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Differential disease control may contribute to racial disparities in outcomes of childhood‐onset systemic lupus erythematosus (cSLE). We evaluated associations of race and individual‐ or neighborhood‐level social determinants of health (SDoH) with achievement of low lupus disease activity state (LLDAS), a clinically relevant treatment target. In this cSLE cohort study using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, the primary exposure was self‐reported race and ethnicity, and collected SDoH included insurance status and area deprivation index (ADI). Outcomes included LLDAS, disease activity, and time‐averaged prednisone exposure. Associations among race and ethnicity, SDoH, and disease activity were estimated with multivariable regression models, adjusting for disease‐related and demographic factors. Among 540 children with cSLE, 27% identified as Black, 25% identified as White, 23% identified as Latino/a, 11% identified as Asian, 9% identified as more than one race, and 5% identified as other. More Black children (41%) lived in neighborhoods of highest ADI compared to White children (16%). Black race was associated with lower LLDAS achievement (adjusted odds ratio 0.56, 95% confidence interval [CI] 0.38–0.82) and higher disease activity (adjusted β 0.94, 95% CI 0.11–1.78). The highest ADI was not associated with lower LLDAS achievement on adjustment for renal disease and insurance. However, renal disease was found to be a significant mediator (P= 0.04) of the association between ADI and prednisone exposure. Children with cSLE who identified as Black are less likely to achieve LLDAS and have a higher disease activity. Living in areas of higher ADI may relate to renal disease and subsequent prednisone exposure. Strategies to address root causes will be important to design interventions mitigating cSLE racial disparities.

Introduction:The thrombo-inflammatory response and outcomes of community-acquired pneumonia (CAP) due to various organisms (non-COVID-19 CAP) versus CAP due to a single virus, SARS-CoV-2 (i.e., COVID-19) may differ. Methods:Adults hospitalized with non-COVID-19 CAP (December 1, 2021–June 15, 2023) or COVID-19 (March 2, 2020–June 15, 2023) in Canada. We compared non-COVID-19 CAP and COVID-19 baseline, thrombo-inflammatory response, and mortality. We measured plasma cytokine and coagulation factor levels in a sample of patients, did hierarchical clustering, and compared cytokine and coagulation factor levels. Results:In 2,485 patients (non-COVID-19 CAP, n= 719; COVID-19 patients, n= 2,157), non-COVID-19 CAP patients had significantly lower 28-day mortality (CAP vs. COVID-19 waves 1 and 2; 10% vs. 18% and 16%, respectively), intensive care unit admission (CAP vs. all waves; 15% vs. 39%, 37%, 33%, and 24%, respectively), invasive ventilation (CAP vs. waves 1, 2, and 3 patients; 11% vs. 25%, 20%, and 16%), vasopressor use (CAP 12% vs. 23%, 21%, and 18%), and renal replacement therapy use (CAP 3% vs. Omicron 7%). Complexity of hierarchical clustering aligned directly with mortality: COVID-19 wave 1 and 2 patients had six clusters at admission and higher mortality than non-COVID-19 CAP and Omicron that had three clusters at admission. Pooling all COVID-19 waves increased complexity with seven clusters on admission. Conclusion:Complex thrombo-inflammatory responses aligned with mortality of CAP. At a fundamental level, the human thrombo-inflammatory response to a brand new virus was “confused” whereas humans had eons of time to develop a more concise efficient thrombo-inflammatory host response to CAP.

Given that the harvested fish from five separate fishing grounds belong to one large mixed population, our objective is to develop an overall abundance index for Lake Whitefish Coregonus clupeaformisin Michigan waters of southern Lake Huron. We analyzed catch‐and‐effort data for individual fishing trips to five separate fishing grounds and used Bayesian information criterion to select the best model struture. The best model included the year × area × month interaction as a random effect, representing the random component in fishery dynamics that were influenced by both fishing practices and fish abundance. The best model also included the fixed effects of area × month interaction, a result consistent with our hypothesis that the seasonal spatial migrations of Lake Whitefish provide the links among the fisheries in separate fishing grounds, and the fishery yields from these separate areas were all dependent on the production in southern Lake Huron as a whole. After adjusting for the random effect of year × area × month interaction and the fixed effects of area × month interaction, the estimated patterns for the fixed year effect indicated that the Lake Whitefish abundance in Michigan waters of southern Lake Huron declined during the late 2000s but has been relatively constant after 2012. The declines in annual fishery yield were due to and could be explained more by the decreases in fish abundance through 2012 but thereafter primarily reflected the declines in annual fishing effort as the fisheries continued to adjust to the changed fishing conditions. We also provided general lessons for studying fisheries without fishery independent surveys but with detailed seasonal and spatial catch‐and‐effort data. Impact statementThis study and its findings have direct implication for current management of the Lake Whitefish fisheries. This study and its findings have direct implication for current management of the Lake Whitefish fisheries.

