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Background: Group A Streptococcus (GAS; Streptococcus pyogenes) is an important human pathogen that can cause life-threatening invasive disease, ranging from skin/soft tissue infections to infective endocarditis. In the fall of 2022, the Center for Disease Control & Prevention (CDC) issued an alert due to a global increase in invasive GAS infections, particularly among children and adults with co-morbidities. An increase in invasive disease was observed at our five-hospital healthcare system in Southeast Michigan. The objective of this study was to describe characteristics of patients with invasive GAS and characterize treatment and outcomes of disease. Methods: This was a retrospective cross-sectional study of patients from June 2013 to August 2023 with positive blood cultures for GAS. Patients were identified using a data query for positive blood cultures for GAS through Microsoft SQL Server. Patients with age < 1 8 years, polymicrobial bacteremia, incomplete data, or who were enrolled in hospice and/or died within 48-hours of admission were excluded. Collected variables included: demographics, infection characteristics (syndrome, duration of bacteremia), microbiological characteristics (antimicrobial susceptibility testing; AST), antimicrobial treatment (empiric and final, antitoxin therapy), and clinical outcomes (length of hospital stay [LOS], treatment-associated adverse events, 30-day mortality and infection-related readmission). Results: 250 patients were included (Table 1). More than half were male with median age of 57.5 years. Diabetes mellitus (38%) and chronic kidney disease (23%) were common comorbidities [Table 1]. Persons experiencing homelessness and persons who use injection drugs accounted for 9% and 13% of the cases, respectively. The most common infective syndrome accompanying bacteremia was cellulitis (57%). The majority of patients received vancomycin for empiric therapy (81%) and penicillin (38%) or cephalosporin (36%) for final regimen [Table 2]. A total of 79 GAS isolates (32%) were clindamycin resistant. Clindamycin was included in the empiric regimen of 20 (8%) patients, the final regimen in 44 (18%) of patients, and as antitoxin adjunct therapy in 135 (54%) of patients. A third (33%) of patients received no antitoxin. The average duration of antitoxin therapy was 3.6 days and antimicrobial therapy 19.9 days. The mean LOS was 11.4 days (Table 3). Thirty nine (16%) patients had treatment failure and 8 (3%) experienced C. difficile infection within 30 days of antimicrobial treatment. Thirty-day mortality was 11%; of these, 9% had in-hospital mortality. Conclusions: Invasive GAS infection confers significant morbidity and mortality, and ongoing research is needed to determine the best treatment regimens in the era of increasing clindamycin resistance.

Introduction: Hospital-onset Clostridioides difficile infection (HO-CDI), reported as laboratory-identified (LabID) event, is common in patients with chronic kidney disease (CKD), especially those with end-stage renal disease (ESRD), and is associated with prolonged length of hospitalization and more severe disease. CKD patients are at increased of developing CDI due to frequent antimicrobial and healthcare exposures. The objective of this study was to assess recent trends of HO-CDI in patients on a nephrology unit at our academic, tertiary care institution. Methods: Retrospective cross-sectional study of patients with HO-CDI who were hospitalized on a nephrology unit between January 2021 to December 2023. Collected variables included: demographic data, characterization of HO-CDI risk factors, infection and diagnosis (including prior history of CDI, toxin versus nucleic acid amplification test [NAAT] positivity, number of loose stools), CDI rate (defined as CDI count/patient days x1000), standardized antimicrobial administration ratio (SAAR) for high-risk for CDI antimicrobials (defined by the National Healthcare Safety Network), and infection prevention and control (IPC) practices, including hand hygiene audit rates. Results: A total of 30 HO-CDI infections were reported on the nephrology unit [Table], with 8 occurring in 2021, 5 in 2022, and 17 in 2023. The median age of patients was 70.8 (range: 37-96) years, and most patients (57%) were female. The majority of patients were admitted from home (73%), and two patients (7%) had a history of CDI in the last 6 months. Among the CDI cases, 60% were NAAT positive and toxin negative, and only 50% had >3 bowel movements (BM) within 24 hours prior to the positive test. Ten percent received promotility agents prior to testing. Most cases (77%) occurred when other CDI patients were on the unit. Hand hygiene compliance rates averaged 81% over the three-year period [Figure 1A]. Eight-four per cent of patients received antibiotics within 30 days of CDI diagnosis; SAAR was >1 for quarters 2 and 4 in 2022, and quarter 1 in 2023 [Figure 1B]. Conclusion: On our nephrology unit, patients often had < 3 BM within 24 hours of CDI diagnosis, and 60% of cases were toxin-negative, NAAT-positive, suggesting possible C. difficile colonization, rather than true infection. In addition, an elevated SAAR correlated with high CDI rates. Multicomponent interventions may be required to reduce the rates of HO-CDI in CKD patients. Opportunities include emphasis on diagnostic and antimicrobial stewardship, environmental cleaning and adherence to IPC practices, including hand hygiene.

