Patients' Perceptions of Nusinersen Effects According to Their Responder Status.

Background and Objective: Patients with spinal muscular atrophy (SMA) treated with a disease-modifying therapy (DMT) are often classified as responders or non-responders based on the attainment of a specific improvement threshold on validated functional scales. This categorization may significantly impact treatment reimbursement in some countries. The aim of this research is to evaluate the perception of treatments and their benefit by patients considered as responders or non-responders. Methods: In this non-commercial multicenter study, 99 post-symptomatically treated SMA type I-III patients with a median age of 11.2 (0.39-57.4) years at treatment initiation were stratified into three groups based on their treatment outcomes, i.e., those exhibiting clinically significant improvement (N = 41), those with non-clinically significant improvement (N = 18), or those showing no improvement (N = 40). Fifteen months after treatment, the initiation patients or patients' caregivers were assessed using a patient-rated scoring system based on the Patient Global Impression of Change (PGIC) scale, comprising 22 questions targeting important aspects and tasks in the daily life of patients with SMA. Results: We found no statistical difference in the patient perception of treatment benefits in 17 out of 22 domains across patient groups. Conclusions: Our results suggest that functional motor scales do not recapitulate patients' and patients' caregivers' experience of the effect of nusinersen treatment in SMA.

Gentrification drives patterns of alpha and beta diversity in cities.

While there is increasing recognition that social processes in cities like gentrification have ecological consequences, we lack nuanced understanding of the ways gentrification affects urban biodiversity. We analyzed a large camera trap dataset of mammals (>500 g) to evaluate how gentrification impacts species richness and community composition across 23 US cities. After controlling for the negative effect of impervious cover, gentrified parts of cities had the highest mammal species richness. Change in community composition was associated with gentrification in a few cities, which were mostly located along the West Coast. At the species level, roughly half (11 of 21 mammals) had higher occupancy in gentrified parts of a city, especially when impervious cover was low. Our results indicate that the impacts of gentrification extend to nonhuman animals, which provides further evidence that some aspects of nature in cities, such as wildlife, are chronically inaccessible to marginalized human populations.

Expression of Ceramide Synthases in Mice and Their Roles in Regulating Acyl-Chain Sphingolipids: A Framework for Baseline Levels and Future Implications in Aging and Disease.

Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths. Although the tissue distribution of CerS mRNA expression in humans and the roles of CerS isoforms in synthesizing ceramides with different acyl chain lengths are known, it is unknown how CerS expression dictates ceramides and downstream metabolites within tissues. In this study, we analyzed sphingolipid levels and CerS mRNA expression in 3-month-old C57BL/6J mouse brain, heart, kidney, liver, lung, and skeletal muscle. The results showed that CerS expression and sphingolipid species abundance varied by tissue and that CerS expression was a predictor of ceramide species within tissues. Interestingly, although CerS expression was not predictive of complex sphingolipid species within all tissues, composite scores for CerSs contributions to total sphingolipids measured in each tissue correlated to CerS expression. Lastly, we determined that the most abundant ceramide species in mouse tissues aligned with CerS mRNA expression in corresponding human tissues (based on chain length preference), suggesting that mice are relevant preclinical models for ceramide and sphingolipid research. SIGNIFICANCE STATEMENT: The current study demonstrates that ceramide synthase (CerS) expression in specific tissues correlates not only with ceramide species but contributes to the generation of complex sphingolipids as well. As many of the CerSs and/or specific ceramide species have been implicated in disease, these studies suggest the potential for CerSs as therapeutic targets and the use of sphingolipid species as diagnostics in specific tissues.

Topological structures and syntenic conservation in sea anemone genomes.