Background: Slower walking is associated with changes in cortical volume and thickness. Computerized cognitive training (CCT) and exercise improve cortical volume and thickness and thus, may promote gait speed. Slowing of gait is predictive of Alzheimer’s disease.Objective: To examine: 1) the effect of CCT, with or without physical exercise, on cortical volume and thickness and; 2) the association of changes in cortical volume and thickness with changes in gait speed.Methods: A subset of 124 adults (n= 53), aged 65–85 years, enrolled in an 8-week randomized controlled trial and completed T1-weighted MRI and 4-meter walk at baseline and 8 weeks. Participants were randomized to: 1) active control (BAT; n= 19); 2) CCT (n= 17); or 3) CCT preceded by exercise (Ex-CCT; n= 17). Change in cortical volume and thickness were assessed and compared across all groups using Freesurfer.RESULTS: BAT versus CCT increased left rostral middle frontal gyrus volume (p= 0.027) and superior temporal gyrus thickness (p= 0.039). Ex-CCT versus CCT increased left cuneus thickness (p< 0.001) and right post central gyrus thickness (p= 0.005), and volume (p< 0.001). Ex-CCT versus BAT increased left (p= 0.001) and right (p= 0.020) superior parietal gyri thickness. There were no significant between-group differences in gait speed (p> 0.175). Increased left superior parietal volume (p= 0.036, r= 0.340) and thickness (p= 0.002, r= 0.348), right post central volume (p= .017, r= 0.341) and thickness (p= 0.001, r= 0.348), left banks of superior temporal sulcus thickness (p= 0.002, r= 0.356), and left precuneus thickness (p< 0.001, r= 0.346) were associated with increased gait speed.CONCLUSIONS: CCT with physical exercise, but not CCT alone, improves cortical volume and thickness in older adults. These changes may contribute to the maintenance of gait speed in aging.

The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non‐TNFi biologic following discontinuation of a TNFi for patients with polyarticular‐course juvenile idiopathic arthritis (pJIA). Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation. There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non‐TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non‐TNFi second biologic received (9% overall, 58% of non‐TNFi). There was no difference between receiving TNFi versus non‐TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47–3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47–2.62) at six months. Most patients with pJIA started receiving TNFi rather than non‐TNFi as their second biologic, and there were no differences in disease activity at six months.

Comparisons and linkage between multiple imaging scales are essential for neural circuit connectomics. Here, we report 20 new recombinant rabies virus (RV) vectors that we have developed for multi-scale and multi-modal neural circuit mapping tools. Our new RV tools for mesoscale imaging express a range of improved fluorescent proteins. Further refinements target specific neuronal subcellular locations of interest. We demonstrate the discovery power of these new tools including the detection of detailed microstructural changes of rabies-labeled neurons in aging and Alzheimer’s disease mouse models, live imaging of neuronal activities using calcium indicators, and automated measurement of infected neurons. RVs that encode GFP and ferritin as electron microscopy (EM) and fluorescence microscopy reporters are used for dual EM and mesoscale imaging. These new viral variants significantly expand the scale and power of rabies virus-mediated neural labeling and circuit mapping across multiple imaging scales in health and disease.