Abstract Objectives Randomized controlled trials (RCTs) are the gold standard for evaluating the comparative efficacy and safety of new cancer therapies. However, enrolling patients in control arms of clinical trials can be challenging for rare cancers, particularly in the context of precision oncology and targeted therapies. External Control Arms (ECAs) are a potential solution to address these challenges in clinical research design. We conducted a scoping review to explore the use of ECAs in oncology. Methods We systematically searched four databases, namely MEDLINE, EMBASE, Web of Science, and Scopus. We screened titles, abstracts, and full texts for eligible articles focusing on patients undergoing therapy for cancer, employing ECAs, and reporting clinical outcomes. Results Of the 629 articles screened, 23 were included in this review. The earliest included studies were published in 1996, while most studies were published in the past 5 years. 44% (10/23) of ECAs were employed in blood‐related cancer studies. Geographically, 30% (7/23) of studies were conducted in the United States, 22% (5/23) in Japan, and 9% (2/23) in South Korea. The primary data sources used to construct the ECAs involved pooled data from previous trials (35%, 8/23), administrative health databases (17%, 4/23) and electronic medical records (17%, 4/23). While 52% (12/23) of the studies employed methods to align treatment and ECAs characteristics, 48% (11/23) lacked explicit strategies. Conclusion ECAs offer a valuable approach in oncology research, particularly when alternative designs are not feasible. However, careful methodological planning and detailed reporting are essential for meaningful and reliable results.

ObjectivesThe Historical Loss Scale (HLS) and Historical Loss Associated Symptoms Scale (HLASS) are standardized measures that have been accepted and previously validated among North American Indigenous communities and allow researchers to measure the impact of Historical Loss. Evidence of the psychometric properties of this instrument have not been assessed for Native Hawaiians, the Indigenous peoples of Hawai‘i. The purpose of this study is to investigate the psychometric properties of the adapted HLS (aHLS) and HLASS for adults from multiple Hawaiian Homestead Communities throughout Hawai‘i.MethodsData are based on cross-sectional surveys administered between 2014 and 2020. The final sample included 491 Native Hawaiian adults who were predominantly female (67.3%) and between the ages of 18–90 years, who were part of the larger study entitled the Hawaiian Homestead Health Survey. Factor analyses were conducted to determine the final model structures of each scale. Reliability and correlation matrices of items are also reported.ResultsThe final factor structure of the aHLS model suggested 3 factors: (1) General loss of culture or cultural loss, (2) Intergenerational loss, and (3) Distrust and destruction of traditional foods. The final HLASS model also suggested 3 factors: (1) Depression and Anger, (2) Shame and Anxiety, and (3) Re-experiencing, fear, and avoidance.ConclusionThese findings have implications for future research, practice, and education that explores the role of Historical Loss and associated symptoms in Native Hawaiians and Indigenous communities at large. In particular, measuring historical loss and associated symptoms in Hawaiian Homestead communities paves the way for quantitative assessments of historical trauma and healing in these communities.

