University of Colorado

Extreme precipitation events are projected to increase in frequency across much of the land‐surface as the global climate warms, but such projections have typically relied on coarse‐resolution (100–250 km) general circulation models (GCMs). The ensemble of HighResMIP GCMs presents an opportunity to evaluate how a more finely resolved atmosphere and land‐surface might enhance the fidelity of the simulated contribution of large‐magnitude storms to total precipitation, particularly across topographically complex terrain. Here, the simulation of large‐storm dominance, that is, the number of wettest days to reach half of the total annual precipitation, is quantified across the western United States (WUS) using four GCMs within the HighResMIP ensemble and their coarse resolution counterparts. Historical GCM simulations (1950–2014) are evaluated against a baseline generated from station‐observed daily precipitation (4,803 GHCN‐D stations) and from three gridded, observationally based precipitation data sets that are coarsened to match the resolution of the GCMs. All coarse‐resolution simulations produce less large‐storm dominance than in observations across the WUS. For two of the four GCMs, bias in the median large‐storm dominance is reduced in the HighResMIP simulation, decreasing by as much as 62% in the intermountain west region. However, the other GCMs show little change or even an increase (+28%) in bias of median large‐storm dominance across multiple sub‐regions. The spread in differences with resolution amongst GCMs suggests that, in addition to resolution, model structure and parameterization of precipitation generating processes also contribute to bias in simulated large‐storm dominance.

Molecular and fossil evidence suggests that complex eukaryotic multicellularity evolved during the late Neoproterozoic era, coincident with Snowball Earth glaciations, where ice sheets covered most of the globe. During this period, environmental conditions—such as seawater temperature and the availability of photosynthetically active light in the oceans–likely changed dramatically. Such changes would have had significant effects on both resource availability and optimal phenotypes. Here, we construct and apply mechanistic models to explore (i) how environmental changes during Snowball Earth and biophysical constraints generated selective pressures, and (ii) how these pressures may have had differential effects on organisms with different forms of biological organization. By testing a series of alternative—and commonly debated—hypotheses, we demonstrate how multicellularity was likely acquired differently in eukaryotes and prokaryotes owing to selective differences on their size due to the biophysical and metabolic regimes they inhabit: decreasing temperatures and resource availability instigated by the onset of glaciations generated selective pressures towards smaller sizes in organisms in the diffusive regime and towards larger sizes in motile heterotrophs. These results suggest that changing environmental conditions during Snowball Earth glaciations gave multicellular eukaryotes an evolutionary advantage, paving the way for the complex multicellular lineages that followed.

A single column model with parameterized large‐scale (LS) dynamics is used to better understand the response of steady‐state tropical precipitation to relative sea surface temperature under various representations of radiation, convection, and circulation. The large‐scale dynamics are parametrized via the weak temperature gradient (WTG), damped gravity wave (DGW), and spectral weak temperature gradient (Spectral WTG) method in NCAR's Single Column Atmosphere Model (SCAM6). Radiative cooling is either specified or interactive, and the convective parameterization is run using two different values of a parameter that controls the degree of convective inhibition. Results are interpreted in the context of the Global Atmospheric System Studies ‐Weak Temperature Gradient (GASS‐WTG) Intercomparison project. Using the same parameter settings and simulation configuration as in the GASS‐WTG Intercomparison project, SCAM6 under the WTG and DGW methods produces erratic results, suggestive of numerical instability. However, when key parameters are changed to weaken the large‐scale circulation's damping of tropospheric temperature variations, SCAM6 performs comparably to single column models in the GASS‐WTG Intercomparison project. The Spectral WTG method is less sensitive to changes in convection and radiation than are the other two methods, performing qualitatively similarly across all configurations considered. Under all three methods, circulation strength, represented in 1D by grid‐scale vertical velocity, is decreased when barriers to convection are reduced. This effect is most extreme under specified radiative cooling, and is shown to come from increased static stability in the column's reference radiative‐convective equilibrium profile. This argument can be extended to interactive radiation cases as well, though perhaps less conclusively.

