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The article shows that the input given by healthcare professionals (HCPs) adds value to the regulatory processes surrounding the development, authorisation, and monitoring of a medicine, but is also an instrument for accountability, trust, mutual exchange as well as an insight into the public health issues that matter most to one of the key stakeholder groups the Agency works with. We highlight the role of HCPs in the EU regulatory process and take stock of the first 10 years of the Framework for Interaction with HCPs to describe how practises have evolved over this time to meet the goals of informing, consulting and improving trust in the EU regulatory system. We will analyse what led European Medicines Agency (EMA) to develop this framework through to the next steps and where the interaction might lead in the future.

Patient experience data (PED), provided by patients/their carers without interpretation by clinicians, directly capture what matters more to patients on their medical condition, treatment and impact of healthcare. PED can be collected through different methodologies and these need to be robust and validated for its intended use. Medicine regulators are increasingly encouraging stakeholders to generate, collect and submit PED to support both scientific advice in development programs and regulatory decisions on the approval and use of these medicines. This article reviews the existing definitions and types of PED and demonstrate the potential for use in different settings of medicines’ life cycle, focusing on Patient-Reported Outcomes (PRO) and Patient Preferences (PP). Furthermore, it addresses some challenges and opportunities, alluding to important regulatory guidance that has been published, methodological aspects and digitalization, highlighting the lack of guidance as a key hurdle to achieve more systematic inclusion of PED in regulatory submissions. In addition, the article discusses opportunities at European and global level that could be implemented to leverage PED use. New digital tools that allow patients to collect PED in real time could also contribute to these advances, but it is equally important not to overlook the challenges they entail. The numerous and relevant initiatives being developed by various stakeholders in this field, including regulators, show their confidence in PED’s value and create an ideal moment to address challenges and consolidate PED use across medicines’ life cycle.

Background Follicular lymphoma (FL), the most common indolent non-Hodgkin’s Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses.Methods To capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability.Results FL-PDLS, mainly composed of tumor B cells (60% on average) and autologous T cells (13% CD4 and 3% CD8 on average, respectively), rapidly organizes into patient-specific three-dimensional (3D) structures of three different morphotypes according to 3D imaging analysis. RNAseq analysis indicates that FL-PDLS reproduces FL hallmarks with the overexpression of cell cycle, BCR, or mTOR signaling related gene sets. FL-PDLS also recapitulates the exhausted immune phenotype typical of FL-LN, including expression of BTLA, TIGIT, PD-1, TIM-3, CD39 and CD73 on CD3+ T cells. These features render FL-PDLS an amenable system for immunotherapy testing. With this aim, we demonstrate that the combination of obinutuzumab (anti-CD20) and nivolumab (anti-PD1) reduces tumor load in a significant proportion of FL-PDLS. Interestingly, B cell depletion inversely correlates with the percentage of CD8+ cells positive for PD-1 and TIM-3.Conclusions In summary, FL-PDLS is a robust patient-derived 3D system that can be used as a tool to mimic FL pathology and to test novel immunotherapeutic approaches in a context of personalized medicine.

Introducción: Los medicamentos de venta libre (OTC por su sigla en inglés Over The Counter), son ampliamente usados por la mayoría de las personas a nivel mundial, sin embargo, solamente son usados de forma responsable en países donde existe una farmacia comunitaria profesional legalizada. Objetivo: Describir los hábitos de consumo de medicamentos de venta libre por estudiantes universitarios del área de la salud. Materiales y métodos: Estudio descriptivo transversal, desarrollado en tres universidades de Cartagena. Se aplicó un instrumento tipo encuesta a 140 estudiantes acerca de hábitos de consumo y conocimiento sobre OTC, creencias, actitudes y prácticas. Resultados: El cuestionario presentó una consistencia interna alta con Alfa de Cronbach’s de 0,77. El 59% fueron mujeres, las en edades entre 16-30 años, el 91% estuvo de acuerdo que la automedicación es perjudicial. Sin embargo, 61% asegura automedicarse porque los padecimientos son menores y frecuentes. Los medicamentos de mayor consumo, fueron el acetaminofén 52,9% y los medicamentos antiinflamatorios no esteroides (AINES) con 16,48%, incluyeron en sus respuestas medicamentos de no venta libre. Conclusión: Los estudiantes son conscientes del riesgo de la automedicación, sin embargo, la practican de forma frecuente. Muchos reportaron consumo de medicamentos como amitriptilina, antibióticos, opiáceos, furosemida y corticoides.

