COVID-19 associated phrenic nerve mononeuritis: a case series.

This study characterised the hemidiaphragm elevation on 3-month interval chest X-rays (CXRs) of patients post COVID-19 pneumonia. 467 CXRs were screened; 19 (4.1%) had an elevated hemidiaphragm. There were 15 (3.2%) patients of interest with new hemidiaphragm elevation, persisting on average 7 months post COVID-19 diagnosis. Symptomatic patients underwent diaphragm ultrasound (n=12), pulmonary function test (n=10), muscle function test (n=6) and neurophysiology (n=5), investigating phrenic nerve function. Ultrasound demonstrated reduced/paradoxical diaphragmatic movements in eight; four of eight had reduced thickening fraction. Neurophysiology peripheral limb studies did not support the differential diagnoses of critical illness neuropathy/myopathy. We propose that, in selected patients, COVID-19 may cause phrenic nerve mononeuritis.

Evaluator empathy in risk assessment interviews.

OBJECTIVE: Should forensic evaluators convey empathy during forensic assessments? Opponents contend that empathy causes harm by leading evaluees to disclose potentially incriminating information, but proponents hold that empathy is crucial for establishing rapport and conveying respect. This study provides a comprehensive examination of experienced forensic evaluators' use of empathy in forensic assessment. HYPOTHESES: The study was exploratory and not hypothesis-driven, but we expected to find identifiable subgroups of evaluators who differed in their use of empathy in the context of a risk assessment interview. We also expected that evaluator subgroups would differ in their attitudes and practices regarding empathy and that higher levels of empathy may be associated with more favorable views of evaluees. METHOD: Experienced forensic evaluators (N = 200) assumed the role of interviewer in a written parole risk assessment interview and chose questions (high or low empathy) they would ask the evaluee if they were conducting the interview. Evaluators also provided ratings of their perceptions of the evaluee and responded to questions regarding their attitudes toward, and use of, empathy in forensic assessment. RESULTS: Latent class analysis results indicated that most evaluators fell into low- (46.0%) or moderate- (43.0%) empathy subgroups, with few falling into a high-empathy subgroup (11.0%). Higher levels of empathy in the interview were associated with attitudes and practices supporting empathy use and higher self-reported understanding of the evaluee, but not with opinions of the evaluee's risk or suitability for parole. CONCLUSIONS: These findings of clear differences in evaluator empathy add to the growing body of research documenting the extent to which forensic evaluators differ in their evaluation styles and tendencies. Although there was support for both very low and very high levels of empathy, support for very high levels of empathy was uncommon. Most evaluators opted for low to moderate empathy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study.

PURPOSE: To validate a novel method of urethral stricture treatment using liquid buccal mucosal grafts (LBMG) to augment direct vision internal urethrotomy (DVIU) in an animal model. MATERIALS AND METHODS: A rabbit stricture model was used to test this method. Strictures were induced in 26 rabbits using electroresection of urethral epithelium. The animals were randomized into two groups: Group-1, treated with DVIU and LBMG in fibrin glue, and Group-2, DVIU with fibrin glue only. LBMG was prepared by suspension of mechanically minced buccal mucosa micrografts in fibrin glue. This LBMG-fibrin glue mixture was later injected into the urethrotomies of Group-1 animals. All animals were killed at 24 weeks after repeat retrograde urethrogram (RUG) and urethroscopy by surgeon blinded to the treatment arm. Radiographic images and histological specimens were reviewed by a radiologist and a pathologist, respectively, blinded to the treatment arm. Stricture treatment was considered a success if a diameter measured on RUG increased by ≥ 50% compared to pre-treatment RUG diameter. Histological specimens were assessed for the presence of BMG engraftment. RESULTS: In Group-1, 8/12(67%) animals demonstrated engraftment of LBMG, compared to none in Group-2 (p = 0.0005). 7/12(58%) in Group-1 showed radiographic resolution/improvement of strictures compared to 5/13 Group-2 rabbits (38%, p = 0.145). The median percent change for the Group-1 was 59%, compared to 41.6% for Group-2 (p = 0.29). CONCLUSION: This proof-of-concept study demonstrates feasibility of LBMG for endoscopic urethral stricture repairs. Further studies are needed to establish the role of this novel concept in treatment of urethral strictures.

