried for all years using terms for “neuroleptic malignant syndrome”, “hyperthermia” AND “vesicular monoamine transporter inhibitors”, “reserpine”, “tetrabenazine”, “valbenazine” or “deutetrabenazine”ResultsThirteen clinical cases, ten of which involved tetrabenazine, were identified in which VMAT2 inhibitors were prescribed in patients with current or past NMS episodes. In most cases, the association was confounded by limited reporting of clinical data, variable temporal correlation with VMAT2 inhibitors, polypharmacy with antipsychotics, and uncertain differential diagnoses.ConclusionWhile rare cases of NMS meeting consensus criteria have been reported primarily with tetrabenazine, the risk with recently developed VMAT2 inhibitors may be even less. Evidence of causality of NMS with VMAT2 inhibitors is confounded by concomitant treatment with antipsychotics and diagnostic uncertainties in patients susceptible to basal ganglia dysfunction. Nevertheless, clinicians should remain vigilant for early signs of NMS in all patients treated with any drugs that affect brain dopamine activity.