TriVAD: Successful use of Impella 5.5 and Protek Duo CentriMag RVAD following Heartware HVAD thrombosis as a bridge to heart transplant.

INTRODUCTION: Pump thrombosis remains a feared complication following placement of durable left ventricular assist devices (LVAD) and can be particularly detrimental to individuals being bridged to heart transplantation. Complications associated with this malfunction not only increase morbidity related to right heart failure, hemolysis, and other organ failure, but may ultimately jeopardize a patient's heart transplant candidacy. Additionally, reoperation for durable ventricular device replacement not only poses additional surgical risks to patients but can potentially complicate or even prohibit transplantation in the future. CASE REPORT: This case report describes a novel configuration of temporary, groin-free, percutaneously-deployed biventricular mechanical circulatory devices to support a patient with biventricular failure due to partial LVAD thrombosis. DISCUSSION/CONCLUSION: The use of less invasive mechanical support measures, such as the approach described here, may help patients achieve adequate hemodynamic support while allowing them to remain ambulatory and facilitate successful bridging to heart transplantation.

Differential Tractography: A Biomarker for Neuronal Function in Neurodegenerative Disease.

GM1 gangliosidosis is an ultra-rare inherited neurodegenerative lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. GM1 is uniformly fatal and has no approved therapies, although clinical trials investigating gene therapy as a potential treatment for this condition are underway. Novel outcome measures or biomarkers demonstrating the longitudinal effects of GM1 and potential recovery due to therapeutic intervention are urgently needed to establish efficacy of potential therapeutics. One promising tool is differential tractography, a novel imaging modality utilizing serial diffusion weighted imaging (DWI) to quantify longitudinal changes in white matter microstructure. In this study, we present the novel use of differential tractography in quantifying the progression of GM1 alongside age-matched neurotypical controls. We analyzed 113 DWI scans from 16 GM1 patients and 32 age-matched neurotypical controls to investigate longitudinal changes in white matter pathology. GM1 patients showed white matter degradation evident by both the number and size of fiber tract loss. In contrast, neurotypical controls showed longitudinal white matter improvements as evident by both the number and size of fiber tract growth. We also corroborated these findings by documenting significant correlations between cognitive global impression (CGI) scores of clinical presentations and our differential tractography derived metrics in our GM1 cohort. Specifically, GM1 patients who lost more neuronal fiber tracts also had a worse clinical presentation. This result demonstrates the importance of differential tractography as an important biomarker for disease progression in GM1 patients with potential extension to other neurodegenerative diseases and therapeutic intervention.

Contrasting Retromer with a Newly Described Retriever in Arabidopsis thaliana.

The tight regulation of protein composition within the plasma membranes of plant cells is crucial for the proper development of plants and for their ability to respond to a changing environment. Upon being endocytosed, integral membrane proteins can be secreted, sorted into multivesicular bodies/late endosomes, and degraded in the lytic vacuole, or recycled back to the plasma membrane to continue functioning. The evolutionarily conserved retromer complex has attracted the interest of plant cell biologists for over a decade as it has emerged as a key regulator of the trafficking of endocytosed integral plasma membrane proteins. Recently, a related recycling complex that shares a subunit with retromer was described in metazoan species. Named "retriever", homologs to the proteins that comprise this new recycling complex and its accessory proteins are found within plant lineages. Initial experiments indicate that there is conservation of function between metazoan and plant retriever proteins, suggesting that it is prudent to re-evaluate the available plant retromer data with the added potential of a plant retriever complex.

Barriers to Mental Health Care in US Military Veterans.

