Search

Abstract Microphysical observations of precipitating particles are critical data sources for numerical weather prediction models and remote sensing retrieval algorithms. However, obtaining coherent data sets of particle microphysics is challenging as they are often unindexed, distributed across disparate institutions, and have not undergone a uniform quality control process. This work introduces a unified, comprehensive Northern Hemisphere particle microphysical data set from the National Aeronautics and Space Administration precipitation imaging package (PIP), accessible in a standardized data format and stored in a centralized, public repository. Data is collected from 10 measurement sites spanning 34° latitude (37°N–71°N) over 10 years (2014–2023), which comprise a set of 1,070,000 precipitating minutes. The provided data set includes measurements of a suite of microphysical attributes for both rain and snow, including distributions of particle size, vertical velocity, and effective density, along with higher‐order products including an approximation of volume‐weighted equivalent particle densities, liquid equivalent snowfall, and rainfall rate estimates. The data underwent a rigorous standardization and quality assurance process to filter out erroneous observations to produce a self‐describing, scalable, and achievable data set. Case study analyses demonstrate the capabilities of the data set in identifying physical processes like precipitation phase‐changes at high temporal resolution. Bulk precipitation characteristics from a multi‐site intercomparison also highlight distinct microphysical properties unique to each location. This curated PIP data set is a robust database of high‐quality particle microphysical observations for constraining future precipitation retrieval algorithms, and offers new insights toward better understanding regional and seasonal differences in bulk precipitation characteristics.

Autoimmune Addison’s disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

Type I interferons (IFN-I) are key immune messenger molecules that play an important role in viral defense. They act as a bridge between microbe sensing, immune function magnitude, and adaptive immunity to fight infections, and they must therefore be tightly regulated. It has become increasingly evident that thymic irregularities and mutations in immune genes affecting thymic tolerance can lead to the production of IFN-I autoantibodies (autoAbs). Whether these biomarkers affect the immune system or tissue integrity of the host is still controversial, but new data show that IFN-I autoAbs may increase susceptibility to severe disease caused by certain viruses, including SARS-CoV-2, herpes zoster, and varicella pneumonia. In this article, we will elaborate on disorders that have been identified with IFN-I autoAbs, discuss models of how tolerance to IFN-Is is lost, and explain the consequences for the host.

The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI.

The International Collaborative Experiment during the PyeongChang Olympics and Paralympic winter games 2018 took place in the PyeongChang region of South Korea. The main goal of this field campaign was to study winter precipitation in an environment that has complex terrain. The NASA dual-frequency, dual-polarization, Doppler radar (D3R) was calibrated and deployed in this field campaign. The positioning error of the radar was calibrated to be within 0.1°. The D3R was deployed for more than four months and was able to capture many interesting snowfall events along with a few rain events. In this article, the deployment and performance of the D3R during the campaign are discussed. The snowfall events captured by the D3R are discussed in detail to interpret the microphysics from a radar's perspective. The reflectivity–snowfall rate relationship is derived at the Ku band, and the snow accumulation computed is in good agreement with a precipitation gauge that was deployed near the radar. The benefit of the dual-frequency ratio for identifying the precipitation particle types is briefly introduced using the data from a large snow event on 28th February 2018. The vertical profile D3R data for this snow event are studied for detecting the presence of pristine-oriented ice crystals in the mixed hydrometeor phase conditions. Various other instruments, such as X-band radar and disdrometers, were deployed in the campaign. The D3R data are compared with the MxPOL X-band radar, and the reflectivity values match within a couple of dB in the common volume region.