Animals exhibit dynamic movement and activity in response to environmental variation including changes in reproductive opportunities, predation risk, or food availability. Yet, it remains unclear which factors are primary in affecting animal movement, and whether the relative importance of these factors are consistent through time. We tracked snowshoe hares (Lepus americanus) using GPS telemetry during eight summers spanning a hare population cycle (2015–2022) in southwestern Yukon, Canada, to determine associations between environmental variation and hare movement and home range size. Hare density varied 25-fold during the study and home range size increased markedly during low hare density, especially for males. Both sexes retained similar core space use and linearity of movements, but at low densities males had greater and more variable movement rates and time spent travelling. Trail cameras revealed that annual changes in hare movement were also correlated with relative abundance of lynx (Lynx canadensis) and coyotes (Canis latrans). However, hare detection rates within a season were not closely associated with seasonal variation in predator detection. Observed differences between male and female hares in some metrics highlighted that different life histories and reproductive behavior are likely the main drivers of hare movement dynamics. Therefore, fitness rewards associated with successful mate search and reproduction appear to outweigh risks associated with increased movement, even in highly variable environments where costs of prioritizing reproduction-related activities are notably high and variable.

MOTS-c, a 16 amino acid mitochondrial derived peptide, is encoded from the 12S rRNA region of the mitochondrial genome. Under stress conditions, MOTS-c translocates to the nucleus where it regulates a wide range of genes in response to metabolic dysfunction. It is colocalized to mitochondria in various tissues and is found in plasma, but the levels decline with age. Since MOTS-c has important cellular functions as well as a possible hormonal role, it has been shown to have beneficial effects on age-related diseases including Diabetes, Cardiovascular diseases, Osteoporosis, postmenopausal obesity and Alzheimer. Aging is characterized by gradual loss of (mitochondrial) metabolic balance, decreased muscle homeostasis and eventual diminished physical capability, which potentially can be reversed with MOTS-c treatment. This review examines the latest findings on biological effects of MOTS-c as a nuclear regulatory peptide and focuses on the role of MOTS-c in aging and age-related disorders, including mechanisms of action and therapeutic potential.

Activation of the Simulator of Interferon Genes (STING) system by mitochondrial (mt) DNA can upregulate type 1 interferon genes and enhance immune responses to combat bacterial and viral infections. In cancers, the tumor-derived DNA activates STING leading to upregulation of IFN-beta and induction of antitumor T cells. The entire mtDNA from the cell lines was sequenced using next-generation sequencing (NGS) technology with independent sequencing of both strands in both directions, allowing identification of low-frequency heteroplasmy SNPs. There were 15 heteroplasmy SNPs showing a range from 3.4% to 40.5% occurrence in the K cybrid cell lines. Three H haplogroup cybrids possessed SNP heteroplasmy that ranged from 4.39% to 30.7%. The present study used qRT-PCR to determine if cybrids of H and K haplogroups differentially regulate expression levels of five cancer genes (BRAC1, ALK, PD1, EGFR, and HER2) and seven STING subunits genes (CGAS, TBK1, IRF3, IκBa, NFκB, TRAF2, and TNFRSF19). Some cybrids underwent siRNA knockdown of STING followed by qRT-PCR in order to determine the impact of STING on gene expression. Rho0 (lacking mtDNA) ARPE-19 cells were used to determine if mtDNA is required for the expression of the cancer genes studied. Our results showed that (a) K cybrids have lower expression levels for BRAC1, ALK, PD1, EGFR, IRF3, and TNFRSF19 genes but increased transcription for IκBa and NFκB compared to H cybrids; (b) STING KD decreases expression of EGFR in both H and K cybrids, and (c) PD1 expression is negligible in Rho0 cells. Our findings suggest that the STING DNA sensing pathway may be a previously unrecognized pathway to target modulation of cancer-related genes and the PD1 expression requires the presence of mtDNA.

Messianic Ideas and Movements in Sunni Islam. By YOHANAN FRIEDMANN. London: ONEWORLD ACADEMIC, 2022. Pp. xvi + 352. $70, [pounds sterling]45 (cloth). The three major monotheistic religions all recognize the [...]

Abstract Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd −/− ) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd −/− mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd −/− animals, while depletion does not have additive protective effects in Gsdmd −/− mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.