Abstract Background The aim of this study was to analyze the shoulder functional profile (rotation range of motion [ROM] and strength), upper and lower body performance, and throwing speed of U13 versus U15 male handball players, and to establish the relationship between these measures of physical fitness and throwing speed. Methods One-hundred and nineteen young male handball players (under (U)-13 (U13) [n = 85]) and U15 [n = 34]) volunteered to participate in this study. The participating athletes had a mean background of sytematic handball training of 5.5 ± 2.8 years and they exercised on average 540 ± 10.1 min per week including sport-specific team handball training and strength and conditioning programs. Players were tested for passive shoulder range-of-motion (ROM) for both internal (IR) and external rotation (ER) and isometric strength (i.e., IR and ER) of the dominant/non-dominant shoulders, overhead medicine ball throw (OMB), hip isometric abductor (ABD) and adductor (ADD) strength, hip ROM, jumps (countermovement jump [CMJ] and triple leg-hop [3H] for distance), linear sprint test, modified 505 change-of-direction (COD) test and handball throwing speed (7 m [HT7] and 9 m [HT9]). Results U15 players outperformed U13 in upper (i.e., HT7 and HT9 speed, OMB, absolute IR and ER strength of the dominant and non-dominant sides; Cohen’s d: 0.76–2.13) and lower body (i.e., CMJ, 3H, 20-m sprint and COD, hip ABD and ADD; d: 0.70–2.33) performance measures. Regarding shoulder ROM outcomes, a lower IR ROM was found of the dominant side in the U15 group compared to the U13 and a higher ER ROM on both sides in U15 (d: 0.76–1.04). It seems that primarily anthropometric characteristics (i.e., body height, body mass) and upper body strength/power (OMB distance) are the most important factors that explain the throw speed variance in male handball players, particularly in U13. Conclusions Findings from this study imply that regular performance monitoring is important for performance development and for minimizing injury risk of the shoulder in both age categories of young male handball players. Besides measures of physical fitness, anthropometric data should be recorded because handball throwing performance is related to these measures.

The COVID-19 pandemic posed challenges to communicating accurate information about vaccines because of the spread of misinformation. The European Medicines Agency (EMA) tried to reassure the public by communicating early on about the development and approval of COVID-19 vaccines. The EMA surveyed patients/consumers, healthcare professional organizations, and individual stakeholders, both at the EU level and in an Italian regional context. The objectives of the study were to see if the EMA’s core information materials were informative and well-understood and which communication channels were preferred by the public. The main findings showed that individual patients/consumers generally prefer to obtain information about COVID-19 vaccines from the internet or mass media, while organizations and individual healthcare professionals prefer to obtain information from national and international health authorities. Both at EU and local levels, participants had a good understanding of the key messages from regulators and found the materials useful and relevant. However, some improvements were recommended to the visual, text, and dissemination formats, including publishing more information on safety and using a more public-friendly language. Also, it was recommended to maintain the EMA’s approach of using media, stakeholder engagement, and web-based formats to communicate about COVID-19 vaccines. In conclusion, user-testing of proactive communication materials aimed to prebunk misinformation during a public health crisis helps to ensure that users understand the development and safety of novel vaccine technologies. This information can then be used as a basis for further evidence-based communication activities by regulators and public health bodies in an emergency context.