Hypertension (HTN) involves genetic variability in the renin‐angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen (AGT) messenger RNA (mRNA) is endogenously bound by miR‐122‐5p and rs699 A > G decreases reporter mRNA in the microRNA functional‐assay PASSPORT‐seq. The AGTpromoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGTtranscription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGTby rs5051 C > T counterbalances AGTdecreased by rs699 A > G, and when these variants occur independently, it translates to HTN‐related phenotypes. We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis. In silico, rs699 A > G is predicted to increase miR‐122‐5p binding affinity by 3%. Mir‐eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA‐binding site in the AGTmRNA. Unexpectedly, rs699 A > G increases AGTmRNA in an AGT‐plasmid‐cDNA HepG2 expression model. Genotype‐Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGTexpression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell‐type‐specific effects on AGTmRNA abundance, and suggest paracrine renal renin‐angiotensin‐system perturbations could mediate the rs699 A > G associations with HTN. We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms.The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure.The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects.Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms. The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure. The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects. Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G.

Among polar bears (Ursus maritimus), only parturient females den for extended periods, emerging from maternal dens in spring after having substantially depleted their energy reserves during a fast that can exceed 8 months. Although den emergence coincides with a period of increasing prey availability, polar bears typically do not depart immediately to hunt, but instead remain at the den for up to a month. This delay suggests that there are likely adaptive advantages to remaining at the den between emergence and departure, but the influence of the timing and duration of this post-emergence period on cub survival has not been evaluated previously. We used temperature and location data from 70 denning bears collared within the Southern Beaufort Sea and Chukchi Sea subpopulations to estimate the phenology of the post-emergence period. We evaluated the influence of various spatial and temporal features on duration of the post-emergence period and evaluated the potential influence of post-emergence duration on litter survival early in the spring following denning. For dens that likely contained viable cubs at emergence (n= 56), mean den emergence occurred on 16 March (SE = 1.4 days) and mean departure on 24 March (SE = 1.6 days), with dates typically occurring later in the Chukchi Sea relative to Southern Beaufort Sea and on land relative to sea ice. Mean duration of the post-emergence period was 7.9 days (SE = 1.4) for bears that were observed with cubs later in the spring, which was over 4 times longer than duration of those observed without cubs (1.9 days). Litter survival in the spring following denning (n= 31 dens) increased from 0.5 to 0.9 when duration of the post-emergence period increased by ~4 days and other variables were held at mean values. Our limited sample size and inability to verify cub presence at emergence suggests that future research is merited to improve our understanding of this relationship. Nonetheless, our results highlight the importance of the post-emergence period in contributing to reproductive success and can assist managers in developing conservation and mitigation strategies in denning areas, which will be increasingly important as human activities expand in the Arctic.Polar bears observed with cubs in the spring following denning stayed at the den site 4 times longer than those observed without cubs, and cub survival during that period increased from 0.5 to 0.9 when time spent at the den increased from 0 to 4 days.

This study introduces a sustainable approach to designing organic cathode materials (OCMs) for lithium-ion batteries as a potential replacement for traditional metal-based electrodes. Utilizing green synthetic methodologies, we synthesized and characterized five distinct quinone derivatives and investigated their electrochemical attributes within Li-ion battery architectures. Notably, the observed specific capacities were lower than the theoretical predictions, suggesting limitations in achieving efficient redox reactions in a coin-cell configuration. Among the quinone derivatives studied, one variant derived from natural vanillin showed superior cycle stability, maintaining 58% capacity retention over 95 charge–discharge cycles, and achieving a Coulombic efficiency of 90%. Importantly, we discovered that the commonly used Super-P conductive carbon did not yield any measurable battery performance; instead, these quinones necessitated the incorporation of graphene nanoplatelets as the conductive matrix. Through a facile one-step synthesis in ethanol or water, we have demonstrated a viable synthetic route for producing OCMs, albeit with moderate performances, which have attempted to address common concerns of high solubility and poor redox reactivity of previous OCMs, thereby offering a sustainable pathway for the development of organic-based energy storage devices.

