Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the ...Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs.
We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses.
We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality.
Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed.
Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.
Few marine taxa have been comprehensively assessed for their conservation status, despite heavy pressures from fishing, habitat degradation and climate change. Here we report on the first global ...assessment of extinction risk for 300 species of syngnathiform fishes known as of 2017, using the IUCN Red List criteria. This order of bony teleosts is dominated by seahorses, pipefishes and seadragons (family Syngnathidae). It also includes trumpetfishes (Aulostomidae), shrimpfishes (Centriscidae), cornetfishes (Fistulariidae) and ghost pipefishes (Solenostomidae). At least 6% are threatened, but data suggest a mid-point estimate of 7.9% and an upper bound of 38%. Most of the threatened species are seahorses (Hippocampus spp.: 14/42 species, with an additional 17 that are Data Deficient) or freshwater pipefishes of the genus Microphis (2/18 species, with seven additional that are Data Deficient). Two species are Near Threatened. Nearly one-third of syngnathiformes (97 species) are Data Deficient and could potentially be threatened, requiring further field research and evaluation. Most species (61%) were, however, evaluated as Least Concern. Primary threats to syngnathids are (1) overexploitation, primarily by non-selective fisheries, for which most assessments were determined by criterion A (Hippocampus) and/or (2) habitat loss and degradation, for which assessments were determined by criterion B (Microphis and some Hippocampus). Threatened species occurred in most regions but more are found in East and South-east Asia and in South African estuaries. Vital conservation action for syngnathids, including constraining fisheries, particularly non-selective extraction, and habitat protection and rehabilitation, will benefit many other aquatic species.
ObjectivesTo estimate COVID-19 infections and deaths in healthcare workers (HCWs) from a global perspective during the early phases of the pandemic.DesignSystematic review.MethodsTwo parallel ...searches of academic bibliographic databases and grey literature were undertaken until 8 May 2020. Governments were also contacted for further information where possible. There were no restrictions on language, information sources used, publication status and types of sources of evidence. The AACODS checklist or the National Institutes of Health study quality assessment tools were used to appraise each source of evidence.Outcome measuresPublication characteristics, country-specific data points, COVID-19-specific data, demographics of affected HCWs and public health measures employed.ResultsA total of 152 888 infections and 1413 deaths were reported. Infections were mainly in women (71.6%, n=14 058) and nurses (38.6%, n=10 706), but deaths were mainly in men (70.8%, n=550) and doctors (51.4%, n=525). Limited data suggested that general practitioners and mental health nurses were the highest risk specialities for deaths. There were 37.2 deaths reported per 100 infections for HCWs aged over 70 years. Europe had the highest absolute numbers of reported infections (119 628) and deaths (712), but the Eastern Mediterranean region had the highest number of reported deaths per 100 infections (5.7).ConclusionsCOVID-19 infections and deaths among HCWs follow that of the general population around the world. The reasons for gender and specialty differences require further exploration, as do the low rates reported in Africa and India. Although physicians working in certain specialities may be considered high risk due to exposure to oronasal secretions, the risk to other specialities must not be underestimated. Elderly HCWs may require assigning to less risky settings such as telemedicine or administrative positions. Our pragmatic approach provides general trends, and highlights the need for universal guidelines for testing and reporting of infections in HCWs.
While climate warming is widely predicted to reduce body size of ectotherms, evidence for this trend is mixed. Body size depends not only on temperature but also on other factors, such as food ...quality and intraspecific competition. Because temperature trends or other long‐term environmental factors may affect population size and food sources, attributing trends in average body size to temperature requires the separation of potentially confounding effects. We evaluated trends in the body size of the midge Tanytarsus gracilentus and potential drivers (water temperature, population size, and food quality) between 1977 and 2015 at Lake Mývatn, Iceland. Although temperatures increased at Mývatn over this period, there was only a slight (non‐significant) decrease in midge adult body size, contrary to theoretical expectations. Using a state‐space model including multiple predictors, body size was negatively associated with both water temperature and midge population abundance, and it was positively associated with 13C enrichment of midges (an indicator of favorable food conditions). The magnitude of these effects were similar, such that simultaneous changes in temperature, abundance, and carbon stable isotopic signature could counteract each other in the long‐term body size trend. Our results illustrate how multiple factors, all of which could be influenced by global change, interact to affect average ectotherm body size.
Warming temperatures reduce the body size of ectotherms at maturity, resulting in expectations that climate warming ought to result in smaller ectotherms; however, other factors also influence size and may exhibit trends over time alongside warming. Combining time series of nonbiting midge (Tanytarsus gracilentus) population size and food quality with temperatures at Lake Mývatn, Iceland, we show these factors all contribute to temporal dynamics in midge body sizes and that the effects of food conditions or population size on midge body size are similar to the effects of warming in magnitude.
