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In adults, viral load and disease severity can differ by SARS-CoV-2 variant, patterns less understood in children. We evaluated symptomatology, cycle threshold (Ct) values, and SARS-CoV-2 variants among 2,299 pediatric SARS-CoV-2 patients (0-21 years of age) in Colorado, USA, to determine whether children infected with Delta or Omicron had different symptom severity or Ct values than during earlier variants. Children infected during the Delta and Omicron periods had lower Ct values than those infected during pre-Delta, and children <1 year of age had lower Ct values than older children. Hospitalized symptomatic children had lower Ct values than asymptomatic patients. Compared with pre-Delta, more children infected during Delta and Omicron were symptomatic (75.4% pre-Delta, 95.3% Delta, 99.5% Omicron), admitted to intensive care (18.8% pre-Delta, 39.5% Delta, 22.9% Omicron), or received oxygen support (42.0% pre-Delta, 66.3% Delta, 62.3% Omicron). Our data reinforce the need to include children, especially younger children, in pathogen surveillance efforts.

Spinal muscular atrophy (SMA) is a progressive recessive genetic disease. Early identification is critical for achieving maximal treatment benefit. Survival motor neuron (SMN) 2 copy number may be a needed descriptor of disease severity than SMA type. Therefore, we assessed knowledge of SMN2 copy number among those with SMA and their caregivers via a phone survey. Only patients with SMA (or their caregivers) registered in the Cure SMA database with no SMN2 copy number on file were eligible. Descriptive results are reported. Backward stepwise multinomial logistic regressions determined if specific factors predicted knowledge of SMN2 copy number. Engagement with the SMA community (odds ratio [OR] 1.82; p<0.0001), ability to walk (OR 1.74; p = 0.006), and current age at time of survey (OR = 0.98; p<0.0001) each positively predicted knowledge of SMN2 copy number. Of 806 completed surveys, the majority (n = 452; 56.3%) did not know SMN2 copy numbers for themselves (n = 190; 62.5%) or their loved ones (n = 261; 52.4%). Of these, 66 respondents (8.2%) said genetic testing had not been done. Motor function increased linearly with increasing SMN2 copy number. SMN2 copy number is emerging as a critical descriptor of severity for SMA as type becomes more obsolete with early drug treatment. Communication of SMN2 copy numbers is recommended as a standard part of the treatment plan.

To compare SARS-CoV-2 antibody seroprevalence among children with seropositive confirmed COVID-19 case counts (case ascertainment by molecular amplification) in Colorado, USA, we conducted a cross-sectional serosurvey during May-July 2021. For a convenience sample of 829 Colorado children, SARS-CoV-2 seroprevalence was 36.7%, compared with prevalence of 6.5% according to individually matched COVID-19 test results reported to public health. Compared with non-Hispanic White children, seroprevalence was higher among Hispanic, non-Hispanic Black, and non-Hispanic other race children, and case ascertainment was significantly lower among Hispanic and non-Hispanic Black children. This serosurvey accurately estimated SARS-CoV-2 prevalence among children compared with confirmed COVID-19 case counts and revealed substantial racial/ethnic disparities in infections and case ascertainment. Continued efforts to address racial and ethnic differences in disease burden and to overcome potential barriers to case ascertainment, including access to testing, may help mitigate these ongoing disparities.

Identifying the factors that favor group living is central to studies of animal social behavior. One demographic parameter that is expected to substantially shape spatial and social relationships is population density. Specifically, high population densities may favor group living by constraining opportunities to live alone. In contrast, low densities may allow individuals to spread out within the habitat, leading to a reduction in the prevalence or size of social groups. Abrupt changes in density following natural catastrophic events provide important opportunities to evaluate the effects of population density on patterns of spatial and social organization. As part of long-term studies of the behavioral ecology of a population of highland tuco-tucos ( Ctenomys opimus ) at Monumento Natural Laguna de los Pozuelos, Jujuy Province, Argentina, we monitored the demographic and behavioral consequences of a flood that inundated our study site during December 2012. Unlike most species of Ctenomys studied to date, highland tuco-tucos are group living, meaning that multiple adults share burrow systems and nest sites. Despite a post-flood reduction in population density of ~75%, animals present on the study site during the 2013 breeding season continued to live in multi-adult social units (groups). No differences between pre- and post-flood home range sizes were detected and although between-unit spatial overlap was reduced in 2013, overlap within social units did not differ from that in pre-flood years. Animals assigned to the same social unit in 2013 had not lived together during 2012, indicating that post-flood groups were not simply the remnants of those present prior to the flood. Collectively, these findings indicate that group living in highland tuco-tucos is not driven by the density of conspecifics in the habitat. In addition to enhancing understanding of the adaptive bases for group living in Ctenomys , our analyses underscore the power of catastrophic events to generate insights into fundamental aspects of social behavior.

