To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents.
Individually linked health data in Denmark (2000−2012), Finland (2005–2014), ...Iceland (2004–2017), Norway (2005–2015), Sweden (2006–2015), Germany (2006–2015), Australia (New South Wales, 2004–2012), Hong Kong (2001–2015), UK (2006–2016), and the US (Medicaid, 2000–2013, and IBM MarketScan, 2012–2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics.
We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries.
Antipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population.
Electronic sports (esports), or competitive video gaming, is a rapidly growing industry and phenomenon. While around 90% of American children play video games recreationally, the average professional ...esports athlete spends 5.5 to 10 h gaming daily. These times and efforts parallel those of traditional sports activities where individuals can participate at the casual to the professional level with the respective time commitments. Given the rapid growth in esports, greater emphasis has been placed on identification, management, and prevention of common health hazards that are associated with esports participation while also focusing on the importance of health promotion for this group of athletes. This review outlines a three-point framework for sports medicine providers, trainers, and coaches to provide a holistic approach for the care of the esports athlete. This esports framework includes awareness and management of common musculoskeletal and health hazards, opportunities for health promotion, and recommendations for performance optimization.
The molecular mechanisms that underlie cell lineage diversification of multipotent progenitors in the pancreas are virtually unknown. Here we show that the early fate choice of pancreatic progenitors ...between the endocrine and acinar cell lineage is restricted by cross-repressive interactions between the transcription factors Nkx6.1/Nkx6.2 (Nkx6) and Ptf1a. Using genetic loss- and gain-of-function approaches, we demonstrate that Nkx6 factors and Ptf1a are required and sufficient to repress the alternative lineage program and to specify progenitors toward an endocrine or acinar fate, respectively. The Nkx6/Ptf1a switch only operates during a critical competence window when progenitors are still multipotent and can be uncoupled from cell differentiation. Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development.
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► Nkx6 factors promote pancreatic endocrine fate and repress an acinar fate choice ► Nkx6 and the preacinar transcription factor Ptf1a function as mutual repressors ► Ptf1a represses endocrine cell fate and promotes acinar cell specification ► The Nkx6/Ptf1a switch only operates during an early competence window
Neural stem cells exist in the developing and adult nervous systems of all mammals, but the basic mechanisms that control their behavior are not yet well understood. Here, we investigated the role of ...Sonic hedgehog (Shh), a factor vital for neural development, in regulating adult hippocampal neural stem cells. We found high expression of the Shh receptor Patched in both the adult rat hippocampus and neural progenitor cells isolated from this region. In addition, Shh elicited a strong, dose-dependent proliferative response in progenitors in vitro. Furthermore, adeno-associated viral vector delivery of shh cDNA to the hippocampus elicited a 3.3-fold increase in cell proliferation. Finally, the pharmacological inhibitor of Shh signaling cyclopamine reduced hippocampal neural progenitor proliferation in vivo. This work identifies Shh as a regulator of adult hippocampal neural stem cells.
Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes ...that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56
NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.
To modulate responses to developmental or environmental cues, plants use Gretchen Hagen 3 (GH3) acyl acid amido synthetases to conjugate an amino acid to a plant hormone, a reaction that regulates ...free hormone concentration and downstream responses. The model plant Arabidopsis thaliana has 19 GH3 proteins, of which 8 have confirmed biochemical functions. One Brassicaceae-specific clade of GH3 proteins was predicted to use benzoate as a substrate and includes AtGH3.7 and AtGH3.12/PBS3. Previously identified as a 4-hydroxybenzoic acid-glutamate synthetase, AtGH3.12/PBS3 influences pathogen defense responses through salicylic acid. Recent work has shown that AtGH3.12/PBS3 uses isochorismate as a substrate, forming an isochorismate-glutamate conjugate that converts into salicylic acid. Here, we show that AtGH3.7 and AtGH3.12/PBS3 can also conjugate chorismate to cysteine and glutamate, which act as precursors to aromatic amino acids and salicylic acid, respectively. The X-ray crystal structure of AtGH3.12/PBS3 in complex with AMP and chorismate at 1.94 Å resolution, along with site-directed mutagenesis, revealed how the active site potentially accommodates this substrate. Examination of Arabidopsis knockout lines indicated that the gh3.7 mutants do not alter growth and showed no increased susceptibility to the pathogen Pseudomonas syringae, unlike gh3.12 mutants, which were more susceptible than WT plants, as was the gh3.7/gh3.12 double mutant. The findings of our study suggest that GH3 proteins can use metabolic precursors of aromatic amino acids as substrates.
We present a catalog of galaxy clusters selected via their Sunyaev-Zel'dovich (SZ) effect signature from 2500 deg super(2) of South Pole Telescope (SPT) data. This work represents the complete sample ...of clusters detected at high significance in the 2500 deg super(2) SPT-SZ survey, which was completed in 2011. A total of 677 (409) cluster candidates are identified above a signal-to-noise threshold of xi = 4.5 (5.0). Ground- and space-based optical and near-infrared (NIR) imaging confirms overdensities of similarly colored galaxies in the direction of 516 (or 76%) of the xi > 4.5 candidates and 387 (or 95%) of the xi > 5 candidates; the measured purity is consistent with expectations from simulations. Of these confirmed clusters, 415 were first identified in SPT data, including 251 new discoveries reported in this work. We estimate photometric redshifts for all candidates with identified optical and/or NIR counterparts; we additionally report redshifts derived from spectroscopic observations for 141 of these systems. The mass threshold of the catalog is roughly independent of redshift above z ~ 0.25 leading to a sample of massive clusters that extends to high redshift. The median mass of the sample is M sub(500c)(rho sub(crit)) ~3.5 x 10 super(14) M sub(middot in circle) h super(-1) sub(70), the median redshift is z sub(med) = 0.55, and the highest-redshift systems are at z > 1.4. The combination of large redshift extent, clean selection, and high typical mass makes this cluster sample of particular interest for cosmological analyses and studies of cluster formation and evolution.
In patients with end‐stage heart failure (ESHF) who are candidates for isolated heart transplant (HRT), dialysis dependence (DD) is considered an indication for combined heart–kidney transplantation ...(HKT). HKT remains controversial in ESHF transplant candidates with nondialysis‐dependent renal insufficiency (NDDRI). Using United Network for Organ Sharing data, we examined the cumulative incidences of transplant and mortality in patients with DD and NDDRI waitlisted for HKT or HRT. In all groups, 3‐month waitlist mortality was dismal: 31% and 21% for HRT‐ and HKT‐listed patients with DD and 12% and 7% for HRT‐ and HKT‐listed patients with NDDRI. Five‐year posttransplant survival was improved in HKT recipients compared with HRT recipients for both patients with DD (73% vs. 51%, p < 0.001) and NDDRI (80% vs. 69%, p < 0.001). Likewise, multivariable analysis associated HKT with better outcomes than HRT in HKT‐listed patients, although both improved survival. These data argue strongly for HKT in ESHF transplant candidates with DD. However, in patients with NDDRI, HKT must be weighed against the possibility of renal recovery with isolated HRT. Whether HRT (followed by a staged kidney transplant in patients who do not recover renal function after HRT), as opposed to HKT, maximizes organ benefit for patients with NDDRI and ESHF requires assessment. Nevertheless, given their dismal waitlist outcomes and excellent posttransplant results, we suggest that patients with DD and NDDRI with ESHF be considered for early listing and transplant.
Patients requiring combined heart–kidney transplantation have poor waitlist survival, and although early transplant may help improve outcomes, the optimal therapy for these patients remains uncertain. See editorial by Kumar and Tallaj on page 253.
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells ...influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.
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