Resilience—a term that originated in mathematical ecology—now commonly refers to the ability to thrive in the face of trauma and adversity. This Position Piece reflects on both the charisma and political lability of resilience in the early 21st century. On the one hand, resilience is easily compatible with neoliberal discourses that demand that individuals protect themselves in the absence of state or community support. On the other hand, resilience can be an important corrective to narratives about the damage caused by trauma, focusing attention on our innate ability to heal. We argue that the ambivalence of resilience requires theoretical and empirical attention to both the wider appeal of the term and the situated definitions deployed by diverse actors. In particular, we look at the rise of the term ‘community resilience’ popularised by academics, community leaders, and activists, which seeks to avoid the pitfalls of the neoliberal definition of resilience and argues that strong interpersonal relationships can support health equity. Despite the ambivalence of resilience, we find “community resilience” to be promising in a time when collective visions of health and immunity are desperately needed.

Background: While current wound treatment strategies often focus on antimicrobials and topical agents, the role of nutrition in wound healing and aesthetic outcomes is crucial but frequently overlooked. This review assesses the impact of specific nutrients and preoperative nutritional status on surgical outcomes. Methods: A comprehensive search was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library, from the inception of the study to October 2023. The study focused on the influence of macronutrients and micronutrients on aesthetic outcomes, the optimization of preoperative nutritional status, and the association between nutritional status and postoperative complications. Inclusion criteria were English language peer-reviewed articles, systematic reviews, meta-analyses, and clinical trials related to the impact of nutrition on skin wound healing and aesthetic outcomes. Exclusion criteria included non-English publications, non-peer-reviewed articles, opinion pieces, and animal studies. Results: Omega-3 fatty acids and specific amino acids were linked to enhanced wound-healing and immune function. Vitamins A, B, and C and zinc positively influenced healing stages, while vitamin E showed variable results. Polyphenolic compounds showed anti-inflammatory effects beneficial for recovery. Malnutrition was associated with increased postoperative complications and infections, whereas preoperative nutritional support correlated with reduced hospital stays and complications. Conclusion: Personalized nutritional plans are essential in surgical care, particularly for enhanced recovery after surgery protocols. Despite the demonstrated benefits of certain nutrients, gaps in research, particularly regarding elements such as iron, necessitate further studies. Nutritional assessments and interventions are vital for optimal preoperative care, underscoring the need for more comprehensive guidelines and research in nutritional management for surgical patients.

Spatially explicit estimates of marine species distribution and abundance are required to quantify potential impacts from human activities such as military training and testing, fisheries interactions, and offshore energy development. There are 4 protected species of sea turtle (loggerhead, green, Kemp’s ridley, and leatherback) commonly found along the east coast of the USA, our study area, and which require impact assessments. Data from 7 different survey organizations were used to create density surface models for the 4 sea turtle species utilizing 1.2 million km of line-transect surveys. A substantial portion (29.7%) of available sightings were not identified to the species level. Not including these sightings would underestimate density, so a conditional random forest model was used to assign unidentified sightings to species. Higher densities of loggerhead, green, and Kemp’s ridley sea turtles were predicted south of the Outer Banks in cool months, transitioning northwards in late spring to occupy seasonal neritic habitats. The highest leatherback densities were predicted off the coasts of Georgia and Florida. Leatherbacks were also predicted throughout offshore areas. The predicted distribution patterns generally matched satellite tracking and strandings data, indicating the models reproduced established seasonal movements. Surveys rarely detect sea turtles smaller than 40 cm, so these age classes are not represented. The models are the first for the study area to apply availability bias estimates developed in or near the study area and attempt to classify unidentified sightings to the species level, providing an updated, critical tool for conservation management along the eastern seaboard.

Abstract Background Low bone mineral density affects 53% of women over age 65 in the US, yet many are unaware and remain untreated. Underdiagnosis of forearm osteoporosis and related fragility fractures represent missed warning signs of more deadly, future fractures. This study aimed to determine if hand radiographs could serve as early, simple screening tools for predicting low forearm bone mineral density (BMD). Methods We evaluated posterior-anterior (PA) hand radiographs (x-rays) and Dual-energy X-ray absorptiometry (DXA) scans of 43 participants. The ratio of the intramedullary cavity to total cortical diameter of the second metacarpal (second metacarpal cortical percentage (2MCP)) was used as a potential diagnostic marker. Mixed-effects linear regression was performed to determine correlation of 2MCP with BMD from various anatomic regions. Repeated measures ANOVAs were used to compare BMD across sites. An optimal 2MCP cutoff for predicting forearm osteopenia and osteoporosis was found using Receiver Operating Curves. Results 2MCP is directly correlated with BMD in the forearm. The optimal 2MCP of 48.3% had 80% sensitivity for detecting osteoporosis of the 1/3 distal forearm. An 2MCP cutoff of 50.8% had 84% sensitivity to detect osteoporosis of the most distal forearm. Both 2MCP cutoffs were more sensitive at predicting forearm osteoporosis than femoral neck T-scores. Conclusions These findings support the expansion of osteoporosis screening to include low-cost hand x-rays, aiming to increase diagnosis and treatment of low forearm BMD and fractures. Proposed next steps include confirming the optimal 2MCP cutoff at scale and integrating automatic 2MCP measurements into PAC systems.