Antibiotic resistance poses mounting risks to human health, as current antibiotics are losing efficacy against increasingly resistant pathogenic bacteria. Of particular concern is the emergence of multidrug-resistant strains, which has been rapid among Gram-negative bacteria such as Escherichia coli. A large body of work has established that antibiotic resistance mechanisms depend on phenotypic heterogeneity, which may be mediated by stochastic expression of antibiotic resistance genes. The link between such molecular-level expression and the population levels that result is complex and multi-scale. Therefore, to better understand antibiotic resistance, what is needed are new mechanistic models that reflect single-cell phenotypic dynamics together with population-level heterogeneity, as an integrated whole. In this work, we sought to bridge single-cell and population-scale modeling by building upon our previous experience in "whole-cell" modeling, an approach which integrates mathematical and mechanistic descriptions of biological processes to recapitulate the experimentally observed behaviors of entire cells. To extend whole-cell modeling to the "whole-colony" scale, we embedded multiple instances of a whole-cell E. coli model within a model of a dynamic spatial environment, allowing us to run large, parallelized simulations on the cloud that contained all the molecular detail of the previous whole-cell model and many interactive effects of a colony growing in a shared environment. The resulting simulations were used to explore the response of E. coli to two antibiotics with different mechanisms of action, tetracycline and ampicillin, enabling us to identify sub-generationally-expressed genes, such as the beta-lactamase ampC, which contributed greatly to dramatic cellular differences in steady-state periplasmic ampicillin and was a significant factor in determining cell survival.

Many countries introduced COVID certificates that were required to access public venues. Here, the authors analyse data from France, Germany, and Italy, and estimate that these policies led to increased vaccine uptake of 6-13 percentage points with subsequent beneficial impacts on health and economic outcomes.

Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) is an inborn error of immunity affecting both multiple endocrine organs and susceptibility to candidiasis, each with an autoimmune basis. Recently, high titer neutralizing anti‐type I interferon (IFN) autoantibodies have been linked with increased severity of SARS‐CoV‐2 and varicella zoster virus infections in APECED patients. Examining immunity against cytomegalovirus (CMV), we found a higher prevalence of anti‐CMV IgG antibodies in patients with APECED (N = 19) than in 44 healthy controls (90% vs 64%, p = 0.04); the similar difference in their IgG levels did not achieve significance (95 ± 74 vs 64 ± 35 IU/mL, ns.). In contrast, the frequency of CMV‐specific T cells was lower (804 ± 718/million vs 1591 ± 972/million PBMC p = 0.03). We saw no correlations between levels of anti‐CMV IgG and anti‐IFN antibodies in APECED patients or in a separate cohort of patients with thymoma (n = 70), over 60% of whom also had anti‐IFN antibodies. Our results suggest a dysregulated response to CMV in APECED patients and highlight immunodeficiency to viral infections as part of the disease spectrum. [ABSTRACT FROM AUTHOR]

Abstract Background Opioid use disorder (OUD) is associated with substantial morbidity and mortality for women, especially during the perinatal period. Opioid overdose has become a significant cause of maternal death in the United States, with rates highest in the immediate postpartum year. While pregnancy is a time of high motivation for healthcare engagement, unique challenges exist for pregnant women with OUD seeking both substance use treatment and maternity care, including managing change after birth. How women successfully navigate these barriers, engage in treatment, and abstain from substance use during pregnancy and postpartum is poorly understood. The aim of this study is to explore the experiences of postpartum women with OUD who successfully engaged in both substance use treatment and maternity care during pregnancy, to understand factors contributing to their ability to access care and social support. Methods We conducted semi-structured, in-depth interviews with postpartum women in sustained recovery (n = 10) engaged in a substance use treatment program in northern New England. Interviews were analyzed using grounded theory methodology. Results Despite multiple barriers, women identified pregnancy as a change point from which they were able to develop self-efficacy and exercise agency in seeking care. A shift in internal motivation enabled women to disclose need for OUD treatment to maternity care providers, a profoundly significant moment. Concurrently, women developed a new capacity for self-care, demonstrated through managing relationships with providers and family members, and overcoming logistical challenges which had previously seemed overwhelming. This transformation was also expressed in making decisions based on pregnancy risk, engaging with and caring for others, and providing peer support. Women developed resilience through the interaction of inner motivation and their ability to positively utilize or transform external factors. Conclusions Complex interactions occurred between individual-level changes in treatment motivation due to pregnancy, emerging self-efficacy in accessing resources, and engagement with clinicians and peers. This transformative process was identified by women as a key factor in entering recovery during pregnancy and sustaining it postpartum. Clinicians and policymakers should target the provision of services which promote resilience in pregnant women with OUD.