Objective To evaluate the sensitivity to change of daily ratings of the comfort (COMF) and behavioral/emotional health (BEH) domains of the Infants with Clefts Observation Outcomes Instrument (iCOO) at 3 time points, and to assess the association of post-surgical interventions on iCOO ratings.Design The COMF and BEH domains were completed by caregivers before (T0), immediately after (T1), and 2-months after (T2) cleft lip (CL) surgery. Analyses included descriptive statistics, correlations, t-tests, and generalized estimating equations.Participants Caregivers (N=  140) of infants with CL with/without cleft palate.Main Outcome Measures The COMF and BEH domain scores of the iCOO: Scale (SCALE), a summary of observable signs; and Global Impression (IMPR), a single item measuring caregivers’ overall impression.Results Daily COMF and BEH SCALE and IMPR scores changed significantly during T1 (P's< 0.001) but not T0 or T2. Day 1 and 7 T0 scores were significantly higher than Day 1 and 7 T1 scores (P's<0.001 to <0.012) but similar at T2 (P's> 0.05). After CL surgery, the combined use of immobilizers and nasal stents and the use of multiple feeding methods with treatment for gastroesophageal reflux were associated with lower daily scores in COMF and BEH SCALE and IMPR (P's: 0.040 to <0.001).Conclusions COMF and BEH iCOO scores were sensitive to daily changes in infant well-being following CL surgery. Future studies should further investigate impact of post-surgical treatments on infant well-being.

IMPORTANCE: Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed. OBJECTIVE: To assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients. DATA SOURCES: PubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022. STUDY SELECTION: Included studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection. DATA EXTRACTION AND SYNTHESIS: In this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. MAIN OUTCOMES AND MEASURES: Hospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs. RESULTS: Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6166 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.9% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.79; 95% CI, 0.48 to 1.29; RD, −0.17%; 95% CI, −0.23% to 0.48%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 1.01; 95% CI, 0.21 to 4.90) or in patients considered at greater risk of hospitalization (RR, 0.65; 0.33 to 1.28). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13 to 1.82) and vomiting (RR, 1.83; 95% CI, 1.28 to 2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46 to1.08). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.

Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal derepression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use multiplexed error-robust fluorescent in situ hybridization (MERFISH) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated myotubes and unfused mononuclear cells (MNCs) of control, isogenic D4Z4 contraction mutant and FSHD patient samples, as well as the individual nuclei within them. We find myocyte nuclei segregate into two clusters defined by the expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, whereas MNCs cluster based on developmental states. Patient/mutant myotubes are found in “FSHD-hi” and “FSHD-lo” states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target-expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared with the control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.

AbstractWe investigated the influence of maternal yellow-pea fiber supplementation in obese pregnancies on offspring metabolic health in adulthood. Sixty newly-weaned female Sprague-Dawley rats were randomized to either a low-calorie control diet (CON) or high calorie obesogenic diet (HC) for 6-weeks. Obese animals were then fed either the HC diet alone or the HC diet supplemented with yellow-pea fiber (HC + FBR) for an additional 4-weeks prior to breeding and throughout gestation and lactation. On postnatal day (PND) 21, 1 male and 1 female offspring from each dam were weaned onto the CON diet until adulthood (PND 120) for metabolic phenotyping. Adult male, but not female, HC offspring demonstrated increased body weight and feed intake vs CON offspring, however no protection was offered by maternal FBR supplementation. HC male and female adult offspring demonstrated increased serum glucose and insulin resistance (HOMA-IR) compared with CON offspring. Maternal FBR supplementation improved glycemic control in male, but not female offspring. Compared with CON offspring, male offspring from HC dams demonstrated marked dyslipidemia (higher serum cholesterol, increased number of TG-rich lipoproteins, and smaller LDL particles) which was largely normalized in offspring from HC + FBR mothers. Male offspring born to obese mothers (HC) had higher hepatic TG, which tended to be lowered (p= 0.07) by maternal FBR supplementation.Supplementation of a maternal high calorie diet with yellow-pea fiber in prepregnancy and throughout gestation and lactation protects male offspring from metabolic dysfunction in the absence of any change in body weight status in adulthood.

