Genome resequencing reveals population divergence and local adaptation of blacklegged ticks in the United States.

Tick vectors and tick-borne disease are increasingly impacting human populations globally. An important challenge is to understand tick movement patterns, as this information can be used to improve management and predictive modelling of tick population dynamics. Evolutionary analysis of genetic divergence, gene flow and local adaptation provides insight on movement patterns at large spatiotemporal scales. We develop low coverage, whole genome resequencing data for 92 blacklegged ticks, Ixodes scapularis, representing range-wide variation across the United States. Through analysis of population genomic data, we find that tick populations are structured geographically, with gradual isolation by distance separating three population clusters in the northern United States, southeastern United States and a unique cluster represented by a sample from Tennessee. Populations in the northern United States underwent population contractions during the last glacial period and diverged from southern populations at least 50 thousand years ago. Genome scans of selection provide strong evidence of local adaptation at genes responding to host defences, blood-feeding and environmental variation. In addition, we explore the potential of low coverage genome sequencing of whole-tick samples for documenting the diversity of microbial pathogens and recover important tick-borne pathogens such as Borrelia burgdorferi. The combination of isolation by distance and local adaptation in blacklegged ticks demonstrates that gene flow, including recent expansion, is limited to geographical scales of a few hundred kilometres.

Interactive Media-Based Approach for an Exception From Informed Consent Trial Involving Patients With Trauma.

Importance: Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive. Objective: To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests. Design, Setting, and Participants: This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024. Exposure: Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial. Main Outcomes and Measures: Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests. Results: Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received. Conclusions and Relevance: The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.

Computational modeling of heart failure in microgravity transitions.

The space tourism industry is growing due to advances in rocket technology. Privatised space travel exposes non-professional astronauts with health profiles comprising underlying conditions to microgravity. Prior research has typically focused on the effects of microgravity on human physiology in healthy astronauts, and little is known how the effects of microgravity may play out in the pathophysiology of underlying medical conditions, such as heart failure. This study used an established, controlled lumped mathematical model of the cardiopulmonary system to simulate the effects of entry into microgravity in the setting of heart failure with both, reduced and preserved ejection fraction. We find that exposure to microgravity eventuates an increased cardiac output, and in patients with heart failure there is an unwanted increase in left atrial pressure, indicating an elevated risk for development of pulmonary oedema. This model gives insight into the risks of space flight for people with heart failure, and the impact this may have on mission success in space tourism.

Diagnostic performance of the ABC score in the PROPPR trial.

INTRODUCTION: The Assessment of Blood Consumption (ABC) score is used to predict massive transfusions (MT). However, its diagnostic performance has not been widely examined, especially when used as an objective tool to enroll patients in multi-center clinical trials. The purpose of this study was to evaluate the performance of the ABC score in enrolling patients in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial. We hypothesized the ABC score would have a similar diagnostic performance to predict the need for massive transfusion as previous studies. METHODS: This is a retrospective analysis of the PROPPR trial. Patients were enrolled either on the basis of an ABC score ≥2, or by Physician Gestalt, when the ABC score was <2. We calculated the sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and likelihood ratios of the ABC score (≥2) for predicting MT (>10 units of red blood cells/24 h or transfusion of >3 units of red blood cells within the first hour). RESULTS: Of the 680 patients, 438 patients (64 %) had an ABC score of ≥2 and 242 (36 %) had an ABC score of <2. An ABC score of ≥2 had 66.8 % sensitivity and 37.0 % specificity for predicting the need for MT, with a PPV of 88.2 % and NPV of 13.1 %. Similarly, an ABC≥2 had 65.6 % sensitivity and 44.6 % specificity for predicting the need for >3 units RBCs in 1 hour, with a PPV of 89.5 % and NPV of 15.3 %. CONCLUSION: The ABC score had lower performance than previously reported for predicting MT, when applied to PROPPR trial patients. The performance for predicting the need for a 3-unit red blood cell transfusion (or more) in the first hour was slightly higher. LEVEL OF EVIDENCE: Level III, Prognostic.

Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis.

Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.

Lizards and the enzootic cycle of Borrelia burgdorferi sensu lato.

Emerging and re-emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard-tick-Borrelia interactions and highlights the importance of an eco-immunology lens for zoonotic pathogen transmission studies.

Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS. METHODS: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures. RESULTS: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule (padj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura (padj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = -2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = -2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = -2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93). DISCUSSION: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.

Is it the People or the Place? The Remarkable 30-Year Period of Integrative Physiology Research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the NIH, Department of Defense, NASA, American Heart Association, and private research foundations totaling ~$80M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ~950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21M in extramural funding. What was accomplished by these few integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

RF coil design strategies for improving SNR at the ultrahigh magnetic field of 10.5 Tesla.

Purpose: To develop multichannel transmit and receive arrays towards capturing the ultimate-intrinsic-SNR (uiSNR) at 10.5 Tesla (T) and to demonstrate the feasibility and potential of whole-brain, high-resolution human brain imaging at this high field strength. Methods: A dual row 16-channel self-decoupled transmit (Tx) array was converted to a 16Tx/Rx transceiver using custom transmit/receive switches. A 64-channel receive-only (64Rx) array was built to fit into the 16Tx/Rx array. Electromagnetic modeling and experiments were employed to define safe operation limits of the resulting 16Tx/80Rx array and obtain FDA approval for human use. Results: The 64Rx array alone captured approximately 50% of the central uiSNR at 10.5T while the identical 7T 64Rx array captured ∼76% of uiSNR at this lower field strength. The 16Tx/80Rx configuration brought the fraction of uiSNR captured at 10.5T to levels comparable to the performance of the 64Rx array at 7T. SNR data obtained at the two field strengths with these arrays displayed dependent increases over a large central region. Whole-brain high resolution T 2 * and T 1 weighted anatomical and gradient-recalled echo EPI BOLD fMRI images were obtained at 10.5T for the first time with such an advanced array, illustrating the promise of >10T fields in studying the human brain. Conclusion: We demonstrated the ability to approach the uiSNR at 10.5T over the human brain with a novel, high channel count array, achieving large SNR gains over 7T, currently the most commonly employed ultrahigh field platform, and demonstrate high resolution and high contrast anatomical and functional imaging at 10.5T.

Survey of Leafminers on American Chestnut and other Castanea spp. (Fagales: Fagaceae) on Long Island, NY.

The effect of the 20th-century functional extinction of the American Chestnut (Fagaceae: Castanea dentata (Marshall) Borkh) on associated herbivorous insects is unknown. These insects include leafminers that spend at least part of their larval phase feeding between the epidermises of leaves. We surveyed leafminers on C. dentata, nonnative Castanea spp., and hybrids on Long Island, NY. We found 10 leafminer species feeding on Castanea spp. A first New York State record was documented for Stigmella castaneaefoliella (Chambers) (Lepidoptera: Nepticulidae). New host records are established for 6 lepidopterans, including a new host genus for Phyllonorycter basistrigella (Clemens) (Lepidoptera: Gracillariidae). We found no significant differences in the mean intensity of S. castaneaefoliella leaf mines on native and nonnative Castanea spp.; however, our sample size was small. Thus, we guardedly conclude that nonnative Castanea spp. can serve as refugia for C. dentata leafminers native to North America while acknowledging that the extent to which nonnative species are utilized requires further investigation.

Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER program.