Iminosugar antivirals: the therapeutic sweet spot.

Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein folding cycle. Viral glycoproteins are thus prevented from interacting with the protein-folding machinery leading to misfolding and an antiviral effect against a wide range of different viral families. As iminosugars target host enzymes, they should be refractory to mutations in the virus. Iminosugars therefore have great potential for development as broad-spectrum antiviral therapeutics. We outline the mechanism giving rise to the antiviral activity of iminosugars, the current progress in the development of iminosugar antivirals and future prospects for this field.

A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia.

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.

Robotic Assisted Caval Replacement for Recurrent Renal Cell Carcinoma Invading the Wall of the Inferior Vena Cava.

OBJECTIVE: To describe a case of robotic inferior vena cava (IVC) resection for an advanced case of renal cell carcinoma with accompanying robotic caval replacement using a synthetic graft. METHODS: In this report and accompanying video we describe a case of complete caval reconstruction with 3 year follow up. A 49-year-old male who at the age of 40 (9 years ago) had undergone right open partial nephrectomy for a pT1b 4.6 cm Fuhrman Grade 2 clear cell RCC with negative margins was found to have a recurrent mass at 6 years of follow up with suspicion of invasion into duodenum and IVC. For his recurrence, he underwent robotic assisted laparoscopic right radical nephrectomy and IVC resection followed by a placement of a 18 mm GORE-TEX graft anastomosed to the caudal and cephalad edges of the resected cava. RESULTS: The surgery was successfully completed using robotic assistance with a total operative time of 6 hours and 40 minutes and 900 cc blood loss. The patient experienced no intraoperative or perioperative complications and was discharged home on postoperative day #2. At 3 year of follow up there is no evidence of local recurrence. The radiology reports repeatedly commented on vascular structures "within normal limits." The patient had experienced no graft issues at a present follow up. CONCLUSION: This case provides a description of the surgery with video demonstration of technique as well as provides a few technical suggestions that may be useful for those who attempt similar surgery in the future.

Pharmacogenomics of Drug Hypersensitivity: Technology and Translation.

Hypersensitivity reactions are caused by many structurally unrelated drugs used for many different diseases. These reactions vary in severity and can be fatal. Only a minority of patients are affected by drug hypersensitivity reactions. Predisposition seems to be mediated by genetic factors, particularly within the HLA system. Apart from HLA-B∗57:01 testing, which is routine to prevent abacavir hypersensitivity, uptake of HLA testing into clinical practice has been slow and challenging. As genomic medicine becomes mainstream, it will be important for genetic testing in this area to move from the current reactive strategy to a more pre-emptive approach.

Factors Affecting Patient and Physician Engagement in Remote Health Care for Heart Failure: Systematic Review.

BACKGROUND: Adult chronic heart failure mainly affects an elderly population with multiple comorbidities that often require frequent medical visits to prevent poor health outcomes. However, the heart failure disease process reduces their independence by reducing mobility, exercise tolerance, and cognitive decline. Remote care technologies can bridge the gap in care for these patients by allowing them to be followed up within the comfort of their home and encourage their self-care. However, patients, carers, and health care professionals need to engage with the technology for it to be useful. OBJECTIVE: This systematic review explores qualitative primary studies of remote care technologies used in heart failure, to determine the factors that affect user engagement with the technology. This is explored from the perspective of patients, carers, and health care professionals. METHODS: Relevant studies published between January 1, 1990, and September 19, 2020, were identified from EMBASE, Ovid MEDLINE, PubMed, Cochrane Library, and Scopus. These studies were then synthesized using thematic analysis. Relevant user experiences with remote care were extracted using line-by-line coding. These codes were summarized into secondary codes and core concepts, which were further merged into overarching themes that encapsulate user experience with remote care. RESULTS: The review included 47 studies, which led to the generation of 5 overarching themes that affect engagement: (1) "Convenience" relates to time saved by the intervention; (2) "Clinical Care" relates to perceived quality of care and health outcomes; (3) "Communication" involves feedback and interaction between patients, staff, and carers; (4) "Education" concerns the tailored information provided; and (5) "Ease of Use" relates to accessibility and technical barriers to engagement. Each theme was applied to each user base of patient, carer, and health care professional in a different manner. CONCLUSIONS: The 5 themes identified highlight aspects of remote care that facilitate engagement, and should be considered in both future design and trials evaluating these technologies.