Abstract Objectives To examine the impact of displacement experiences on 0- to 6-year-old children’s social-emotional and cognitive development, as well as influencing factors on reported outcomes. Study design We systematically searched MEDline, Psyndex, Cochrane Library, Web of Science, Elsevier, TandF, Oxford Journal of Refugee Studies, Journal of Immigrant & Refugee Studies, and Canada’s Journal on Refugees for existing literature regarding social-emotional and cognitive outcomes in children directly exposed to forced displacement due to political violence. Results were synthesized in the discussion and displayed using harvest plots. Results Our search generated 9,791 articles of which 32 were selected for review and evaluation according to NICE criteria. Included studies provided results for 6,878 forcibly displaced children. Measured outcomes were diverse and included areas such as peer relations, prosocial behavior, family functioning, play, intelligence, learning performance, and language development. Repeated exposure to adverse experiences, separation from parents, parental distress, as well as duration and quality of resettlement in the host country were reported as influencing factors in the reviewed studies. Conclusion As protective factors like secure and stable living conditions help to promote children’s development, we call for policies that enhance participation in the welcoming society for refugee families. Early integration with low-threshold access to health and educational facilities can help to mitigate the wide-ranging negative consequences of forced displacement on young children’s development.

Abstract Abrupt environmental changes can lead to evolutionary shifts in trait evolution. Identifying these shifts is an important step in understanding the evolutionary history of phenotypes. The detection performances of different methods are influenced by many factors, including different numbers of shifts, shift sizes, where a shift occurs on a tree, and the types of phylogenetic structure. Furthermore, the model assumptions are oversimplified, so are likely to be violated in real data, which could cause the methods to fail. We perform simulations to assess the effect of these factors on the performance of shift detection methods. To make the comparisons more complete, we also propose an ensemble variable selection method (R package ELPASO) and compare it with existing methods (R packages $$\ell$$ ℓ 1ou and PhylogeneticEM). The performances of methods are highly dependent on the selection criterion. $$\ell$$ ℓ 1ou+pBIC is usually the most conservative method and it performs well when signal sizes are large. $$\ell$$ ℓ 1ou+BIC is the least conservative method and it performs well when signal sizes are small. The ensemble method provides more balanced choices between those two methods. Moreover, the performances of all methods are heavily impacted by measurement error, tree reconstruction error and shifts in variance.

Abstract Background Pre-referral treatment aims to stabilize the child’s condition before transferring them to a higher level of healthcare. This study explored pre-referral treatment for diarrhea, malaria and pneumonia in children U5. The study aims to assess pre-referral treatment practices among community health workers (CHWs) for children aged 2 to 59 months diagnosed with malaria, diarrhea, and pneumonia. Methods Conducted in 2023, this study employed a quantitative retrospective analysis of secondary data gathered from March 2014 to December 2018. Among the subjects, 171 patients received pre-referral treatment, serving as the foundation for categorical data analysis, presenting proportions and 95% confidence intervals across different categories. Results In this cohort, 90 (53%) of the 177 children U5 were male, and age distribution showed 39 (23%), 70 (41%), and 62 (36%) in the 2–11 months, 12–35 months, and 36–60 months categories, respectively. Rapid Diagnostic Test (RDT) malaria results indicated a negative outcome in 83(60%) and positive in 55 (40%) of cases. Symptomatically, 45 (26%) had diarrhea, 52 (30%) exhibited fast breathing, and 109 (63%) presented with fever. Furthermore, 59 (35%) displayed danger signs, while 104 (61%) sought medical attention within 24 h. Conclusion The study analyzed a sample of 171 children under 5 years old to assess various characteristics and variables related to pre-referral treatment. The findings reveal notable proportions in gender distribution, age categories, RDT results, presence of diarrhea, fast breathing, fever, danger signs, and timely medical visits. The results highlight the need to strengthen pre-referral treatment interventions and enhance iCCM programs.