IMPORTANCE: The frequency and characteristics of post-acute sequelae of SARS-CoV-2 infection (PASC) may vary by SARS-CoV-2 variant. OBJECTIVE: To characterize PASC-related conditions among individuals likely infected by the ancestral strain in 2020 and individuals likely infected by the Delta variant in 2021. DESIGN: Retrospective cohort study of electronic medical record data for approximately 27 million patients from March 1, 2020-November 30, 2021. SETTING: Healthcare facilities in New York and Florida. PARTICIPANTS: Patients who were at least 20 years old and had diagnosis codes that included at least one SARS-CoV-2 viral test during the study period. EXPOSURE: Laboratory-confirmed COVID-19 infection, classified by the most common variant prevalent in those regions at the time. MAIN OUTCOME(S) AND MEASURE(S): Relative risk (estimated by adjusted hazard ratio [aHR]) and absolute risk difference (estimated by adjusted excess burden) of new conditions, defined as new documentation of symptoms or diagnoses, in persons between 31-180 days after a positive COVID-19 test compared to persons without a COVID-19 test or diagnosis during the 31-180 days after the last negative test. RESULTS: We analyzed data from 560,752 patients. The median age was 57 years; 60.3% were female, 20.0% non-Hispanic Black, and 19.6% Hispanic. During the study period, 57,616 patients had a positive SARS-CoV-2 test; 503,136 did not. For infections during the ancestral strain period, pulmonary fibrosis, edema (excess fluid), and inflammation had the largest aHR, comparing those with a positive test to those without a COVID-19 test or diagnosis (aHR 2.32 [95% CI 2.09 2.57]), and dyspnea (shortness of breath) carried the largest excess burden (47.6 more cases per 1,000 persons). For infections during the Delta period, pulmonary embolism had the largest aHR comparing those with a positive test to a negative test (aHR 2.18 [95% CI 1.57, 3.01]), and abdominal pain carried the largest excess burden (85.3 more cases per 1,000 persons). CONCLUSIONS AND RELEVANCE: We documented a substantial relative risk of pulmonary embolism and a large absolute risk difference of abdomen-related symptoms after SARS-CoV-2 infection during the Delta variant period. As new SARS-CoV-2 variants emerge, researchers and clinicians should monitor patients for changing symptoms and conditions that develop after infection.

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

The Effect of an Obesity Prevention Intervention Among Specific Subpopulations: A Heterogeneity of Treatment Effect Analysis of the Greenlight Trial.

Background: Understanding how different populations respond to a childhood obesity intervention could help optimize personalized treatment strategies, especially with the goal to reduce disparities in obesity. Methods: We conducted a secondary analysis of the Greenlight Cluster Randomized Controlled Trial, a health communication focused pediatric obesity prevention trial, to evaluate for heterogeneity of treatment effect (HTE) by child biological sex, caregiver BMI, caregiver reported race and ethnicity, primary language, and health literacy. To examine HTE on BMI z-score from 2 to 24 months of age, we fit linear mixed effects models. Results: We analyzed 802 caregiver-child pairs, of which 52% of children were female, 58% of households reported annual family income of <$20,000, and 83% did not have a college degree. We observed evidence to suggest HTE by primary language (p = 0.047 for Spanish vs. English) and the combination of primary language and health literacy (p = 0.01). There was insufficient evidence to suggest that the Greenlight intervention effect differed by biological sex, caregiver BMI, or by race/ethnicity. Conclusions: This HTE analysis found that the Greenlight obesity prevention intervention had a more beneficial effect on child BMI z-score over 2 years for children of caregivers with limited health literacy and for caregivers for whom Spanish was the primary language.

Short-term behavioral and histological findings following a single concussive and repeated subconcussive brain injury in a rodent model.

PRIMARY OBJECTIVE: It is unclear of the correlation between a mild traumatic brain injury (mTBI) and repeated subconcussive (RSC) impacts with respect to injury biomechanics. Thus, the present study was designed to determine the behavioral and histological differences between a single mTBI impact and RSC impacts with subdivided cumulative kinetic energies of the single mTBI impact. RESEARCH DESIGN: Adult male Sprague-Dawley rats were randomly assigned to a single mTBI impact, RSC impact, sham, or repeated sham groups. METHODS AND PROCEDURES: Following a weight drop injury, anxiety-like behavior and general locomotive activity and were assessed using the open field test, while motor coordination was evaluated using a rotarod unit. Neuronal loss, astrogliosis, and microgliosis were assessed using NeuN, GFAP and Iba-1 immunohistochemistry. All assessments were undertaken at 3- and 7-days post impact. MAIN OUTCOMES AND RESULTS: No behavioral disturbances were observed in injury groups, however, both injury groups did lead to microgliosis following 3-days post-impact. CONCLUSIONS: No pathophysiological differences were observed between a single mTBI impact and RSC impacts of the same energy input. Even though a cumulative injury threshold for RSC impacts was not determined, a threshold still may exist where no pathodynamic shift occurs.