There is currently little information about the evolution of gene clusters, genome architectures and karyotypes in early branching animals. Slowly evolving anthozoan cnidarians can be particularly informative about the evolution of these genome features. Here we report chromosome-level genome assemblies of two related anthozoans, the sea anemones Nematostella vectensis and Scolanthus callimorphus. We find a robust set of 15 chromosomes with a clear one-to-one correspondence between the two species. Both genomes show chromosomal conservation, allowing us to reconstruct ancestral cnidarian and metazoan chromosomal blocks, consisting of at least 19 and 16 ancestral linkage groups, respectively. We show that, in contrast to Bilateria, the Hox and NK clusters of investigated cnidarians are largely disintegrated, despite the presence of staggered hox/gbx expression in Nematostella. This loss of microsynteny conservation may be facilitated by shorter distances between cis-regulatory sequences and their cognate transcriptional start sites. We find no clear evidence for topologically associated domains, suggesting fundamental differences in long-range gene regulation compared to vertebrates. These data suggest that large sets of ancestral metazoan genes have been retained in ancestral linkage groups of some extant lineages; yet, higher order gene regulation with associated 3D architecture may have evolved only after the cnidarian-bilaterian split.

APOBEC3G Is a p53-Dependent Restriction Factor in Respiratory Syncytial Virus Infection of Human Cells Included in the p53/Immune Axis.

Identifying and understanding genetic factors that influence the propagation of the human respiratory syncytial virus (RSV) can lead to health benefits and possibly augment recent vaccine approaches. We previously identified a p53/immune axis in which the tumor suppressor p53 directly regulates the expression of immune system genes, including the seven members of the APOBEC3 family of DNA cytidine deaminases (A3), which are innate immune sentinels against viral infections. Here, we examined the potential p53 and A3 influence in RSV infection, as well as the overall p53-dependent cellular and p53/immune axis responses to infection. Using a paired p53 model system of p53+ and p53- human lung tumor cells, we found that RSV infection activates p53, leading to the altered p53-dependent expression of A3D, A3F, and A3G, along with p53 site-specific binding. Focusing on A3G because of its 10-fold-greater p53 responsiveness to RSV, the overexpression of A3G can reduce RSV viral replication and syncytial formation. We also observed that RSV-infected cells undergo p53-dependent apoptosis. The study was expanded to globally address at the transcriptional level the p53/immune axis response to RSV. Nearly 100 genes can be directly targeted by the p53/immune axis during RSV infection based on our p53BAER analysis (Binding And Expression Resource). Overall, we identify A3G as a potential p53-responsive restriction factor in RSV infection. These findings have significant implications for RSV clinical and therapeutic studies and other p53-influenced viral infections, including using p53 adjuvants to boost the response of A3 genes.

Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA).

Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

Urbanization, climate and species traits shape mammal communities from local to continental scales.

Human-driven environmental changes shape ecological communities from local to global scales. Within cities, landscape-scale patterns and processes and species characteristics generally drive local-scale wildlife diversity. However, cities differ in their structure, species pools, geographies and histories, calling into question the extent to which these drivers of wildlife diversity are predictive at continental scales. In partnership with the Urban Wildlife Information Network, we used occurrence data from 725 sites located across 20 North American cities and a multi-city, multi-species occupancy modelling approach to evaluate the effects of ecoregional characteristics and mammal species traits on the urbanization-diversity relationship. Among 37 native terrestrial mammal species, regional environmental characteristics and species traits influenced within-city effects of urbanization on species occupancy and community composition. Species occupancy and diversity were most negatively related to urbanization in the warmer, less vegetated cities. Additionally, larger-bodied species were most negatively impacted by urbanization across North America. Our results suggest that shifting climate conditions could worsen the effects of urbanization on native wildlife communities, such that conservation strategies should seek to mitigate the combined effects of a warming and urbanizing world.

Optimizing spinal cord injury in zebrafish larvae: effects of age on the injury response.