Background Functional constipation (FC), a disorder of the gut–brain interaction of multifactorial pathophysiology that is prevalent in paediatrics. It is associated with bothersome symptoms, increased healthcare costs, disgruntled caregivers and impaired health‐related quality of life. Paediatric FC is a clinical diagnosis based on the Rome IV criteria and is characterised by decreased bowel movement frequency and/or hard, painful stools and can be complicated by retentive faecal incontinence. Stressful life events, difficult temperaments and emotional and behavioural challenges have been implicated in increasing risk of developing paediatric FC. Aims To provide current concepts in pathophysiology, evaluation and management of paediatric FC. Methods We reviewed pertinent literature after a comprehensive search utilising PubMed with keywords FC, chronic childhood constipation and paediatric FC. Results In the last decade, advances in our understanding of paediatric FC have changed the landscape of diagnosing and treating this disorder. Although polyethylene glycol is the first‐line treatment for maintenance of FC, the armamentarium of therapeutics has expanded including the first Food and Drug Administration‐ agent, linaclotide, for children 6–17 years of age in conjunction with more emphasis on behavioural and physical therapy interventions. Conclusions Treatment approach to paediatric FC should be individualised and integrated focusing on parental education, lifestyle and behavioural modifications, and pharmacological therapy to maximise therapeutic success. This review highlights advances in pathophysiology, diagnosis and treatment of FC in children.

Mixed pituitary adenoma/PitNET-gangliocytomas (PA/PitNET-GC) have been reported in small series over the past 20 years; some had limited immunohistochemistry (IHC) data. We interrogated our experience over 20 years, focusing on patterns of the GC component and IHC results for anterior pituitary hormones, transcription factors, NFP, and CAM5.2. A search of cases from 2002 to 2023 yielded 20 cases: 7M:13F, ages 20–71 years; 17 macroadenomas, 1 microadenoma, 2 ectopic. GC was co-associated with 4 corticotroph, 2 densely granulated lactotroph, 5 mixed lactotroph-somatotroph, 1 immature PIT1-lineage tumor, and 8 sparsely granulated GH; the latter all had a minor lactotroph component. Patterns were: discrete nodular foci of GC (9/20), extensive GC differentiation often overshadowing the PA/PitNET (7/20), and intimate admixture of smaller bands of neuropil and individual metaplastic ganglion cells within PA/PitNET (4/20). NFP highlighted small cohesive regions of neuropil and identified greater axonal content, including individual axons within “pure” PA/PitNET areas, than appreciated on H&E. CAM5.2 IHC often revealed cells with neuronal morphologies to a greater extent than NFP and in different areas within the same tumor. These data suggest that the combined use of NFP and CAM5.2 IHC best reveals transition from PA to GC phenotype, with CAM5.2 positivity reflecting earlier stages of transformation.

Background Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. Methods 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m² who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. Results Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m², and baseline BMI was 30.5 ± 5.9 kg/m². None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. Conclusions Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.

Background Meaning in life is positively associated with health, well-being, and longevity, which may be partially explained by engagement in healthier behaviors, including physical activity (PA). However, promoting awareness of meaning is a behavior change strategy that has not been tested in previous PA interventions. Objective This study aims to develop, refine, and pilot-test the Meaningful Activity Program (MAP; MAP to Health), a web-based mobile health PA intervention, theoretically grounded in meaning and self-determination theory, for insufficiently active middle-aged adults. Methods Following an iterative user-testing and refinement phase, we used a single-arm double baseline proof-of-concept pilot trial design. Participants included 35 insufficiently active adults in midlife (aged 40-64 years) interested in increasing their PA. After a 4-week baseline period, participants engaged in MAP to Health for 8 weeks. MAP to Health used a web-based assessment and just-in-time SMS text messaging to individualize the intervention; promote meaning salience; support the basic psychological needs of autonomy, competence, and relatedness; and increase PA. Participants completed measures of the hypothesized mechanisms of behavior change, including meaning salience, needs satisfaction, and autonomous motivation at pretest (−4 weeks), baseline (0 weeks), midpoint (4 weeks), and posttest (8 weeks) time points, and wore accelerometers for the study duration. At the end of the intervention, participants completed a qualitative interview. Mixed models compared changes in behavioral mechanisms during the intervention to changes before the intervention. Framework matrix analyses were used to analyze qualitative data. Results Participants were aged 50.8 (SD 8.2) years on average; predominantly female (27/35, 77%); and 20% (7/35) Asian, 9% (3/35) Black or African American, 66% (23/35) White, and 6% (2/35) other race. Most (32/35, 91%) used MAP to Health for ≥5 of 8 weeks. Participants rated the intervention as easy to use (mean 4.3, SD 0.8 [out of 5.0]) and useful (mean 4.3, SD 0.6). None of the hypothesized mechanisms changed significantly during the preintervention phase (Cohen d values <0.15). However, autonomy (P<.001; Cohen d=0.76), competence (P<.001; Cohen d=0.65), relatedness (P=.004; Cohen d=0.46), autonomous motivation (P<.001; Cohen d=0.37), and meaning salience (P<.001; Cohen d=0.40) increased significantly during the intervention. Comparison of slopes before the intervention versus during the intervention revealed that increases during the intervention were significantly greater for autonomy (P=.002), competence (P<.001), and meaning salience (P=.001); however, slopes were not significantly different for relatedness (P=.10) and autonomous motivation (P=.17). Qualitative themes offered suggestions for improvement. Conclusions MAP to Health was acceptable to participants, feasible to deliver, and associated with increases in the target mechanisms of behavior change. This is the first intervention to use meaning as a behavior change strategy in a PA intervention. Future research will test the efficacy of the intervention in increasing PA compared to a control condition.