Summary: There is increasing evidence that elimination strategies have resulted in better outcomes for public health, the economy, and civil liberties than have mitigation strategies throughout the first year of the COVID-19 pandemic. With vaccines that offer high protection against severe forms of COVID-19, and increasing vaccination coverage, policy makers have had to reassess the trade-offs between different options. The desirability and feasibility of eliminating SARS-CoV-2 compared with other strategies should also be re-evaluated from the perspective of different fields, including epidemiology, public health, and economics. To end the pandemic as soon as possible—be it through elimination or reaching an acceptable endemic level—several key topics have emerged centring around coordination, both locally and internationally, and vaccine distribution. Without coordination it is difficult if not impossible to sustain elimination, which is particularly relevant in highly connected regions, such as Europe. Regarding vaccination, concerns remain with respect to equitable distribution, and the risk of the emergence of new variants of concern. Looking forward, it is crucial to overcome the dichotomy between elimination and mitigation, and to jointly define a long-term objective that can accommodate different political and societal realities.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells. Here, we give an overview of the role of B cells in thymic and peripheral tolerance in APS-1 patients and different AIRE-deficient mouse models. We also look closely into which autoantibodies have been described for this disorder, and their implications. Based on what is known about B cell therapy in other autoimmune disorders, we outline the potential of B cell therapies in APS-1 and highlight the unresolved research questions to be answered.

Surface precipitation phase is a fundamental meteorological property with immense importance. Accurate classification of phase from satellite remotely sensed observations is difficult. This study demonstrates the ability of the Precipitation Imaging Package (PIP), a ground-based, in situ precipitation imager, to distinguish precipitation phase. The PIP precipitation phase identification capabilities are compared to observer records from the National Weather Service (NWS) office in Marquette, Michigan, as well as co-located observations from profiling and scanning radars, disdrometer data, and surface meteorological measurements. Examined are 13 events with at least one precipitation phase transition. The PIP-determined onsets and endings of the respective precipitation phase periods agree to within 15 min of NWS observer records for the vast majority of the events. Additionally, the PIP and NWS liquid water equivalent accumulations for 12 of the 13 events were within 10%. Co-located observations from scanning and profiling radars, as well as reanalysis-derived synoptic and thermodynamic conditions, support the accuracy of the precipitation phases identified by the PIP. PIP observations for the phase transition events are compared to output from a parameterization based on wet bulb and near-surface lapse rates to produce a probability of solid precipitation. The PIP phase identification and the parameterization output are consistent. This work highlights the ability of the PIP to properly characterize hydrometeor phase and provide dependable precipitation accumulations under complicated mixed-phase and rain and snow (or vice versa) transition events.

Chronic disease rates have become more prevalent in the modern American workforce, which has negative implications for workplace productivity and healthcare costs. Offering workplace health interventions is recognized as an effective strategy to reduce chronic disease progression, absenteeism, and healthcare costs as well as improve population health. This review documents intervention and evaluation strategies used for health promotion programs delivered in workplaces. Using predetermined search terms in five online databases, we identified 1,131 published items from 1995 to 2014. Of these items, 27 peer-reviewed articles met the inclusion criteria; reporting data from completed United States-based workplace interventions that recruited at-risk employees based on their disease or disease-related risk factors. A content rubric was developed and used to catalogue these 27 published field studies. Selected workplace interventions targeted obesity (n = 13), cardiovascular diseases (n = 8), and diabetes (n = 6). Intervention strategies included instructional education/counseling (n = 20), workplace environmental change (n = 6), physical activity (n = 10), use of technology (n = 10), and incentives (n = 13). Self-reported data (n = 21), anthropometric measurements (n = 17), and laboratory tests (n = 14) were used most often in studies with outcome evaluation. This is the first literature review to focus on interventions for employees with elevated risk for chronic diseases. The review has the potential to inform future workplace health interventions by presenting strategies related to implementation and evaluation strategies in workplace settings. These strategies can help determine optimal worksite health programs based on the unique characteristics of work settings and the health risk factors of their employee populations.