Zebrafish are an increasingly popular model to study spinal cord injury (SCI) regeneration. The transparency of larval zebrafish makes them ideal to study cellular processes in real time. Standardized approaches, including age of injury, are not readily available making comparisons of the results with other models challenging. In this study, we systematically examined the response to spinal cord transection of larval zebrafish at three different ages (3-7 days post fertilization or dpf) to determine whether the developmental complexity of the central nervous system affects the overall response to SCI. We then used imaging and behavioral analysis to evaluate whether differences existed based on the age of injury. All ages of larval zebrafish upregulated the required genes for glial bridge formation, ctgfa and gfap, at the site of injury, consistent with studies from adult zebrafish. Though all larval ages upregulated factors required to promote glial bridging, young larval zebrafish (3 dpf) were better able to regenerate axons independent of the glial bridge, unlike older zebrafish (7 dpf). Consistent with this data, locomotor experiments demonstrated that some swimming behavior occurs independent of glial bridge formation, further highlighting the need for standardization of this model and recovery assays. Overall, we found subtle cellular differences based on the age of transection in zebrafish, underlining the importance of considering age when designing experiments aimed at understanding regeneration.

HostSeq: a Canadian whole genome sequencing and clinical data resource.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Association between RCT methodology and disease indication with mineralocorticoid-related toxicity for patients receiving abiraterone acetate for advanced prostate cancer: A meta-analysis of RCTs.

INTRODUCTION: While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration. METHODS: We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids. RESULTS: Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC. CONCLUSIONS: The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

Improved postoperative blood glucose control through implementation of clinical pharmacist driven glycemic management model after colorectal surgery.

BACKGROUND: Poor postoperative glycemic control has been linked with higher mortality, cardiovascular complications, stroke, infection, impaired wound healing, and increased length of stay. METHODS: This multicenter, retrospective study of colorectal surgery patients with Type 2 Diabetes Mellitus evaluated the difference in mean blood glucose levels postoperatively in a pharmacist driven glycemic management model vs standard of care. Secondary objectives assessed hyperglycemic events, severe hyperglycemia, hypoglycemia, postoperative infection, and rates of endocrinology consults. RESULTS: 186 patients were included, 120 in the pharmacist driven cohort and 66 in the standard of care. The pharmacist managed cohort demonstrated significantly lower mean blood glucose (133.9 vs 148.3 mg/dL, 95% CI [-17 to -11] p < 0.001), significantly fewer hyperglycemic events (9.6% vs 20.5%, p < 0.0001), and non-significant reduction of hypoglycemic events (0.7% vs 1.2%, p = 0.1443). CONCLUSIONS: Expansion of the postoperative care team by utilizing pharmacists to manage postoperative blood glucose resulted in improved glycemic control.

Incorporation of pharmacist pre-surgical calls to improve medication history completion rates.

BACKGROUND: The accuracy and timeliness of documenting a medication history is an important aspect to ensure appropriate medication reconciliation during transitions of care. Surgical patients often have their medication history recorded just moments before surgery which may be rushed, incomplete or missed entirely. Between January and May 2020, 76.7% of surgical patients admitted to our institution had a medication history completed by a pharmacist prior to surgery. OBJECTIVE: The objective of this work is to improve the pharmacist medication history completion rates for pre-surgical patients before surgery by integrating pharmacist-led medication histories into the pre-operative pathway. METHODS: Through interdisciplinary collaboration, the pre-operative pathway for surgical patients was evaluated for opportunities to complete medication histories days prior to their scheduled procedure. Plan-Do-Study-Act (PDSA) cycles were utilized to make incremental improvements in practice. INTERVENTIONS: Through an iterative process, the pathway for cardiovascular surgery (CVS) patients was modified to include a scheduled pharmacist phone appointment in the days leading up to their surgical procedure. Utilizing these phone appointments, pharmacists complete patient medication history reviews and share a feedback loop to cardiovascular and peri-operative health care providers. RESULTS: The iterative PDSA cycles revealed challenges to completing pre-surgical medication history calls without advance notice. Patient responsiveness to pre-surgical medication history calls improved with the incorporation of scheduled phone appointments. Between January 18 and May 31, 2021, pharmacists completed 359 of 376 scheduled CVS appointments (95.5%), improving the medication history completion rates for cardiovascular surgery patients from 84.8 to 93.0% (p = 0.000025). The completion rate for all surgical patients also improved from 76.7 to 85.1% (p < 0.00001). CONCLUSIONS: Incorporating scheduled pharmacist medication history appointments as a part of the pre-operative pathway was shown to expand the capacity for pharmacists to complete medication histories for patients prior to surgery. By reducing pharmacist workload on the morning of surgery, fewer patients were admitted to surgery without having their medication history reviewed by pharmacy. Future investigation should be considered to evaluate the impact on patient outcomes.