The Glucose transporter 1 (GLUT1) is one of the most abundant proteins within the erythrocyte membrane and is required for glucose and dehydroascorbic acid (Vitamin C precursor) transport. It is widely recognized as a key protein for red cell structure, function, and metabolism. Previous reports highlighted the importance of GLUT1 activity within these uniquely glycolysis-dependent cells, in particular for increasing antioxidant capacity needed to avoid irreversible damage from oxidative stress in humans. However, studies of glucose transporter roles in erythroid cells are complicated by species-specific differences between humans and mice. Here, using CRISPR-mediated gene editing of immortalized erythroblasts and adult CD34+ hematopoietic progenitor cells, we generate committed human erythroid cells completely deficient in expression of GLUT1. We show that absence of GLUT1 does not impede human erythroblast proliferation, differentiation, or enucleation. This work demonstrates for the first-time generation of enucleated human reticulocytes lacking GLUT1. The GLUT1-deficient reticulocytes possess no tangible alterations to membrane composition or deformability in reticulocytes. Metabolomic analyses of GLUT1-deficient reticulocytes reveal hallmarks of reduced glucose import, downregulated metabolic processes and upregulated AMPK-signalling, alongside alterations in antioxidant metabolism, resulting in increased osmotic fragility and metabolic shifts indicative of higher oxidant stress. Despite detectable metabolic changes in GLUT1 deficient reticulocytes, the absence of developmental phenotype, detectable proteomic compensation or impaired deformability comprehensively alters our understanding of the role of GLUT1 in red blood cell structure, function and metabolism. It also provides cell biological evidence supporting clinical consensus that reduced GLUT1 expression does not cause anaemia in GLUT1 deficiency syndrome.

Background Evidence-based medicine (EBM) has the potential to improve health outcomes, but EBM has not been widely integrated into the systems used for research or clinical decision-making. There has not been a scalable and reusable computer-readable standard for distributing research results and synthesized evidence among creators, implementers, and the ultimate users of that evidence. Evidence that is more rapidly updated, synthesized, disseminated, and implemented would improve both the delivery of EBM and evidence-based health care policy. Objective This study aimed to introduce the EBM on Fast Healthcare Interoperability Resources (FHIR) project (EBMonFHIR), which is extending the methods and infrastructure of Health Level Seven (HL7) FHIR to provide an interoperability standard for the electronic exchange of health-related scientific knowledge. Methods As an ongoing process, the project creates and refines FHIR resources to represent evidence from clinical studies and syntheses of those studies and develops tools to assist with the creation and visualization of FHIR resources. Results The EBMonFHIR project created FHIR resources (ie, ArtifactAssessment, Citation, Evidence, EvidenceReport, and EvidenceVariable) for representing evidence. The COVID-19 Knowledge Accelerator (COKA) project, now Health Evidence Knowledge Accelerator (HEvKA), took this work further and created FHIR resources that express EvidenceReport, Citation, and ArtifactAssessment concepts. The group is (1) continually refining FHIR resources to support the representation of EBM; (2) developing controlled terminology related to EBM (ie, study design, statistic type, statistical model, and risk of bias); and (3) developing tools to facilitate the visualization and data entry of EBM information into FHIR resources, including human-readable interfaces and JSON viewers. Conclusions EBMonFHIR resources in conjunction with other FHIR resources can support relaying EBM components in a manner that is interoperable and consumable by downstream tools and health information technology systems to support the users of evidence.