Enrichment of Bioactive Lipids in Urinary Extracellular Vesicles and Evidence of Apoptosis in Kidneys of Hypertensive Diabetic Cathepsin B Knockout Mice after Streptozotocin Treatment.

Cathepsin B (CtsB) is a ubiquitously expressed cysteine protease that plays important roles in health and disease. Urinary extracellular vesicles (uEVs) are released from cells associated with urinary organs. The antibiotic streptozotocin (STZ) is known to induce pancreatic islet beta cell destruction, diabetic nephropathy, and hypertension. We hypothesized that streptozotocin-induced diabetic kidney disease and hypertension result in the release of bioactive lipids from kidney cells that induce oxidative stress and renal cell death. Lipidomics was performed on uEVs isolated from CtsB knockout mice treated with or without STZ, and their kidneys were used to investigate changes in proteins associated with cell death. Lysophosphatidylethanolamine (LPE) (18:1), lysophosphatidylserine (LPS) (22:6), and lysophosphatidylglycerol (LPG) (22:5) were among the bioactive lipids enriched in uEVs from CtsB knockout mice treated with STZ compared to untreated CtsB mice (n = 3 uEV preparations per group). Anti-oxidant programming was activated in the kidneys of the CtsB knockout mice treated with STZ, as indicated by increased expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter SLC7A11 (XCT) (n = 4 mice per group), which was supported by a higher reactivity to 4-hydroxy-2-nonenal (4-HNE), a marker for oxidative stress (n = 3 mice per group). Apoptosis but not ferroptosis was the ongoing form of cell death in these kidneys as cleaved caspase-3 levels were significantly elevated in the STZ-treated CtsB knockout mice (n = 4 mice per group). There were no appreciable differences in the pro-ferroptosis enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) or the inflammatory marker CD93 in the kidneys (n = 3 mice per group), which further supports apoptosis as the prevalent mechanism of pathology. These data suggest that STZ treatment leads to oxidative stress, inducing apoptotic injury in the kidneys during the development of diabetic kidney disease and hypertension.

Generation of a human induced pluripotent stem cell line JHUi004-A with heterozygous mutation for spinocerebellar ataxia type 12 using genome editing.

Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9n genome editing, we have generated a human heterozygous SCA12 iPSC line with 73 triplets for the mutant allele. The heterozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Role of Bß1 overexpression in the pathogenesis of SCA12.

BACKGROUND: Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by a CAG/CTG repeat expansion at the PPP2R2B locus. OBJECTIVE: We investigated how the CAG repeat expansion within the PPP2R2B 7B7D transcript influences the expression of Bß1 and a potential protein containing a long polyserine tract. METHODS: Transcript and protein expression were measured using quantitative PCR (qPCR) Role of Bß1 overexpression in the pathogenesis of SCA12 and Western blot, respectively, in an SK-N-MC cell model that overexpresses the full-length PPP2R2B 7B7D transcript. The apoptotic effect of a protein containing a long polyserine tract on SK-N-MC cells was evaluated using caspase 3/7 activity. RESULTS: The CAG repeat expansion increases the expression of the PPP2R2B 7B7D transcript, as well as Bß1 protein, in an SK-N-MC cell model in which the full-length PPP2R2B 7B7D transcript is overexpressed. The CAG repeat expansion within the 7B7D transcript is translated into a long polyserine tract that triggers apoptosis in SK-N-MC cells. CONCLUSIONS: The SCA12 mutation leads to overexpression of PPP2R2B Bß1 and to expression of a protein containing a long polyserine tract; both these effects potentially contribute to SCA12 pathogenesis. © 2024 International Parkinson and Movement Disorder Society.