Coordination of autonomic and endocrine stress responses to the Trier Social Stress Test in adolescence.

Dysregulations in autonomic and endocrine stress responses are linked to the emergence of psychopathology in adolescence. However, most studies fail to consider the interplay between these systems giving rise to conflicting findings and a gap in understanding adolescent stress response regulation. A multisystem framework-investigation of parasympathetic (PNS), sympathetic (SNS), and hypothalamic pituitary adrenal (HPA) axis components and their coordination-is necessary to understand individual differences in stress response coordination which contribute to stress vulnerabilities. As the first investigation to comprehensively evaluate these three systems in adolescence, the current study employed the Trier Social Stress Test in 72 typically developing adolescents (mean age = 13) to address how PNS, SNS, and HPA stress responses are coordinated in adolescence. Hypotheses tested key predictions of the Adaptive Calibration Model (ACM) of stress response coordination. PNS and SNS responses were assessed via heart rate variability (HRV) and salivary alpha amylase (sAA) respectively. HPA responses were indexed by salivary cortisol. Analyses utilized piecewise growth curve modeling to investigate these aims. Supporting the ACM theory, there was significant hierarchical coordination between the systems such that those with low HRV had higher sAA and cortisol reactivity and those with high HRV had low-to-moderate sAA and cortisol responsivity. Our novel results reveal the necessity of studying multisystem dynamics in an integrative fashion to uncover the true mechanisms of stress response and regulation during development. Additionally, our findings support the existence of characteristic stress response profiles as predicted by the ACM model.

Effectiveness of the Med Safety mobile application in improving adverse drug reaction reporting by healthcare professionals in Uganda: a protocol for a pragmatic cluster-randomised controlled trial.

INTRODUCTION: Combination antiretroviral therapy (cART) has massively reduced HIV mortality. However, long-term cART increases the risk of adverse drug reactions (ADRs), which can lead to higher morbidity, mortality and healthcare costs for people living with HIV (PLHIV).Pharmacovigilance-monitoring the effects of medicines-is essential for understanding real-world drug safety. In Uganda, pharmacovigilance systems have only recently been developed, and rates of ADR reporting for cART are very low. Thus, the safety profile of medicines currently used to treat HIV and tuberculosis in our population is poorly understood.The Med Safety mobile application has been developed through the European Union's Innovative Medicines Initiative WEB-Recognising Adverse Drug Reactions project to promote digital pharmacovigilance. This mobile application has been approved for ADR-reporting by Uganda's National Drug Authority. However, the barriers and facilitators to Med Safety uptake, and its effectiveness in improving pharmacovigilance, are as yet unknown. METHODS AND ANALYSIS: A pragmatic cluster-randomised controlled trial will be implemented over 30 months at 191 intervention and 191 comparison cART sites to evaluate Med Safety. Using a randomisation sequence generated by the sealed envelope software, we shall randomly assign the 382 prescreened cART sites to the intervention and comparison arms. Each cART site is a cluster that consists of healthcare professionals and PLHIV receiving dolutegravir-based cART and/or isoniazid preventive therapy. Healthcare professionals enrolled in the intervention arm will be trained in the use of mobile-based, paper-based and web-based reporting, while those in the comparison arm will be trained in paper-based and web-based reporting only. ETHICS AND DISSEMINATION: Ethical approval was given by the School of Biomedical Sciences Research and Ethics Committee at Makerere University (SBS-REC-720), and administrative clearance was obtained from Uganda National Council for Science and Technology (HS1366ES). Study results will be shared with healthcare professionals, policymakers, the public and academia. TRIAL REGISTRATION NUMBER: PACTR202009822379650.

Specificity of localization and phosphotransfer in the CheA proteins of Rhodobacter sphaeroides.