We have developed a technique to determine the electrical substitution power of a cryogenic optical radiant power detector, that directly implements a frequency-programmable Josephson voltage standard (FPJVS), thus reducing the traceability chain. The optical power detector and the Josephson voltage reference are combined inside a common cryogenic environment. We demonstrate the practicality of the technique by using a FPJVS to apply a known voltage across the resistive heater of a standard NIST cryogenic planar radiometric detector. The power applied to the detector heater is calculated from a measurement of the heater resistance and the known applied voltage. The FPJVS dc bias current source supplies dc current to the resistive heater. In this demonstration, the standard uncertainty of the substituted electrical power is limited by the uncertainty of the electrical heater four-wire resistance measurement at 4 K. The uncertainty due to the resistance measurement is 1 part in 10⁵ out of a total uncertainty of 1 part in 10⁴ (k = 2) on the 1 mW optical power measurement. We aim to develop the technique, to provide traceability to the International System of Units for the picowatt power measurement of single-photon emitters such as quantum dot sources.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb⁺) children and adults who are at risk of (confirmed single IAb⁺) or living with (multiple IAb⁺) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb⁺; (2) when people who are IAb⁺ are initially identified there is a need for confirmation using a second sample; (3) single IAb⁺ individuals are at lower risk of progression than multiple IAb⁺ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care. Graphical Abstract

Routine HIV viral load testing is important for evaluating HIV treatment outcomes, but conventional viral load testing has many barriers including expensive laboratory equipment and lengthy results return times to patients. A point-of-care viral load testing technology, such as GeneXpert HIV-1 quantification assay, could reduce these barriers by decreasing cost and turnaround time, however real-world performance is limited. We conducted a secondary analysis using 900 samples collected from participants in two studies to examine the performance of GeneXpert as point-of-care viral load compared to standard-of-care testing (which was conducted with two centralized laboratories using traditional HIV-1 RNA PCR quantification assays). The two studies, Opt4Kids (n = 704 participants) and Opt4Mamas (n = 820 participants), were conducted in western Kenya from 2019–2021 to evaluate the effectiveness of a combined intervention strategy, which included point-of-care viral load testing. Paired viral load results were compared using four different thresholds for virological non-suppression, namely ≥50, ≥200, ≥400, ≥1000 copies/ml. At a threshold of ≥1000 copies/mL, paired samples collected on the same day: demonstrated sensitivities of 90.0% (95% confidence interval [CI] 68.3, 98.8) and 66.7% (9.4, 99.2), specificities of 98.4% (95.5, 99.7) and 100% (96.5, 100), and percent agreements of 97.7% (94.6, 99.2) and 99.1% (95.0, 100) in Opt4Kids and Opt4Mamas studies, respectively. When lower viral load thresholds were used and the paired samples were collected an increasing number of days apart, sensitivity, specificity, and percent agreement generally decreased. While specificity and percent agreement were uniformly high, sensitivity was lower than expected. Non-specificity of the standard of care testing may have been responsible for the sensitivity values. Nonetheless, our results demonstrate that GeneXpert may be used reliably to monitor HIV treatment in low- and middle- income countries to attain UNAID’s 95-95-95 HIV goals.

Background Religiousness and spirituality (R/S) are associated with lower morbidity and mortality, yet the physiological mechanisms underlying these associations are under-studied. Chronic inflammation is a plausible biological mechanism linking R/S to downstream health given the sensitivity of the immune system to the social environment and the role of inflammation in many chronic diseases. Purpose The purpose of the present study was to examine associations between multiple R/S dimensions and two markers of chronic inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP). Methods In this cross-sectional study, data came from biological subsamples of two cohorts from the Midlife in the United States (MIDUS) Study (combined N = 2,118). Predictors include six R/S measures (service attendance, spirituality, private religious practices, daily spiritual experiences, religious coping, and R/S-based mindfulness). Outcomes include log-transformed IL-6 and CRP. Covariates include age, gender, cohort, race, educational attainment, body mass index (BMI), smoking status, and physical activity. Results Older adults, women (vs. men), non-White (vs. White) adults, those with higher BMIs, current smokers, and those not meeting physical activity guidelines had significantly higher IL-6 and CRP. In fully adjusted models, greater spirituality, daily spiritual experiences, religious coping, and R/S-based mindfulness were associated with lower IL-6. Higher spirituality was also associated with lower CRP. Conclusions Many dimensions of R/S may be health protective for adults given their associations with lower levels of chronic inflammation. Findings underscore the importance of examining multiple dimensions of R/S to understand mechanistic pathways.