Inhibitory interneurons are crucial to brain function and their dysfunction is implicated in neuropsychiatric conditions. Emerging evidence indicates that cholecystokinin (CCK)-expressing interneurons (CCK+) are highly heterogenous. We find that a large subset of parvalbumin-expressing (PV+) interneurons express CCK strongly; between 40 and 56% of PV+ interneurons in mouse hippocampal CA1 express CCK. Primate interneurons also exhibit substantial PV/CCK co-expression. Mouse PV+/CCK+ and PV+/CCK- cells show distinguishable electrophysiological and molecular characteristics. Analysis of single nuclei RNA-seq and ATAC-seq data shows that PV+/CCK+ cells are a subset of PV+ cells, not of synuclein gamma positive (SNCG+) cells, and that they strongly express oxidative phosphorylation (OXPHOS) genes. We find that mitochondrial complex I and IV-associated OXPHOS gene expression is strongly correlated with CCK expression in PV+ interneurons at both the transcriptomic and protein levels. Both PV+ interneurons and dysregulation of OXPHOS processes are implicated in neuropsychiatric conditions, including autism spectrum (ASD) disorder and schizophrenia (SCZ). Analysis of human brain samples from patients with these conditions shows alterations in OXPHOS gene expression. Together these data reveal important molecular characteristics of PV-CCK co-expressing interneurons and support their implication in neuropsychiatric conditions.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N= 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78–1.18), serious ADEs (OR: 0.91, 95% CI: 0.58–1.40), or mortality (OR: 0.60, 95% CI: 0.28–1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12–0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

The study of Alzheimer’s Disease (AD) has traditionally focused on neuropathological mechanisms that has guided therapies that attenuate neuropathological features. A new direction is emerging in AD research that focuses on the progressive loss of cognitive function due to disrupted neural circuit mechanisms. Evidence from humans and animal models of AD show that dysregulated circuits initiate a cascade of pathological events that culminate in functional loss of learning, memory, and other aspects of cognition. Recent progress in single-cell, spatial, and circuit omics informs this circuit-focused approach by determining the identities, locations, and circuitry of the specific cells affected by AD. Recently developed neuroscience tools allow for precise access to cell type-specific circuitry so that their functional roles in AD-related cognitive deficits and disease progression can be tested. An integrated systems-level understanding of AD-associated neural circuit mechanisms requires new multimodal and multi-scale interrogations that longitudinally measure and/or manipulate the ensemble properties of specific molecularly-defined neuron populations first susceptible to AD. These newly developed technological and conceptual advances present new opportunities for studying and treating circuits vulnerable in AD and represent the beginning of a new era for circuit-based AD research.

The Lake Sturgeon Acipenser fulvescensis listed as threatened or endangered in 15 states or provinces within the species' native range. Accordingly, investments in habitat and population restoration for this species have increased throughout the Great Lakes. To aid in the evaluation of restoration efficacy, robust population parameters are needed to inform management decisions. The St. Clair–Detroit River system (SCDRS) contains one of the largest self‐sustaining Lake Sturgeon populations in the Great Lakes; however, recent estimates of population abundance and growth parameters have not been assessed. Our study used baited setline and mark–recapture data collected between 2001 and 2019 to estimate whether the number of Lake Sturgeon captured varied annually and/or with water temperature and whether population abundance and the population growth rate (λ) varied among three subpopulations located in the SCDRS. Trends in the number of Lake Sturgeon captured on setlines varied among subpopulations and by life stage. Annual trends in the number of Lake Sturgeon captured remained consistent over time in the upper St. Clair River, decreased for adults and increased for subadults in the lower St. Clair River, and increased in the Detroit River. With subpopulation abundances of 20,184 (95% confidence interval [CI] = 12,533–27,816) in the upper St. Clair River/southern Lake Huron, 6523 (95% CI = 5720–7327) in the lower St. Clair River, and 6416 (95% CI = 4065–8767) in the Detroit River, our study confirms that the SCDRS contains the largest Lake Sturgeon population with unimpeded access to the Great Lakes. The geometric mean λ for all subpopulations indicated stable populations and ranged from 1.00 to 1.16. Our study provides an updated assessment of Lake Sturgeon population parameters that serve as a baseline to evaluate habitat restoration efforts and to inform management of the SCDRS recreational Lake Sturgeon fishery. Impact statementLake Sturgeon are a threatened or endangered fish species throughout much of their native range. The sturgeon population in the St. Clair–Detroit River system is one of the largest in the Great Lakes with nearly 30,000 individuals and is in stable condition. Lake Sturgeon are a threatened or endangered fish species throughout much of their native range. The sturgeon population in the St. Clair–Detroit River system is one of the largest in the Great Lakes with nearly 30,000 individuals and is in stable condition.

