Seasonal rhythms are endogenous timing mechanisms that allow animals living at temperate latitudes to synchronize their physiology to the seasons. Human viral respiratory disease is prevalent in the ...winter at temperate latitudes, but the role of endogenous mechanisms in these recurring annual patterns is unclear. The Common Cold Project is a repository of data describing the experimental viral challenge of 1,337 participants across the seasons of the year. We report a secondary analysis of these data to investigate if susceptibility to the common cold is associated with day length. The majority of the participants (78%) showed signs of infection but only 32% developed clinical signs of disease, and the probability of infection was significantly higher in longer day lengths (summer), but the disease was more likely in short (winter) day lengths. The persistence of winter disease patterns in experimental conditions supports the role of endogenous seasonality in human susceptibility to viral infection.
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•Outbreaks of viral respiratory disease recur in winter in the northern hemisphere•In controlled experiments, common cold infection was more likely in summer•Infection was more likely to progress to the development of cold in winter•Innate seasonality of human immunity could affect the prevalence of the common cold
Chronobiology; Virology
Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with ...hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader–Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a ∼187 kb microdeletion at chromosome 15q11–13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11–13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11–13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
This study examined older adults' experiences of participating in the Ballistic Exercise of the Lower Limb (BELL) trial, involving 12-weeks of group-based hardstyle kettlebell training.
In the BELL ...trial, 28 insufficiently active older adults (15 women, 13 men, 59-79 years) completed six weeks of face-to-face group training, and six weeks of home-based training. In-depth semi-structured interviews were audio recorded, transcribed, and inductively coded, with themes constructed from patterns of shared meaning.
Four higher-order themes were developed that reflect older adults' experiences participating in a group-exercise program of hardstyle kettlebell training. These included: (1) "It's one of the best things we've done"-enjoying the physical and psychosocial benefits, (2) "It's improved it tremendously!"-change in a long-term health condition, (3) "It put me on a better course"-overcoming challenges, and (4) "I wasn't just a number"-feeling part of a group/community.
Findings highlight the perceived physical and psychological benefits of older adults participating in hardstyle group kettlebell training, and the value attributed to being part of an age-matched community of like-minded people engaged in group exercise. Implications for program design and delivery, and future research, are discussed.
Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies ...of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major hepatic fibrogenic cell population. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human livers. In conjunction with public single-cell data of fibrotic/cirrhotic human livers, these profiles enable the identification of potential intercellular signaling axes (e.g., ITGAV-LAMC1, TNFRSF11B-VWF and NOTCH2-DLL4) and master regulators (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH-related fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study highlights potential cell-cell interactions and master regulators that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.
Butyrate and other SCFA produced by bacterial fermentation of resistant starch (RS) or nonstarch polysaccharides (NSP) promote human colonic health. To examine variation in fecal variables, ...especially butyrate, among individuals and the response to these fibers, a randomized cross-over study was conducted that compared the effects of foods supplying 25 g of NSP or 25 g of NSP plus 22 g of RS/d over 4 wk in 46 healthy adults (16 males, 30 females; age 31-66 y). Fecal SCFA levels varied widely among participants at entry (butyrate concentrations: 3.5-32.6 mmol/kg; butyrate excretions: 0.3-18.2 mmol/48 h). BMI explained 27% of inter-individual butyrate variation, whereas protein, starch, carbohydrate, fiber, and fat intake explained up to 16, 6, 2, 4, and 2% of butyrate variation, respectively. Overall, acetate, butyrate, and total SCFA concentrations were higher when participants consumed RS compared with entry and NSP diets, but individual responses varied. Individual and total fecal SCFA excretion, weight, and moisture were higher than those for habitual diets when either fiber diet was consumed. SCFA concentrations (except butyrate) and excretions were higher for males than for females. Butyrate levels increased in response to RS in most individuals but often decreased when entry levels were high. Fecal butyrate and ammonia excretions were positively associated ((2) = 0.76; P < 0.001). In conclusion, fecal butyrate levels vary widely among individuals but consuming a diet high in RS usually increases levels and may help maintain colorectal health.
Relationships among multilocus genetic variation, geography, and environment can reveal how evolutionary processes affect genomes. We examined the evolution of an Australian bird, the eastern yellow ...robin Eopsaltria australis, using mitochondrial (mtDNA) and nuclear (nDNA) genetic markers, and bioclimatic variables. In southeastern Australia, two divergent mtDNA lineages occur east and west of the Great Dividing Range, perpendicular to latitudinal nDNA structure. We evaluated alternative scenarios to explain this striking discordance in landscape genetic patterning. Stochastic mtDNA lineage sorting can be rejected because the mtDNA lineages are essentially distinct geographically for > 1500 km. Vicariance is unlikely: the Great Dividing Range is neither a current barrier nor was it at the Last Glacial Maximum according to species distribution modeling; nuclear gene flow inferred from coalescent analysis affirms this. Female philopatry contradicts known female-biased dispersal. Contrasting mtDNA and nDNA demographies indicate their evolutionary histories are decoupled. Distance-based redundancy analysis, in which environmental temperatures explain mtDNA variance above that explained by geographic position and isolation-by-distance, favors a nonneutral explanation for mitochondrial phylogeographic patterning. Thus, observed mito-nuclear discordance accords with environmental selection on a female-linked trait, such as mtDNA, mtDNA–nDNA interactions or genes on W-chromosome, driving mitochondrial divergence in the presence of nuclear gene flow.
Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The
(PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden ...in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months-19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.
Abstract
Aim
To test the feasibility of a study protocol that compared the efficacy of neutral‐ and negative‐pressure needleless connectors (NCs).
Design
A single‐centre, parallel‐group, pilot ...randomised control trial.
Methods
Our study compared neutral‐(intervention) and negative‐pressure (control) NCs among adult patients in an Australian hospital. The primary feasibility outcome was measured against predetermined criteria (e.g. eligibility, attrition). The primary efficacy outcome was all‐cause peripheral intravenous catheter failure, analysed as time‐to‐event data.
Results
In total, 201 (100 control; 101 intervention) participants were enrolled between March 2020 and September 2020. All feasibility criteria were met except eligibility, which was lower (78%) than the 90% criterion. All‐cause peripheral intravenous catheter failure was significantly higher in the intervention group (39%) compared to control (19%).
Conclusion
With minor modifications to participant screening for eligibility, this randomised control trial is feasible for a large multicentre randomised control trial. The neutral NC was associated with an increased risk of peripheral intravenous catheter failure.
Implications for the Profession and/or Patient Care
There are several NC designs available, often identified by their mechanism of pressure (positive, negative and neutral). However, NCs can contribute to peripheral intravenous catheter failure. This is the first randomised controlled trial to compare neutral and negative NC designs. Negative pressure NCs had lower PIVC failure compared to neutral NCs, however the results might not be generalisable to other brands or treatment settings. Further high‐quality research is needed to explore NC design.
Reporting Method
Study methods and results reported in adherence to the CONSORT Statement.
Patient or Public Contribution
No patient or public contribution.
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