BACKGROUND: Military veterans often encounter multiple obstacles to mental health care, such as stigma, practical barriers (e.g., high cost), and negative beliefs about mental health care. To date, however, nationally representative data on the prevalence and key correlates of these barriers to care are lacking. Such data are critical to informing population-based efforts to reduce barriers and promote engagement in mental health treatment in this population. METHODS: Data were analyzed from the National Health and Resilience in Veterans Study, which surveyed 4,069 US veterans, 531 (weighted 15.0%) of whom screened positive for a mental disorder but never received mental health treatment. Multivariable logistic regression and relative importance analyses were conducted to identify key predisposing, enabling, and need-based factors associated with endorsement of stigma, instrumental barriers, and negative beliefs about mental health care. RESULTS: A total 47.1% of veterans endorsed any barrier to care, with 38.7% endorsing instrumental barriers to care, 28.8% perceived stigma, and 22.0% negative beliefs about mental health care. Lower purpose in life, grit, and received social support were most consistently associated with these barriers to care. CONCLUSIONS: Nearly half of US veterans with psychiatric need and no history of mental health treatment report barriers to care. Modifiable characteristics such as a low purpose in life, grit, and received support were associated with endorsement of these barriers. Results may help inform resource allocation, as well as prevention, psychoeducation, and treatment efforts to help reduce barriers and promote engagement with mental health services in this population.

Bodyweight support alters the relationship between preferred walking speed and cost of transport.

Humans tend to select a preferred walking speed (PWS) that minimizes the metabolic energy consumed per distance traveled, i.e. the Cost of Transport (CoT). The aims of this study were to: 1. compare PWS overground vs. on a treadmill at 100 and 50% of body weight, and 2. explore whether with body weight support, PWS corresponds to the speed that minimizes CoT. Fifteen healthy adults walked overground and on a lower body positive pressure treadmill with and without bodyweight support. Walking speeds (m.s-1) were recorded for each condition. Rate of energy expenditure (J.kg-1.min-1) and CoT (J.kg-1.m-1) were then determined from 5-min walking trials with 50% bodyweight support at PWS and ± 30% of the self-selected walking speed for that condition. PWS did not differ across conditions. With 50% body weight support, for each 30% increase in walking speed, rates of metabolic energy expenditure increased ∼15% while CoT decreased by ∼14%. Thus, with 50% body weight support, PWS did not correspond with the speed that minimized CoT. Bodyweight support decreases cost of maintaining an upright body but does not decrease the metabolic demand of limb advancement, contributing to the linear yet not proportional changes in rates of energy expenditure and CoT. We conclude that bodyweight support via an AlterG® treadmill disconnects the association between PWS and minimum CoT. These findings have implications for clinical populations (e.g., obese, elderly) who may benefit from walking on a bodyweight supporting treadmill but may select speeds incompatible with their physical activity goals.

An Atypical Case of Prolonged COVID-19 Infection.

Immunocompromised patients with COVID-19 can have prolonged disease courses that require escalation in care to inpatient or ICU settings. We report a case of a prolonged, active COVID-19 infection in an immunocompromised 61-year-old female with a history of non-Hodgkin's lymphoma. During her hospitalization, her cycle thresholds (CT) continued to worsen despite clinical improvement. We compared our patient's course and CTs to other reported cases in immunocompromised patients, investigating the efficacy of CTs and their use in evaluating disease progression and severity. RT-PCR tests targeting specific types of replicative viral RNA may have more utility in assessing disease severity and infectivity in immunocompromised patients. Our patient's disease course, similar to other reported cases, illustrates the need for improved treatment protocols and infection prevention for the immunocompromised population against SARS-CoV-2.

Effect of neuroanatomy on corticomotor excitability during and after transcranial magnetic stimulation and intermittent theta burst stimulation.