Pheochromocytomas predominantly produce catecholamines, and rarely also produce ACTH, causing Cushing syndrome (CS). Cyclic CS, an uncommon presentation of hypercortisolism, poses a diagnostic challenge. We report a 71-year-old woman who developed cyclic ectopic ACTH secretion from a pheochromocytoma. Previous evaluations showed intermittent elevations in cortisol and ACTH levels, normal pituitary magnetic resonance imaging, and an adrenal nodule. On admission, she was hypertensive and had cushingoid features. Bilateral inferior petrosal sinus sampling with desmopressin stimulation and an 8-mg dexamethasone suppression test suggested ectopic ACTH secretion, but ACTH increased during the peripheral desmopressin stimulation test. Plasma normetanephrines were about 2-fold above the upper reference limit. 18F-fluoro-dopa and 68Gallium-DOTATATE positron emission tomography/computed tomography scans, computed tomography, and magnetic resonance imaging identified an adrenal mass. After doxazosin adrenoceptor blockade, she underwent right adrenalectomy; histopathology and immunohistochemistry confirmed an ACTH-secreting pheochromocytoma. Postoperative blood pressure normalized and serum cortisol and plasma ACTH levels were suppressed, requiring physiologic hydrocortisone replacement. This case underscores the importance of considering pheochromocytoma in ACTH-dependent hypercortisolism with elevated metanephrines and an adrenal mass. Timely diagnosis and treatment can reduce morbidity and improve quality of life.

The vertical accuracy of elevation data in coastal environments is critical because small variations in elevation can affect an area's exposure to waves, tides, and storm-related flooding. Elevation data contractors typically quantify the vertical accuracy of lidar-derived digital elevation models (DEMs) on a per-project basis to gauge whether the datasets meet quality and accuracy standards. Here, we collated over 5200 contractor elevation checkpoints along the Atlantic and Gulf of Mexico coasts of the United States that were collected for project-level analyses produced for assessing DEMs acquired for the U.S. Geological Survey's Three-Dimensional Elevation Program. We used land cover data to quantify non-vegetated vertical accuracy and vegetated vertical accuracy statistics (overall and by point spacing bins) and assessed elevation error by land cover class. We found the non-vegetated vertical accuracy had an overall root mean square error of 6.9 cm and vegetated areas had a 95th percentile vertical error of 22.3 cm. Point spacing was generally positively correlated to elevation accuracy, but sample size limited the ability to interpret results from accuracy by land cover, particularly in wetlands. Based on the specific questions a researcher may be asking, use of literature or fieldwork could assist with enhancing error statistics in underrepresented classes.

Background It is well established that the tobacco industry used research funding as a deliberate tactic to subvert science. There has been little wider attention to how researchers think about accepting industry funding. We developed, then tested, hypotheses about two psychological constructs, namely, entitlement and conflict of interest contrarianism (CoI-C) among alcohol researchers who had previously received industry funding. Methods A mixed-methods pilot study involved construct and instrument development, followed by an online survey and nested 3-arm randomised trial. We randomly allocated alcohol industry funding recipients to one of three conditions. In two experimental conditions we asked participants questions to remind them (and thus increase the salience) of their sense of entitlement or CoI-C. We compared these groups with a control group who did not receive any reminder. The outcome was a composite measure of openness to working with the alcohol industry. Results 133 researchers were randomised of whom 79 completed the experiment. The posterior distribution over effect estimates revealed that there was a 94.8% probability that reminding researchers of their CoI-C led them to self-report being more receptive to industry funding, whereas the probability was 68.1% that reminding them of their sense of entitlement did so. Biomedical researchers reported being more open to working with industry than did psychosocial researchers. Conclusion Holding contrarian views on conflict of interest could make researchers more open to working with industry. This study shows how it is possible to study researcher decision-making using quantitative experimental methods.