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Movement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2+) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2+ neurons, directly with optogenetics or indirectly by cutaneous stimulation, facilitates sensory feedback to motoneurons in awake rodents and humans. GABAA receptors and GAD2+ innervation at or near nodes of Ranvier of sensory axons cause this facilitation, preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA. In contrast, GABAA receptors are generally lacking from axon terminals (unlike GABAB) and do not presynaptically inhibit transmitter release onto motoneurons. GABAergic innervation near nodes and branch points allows individual branches to function autonomously, with GAD2+ neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other CNS axons.

Background The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. Methods We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. Results With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73–.82), an equal risk of progressing from stage 2 to 3 (1.00; .92–.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60–3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. Conclusions The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

To examine the association of drug use stigma with antiretroviral therapy (ART) use and HIV viral suppression among people with HIV who inject drugs in India.Cross-sectional biobehavioral survey.Between August 2016 and May 2017, persons aged at least 18 years who reported injection drug use in the past 2 years were recruited via respondent-driven sampling (RDS) in 12 Indian cities (approximately 1000 per city). The analysis was restricted to participants with laboratory-confirmed HIV infection who self-reported a prior HIV diagnosis and were eligible for ART per concurrent national HIV treatment guidelines. Enacted and internalized drug use stigma were each measured by five to six-item subscales. The study outcomes were HIV viral suppression (150 copies/ml) and self-reported past 30-day ART use. RDS-II weighted multivariable logistic regression with a city-level random-intercept was used to estimate adjusted odds ratios (aOR) and corresponding 95% confidence intervals (CIs).Among 971 ART-eligible participants previously diagnosed with HIV, 65.1% reported ART use and 56.1% were virally suppressed. Reporting any enacted stigma (vs. none) was associated with lower odds of ART use [aOR = 0.26 (95% CI = 0.15-0.44)] and viral suppression [aOR = 0.49 (95% CI = 0.31-0.78)]. High internalized stigma scores (median vs. ≤median) were associated with lower odds of viral suppression among participants aged at least 35 years [aOR = 0.51 (95% CI = 0.27-0.97)] but not among participants aged less than 35 years [aOR = 1.22 (95% CI = 0.57-2.60)]. Similar associations were observed in analyses restricted to participants ever linked to HIV care.Drug use stigma may be a barrier to HIV viral suppression among people with HIV who inject drugs, thereby hindering efforts to achieve HIV control.

International audience; Drought severity has pervasive impacts on honey production via direct impacts on water resources and nectar availability. The current mega-drought in Chile has impacts on water resources and forest vigor, particularly in the Mediterranean and Temperate regions where honey production is concentrated. While honey production plays an important role in the local rural economy and providing pollination services to other agricultural activities, studies of the long-term impacts of the mega-drought on honey production are scarce. Here, we evaluate the impact of climate variability on historical changes in honey production in the Mediterranean (32°S–37°S) and Temperate (37°S–41°S) regions of Chile, using annual honey production records of beekeepers together with national records of honey exports. We also used questionnaires and interviews to evaluate beekeeper perceptions regarding the effects of climate change on honey production and adaptation practices in both regions. Results indicated a declining trend in honey production and exports in the last decade, largely related to changes in precipitation and temperature in both regions. Declines in honey production affected 82% of beekeepers, 80% of whom had employed adaptive measures, and 74% considered that these measures were effective. The drier, warmer Mediterranean region showed more severe declines in precipitation and honey production, which beekeepers reported as a main contributing factor to transhumance from the Mediterranean to the Temperate region. This is the first study to show the effects of drought on honey production in Chile, providing a foundation for future climate change adaptation strategies within apiculture.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is the first-line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by IHC and RNA sequencing, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacologic ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases, we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a novel SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5 of 52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacologic ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Furthermore, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer. Significance: Anaplastic lymphoma kinase (ALK) is a validated drug target in cancer. Here we delineate the spectrum of ALK alterations in prostate cancer. We show that ALK overexpression is present in advanced prostate cancers, in particular in cases with features of neuroendocrine carcinoma. Furthermore, ALK expression is associated with responses to pharmacologic ALK inhibition. Our study demonstrates that ALK-directed therapies should be considered in selected prostate cancer cases.

Using two RCTs in middle schools in Pakistan, we show that brief, expert-led, curriculum-based videos integrated into the classroom experience improved teaching effectiveness: student test scores in math and science increased by 0.3 standard deviations, 60 percent more than the control group, after 4 months of exposure. Students and teachers increased their attendance, and students were more likely to pass the high-stakes government exams. By contrast, providing similar content to students on personal tablets decreased student scores by 0.4 SD. The contrast between the two effects shows the importance of engaging teachers and the potential for technology to do so. (JEL I21, I28, J45, O15, O30)

Funding Acknowledgements Type of funding sources: None. Introduction Cardiac rehabilitation (CR) has become a basic element in the recovery of patients with acute coronary syndrome, since it achieves greater therapeutic adherence and better control of cardiovascular risk factors. Purpose We aim to describe the characteristics of patients with ST-elevation acute coronary syndrome (STEACS) included in a Cardiac rehabilitation program, as well as the achievement of prevention objectives and the occurrence of mayor adverse cardiovascular events (MACE). Methods Observational prospective study where a total of 664 STEMI patients admitted to a Coronary Unit during the years 2017-2020 were included. They were classified according to their participation in a CR program. We compared medical history, lipid-lowering treatment (prior, at discharge and titration), lipid levels at discharge and at 1-year follow-up, and degree of achievement of lipid targets. MACE (mortality, reinfarction, coronary revascularisation and restenosis) were observed at 2-year follow-up. Results From 664 patients, 351 were excluded due to lack of follow-up or early mortality. From a total of 313 patients (mean age 59.9±11.2 years; 81% male), 55.3% were included in the CR program. This group had a lower mean age (55.46±8.7 vs 65.39±11.5, P Conclusions Participation in a CR program is associated with better lipid control in patients admitted for STEACS. These programmes represent a basic tool for achieving lipid and cardiovascular risk factor targets and improved long-term clinical outcomes.