Individual neuroanatomy can influence motor responses to transcranial magnetic stimulation (TMS) and corticomotor excitability after intermittent theta burst stimulation (iTBS). The purpose of this study was to examine the relationship between individual neuroanatomy and both TMS response measured using resting motor threshold (RMT) and iTBS measured using motor evoked potentials (MEPs) targeting the biceps brachii and first dorsal interosseus (FDI). Ten nonimpaired individuals completed sham-controlled iTBS sessions and underwent MRI, from which anatomically accurate head models were generated. Neuroanatomical parameters established through fiber tractography were fiber tract surface area (FTSA), tract fiber count (TFC), and brain scalp distance (BSD) at the point of stimulation. Cortical magnetic field induced electric field strength (EFS) was obtained using finite element simulations. A linear mixed effects model was used to assess effects of these parameters on RMT and iTBS (post-iTBS MEPs). FDI RMT was dependent on interactions between EFS and both FTSA and TFC. Biceps RMT was dependent on interactions between EFS and and both FTSA and BSD. There was no groupwide effect of iTBS on the FDI but individual changes in corticomotor excitability scaled with RMT, EFS, BSD, and FTSA. iTBS targeting the biceps was facilitatory, and dependent on FTSA and TFC. MRI-based measures of neuroanatomy highlight how individual anatomy affects motor system responses to different TMS paradigms and may be useful for selecting appropriate motor targets when designing TMS based therapies.

Hypoglycemia as a Manifestation of Shapiro Syndrome.

Shapiro syndrome is an extremely rare disorder of dysautonomia characterized by paroxysmal episodic hypothermia to below 95°F. Many patients with Shapiro syndrome improve with medical management, though a minority of cases are refractory to treatment. Our patient with adult-onset Shapiro syndrome is an atypical case. Our patient has been refractory to medical treatment as well as chemical sympathectomy. Based on a review of the literature, this is also the first reported case of hypoglycemia with Shapiro syndrome episodes in the absence of other metabolic diseases. This case suggests that hypoglycemia could be a potential manifestation of Shapiro syndrome.

CCDC22 and CCDC93, two potential retriever-interacting proteins, are required for root and root hair growth in Arabidopsis.

Endomembrane trafficking is essential for plant growth and often depends on a balance between secretory and endocytic pathways. VPS26C is a component of the retriever complex which has been shown to function in the recycling of integral plasma membrane proteins in human cell culture and is part of a core retriever complex in Arabidopsis that is required for root hair growth. In this work, we report a characterization of the Arabidopsis homologues of CCDC22 and CCDC93, two additional proteins required for retriever function in humans. Phylogenetic analysis indicates that CCDC22 (AT1G55830) and CCDC93 (AT4G32560) are single copy genes in plants that are present across the angiosperms, but like VPS26C, are absent from the grasses. Both CCDC22 and CCDC93 are required for root and root hair growth in Arabidopsis and localize primarily to the cytoplasm in root epidermal cells. Previous work has demonstrated a genetic interaction between VPS26C function and a VTI13-dependent trafficking pathway to the vacuole. To further test this model, we characterized the vti13 ccdc93 double mutant and show that like vps26c, ccdc93 is a suppressor of the vti13 root hair phenotype. Together this work identifies two new proteins essential for root and root hair growth in plants and demonstrate that the endosomal pathway(s) in which CCDC93 functions is genetically linked to a VTI13-dependent trafficking pathway to the vacuole.

Phage Cocktail Therapy: Multiple Ways to Suppress Pathogenicity.

Phage cocktails have emerged as precision tools for controlling plant bacterial diseases. Wang et al. now report that phage cocktails decreased the occurrence of tomato bacterial wilt disease efficiently by infecting and destroying bacterial pathogens, selecting phage-resistant but slow-growing pathogen strains, and fostering bacterial species that are antagonistic to the pathogens.

Borrowing from Historical Control Data in Cancer Drug Development: A Cautionary Tale and Practical Guidelines.

Some clinical trialists, especially those working in rare or pediatric disease, have suggested borrowing information from similar but already-completed clinical trials. This paper begins with a case study in which relying solely on historical control information would have erroneously resulted in concluding a significant treatment effect. We then attempt to catalog situations where borrowing historical information may or may not be advisable using a series of carefully designed simulation studies. We use an MCMC-driven Bayesian hierarchical parametric survival modeling approach to analyze data from a sponsor's colorectal cancer study. We also apply these same models to simulated data comparing the effective historical sample size, bias, 95% credible interval widths, and empirical coverage probabilities across the simulated cases. We find that even after accounting for variations in study design, baseline characteristics, and standard-of-care improvement, our approach consistently identifies Bayesianly significant differences between the historical and concurrent controls under a range of priors on the degree of historical data borrowing. Our simulation studies are far from exhaustive, but inform the design of future trials. When the historical and current controls are not dissimilar, Bayesian methods can still moderate borrowing to a more appropriate level by adjusting for important covariates and adopting sensible priors.