Autoimmune polyendocrine syndrome type I (APS-I) is a severe disease caused by mutations in the autoimmune regulator (AIRE) gene. We hypothesized that salivary gland dysfunction could be a possible unexplored component of these patients and here aimed to investigate salivary and lachrymal symptoms in the Norwegian cohort of APS-I patients (N = 41) and the aetiology behind it. Sicca symptoms and possible corresponding underlying factors were assessed by subjective reports combined with objective measures of saliva and tear flow, serological testing, immune fluorescence microscopy, ultrasonography and searching for putative autoantibodies in the salivary glands. In addition, defensin and anti-defensin levels were analysed in patients and compared with healthy controls. Our results indicate mild salivary and/or lachrymal gland dysfunction manifesting in low saliva or tear flow in a total of 62% of APS-I patients. Serum IgG from 9 of 12 patients bound to targets in salivary gland biopsy slides, although the specificity and pattern of binding varied. There was no reactivity against known Sjögren-associated autoantigens in sera from APS-I patients using quantitative methods, but 11% were ANA positive by immunofluorescence microscopy. We identified several putative autoantigens in one patient, although none of these were verified as APS-I specific. We conclude that impaired salivary gland activity is part of the clinical picture of APS-I and our findings could indicate an autoimmune aetiology. We further show that APS-I patients have an altered antimicrobial signature in both sera and saliva, which requires further investigations.

Background: Underlying causes of adrenal insufficiency include congenital adrenal hyperplasia (CAH) and autoimmune adrenocortical destruction leading to autoimmune Addison's disease (AAD). Here, we report a patient with a homozygous stop-gain mutation in 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2), in addition to impaired steroidogenesis due to AAD.Case Report: Whole exome sequencing revealed an extremely rare homozygous nonsense mutation in exon 2 of the HSD3B2 gene, leading to a premature stop codon (NM_000198.3: c.15C>A, p.Cys5Ter) in a patient with AAD and premature ovarian insufficiency. Scrutiny of old medical records revealed that the patient was initially diagnosed with CAH with hyperandrogenism and severe salt-wasting shortly after birth. However, the current steroid profile show complete adrenal insufficiency including low production of pregnenolone, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), without signs of overtreatment with steroids.Conclusion: To the best of our knowledge, this is the first description of autoimmune adrenalitis in a patient with 3βHSD2 deficiency and suggests a possible association between AAD and inborn errors of the steroidogenesis.

Autoimmune Addison's disease (AAD) is a classic organ-specific autoimmune disease characterized by an immune-mediated attack on the adrenal cortex. As most autoimmune diseases, AAD is believed to be caused by a combination of genetic and environmental factors, and probably interactions between the two. Persistent viral infections have been suggested to play a triggering role, by invoking inflammation and autoimmune destruction. The inability of clearing infections can be due to aberrations in innate immunity, including mutations in genes involved in the recognition of conserved microbial patterns. In a whole exome sequencing study of anonymized AAD patients, we discovered several rare variants predicted to be damaging in the gene encoding Toll-like receptor 3 (TLR3). TLR3 recognizes double stranded RNAs, and is therefore a major factor in antiviral defense. We here report the occurrence and functional characterization of five rare missense variants in TLR3 of patients with AAD. Most of these variants occurred together with a common TLR3 variant that has been associated with a wide range of immunopathologies. The biological implications of these variants on TLR3 function were evaluated in a cell-based assay, revealing a partial loss-of-function effect of three of the rare variants. In addition, rare mutations in other members of the TLR3-interferon (IFN) signaling pathway were detected in the AAD patients. Together, these findings indicate a potential role for TLR3 and downstream signaling proteins in the pathogenesis in a subset of AAD patients. Keywords: Autoimmunity, Addison's disease, Immunodeficiency, Innate immunity, Anti-viral immunity, Toll-like receptor 3

It is important to understand the statistical–physical structure of the rain in the vertical so that observations aloft can be translated meaningfully into what will occur at the surface. In order to achieve this understanding, it is necessary to gather high temporal and spatial resolution observations of rain in the vertical. This can be achieved by translating radar Doppler spectra into drop size distributions. A long-standing difficulty in using such measurements, however, is the problem of vertical air motion, which can shift the Doppler spectra and therefore significantly alter the deduced drop size distributions and integrated variables. In this work, we overcome this difficulty by requiring that the measured radar reflectivity and the calculated rainfall rates satisfy fundamental physical theory. As a consequence, the mean vertical airspeed can be estimated and removed. Application of this new approach is demonstrated using vertically pointing Doppler radar observations in weak convection. It is shown that the new approach produces what appear to be better estimates of the rainfall rates as well as estimates of the temporal and spatial regionally coherent updraft and downdrafts occurring in the precipitation. The technique is readily applicable to other radars, especially those operating at non-attenuating frequencies.