An enhancement of the Genium™ microprocessor-controlled knee improves safety and different aspects of the perceived prosthetic experience for unilateral and bilateral users.

Introduction: Bilateral microprocessor-controlled prosthetic knee (MPK) users have unique needs in traversing environmental barriers compared to unilateral users. An enhancement to the Genium™/Genium X3™ MPK which included an updated ruleset, hydraulics, and new bilateral parameter presets was made to improve safety while stumbling and the smoothness of gait for all users while also improving the experience of bilateral users. The purpose of the study was to evaluate the effectiveness of the enhancements in a sample with unilateral and bilateral amputation. Methods: A convenience sample of MPK users was recruited from two sites in the USA in two phases. Assessments included the L-Test of Functional Mobility, Activity-specific Balance Confidence Scale, Prosthetic Limb User Survey of Mobility, a study-specific questionnaire, and the Comparative Activities of Daily Living (ADL) Questionnaire. Statistical significance of extracted data was tested with the Wilcoxon Rank-Sum Test for independent data and Wilcoxon Signed-Rank for paired data with an a priori significance level of p < 0.05. Unilateral subjects were age-matched to the group of bilateral subjects for between-groups and within-groups analyses. Results: Twenty-six subjects (n = 26) were enrolled. Stumble frequency reduced 85% from 16.0 ± 39.7 to 2.4 ± 2.3 (p = 0.008) between baseline and final assessment overall. The bilateral group reported 50% (p = 0.009) and 57% (p = 0.009) greater relative improvement in patient-reported ease and safety, respectively, of completing ADLs compared to the unilateral group. The unilateral group reported residual limb pain and low back pain reduced from 2.3 to 1.4 (p = 0.020) and 3.8 to 1.8 (p = 0.027), respectively, whereas the bilateral group did not. Discussion: Substantial reductions in stumbles, residual limb pain, and back pain were shown overall. These reductions were driven by the unilateral group who also showed improvements in comfort, exertion, and concentration while walking. The enhancements to the knee likely reduced some gait asymmetry for unilateral users. Improvements in patient-reported ease and safety of completing ADLs were shown overall and were driven by the bilateral group. This study shows further improvement in patient experience is achievable through innovation in MPK technology even for patients who appear to be functioning well.

Patient-reported predictors of postdischarge mortality after cardiac hospitalization.

BACKGROUND: Adults hospitalized for cardiovascular events are at high risk for postdischarge mortality. Screening of psychosocial risk is prioritized by the Joint Commission. We tested whether key patient-reported psychosocial and behavioral measures could predict posthospitalization mortality in a cohort of adults hospitalized for a cardiovascular event. METHODS: We conducted a prospective cohort study to test the prognostic utility of validated patient-reported measures, including health literacy, social support, health behaviors and disease management, and socioeconomic status. Cox survival analyses of mortality were conducted over a median of 3.5 years. RESULTS: Among 2977 adults hospitalized for either acute coronary syndrome or acute decompensated heart failure, the mean age was 53 years, and 60% were male. After adjusting for demographic, clinical, and other psychosocial factors, mortality risk was greatest among patients who reported being unemployed (hazard ratio [HR]: 1.99, 95% confidence interval [CI]): 1.30-3.06), retired (HR: 2.14, 95% CI: 1.60-2.87), or unable to work due to disability (HR: 2.36, 95% CI: 1.73-3.21), as compared to those who were employed. Patient-reported perceived health competence (PHCS-2) and exercise frequency were also associated with mortality risk after adjusting for all other variables (HR: 0.86, 95% CI: 0.73-1.00 per four-point increase in PHCS-2; HR: 0.86, 95% CI: 0.77-0.96 per 3-day increase in exercise frequency, respectively). CONCLUSIONS: Patient-reported measures of employment status, perceived health competence, and exercise frequency independently predict mortality after a cardiac hospitalization. Incorporating these brief, valid measures into hospital-based screening may help with prognostication and targeting patients for resources during post-discharge transitions of care.