We present a design study into an ion trap electrode geometry for applying near-field microwave two-qubit gates. This design features an ‘S’-shaped meander electrode to passively null the microwave field. It has ground planes separating the meander electrode from all of the DC and single-qubit microwave electrodes, which should reduce the sensitivity of the microwave field distribution to the boundary conditions of these electrodes. We show that it is possible to design a single-layer trap with this geometry such that the simulated microwave field null overlaps with the RF field null, and that the positions of these nulls can be simulated to a precision of 100 nm with moderate computing resources. We also show that such a trap can be designed such that ion chains can be trapped, transported and split with feasible DC and RF voltages. While this particular design is optimized for $$^{43}$$ 43 Ca$$^{+}$$ + ions, our approach could be applied to other ions by changing the microwave frequency to match the corresponding qubit transition frequency.

Funding Acknowledgements Type of funding sources: None. Introduction According to the literature, cardiogenic shock in the setting of right ventricular infarction (RV) has a high mortality, even equal to that related to left ventricular anterior infarction in some series. However, as well as many of the topics in acute cardiovascular care, more information is still necessary. Purpose We aim to assess the presence of differences in a cohort of patients with cardiogenic shock due to RV infarction versus anterior infarction. In order to achieve it, we analyzed the differences in baseline characteristics, in-hospital complications and mortality. Methods Descriptive, retrospective, observational, and single-center analysis of patients with ST-elevation myocardial infarction (STEMI) and cardiogenic shock admitted to our Coronary Care Unit between July 2011 and August 2022. We collected the data of patients with cardiogenic shock and compared basal characteristics and prognosis according to the infarction location (anterior or RV). Results A total of 241 patients were included, 30.7% with RV infarction. The mean age of our patients was 68.6 years and 68% were male. There were no differences in the main cardiovascular risk factors between the two groups. Regarding complications during their hospitalization, there was a significantly higher percentage of patients requiring invasive mechanical ventilation and hemodialysis in patients with shock due to anterior infarction. There was also no significant differences in the frequency of ventricular arrhythmias or atrioventricular block. At last, in our cohort, there is a higher in-hospital mortality rate among patients with shock associated with anterior infarction. Conclusions Despite the fact that in some series the high mortality in shock due to RV infarction is similar to the shock caused by anterior infarction, in our study cardiogenic shock related to anterior infarction involve worse prognosis with higher in-hospital mortality, as well as a higher need of mechanical ventilation and renal replacement therapy.

Feature-region combination AUCs and benchmarking Sheet 1: Log2 fold-change, p-value, and q-value between ARPC and NEPC lines for central mean coverage in all queried (338) TFs (two tailed Mann-Whitney U test, Benjamini-Hochberg adjusted). Sheet 2: 100-fold cross-validation AUCs for all region and feature combinations subset by the ‘AR10’ overlapping features (see Methods). Sheet 3: 100-fold cross-validation AUCs for all region and feature combinations subset by the ‘Phenotype 47-defining’ overlapping features. Sheet 4: 100-fold cross-validation AUCs for all region and feature combinations (global). Sheet 5: Predictions scores, tumor fraction, depth of coverage, and subtype for benchmarking admixtures. Sheet 6: AUCs for unsupervised prediction of admixture subtypes grouped by tumor fraction and depth. Sheet 7: NEPC:ARPC ratio, tumor fraction, and ARPC and NEPC fraction predictions for mixed phenotype admixtures using Keraon (see Methods).

Supplementary Figures S1-S18 and Supplementary Table legends.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is the first-line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by IHC and RNA sequencing, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacologic ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases, we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a novel SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5 of 52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacologic ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Furthermore, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.Significance:Anaplastic lymphoma kinase (ALK) is a validated drug target in cancer. Here we delineate the spectrum of ALK alterations in prostate cancer. We show that ALK overexpression is present in advanced prostate cancers, in particular in cases with features of neuroendocrine carcinoma. Furthermore, ALK expression is associated with responses to pharmacologic ALK inhibition. Our study demonstrates that ALK-directed therapies should be considered in selected prostate cancer cases.

Supplementary Figures 1-19, Tables 1-2

Supplementary Methods from The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis

Supplementary Figure S1. TMPRSS2 expression is associated with androgen receptor (AR) levels and is regulated by androgens in vivo. Supplementary Figure S2. Characterization of the differentiation status, Tmprss2 and AR expression in Tmprss2+/+ TRAMP and Tmprss2 -/- TRAMP mice. Supplementary Figure S3. Suppression of TMPRSS2 inhibits cell proliferation and invasion. Supplementary Figure S4. TMPRSS2 influences tumor cell clearance and growth in metastatic sites. Supplementary Figure S5. Comparison of cleavage specificities for type II transmembrane serine proteases expressed in prostate epithelium. Supplementary Figure S6. Identification of putative TMPRSS2 substrates based on peptide cleavage specificities determined by PS-SCL. Supplementary Figure S7. Assessment of TMPRSS2 substrate activity. Supplementary Figure S8. Characterization of TMPRSS2 chemical inhibitors. Supplementary Figure S9. Bromhexine suppresses prostate cancer cell invasion but but does not influence proliferation in vitro.

Supplementary Figures S1-S7 with captions and Supplementary Tables

Supplementary Methods