Background Caregiver and observer-reported measures are frequently used as outcomes for research on infants and young children who are unable to report on their own health. Our team developed the Infant with Clefts Observation Outcomes Instrument (iCOO) for infants with cleft lip with or without cleft palate. This exploratory study compared test-retest and interrater reliabilities to inform whether differences in caregiver perspective might affect the iCOO.Methods This study is a secondary analysis comparing caregiver interrater agreement to test-retest reliability. Twenty-five pairs of caregivers completed the iCOO before surgery, 1 week later for test-retest reliability, 2 days after surgery, and 2 months after surgery. Reliability was assessed using intraclass correlations (ICCs) and t-tests were used to compare ratings between caregivers.Results Infants had cleft lip (28%) or cleft lip and palate (72%). Primary caregivers were predominantly mothers (92%) and secondary caregivers were predominantly fathers (80%). Test-retest reliability met psychometric standards for most items on the iCOO (81%-86% of items). Caregiver agreement on the iCOO items was lower than test-retest reliability (33%-46% of items met psychometric standards). Caregivers did not systematically differ in whether they rated infants as healthier or less healthy than the other caregiver (5%-16% of items had statistically significant differences).Conclusions Caregivers used the measure consistently, but had different experiences and perceptions of their infant’s health and functioning. Future studies are needed to explore mechanisms for the differences in test-retest and interrater reliability. Whenever possible, the same caregiver should provide ratings of the infant, including on the iCOO.

Aquatic organisms and the habitats they live in are declining globally, yet managers often lack even basic biological information for individual imperiled species. This makes assessment of the current status, management needs, and recovery targets for these species challenging. One such organism is the Northern Madtom Noturus stigmosus,a small, bottom‐dwelling catfish of the family Ictaluridae. Northern Madtom are listed as endangered in the state of Michigan and the province of Ontario, with only a handful of isolated populations known in each region. To address life history uncertainties and to provide fisheries managers with baseline information to inform decision making, the Michigan Department of Natural Resources annually sampled Northern Madtom in the St. Clair River using minnow traps and amassed the largest known data set for this species. We handled 871 individuals from 2010 to 2022, with yearly catch rates ranging from 0.17 to 1.33 individuals/trap. Age estimates derived from otoliths and dorsal spines of 17 individuals showed no clear pattern of bias, indicating that nonlethally collected dorsal spines provide a suitable age estimation method. We developed an age–length key to assign ages to all individuals in our data set, calculated growth parameters, and determined that annual mortality rates across all ages ranged from 46% to 69%. Diet analysis revealed that caddisfly (order Trichoptera) larvae were the dominant prey item and fecundity averaged 178 eggs/female. We compared microsatellite allele frequencies and mitochondrial DNA haplotypes among samples collected in the St. Clair River and the Detroit River. Significant evidence of genetic structure was present, indicating limited gene flow and suggesting that separate management of these two populations may be warranted. Collectively, these data provide context for managers interested in the development of biological reference points and planning for the conservation and management of this species.

The University of California Irvine (UCI) Center for Neural Circuit Mapping (CNCM) held its 4th annual Summer Conference entitled “Brain Cell Types, Circuits, and Disorders” at the Beckman Center of the National Academies of Science and Engineering in Irvine, California. Herein, we provide a Meeting Report highlighting the conference and the work of its attendees. The conference hosted 204 formal registrants from 41 diverse academic institutions and 6 industrial organizations in the US and internationally, with 78 accepted abstract submissions (including 25 invited talks, 7 special/selected short talks, 4 workshop lectures, and 42 poster presentations). The conference had six major sessions with the themes of 1) Brain Cell Types, Connectivity and Genomics, 2) Precision Brain Cell Access and Imaging, 3) Neural Circuits and Networks, 4) Brain Disorders, 5) Frontiers, New Concepts and Approaches, and 6) International Collaboration Program and Viral Vector Workshop. This year’s conference continued to be highly successful, and we have opened up registration for our 2025 summer conference entitled “The Changing Brain”.