Specificity of protein-protein interactions plays a vital role in signal transduction. The chemosensory pathway of Rhodobacter sphaeroides comprises multiple homologues of chemotaxis proteins characterized in organisms such as Escherichia coli. Three CheA homologues are essential for chemotaxis in R. sphaeroides under laboratory conditions. These CheAs are differentially localized to two chemosensory clusters, one at the cell pole and one in the cytoplasm. The polar CheA, CheA(2), has the same domain structure as E. coli CheA and can phosphorylate all R. sphaeroides chemotaxis response regulators. CheA(3) and CheA(4) independently localize to the cytoplasmic cluster; each protein has a subset of the CheA domains, with CheA(3) phosphorylating CheA(4) together making a functional CheA protein. Interestingly, CheA(3)-P can only phosphorylate two response regulators, CheY(6) and CheB(2). R. sphaeroides CheAs exhibit two interesting differences in specificity: (i) the response regulators that they phosphorylate and (ii) the chemosensory cluster to which they localize. Using a domain-swapping approach we investigated the role of the P1 and P5 CheA domains in determining these specificities. We show that the P1 domain is sufficient to determine which response regulators will be phosphorylated in vitro while the P5 domain is sufficient to localize the CheAs to a specific chemosensory cluster.

Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature.

Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.

Patterns of balance loss with systematic perturbations in Parkinson's disease and multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) and Parkinson's disease (PD) may affect balance differently. However, no studies have compared loss of balance (LOB) patterns following multi-directional perturbations. OBJECTIVE: 1) determine reliability of LOB ratings following standardized manual perturbations; 2) compare LOB ratings in MS, PD, and healthy control (HC) groups following perturbations at upper/lower torso, in anterior/posterior, right/left, and rotational directions. METHODS: 1) reviewers rated videotaped LOB following perturbations applied by 4 clinicians in 6-10 HCs. 2) three groups (64 MS, 42 PD and 32 HC) received perturbations. LOB ratings following perturbations were analyzed using two-factor mixed ANOVAs for magnitude and prevalence. RESULTS: 1) LOB ratings showed moderate to good ICC and good to excellent agreement. 2) MS group showed greater magnitude and prevalence of LOB than PD or HC groups (p < .001). All groups showed greater LOB from right/left versus anterior/posterior perturbations (p < .01). PD showed greater LOB from perturbations at upper versus lower torso; MS and HC showed greater LOB from posterior versus anterior perturbations. CONCLUSIONS: Our reliable rating scale showed differences in patterns of LOB following manual perturbations in MS, PD, and HC. Clinically accessible and reliable assessment of LOB could facilitate targeted perturbation-based interventions and reduce falls in vulnerable populations.

Coarse-grained MD simulations of membrane protein-bilayer self-assembly.

Complete determination of a membrane protein structure requires knowledge of the protein position within the lipid bilayer. As the number of determined structures of membrane proteins increases so does the need for computational methods which predict their position in the lipid bilayer. Here we present a coarse-grained molecular dynamics approach to lipid bilayer self-assembly around membrane proteins. We demonstrate that this method can be used to predict accurately the protein position in the bilayer for membrane proteins with a range of different sizes and architectures.

Dynameomics: a consensus view of the protein unfolding/folding transition state ensemble across a diverse set of protein folds.

The Dynameomics project aims to simulate a representative sample of all globular protein metafolds under both native and unfolding conditions. We have identified protein unfolding transition state (TS) ensembles from multiple molecular dynamics simulations of high-temperature unfolding in 183 structurally distinct proteins. These data can be used to study individual proteins and individual protein metafolds and to mine for TS structural features common across all proteins. Separating the TS structures into four different fold classes (all proteins, all-alpha, all-beta, and mixed alpha/beta and alpha +beta) resulted in no significant difference in the overall protein properties. The residues with the most contacts in the native state lost the most contacts in the TS ensemble. On average, residues beginning in an alpha-helix maintained more structure in the TS ensemble than did residues starting in beta-strands or any other conformation. The metafolds studied here represent 67% of all known protein structures, and this is, to our knowledge, the largest, most comprehensive study of the protein folding/unfolding TS ensemble to date. One might have expected broad distributions in the average global properties of the TS relative to the native state, indicating variability in the amount of structure present in the TS. Instead, the average global properties converged with low standard deviations across metafolds, suggesting that there are general rules governing the structure and properties of the TS.