Background Approximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.Methods Here, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.Results Venetoclax treatment demonstrated specific killing of MYC+/BCL2+ lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.Conclusions These results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.

Human brain activity generates scalp potentials (electroencephalography – EEG), intracranial potentials (iEEG), and external magnetic fields (magnetoencephalography – MEG). These electrophysiology (e-phys) signals can often be measured simultaneously for research and clinical applications. The forward problem involves modeling these signals at their sensors for a given equivalent current dipole configuration within the brain. While earlier researchers modeled the head as a simple set of isotropic spheres, today's magnetic resonance imaging (MRI) data allow for a detailed anatomic description of brain structures and anisotropic characterization of tissue conductivities. We present a complete pipeline, integrated into the Brainstorm software, that allows users to automatically generate an individual and accurate head model based on the subject's MRI and calculate the electromagnetic forward solution using the finite element method (FEM). The head model generation is performed by integrating the latest tools for MRI segmentation and FEM mesh generation. The final head model comprises the five main compartments: white-matter, gray-matter, CSF, skull, and scalp. The anisotropic brain conductivity model is based on the effective medium approach (EMA), which estimates anisotropic conductivity tensors from diffusion-weighted imaging (DWI) data. The FEM electromagnetic forward solution is obtained through the DUNEuro library, integrated into Brainstorm, and accessible with either a user-friendly graphical interface or scripting. With tutorials and example data sets available in an open-source format on the Brainstorm website, this integrated pipeline provides access to advanced FEM tools for electromagnetic modeling to a broader neuroscience community.

Abstract Background Hypokalemia has been rarely attributed to tizanidine, although the precise mechanism is unclear. Severe hypokalemia is a well-established cause of abnormalities involving cardiac conduction. Given this agent’s well-known cardiac arrhythmogenic potential, awareness of potential concomitant electrolyte abnormalities is important. Case presentation Electrolyte disorders, including hypokalemia, are rare complications of the antispasmodic medicine tizanidine when taken in doses as outlined by the manufacturer’s prescribing instructions. Although cases of severe hypokalemia have also been described in the literature in association with this agent, such reports are few. We report a Caucasian case of an intentional overdose involving a very large ingestion of tizanidine. In addition to the characteristic abnormalities on the electrocardiogram, our patient developed electrolyte derangements as well as self-limited acute kidney injury. These biochemical abnormalities included profound hypokalemia that was refractory to aggressive replacement over the ensuing several days, before eventually dissipating. A thorough assessment of the etiology of this hypokalemia was consistent with a defect in renal potassium handling. Conclusion In our patient with intentional tizanidine overdose, severe and refractory hypokalemia appears to have been due to a transient potassium wasting nephropathy.

Ipconazole is an antifungal agrochemical widely used in agriculture against seed diseases of rice, vegetables, and other crops; due to its easy accumulation in the environment, it poses a hazard to human, animal, and environmental health. Therefore, we investigated the cytotoxic effect of ipconazole on SH-SY5Y neuroblastoma cells using cell viability tests (MTT), ROS production, caspase3/7 activity, and molecular assays of the biomarkers of cell death (Bax, Casp3, APAF1, BNIP3, and Bcl2); inflammasome (NLRP3, Casp1, and IL1β); inflammation (NFκB, TNFα, and IL6); and antioxidants (NRF2, SOD, and GPx). SH-SY5Y cells were exposed to ipconazole (1, 5, 10, 20, 50, and 100 µM) for 24 h. The ipconazole, in a dose-dependent manner, reduced cell viability and produced an IC50 of 32.3 µM; it also produced an increase in ROS production and caspase3/7 enzyme activity in SH-SY5Y cells. In addition, ipconazole at 50 µM induced an overexpression of Bax, Casp3, APAF1, and BNIP3 (cell death genes); NLRP3, Casp1, and IL1B (inflammasome complex genes); and NFκB, TNFα, and IL6 (inflammation genes); it also reduced the expression of NRF2, SOD, and GPx (antioxidant genes). Our results show that ipconazole produces cytotoxic effects by reducing cell viability, generating oxidative stress, and inducing cell death in SH-SY5Y cells, so ipconazole exposure should be considered as a factor in the presentation of neurotoxicity or neurodegeneration.