Heritability estimates of traits assist breeders in optimizing cultivar development and can help predict gain from selection in breeding programs. Narrow‐sense heritabilities were measured in agronomic traits and glycoside concentration in four elite stevia (Stevia rebaudianaBertoni) populations using half‐sib family analysis. Gain from selection at 20% selection intensity was estimated for morphological, yield, and glycoside traits. Experiments were conducted in two field locations in North Carolina. Variation was observed across cultigens for agronomic traits including stem height, branch width, and leaf size, for both subjective and objective measurements. Yield, lodging resistance, disease resistance, and percent survival showed a high genetic variation across cultigens. In addition, glycosides including Reb A, Reb C, and Reb D also showed high variation by cultigen. Heritability estimates for plant morphological traits were highest for stem height, and moderate for yield and branch width. However, other traits such as leaf area and lodging resistance showed low heritability (0.10). Glycosides including Reb A, Reb C, Reb D, stevioside and total steviol glycosides (TSG) showed high heritability. The estimated gain from selection per year for stem height (24 mm/year), leaf area (131 mm2/year) and yield (dry weight) (1.2 Mg/ha per year) suggest significant improvements are possible per breeding cycle. The estimated gain for glycoside concentration and percent of TSG of Reb A (26.44 mg/g, 14.51%), Reb C (20.20 mg/g, 20.17%), Reb D (1.70 mg/g, 1.49%), stevioside (6.73 mg/g, 10.72%), and TSG (20.90 mg/g), similarly, indicate significant gains are possible per breeding cycle. The stevia cultigens evaluated showed high variability for yield and glycoside traits.Heritability estimates for morphological traits were medium to high for plant height, width, and yield.Heritability estimates for Reb A, Reb C, Reb D, stevioside, and total steviol glycosides showed high heritability.Estimated gain from selection for yield and glycosides suggest significant improvement are possible.

Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups.

The SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication–transcription complex (RTC)1. Accordingly, the RTC is a target for clinically approved antiviral nucleoside analogues, including remdesivir2. Faithful synthesis of viral RNAs by the RTC requires recognition of the correct nucleotide triphosphate (NTP) for incorporation into the nascent RNA. To be effective inhibitors, antiviral nucleoside analogues must compete with the natural NTPs for incorporation. How the SARS-CoV-2 RTC discriminates between the natural NTPs, and how antiviral nucleoside analogues compete, has not been discerned in detail. Here, we use cryogenic-electron microscopy to visualize the RTC bound to each of the natural NTPs in states poised for incorporation. Furthermore, we investigate the RTC with the active metabolite of remdesivir, remdesivir triphosphate (RDV-TP), highlighting the structural basis for the selective incorporation of RDV-TP over its natural counterpart adenosine triphosphate3,4. Our results explain the suite of interactions required for NTP recognition, informing the rational design of antivirals. Our analysis also yields insights into nucleotide recognition by the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase), an enigmatic catalytic domain essential for viral propagation5. The NiRAN selectively binds guanosine triphosphate, strengthening proposals for the role of this domain in the formation of the 5′ RNA cap6.

Objective: Establish the feasibility of pediatric intensive care unit (PICU) nurse-directed ultrasound assessment (UA) of peripheral intravenous (PIV) catheters, compare the results of UA to traditional assessment (TA), and determine PIV survival after UA.Design: Prospective observational cohort study.Setting: PICU within a children’s hospital.Patients: PICU patients with a PIV.Interventions: None.Measurements and main results: Eight nurses performed UA on 131 PIVs in 85 patients. Median age was 3.0 years (IQR 1.0–13.8) and median weight was 15.0 kg (IQR 9.6–59.3). The most common PIV location was the arm (43%) and extravasation occurred in 15% of PIVs. Agreement between TA and UA was moderate with a Kappa of 0.47 (95% CI 0.28–0.66). Nursing confidence in the UA was significantly higher than TA (92% vs 21% very confident, p< 0.0001). In 106 PIVs with a UA that indicated the PIV was intravascular (i.e. negative UA), the median survival was 50.0 h (IQR 21.8–100.3).Conclusions: Nurses can perform UA of PIV status in PICU patients and express greater confidence in the findings of UA than TA. Further study is necessary to determine the impact of UA on the rate of PIV complications.