CGDB: a database of membrane protein/lipid interactions by coarse-grained molecular dynamics simulations.

Membrane protein function and stability has been shown to be dependent on the lipid environment. Recently, we developed a high-throughput computational approach for the prediction of membrane protein/lipid interactions. In the current study, we enhanced this approach with the addition of a new measure of the distortion caused by membrane proteins on a lipid bilayer. This is illustrated by considering the effect of lipid tail length and headgroup charge on the distortion caused by the integral membrane proteins MscS and FLAP, and by the voltage sensing domain from the channel KvAP. Changing the chain length of lipids alters the extent but not the pattern of distortion caused by MscS and FLAP; lipid headgroups distort in order to interact with very similar but not identical regions in these proteins for all bilayer widths investigated. Introducing anionic lipids into a DPPC bilayer containing the KvAP voltage sensor does not affect the extent of bilayer distortion.

Gating at both ends and breathing in the middle: conformational dynamics of TolC.

Drug extrusion via efflux through a tripartite complex (an inner membrane pump, an outer membrane protein, and a periplasmic protein) is a widely used mechanism in Gram-negative bacteria. The outer membrane protein (TolC in Escherichia coli; OprM in Pseudomonas aeruginosa) forms a tunnel-like pore through the periplasmic space and the outer membrane. Molecular dynamics simulations of TolC have been performed, and are compared to simulations of Y362F/R367S mutant, and to simulations of its homolog OprM. The results reveal a complex pattern of conformation dynamics in the TolC protein. Two putative gate regions, located at either end of the protein, can be distinguished. These regions are the extracellular loops and the mouth of the periplasmic domain, respectively. The periplasmic gate has been implicated in the conformational changes leading from the closed x-ray structure to a proposed open state of TolC. Between the two gates, a peristaltic motion of the periplasmic domain is observed, which may facilitate transport of the solutes from one end of the tunnel to the other. The motions observed in the atomistic simulations are also seen in coarse-grained simulations in which the protein tertiary structure is represented by an elastic network model.

MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer.

Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (-93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 -93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 -93G>A polymorphism defines a low penetrance risk allele for CRC.

Dynameomics: mass annotation of protein dynamics and unfolding in water by high-throughput atomistic molecular dynamics simulations.

The goal of Dynameomics is to perform atomistic molecular dynamics (MD) simulations of representative proteins from all known folds in explicit water in their native state and along their thermal unfolding pathways. Here we present 188-fold representatives and their native state simulations and analyses. These 188 targets represent 67% of all the structures in the Protein Data Bank. The behavior of several specific targets is highlighted to illustrate general properties in the full dataset and to demonstrate the role of MD in understanding protein function and stability. As an example of what can be learned from mining the Dynameomics database, we identified a protein fold with heightened localized dynamics. In one member of this fold family, the motion affects the exposure of its phosphorylation site and acts as an entropy sink to offset another portion of the protein that is relatively immobile in order to present a consistent interface for protein docking. In another member of this family, a polymorphism in the highly mobile region leads to a host of disease phenotypes. We have constructed a web site to provide access to a novel hybrid relational/multidimensional database (described in the succeeding two papers) to view and interrogate simulations of the top 30 targets: http://www.dynameomics.org. The Dynameomics database, currently the largest collection of protein simulations and protein structures in the world, should also be useful for determining the rules governing protein folding and kinetic stability, which should aid in deciphering genomic information and for protein engineering and design.

When the cat is out of the bag: a case study in public health rationing in Oregon during the 2004-2005 influenza vaccine shortage.

Whereas the annual influenza season in the United States is fairly predictable, the influenza vaccine supply is variable, leaving providers vulnerable to supply and demand fluctuations each season. During the 2004-2005 influenza vaccine shortage, Oregon invoked Oregon Revised Statute 433-030 to target vaccine supplies to protect persons at highest risk for complications from influenza. This case study describes Oregon's efforts to ration vaccine at the point of administration by limiting the number of individuals eligible for vaccination. An evaluation of this process found that providers responded positively to the mandatory prioritization of vaccine recipients; however, limitations in assessing and affecting redistribution of privately held vaccine supplies and challenges in enforcement of the plan were revealed.