Monodelphis domestica (the laboratory opossum) is a marsupial native to South America. At birth, these animals are developmentally equivalent to human embryos at approximately 5 weeks of gestation, which, when coupled with other characteristics including the size of the animals, the development of a robust immune system during juvenile development, and the relative ease of experimental manipulation, have made M. domestica a valuable model in many areas of biomedical research. However, their suitability as models for infectious diseases, especially neurotropic viruses such as Zika virus (ZIKV), is currently unknown. Here, we describe the replicative effects of ZIKV using a fetal intra-cerebral model of inoculation. Using immunohistology and in situ hybridization, we found that opossum embryos and fetuses are susceptible to infection by ZIKV administered intra-cerebrally, that the infection persists, and that viral replication results in neural pathology and may occasionally result in global growth restriction. These results demonstrate the utility of M. domestica as a new animal model for investigating ZIKV infection in vivo and facilitate further inquiry into viral pathogenesis, particularly for those viruses that are neurotropic, that require a host with the ability to sustain sustained viremia, and/or that may require intra-cerebral inoculations of large numbers of embryos or fetuses.

OBJECTIVES:. To describe the prevalence, associated risk factors, and outcomes of serious neurologic manifestations (encephalopathy, stroke, seizure, and meningitis/encephalitis) among patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN:. Prospective observational study. SETTING:. One hundred seventy-nine hospitals in 24 countries within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 Registry. PATIENTS:. Hospitalized adults with laboratory-confirmed SARS-CoV-2 infection. INTERVENTIONS:. None. RESULTS:. Of 16,225 patients enrolled in the registry with hospital discharge status available, 2,092 (12.9%) developed serious neurologic manifestations including 1,656 (10.2%) with encephalopathy at admission, 331 (2.0%) with stroke, 243 (1.5%) with seizure, and 73 (0.5%) with meningitis/encephalitis at admission or during hospitalization. Patients with serious neurologic manifestations of COVID-19 were older with median (interquartile range) age 72 years (61.0–81.0 yr) versus 61 years (48.0–72.0 yr) and had higher prevalence of chronic medical conditions, including vascular risk factors. Adjusting for age, sex, and time since the onset of the pandemic, serious neurologic manifestations were associated with more severe disease (odds ratio [OR], 1.49; p < 0.001) as defined by the World Health Organization ordinal disease severity scale for COVID-19 infection. Patients with neurologic manifestations were more likely to be admitted to the ICU (OR, 1.45; p < 0.001) and require critical care interventions (extracorporeal membrane oxygenation: OR, 1.78; p = 0.009 and renal replacement therapy: OR, 1.99; p < 0.001). Hospital, ICU, and 28-day mortality for patients with neurologic manifestations was higher (OR, 1.51, 1.37, and 1.58; p < 0.001), and patients had fewer ICU-free, hospital-free, and ventilator-free days (estimated difference in days, –0.84, –1.34, and –0.84; p < 0.001). CONCLUSIONS:. Encephalopathy at admission is common in hospitalized patients with SARS-CoV-2 infection and is associated with worse outcomes. While serious neurologic manifestations including stroke, seizure, and meningitis/encephalitis were less common, all were associated with increased ICU support utilization, more severe disease, and worse outcomes.

Cough is a defense mechanism for airway protection and is associated with multiple systemic complications such as ribs fracture. Diaphragmatic rupture is commonly caused by blunt or penetrating trauma. We presented a case of a 72-year-old female with a 1-year history of chronic cough, not responding to medical management. Imaging showing abdominal herniation into the thoracic cavity and rib fracture due to diaphragmatic and chest wall rupture. Abdominal herniation and diaphragmatic rupture were repaired through surgery allowing resolution of symptoms. This is a life-threatening condition with a high-mortality rate in which early diagnosis and repair are desirable. Therefore, awareness of this uncommon complication of cough should be acknowledged. Keywords: Cough, Diaphragmatic rupture

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.