Modern navigation solutions rely on a combination of inertial measurement units (IMUs) and a global navigation satellite system (GNSS) receiver to estimate a navigating body's position. In order to produce a high-fidelity solution, the current approach is to utilize a single ultra-low bias navigational grade IMU in the system. However, these high-quality IMUs are expensive, bulky, heavy, and require significant power consumption. This article proposes the fusion of multiple lower-quality IMUs to achieve near-identical or better positional accuracy as a single high-quality sensor to minimize cost, size, weight, and power (C-SWaP) without sacrificing the positional estimation accuracy. The primary focus is on a generalized method to fuse multiple position estimations from multiple co-located IMUs for a single navigating body. The proposed fusion algorithm is applied to simulated data produced by three precision micro-electromechanical systems (MEMS) grade IMU modules (Analog Devices ADIS16465) from two different simulated flight paths. The absolute error is calculated between the position estimation generated by the proposed algorithm and the “truth” position provided by the simulation to determine the accuracy of the final result. The error of the proposed algorithm using the Analog Devices modules is then compared to the error between a single navigational grade IMU (NovAtel IMU-ISA-100 C) and the simulated “truth” position. The results show that using only three precision MEMS grade IMUs; the proposed method can produce identically accurate position estimations as a navigational grade IMU while drastically reducing C-SWaP. This result is further validated in measured data from an instrumented test setup using the above mentioned IMU configurations fused with a standard GPS and compared to a real-time kinematic GNSS setup used as a the third-party ground truth. In addition, the proposed method is further validated by integrating the two navigation systems with a Ku-band radar to produce synthetic aperture radar images. The image produced using the multi-IMU configuration as opposed to the navigation-grade IMU is more focused. Given these results, the proposed method has been validated in theory, simulation, and measurement, resulting in an order of magnitude reduction in cost, size, and power consumption, as well as a three-and-a-half times weight reduction of the overall IMU solution.

Intensifying concerns about online platform firms’ rapid rise, expansion, and growing asymmetric power have attracted political scrutiny and undermined the legitimacy of a minimalist regulatory regime that is giving way to intense debate and increasingly interventionist governmental policies and enforcement actions. First, we view the rise of, and recent political responses to, the often-predatory power and manipulative conduct of platform firm in terms of a ‘Polanyian’ double movement in which the destabilising and destructive effects of unchecked corporate activities and market development eventually generates political and regulatory responses to constrain private power that threaten the social, political, and economic order. Second, incipient legal changes, most notably the EU’s proposed Digital Markets Act and Digital Services Act, indicate a shift in regulatory emphasis from competition (and antitrust) policy and law towards more intensive and encompassing forms of socio-economic regulation. Finally, these regulatory changes will likely vary in character and significance across political jurisdictions, and embody distinctive and possibly divergent developmental trajectories. The EU may have a first-mover advantage in regulating platform firms, but we are only at the very beginning of a protracted and conflictual transformational process.

The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought to determine whether there were common patterns of disease progression that could aid in the design and analysis of clinical trials. We developed an approach based on a mixture of Gaussian processes to identify clusters of patients sharing similar disease progression patterns, modeling their average trajectories and the variability in each cluster. We show that ALS progression is frequently nonlinear, with periods of stable disease preceded or followed by rapid decline. We also show that our approach can be extended to Alzheimers and Parkinsons diseases. Our results advance the characterization of disease progression of ALS and provide a flexible modeling approach that can be applied to other progressive diseases.