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Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy, with the potential to induce protein production to treat and prevent a range of diseases. ...However, the widespread use of mRNA as a therapeutic requires safe and effective in vivo delivery technologies. Libraries of ionizable lipid nanoparticles (LNPs) have been designed to encapsulate mRNA, prevent its degradation, and mediate intracellular delivery. However, these LNPs are typically characterized and screened in an in vitro setting, which may not fully replicate the biological barriers that they encounter in vivo. Here, we designed and evaluated a library of engineered LNPs containing barcoded mRNA (b-mRNA) to accelerate the screening of mRNA delivery platforms in vivo. These b-mRNA are similar in structure and function to regular mRNA, and contain barcodes that enable their delivery to be quantified via deep sequencing. Using a mini-library of b-mRNA LNPs formulated via microfluidic mixing, we show that these different formulations can be pooled together, administered intravenously into mice as a single pool, and their delivery to multiple organs (liver, spleen, brain, lung, heart, kidney, pancreas, and muscle) can be quantified simultaneously using deep sequencing. In the context of liver and spleen delivery, LNPs that exhibited high b-mRNA delivery also yielded high luciferase expression, indicating that this platform can identify lead LNP candidates as well as optimal formulation parameters for in vivo mRNA delivery. Interestingly, LNPs with identical formulation parameters that encapsulated different types of nucleic acid barcodes (b-mRNA versus a DNA barcode) altered in vivo delivery, suggesting that the structure of the barcoded nucleic acid affects LNP in vivo delivery. This platform, which enables direct barcoding and subsequent quantification of a functional mRNA, can accelerate the in vivo screening and design of LNPs for mRNA therapeutic applications such as CRISPR-Cas9 gene editing, mRNA vaccination, and other mRNA-based regenerative medicine and protein replacement therapies.
The equine chorionic girdle is comprised of specialized invasive trophoblast cells that begin formation approximately 25 days after ovulation (day 0) and invade the endometrium to become endometrial ...cups. These specialized trophoblast cells transition from uninucleate to differentiated binucleate trophoblast cells that secrete the glycoprotein hormone equine chorionic gonadotropin (eCG; formerly known as pregnant mare serum gonadotropin or PMSG). This eCG has LH-like activity in the horse but variable LH- and FSH-like activity in other species and has been utilized for these properties both in vivo and in vitro. To produce eCG commercially, large volumes of whole blood must be collected from pregnant mares, which negatively impacts equine welfare due to repeated blood collections and the birth of an unwanted foal. Attempts to produce eCG in vitro using long-term culture of chorionic girdle explants have not been successful beyond 180 days, with peak eCG production at 30 days of culture. Organoids are three-dimensional cell clusters that self-organize and can remain genetically and phenotypically stable throughout long-term culture (i.e., months). Human trophoblast organoids have been reported to successfully produce human chorionic gonadotropin (hCG) and proliferate long-term (>1 year). The objective of this study was to evaluate whether organoids derived from equine chorionic girdle maintain physiological functionality. Here we show generation of chorionic girdle organoids for the first time and demonstrate in vitro production of eCG for up to 6 weeks in culture. Therefore, equine chorionic girdle organoids provide a physiologically representative 3D in vitro model for chorionic girdle development of early equine pregnancy.
There is a significant interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an ...individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell-type-specific proteomic approach to generate a 21-cell-type, 10-tissue map of exercise training-regulated secretomes in mice. Our dataset identifies >200 exercise training-regulated cell-type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Finally, we show anti-obesity, anti-diabetic, and exercise performance-enhancing activities for proteoforms of intracellular carboxylesterases whose secretion from the liver is induced by exercise training.
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•An organism-wide cell-type-specific secretome atlas after exercise training in mice•Exercise training induces cell-type-specific and bidirectional secretome changes•Pdgfra+ cells are highly responsive to exercise training•Secreted CES2 proteins improve metabolic health and enhance running endurance
Wei et al. use proteomics to identify cellular secretome changes in response to exercise training at an organism-wide scale. Using this dataset, Wei et al. identified two exercise-inducible secreted proteins from the liver that enhance running performance and improve metabolic health.
The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the ...catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small-molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1.
Adolescents face many academic pressures that require good coping skills, but coping skills can also depend on social resources, such as parental support and fewer negative interactions. The aim of ...this study was to determine if parental support and parental negative interactions concurrently and longitudinally relate to adolescents’ ways of academic coping, above and beyond the impact of three types of academic stress, students’ achievement at school (i.e., grades in school), and age. Survey data were collected from 839 Australian students in grades 5 to 10 (
M
age
= 12.2,
SD
= 1.72; 50% girls). Students completed measures of support and negative interactions with parents; academic stress from workload, external pressure (teachers/parents) to achieve, and intrapsychic pressure for high achievement; and ways of academic coping that were grouped into two positive and two negative types. Hypothesized associations were tested concurrently and from one year to the next using path modeling. Beyond the numerous significant influences of academic stress and achievement on coping, and control for age and COVID-19 timing, adolescents with more parental support reported more use of engagement coping (e.g., strategizing) and comfort-seeking, whereas those who reported more negative interactions with parents reported more use of disengagement coping (e.g., concealment) and escape. In the longitudinal model, parental support predicted an increase in engagement and comfort-seeking and a decrease in disengagement coping, whereas negative interaction with parents predicted an increase in disengagement coping. Overall, the findings support the view that coping with academic stressors will continue to depend on parent-adolescent relationships even into the teen years.
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