The global COVID-19 pandemic illustrates the importance of a close partnership between public health and juvenile justice systems when responding to communicable diseases. Many setting-specific obstacles must be navigated to respond effectively to limit disease transmission and negative health outcomes while maintaining necessary services for youth in confinement facilities. The response requires multidisciplinary expertise and collaboration to address unique considerations. Public health mitigation strategies must balance the risk for disease against the negative effects of restrictions. Key aspects of the COVID-19 response in the juvenile justice system of Colorado, USA, involved establishing robust communication and data reporting infrastructures, building a multidisciplinary response team, adapting existing infection prevention guidelines, and focusing on a whole-person health approach to infection prevention. We examine lessons learned and offer recommendations on pandemic emergency response planning and managing a statewide public health emergency in youth confinement settings that ensure ongoing readiness.

In some species, populations routinely contain a mixture of lone and group-living individuals. Such facultative sociality may reflect individual differences in behavior as well as adaptive responses to variation in local environmental conditions. To explore interactions between individual-and population-level variabilities in behavior in a species provisionally described as facultatively social, we examined spatial and social relationships within a population of highland tuco-tucos (Ctenomys opimus) at Laguna de los Pozuelos, Jujuy Province, Argentina. Using data collected over 5 consecutive years, we sought to (1) confirm the regular occurrence of both lone and group-living individuals and (2) characterize the temporal consistency of individual social relationships. Our analyses revealed that although the study population typically contained lone as well as group-living animals, individual spatial and social relationships varied markedly over time. Specifically, the extent to which individuals remained resident in the same location across years varied, as did the number of conspecifics with which an animal lived, with an overall tendency for individuals to live in larger groups over successive years. Collectively, these analyses indicate that population-level patterns of behavior in C. opimus are consistent with facultative sociality but that this variation does not arise due to persistent differences in individual behavior (i.e., living alone versus with conspecifics). Instead, based on changes in spatial and social relationships across years, we suggest that variation in the tendency to live in groups is shaped primarily by local ecological and demographic conditions.

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d -/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d -/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d -/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d -/- mice. miR-181c/d -/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d -/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia. To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness. Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants. Endogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose. In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg-1·min-1) but improved after 18 months (0.84 ± 0.15 mg·kg-1·min-1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg-1·min-1; P ≤ 0.01 vs all). Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.

Carvedilol is among the most effective β-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of β 1 -adrenoceptors, arrestin-biased signalling via β 2 -adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilol’s cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through β 2 ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the β-adrenoceptor system. How carvedilol, a β1-blocker, activates β2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular β2-adrenoceptor signals by slow and low efficacy G protein activation.

Spatial relationships among conspecifics can provide insights into numerous aspects of social behavior. Spatial data may be particularly important for characterizing the behavior of difficult-to-study species such as subterranean rodents, direct observations of which are challenging. To characterize the social organization of the cururo (Spalacopus cyanus), a subterranean species in the rodent family Octodontidae, we used radiotelemetry to quantify spatial relationships within populations of this species located in Parque Nacional Bosque Fray Jorge and Santuario de la Naturaleza Yerba Loca, Chile. Specifically, we sought to determine if adults in this diurnal species share burrows and subterranean nests, the two criteria typically used to identify subterranean rodents as social. Analyses of radio fixes collected during February–March 2003 revealed that cururos at both Fray Jorge and Yerba Loca shared nighttime nest sites; cluster analyses of these data identified multiple spatially distinct subsets of adults in each population. Overlap of minimum convex polygons constructed from radio fixes collected during daylight hours suggested burrow sharing by animals in both populations. Cluster analyses of overlap values revealed the same spatially distinct groups of individuals identified from analyses of nest sharing; in addition, these analyses revealed one cluster of animals in each population that was not evident from analyses of nighttime data. Collectively, these results confirm that cururos are social, with adults in both study populations sharing burrow systems and communal nests. Our findings add to the growing understanding of social organization in octodontid rodents and reveal a new system for comparative studies of the ecology and evolution of behavioral variation in burrow-dwelling mammals.