Nonadherence with Employer-Mandated Sleep Apnea Treatment and Increased Risk of Serious Truck Crashes.

STUDY OBJECTIVES: To evaluate the effect of an employer-mandated obstructive sleep apnea (OSA) program on the risk of serious preventable truck crashes. METHODS: Data are from the first large-scale, employer-mandated program to screen, diagnose, and monitor OSA treatment adherence in the US trucking industry. A retrospective analysis of cohorts was constructed: polysomnogram-diagnosed drivers (OSA positive n = 1,613, OSA negative n = 403) were matched to control drivers unlikely to have OSA (n = 2,016) on two factors affecting crash risk, experience-at-hire and length of job tenure; tenure was matched on the date of each diagnosed driver's polysomnogram. Auto-adjusting positive airway pressure (APAP) treatment was provided to all cases (i.e. OSA positive drivers); treatment adherence was objectively monitored. Cases were grouped by treatment adherence: "Full Adherence" (n = 682), "Partial Adherence" (n = 571), or "No Adherence" (n = 360). Preventable Department-of-Transportation-reportable crashes/100,000 miles were compared across study subgroups. Robustness was assessed. RESULTS: After the matching date, "No Adherence" cases had a preventable Department of Transportation-reportable crash rate that was fivefold greater (incidence rate ratio = 4.97, 95% confidence interval: 2.09, 10.63) than that of matched controls (0.070 versus 0.014 per 100,000 miles). The crash rate of "Full Adherence" cases was statistically similar to controls (incidence rate ratio = 1.02, 95% confidence interval: 0.48, 2.04; 0.014 per 100,000 miles). CONCLUSIONS: Nontreatment-adherent OSA-positive drivers had a fivefold greater risk of serious preventable crashes, but were discharged or quit rapidly, being retained only one-third as long as other subjects. Thus, the mandated program removed risky nontreatment-adherent drivers and retained adherent drivers at the study firm. Current regulations allow nonadherent OSA cases to drive at another firm by keeping their diagnosis private. COMMENTARY: A commentary on this article appears in this issue on page 961.

Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex.

RATIONALE: Diabetes is associated with increased mortality in cystic fibrosis. Aggressive screening and early institution of insulin treatment significantly reduced this risk over the period of 1992-2008. OBJECTIVES: To determine if progressive improvement in cystic fibrosis-related diabetes (CFRD) mortality has continued since 2008, and examine associations with CFTR genotypes linked to pancreatic insufficiency and to sex. METHODS: Chart review was performed on 664 patients followed from 2008 to 2012. MEASUREMENTS AND MAIN RESULTS: Overall mortality for patients with CFRD was 1.8 per 100 person-years, compared with 0.5 in patients with CF without diabetes (P = 0.0002); neither rate changed significantly from mortality reported for 2003-2008. Genotype impacted both mortality and diabetes risk: adults with severe CFTR genotypes experienced greater mortality at every age older than 32 years than those with mild genotypes (P = 0.002), and the risk of developing CFRD was also greatly increased in those with severe genotypes (prevalence 60% in adult patients with severe vs. 14% in adults with mild mutations). CFRD had a direct influence on mortality because it was associated with increased risk of death within each genotype category (20 vs. 2%, P = 0.007 for mild; 12 vs. 4%, P = 0.012 for severe). There was also a sex difference in adults with severe CFTR genotypes; both mortality and CFRD prevalence were higher at every age in females than males. CONCLUSIONS: Despite substantial improvement over time, mortality for CFRD patients greater than 30 years remains higher than for patients with CF without diabetes.