Evaluation of early de-escalation of empiric antimicrobial therapy in acute leukemia patients with febrile neutropenia at a large academic medical center.

INTRODUCTION: Recent trials have shown early de-escalation of empiric antimicrobial therapy (EAT) in febrile neutropenia has led to less adverse effects with no difference in patient mortality. In 2019, our institution adjusted internal guidelines to de-escalate EAT after 7 days of intravenous anti-pseudomonal therapy in patients with signs of clinical recovery from febrile neutropenia and no evidence of infection. METHODS: This was a retrospective, single-center, observational, cohort study. Eligible patients were adults with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received induction chemotherapy and developed febrile neutropenia without documented infection. Patients were separated based on EAT duration: ≤ 9 days and > 9 days. Empiric antimicrobial therapy was defined as the initiation of an anti-pseudomonal beta-lactam. The primary outcome was the difference in number of EAT-free days. Secondary outcomes included fever recurrence, ICU admissions, fever duration, infections post de-escalation, and Clostridioides difficile infection (CDI). RESULTS: Forty-four encounters met inclusion. The EAT ≤ 9 days group had 7 more EAT-free days compared to the EAT > 9 days group (p < 0.001). No between-group differences were identified in terms of fever after EAT discontinuation (p = 0.335), ICU admission (p = 0.498), or CDI (p = 0.498). The EAT > 9 days group experienced longer initial fever (p < 0.001) and received addition of resistant Gram-positive coverage (p = 0.014). More patients receiving EAT > 9 days had a diagnosis of AML (p = 0.001). CONCLUSIONS: Shorter EAT duration did not lead to worse outcomes in patients with AML or ALL who received induction chemotherapy and developed febrile neutropenia without a documented infection source.

Trophic and spatial patterns of contaminants in fishes from the Republic of the Marshall Islands in the equatorial Pacific.

The Republic of the Marshall Islands (RMI) has been affected by marine pollution from militarization and urbanization. To address concerns raised by the Marshall Islands Marine Resources Authority, this study examined concentrations of dissolved contaminants in reef and pelagic fishes in the RMI and assessed potential associated risks. Metals, organochlorine pesticides, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) were examined in reef and pelagic fishes from six atolls: Kwajalein, Majuro, Jaluit, Utirik, Rongelap, and Wotje. Clear trophic patterns emerged for metals. Total arsenic was highest in higher trophic level reef fishes, particularly in the camouflage grouper (Epinephelus polyphekadion) (>100 µg g-1 total As), but inorganic arsenic was negligible in higher trophic levels and showed an inverse trend with the highest percentages present in parrotfishes and herbivores. Copper and mercury were elevated in higher trophic level reef and pelagic fishes, respectively, and the maximum mercury concentrations (6.45 µg g-1 in Gymnosarda unicolor) were among the highest reported in the Pacific. Conversely, cadmium and lead were highest in lower trophic levels, like surgeonfishes and parrotfishes. PCBs were more clearly linked to locations and were highest at two atolls with military history (Kwajalein and Jaluit) (>U.S. EPA Screening Value of 2.5 ppb). PAHs were ubiquitous across taxa (detected in 97% of samples), but the highest concentrations were in lower trophic levels. Organochlorine pesticides were detected at very low concentrations that do not likely pose a risk. We compare concentrations to established thresholds for human health and find that - for specific locations and species - contaminant concentrations may pose a risk to fish and other marine taxa, as well as human consumers. This study provides baseline information that aids the development of marine conservation and public health recommendations and addresses a data gap that persists for marine pollution throughout the Pacific Islands.

Adapting a preschool disruptive behavior group for the underserved in pediatric primary care practice.