ObjectiveTo assess whether private equity (PE) acquisitions of urology practices were associated with changes in Medicare payments and patient volume.MethodsWe identified PE acquisitions of urology practices through financial databases, industry news outlets, practice websites, and Google search. Using the Centers for Medicare and Medicaid Service's Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (2012-2019), we conducted descriptive statistics and trends analysis to examine whether PE acquisition was associated with changes in Medicare payments and patient volume in comparison to non-PE affiliated urologists within the same states.ResultsWe identified PE acquisitions of 10 independent urology practices across 6 states during the study period. In the preacquisition period, urologists later joining private-equity groups received greater mean inflation-adjusted Medicare payments ($246,977 vs $160,038; P

Purpose: Oxidative stress contributes to the pathogenesis of vision-impairing diseases. In the retina, retinal pigment epithelium (RPE) and Müller cells support neuronal homeostasis, but also contribute to pathological development under stressed conditions. Recent studies found that the investigational drug risuteganib (RSG) has a good safety profile, provided protection in experimental models, and improved visual acuity in patients. The present in vitro study evaluated the effects of RSG in RPE and Müller cell lines stressed with the oxidant hydrogen peroxide (H2O2). Methods: Human RPE (ARPE-19) and Müller (MIO-M1) cell lines were treated with various combinations of RSG and H2O2. Trypan blue assay was used to investigate the effect of compounds on cell viability. Gene expression was measured using RNA sequencing to identify regulated genes and the biological processes and pathways involved. Results: Trypan blue assay found RSG pre-treatment significantly protected against H2O2-induced cell death in ARPE-19 and MIO-M1 cells. Transcriptome analysis found H2O2 regulated genes in several disease-relevant biological processes, including cell adhesion, migration, death, and proliferation; ECM organization; angiogenesis; metabolism; and immune system processes. RSG pre-treatment modulated these gene expression profiles in the opposite direction of H2O2. Pathway analysis found genes in integrin, AP-1, and syndecan signaling pathways were regulated. Expression of selected RSG-regulated genes was validated using qRT-PCR. Conclusions: RSG protected cultured human RPE and Müller cell lines against H2O2-induced cell death and mitigated the associated transcriptome changes in biological processes and pathways relevant to the pathogenesis of retinal diseases. These results demonstrate RSG reduced oxidative stress-induced toxicity in two retinal cell lines with potential relevance to the treatment of human diseases.

Mitochondrial (mt) DNA can be classified into haplogroups, which represent populations with different geographic origins. Individuals of maternal African backgrounds (L haplogroup) are more prone to develop specific diseases compared those with maternal European-H haplogroups. Using a cybrid model, effects of amyloid-β (Amyβ), sub-lethal ultraviolet (UV) radiation, and 5-Aza-2'-deoxycytidine (5-aza-dC), a methylation inhibitor, were investigated. Amyβ treatment decreased cell metabolism and increased levels of reactive oxygen species in European-H and African-L cybrids, but lower mitochondrial membrane potential (ΔΨM) was found only in African-L cybrids. Sub-lethal UV radiation induced higher expression levels of CFH, EFEMP1, BBC3, and BCL2L13 in European-H cybrids compared to African-L cybrids. With respect to epigenetic status, the African-L cybrids had (a) 4.7-fold higher total global methylation levels (p = 0.005); (b) lower expression patterns for DNMT3B; and (c) elevated levels for HIST1H3F. The European-H and African-L cybrids showed different transcription levels for CFH, EFEMP1, CXCL1, CXCL8, USP25, and VEGF after treatment with 5-aza-dC. In conclusion, compared to European-H haplogroup cybrids, the African-L cybrids have different (i) responses to exogenous stressors (Amyβ and UV radiation), (ii) epigenetic status, and (iii) modulation profiles of methylation-mediated downstream complement, inflammation, and angiogenesis genes, commonly associated with various human diseases.

Mathematics teacher educators play a key role in supporting secondary mathematics teachers' development of effective, research-based formative assessment (FA) practices. We used qualitative research synthesis as a tool to identify actionable recommendations for mathematics teacher educators as they work with teachers on FA practices in secondary classrooms. These recommendations can strengthen the research-based practices of mathematics teacher educators as they support teachers' collections and uses of FA data to move student thinking forward in secondary mathematics. We share and discuss recommendations for mathematics teacher educators to connect pedagogical content knowledge of students, teaching, and curriculum to FA practices. We also highlight the usefulness of the qualitative synthesis method, meta-aggregation, for generating research-based connections between theory and practice in mathematics education.