INTRODUCTION: While behavioral parent training (BPT) is the first line treatment for preschool aged children with disruptive behavior, only a fraction of families receive these therapies. The integration of BPT within the pediatric primary care (PPC) setting is a promising way to address this need, as the PPC setting is the first and only point of contact for most children diagnosed with mental health disorders. We piloted a clinical innovation by implementing an adapted BPT group in an urban, academic, PPC practice, serving a low-income, predominantly Black population. METHOD: Using a formative program development approach and a cultural adaptation framework, structural and cultural adaptations to the program were implemented to increase engagement and adaptability of the group to meet the needs of our PPC population. RESULTS: Learnings indicated that these adaptations were feasible and acceptable to families. Specifically, they were effective in engaging families and transforming the practice of primary care providers. DISCUSSION: Our work offers a case example to guide efforts to thoughtfully and effectively adapt evidence-based interventions for disruptive behavior in primary care settings. These processes provide one strategy to ameliorate behavioral health disparities in diverse, racial/ethnic minority populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The relationship of the clinician-rated Functional Status Interview with executive functioning.

Self/informant-report and performance-based instruments are typically used to measure activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Minimal attention has focused on clinician-rated measures. Executive functioning (EF) contributes significantly to functional independence, and the validity of functional status measures has been examined through its relationship to EF scores. The current study used a clinical sample of older U.S. Veterans who completed a neurocognitive evaluation (n = 266). The psychometric properties of a novel, clinician-rated Functional Status Interview (FSI) and its relationship to EF measures, including the Frontal Assessment Battery (FAB) and Trail Making Test (TMT-A and TMT-B), were explored. Two FSI factors (IADL and ADL) emerged with all items loading strongly onto the subscales as predicted. EF correlated strongly with IADL but had small to medium correlations with ADL. In regression models that controlled for sociodemographic variables, all EF measures uniquely contributed to the IADL model, but only FAB and TMT-A contributed to the model for ADL. Notably, results may have been limited by prominent floor effects on TMT-B. Overall, the FSI is a promising measure with demonstrated content validity. Thus, there is preliminary support for clinicians to incorporate multiple sources of information to rate functional status using the FSI.

Correction: Racial and geographic variation in effects of maternal education and neighborhood-level measures of socioeconomic status on gestational age at birth: Findings from the ECHO cohorts.

[This corrects the article DOI: 10.1371/journal.pone.0245064.].

COVID-19 pharmacotherapy utilization patterns during pregnancy: International Registry of Coronavirus Exposure in Pregnancy.

PURPOSE: Women infected with SARS-CoV-2 during pregnancy are at increased risk of developing severe illness and experience a higher rate of preterm births than pregnant women who are not infected. The use of innovative or repurposed therapies to treat COVID-19 patients is widespread; however, there are very limited data regarding the patterns of use and safety profile of most of these therapeutics in pregnant women. We assessed the patterns of use of COVID-19 therapeutics during pregnancy using data from the International Registry of Coronavirus in Pregnancy (IRCEP). METHODS: The IRCEP is an international observational cohort study intended to assess the risk of major obstetric and neonatal outcomes among pregnant women with COVID-19. Women enrolled while pregnant or within 6 months after end of pregnancy. Follow-up for women enrolled while pregnant includes monthly online questionnaires throughout the pregnancy and, for live births, through the infant's first 90 days of life. Participants provide information on demographic characteristics, health history, COVID-19 tests and symptoms, medications, and obstetric and neonatal outcomes. RESULTS: A total of 5780 women with COVID-19 during pregnancy were identified from the IRCEP. Severity of COVID-19 was classified in 372 of them as severe, 3053 moderate, and 2355 mild. The most frequently reported COVID-19 therapies, other than analgesics, included azithromycin (12.8%), steroids (3.5%), interferon (2.4%), oseltamivir (2.1%), chloroquine/hydroxychloroquine (1.7%), anticoagulants (2.0%), antibodies (0.9%), and remdesivir (0.3%). Most drugs were preferentially used for severe cases. Patterns of use varied by country. CONCLUSIONS: IRCEP participants reported use of therapeutics for COVID-19 during pregnancy for which there is little safety information. Findings on COVID-19 pharmacotherapy utilization patterns can guide future studies examining the safety of COVID-19 therapies during pregnancy.