OBJECTIVES:. To describe hospital variation in use of “guideline-based care” for acute respiratory distress syndrome (ARDS) due to COVID-19. DESIGN:. Retrospective, observational study. SETTING:. The Society of Critical Care Medicine’s Discovery Viral Infection and RESPIRATORY ILLNESS UNIVERSAL STUDY COVID-19 REGISTRY. PATIENTS:. Adult patients with ARDS due to COVID-19 between February 15, 2020, and April 12, 2021. INTERVENTIONS:. Hospital-level use of “guideline-based care” for ARDS including low-tidal-volume ventilation, plateau pressure less than 30 cm H2O, and prone ventilation for a Pao2/Fio2 ratio less than 100. MEASUREMENTS AND MAIN RESULTS:. Among 1,495 adults with COVID-19 ARDS receiving care across 42 hospitals, 50.4% ever received care consistent with ARDS clinical practice guidelines. After adjusting for patient demographics and severity of illness, hospital characteristics, and pandemic timing, hospital of admission contributed to 14% of the risk-adjusted variation in “guideline-based care.” A patient treated at a randomly selected hospital with higher use of guideline-based care had a median odds ratio of 2.0 (95% CI, 1.1–3.4) for receipt of “guideline-based care” compared with a patient receiving treatment at a randomly selected hospital with low use of recommended therapies. Median-adjusted inhospital mortality was 53% (interquartile range, 47–62%), with a nonsignificantly decreased risk of mortality for patients admitted to hospitals in the highest use “guideline-based care” quartile (49%) compared with the lowest use quartile (60%) (odds ratio, 0.7; 95% CI, 0.3–1.9; p = 0.49). CONCLUSIONS:. During the first year of the COVID-19 pandemic, only half of patients received “guideline-based care” for ARDS management, with wide practice variation across hospitals. Strategies that improve adherence to recommended ARDS management strategies are needed.

IntroductionKidney transplantation is the best therapeutical option for CKD patients. Graft loss risk factors are usually estimated with the cox method. Competing risk analysis could be useful to determine the impact of different events affecting graft survival, the occurrence of an outcome of interest can be precluded by another. We aimed to determine the risk factors for graft loss in the presence of mortality as a competing event.MethodsA retrospective cohort of 1454 kidney transplant recipients who were transplanted between July 1, 2008, to May 31, 2019, in Colombiana de Trasplantes, were analyzed to determine risk factors of graft loss and mortality at 5 years post-transplantation. Kidney and patient survival probabilities were estimated by the competing risk analysis. The Fine and Gray method was used to fit a multivariable model for each outcome. Three variable selection methods were compared, and the bootstrapping technique was used for internal validation as split method for resample. The performance of the final model was assessed calculating the prediction error, brier score, c-index and calibration plot.ResultsGraft loss occurred in 169 patients (11.6%) and death in 137 (9.4%). Cumulative incidence for graft loss and death was 15.8% and 13.8% respectively. In a multivariable analysis, we found that BKV nephropathy, serum creatinine and increased number of renal biopsies were significant risk factors for graft loss. On the other hand, recipient age, acute cellular rejection, CMV disease were risk factors for death, and recipients with living donor had better survival compared to deceased-donor transplant and coronary stent. The c-index were 0.6 and 0.72 for graft loss and death model respectively.ConclusionWe developed two prediction models for graft loss and death 5 years post-transplantation by a unique transplant program in Colombia. Using a competing risk multivariable analysis, we were able to identify 3 significant risk factors for graft loss and 5 significant risk factors for death. This contributes to have a better understanding of risk factors for graft loss in a Latin-American population. The predictive performance of the models was mild.

Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results: ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface (p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface (p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 (p = 0.048) and CD4_ICOS_TIGIT (p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy.

We present findings of the detection of Magnesium II (Mg ii , λ = 2796, 2803 Å) absorbers from the early data release of the Dark Energy Spectroscopic Instrument (DESI). DESI is projected to obtain spectroscopy of approximately 3 million quasars (QSOs), of which over 99% are anticipated to be at redshifts greater than z > 0.3, such that DESI would be able to observe an associated or intervening Mg ii absorber illuminated by the background QSO. We have developed an autonomous supplementary spectral pipeline that detects these systems through an initial line-fitting process and then confirms the line properties using a Markov Chain Monte Carlo sampler. Based upon a visual inspection of the resulting systems, we estimate that this sample has a purity greater than 99%. We have also investigated the completeness of our sample in regard to both the signal-to-noise properties of the input spectra and the rest-frame equivalent width ( W _0 ) of the absorber systems. From a parent catalog containing 83,207 quasars, we detect a total of 23,921 Mg ii absorption systems following a series of quality cuts. Extrapolating from this occurrence rate of 28.8% implies a catalog at the completion of the five-year DESI survey that will contain over eight hundred thousand Mg ii absorbers. The cataloging of these systems will enable significant further research because they carry information regarding circumgalactic medium environments, the distribution of intervening galaxies, and the growth of metallicity across the redshift range 0.3 ≤ z < 2.5.

We outline the “dark siren” galaxy catalog method for cosmological inference using gravitational wave (GW) standard sirens, clarifying some common misconceptions in the implementation of this method. When a confident transient electromagnetic counterpart to a GW event is unavailable, the identification of a unique host galaxy is in general challenging. Instead, as originally proposed by Schutz, one can consult a galaxy catalog and implement a dark siren statistical approach incorporating all potential host galaxies within the localization volume. Trott & Huterer recently claimed that this approach results in a biased estimate of the Hubble constant, H _0 , when implemented on mock data, even if optimistic assumptions are made. We demonstrate explicitly that, as previously shown by multiple independent groups, the dark siren statistical method leads to an unbiased posterior when the method is applied to the data correctly. We highlight common sources of error possible to make in the generation of mock data and implementation of the statistical framework, including the mismodeling of selection effects and inconsistent implementations of the Bayesian framework, which can lead to a spurious bias.

IMPORTANCE:. At the start of the coronavirus disease 2019 pandemic, medications repurposed for management of coronavirus disease 2019 were used in the absence of clinical trial evidence. OBJECTIVES:. To describe the variation and evolution in use of repurposed medications for coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Observational cohort study of adults hospitalized with coronavirus disease 2019 between February 15, 2020, and April 12, 2021, across 76 United States and international hospitals within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry. MAIN OUTCOMES AND MEASURES:. Hospital variation was quantified using multivariable adjusted random effects logistic regression models and unsupervised clustering. Repurposed medications included antivirals, corticosteroids, hydroxychloroquine, immunomodulators, and therapeutic dose anticoagulants. RESULTS:. Among 7,069 adults hospitalized with coronavirus disease 2019, 1,979 (28%) received antivirals, 2,876 (41%) received corticosteroids, 1,779 (25%) received hydroxychloroquine, 620 (9%) received immunomodulators, and 2,154 (31%) received therapeutic dose anticoagulants. Contribution of hospital site to risk-adjusted variation was 46% for antivirals, 30% for corticosteroids, 48% for hydroxychloroquine, 46% for immunomodulators, and 52% for therapeutic dose anticoagulants. Compared with the early pandemic, the later pandemic practice phenotypes converged with increased use of antivirals (odds ratio, 3.14; 95% CI, 2.40–4.10) and corticosteroids (odds ratio, 5.43; 95% CI, 4.23–6.97), with decreased use of hydroxychloroquine (odds ratio, 0.02; 95% CI, 0.01–0.04) and immunomodulators (odds ratio, 0.49; 95% CI, 0.34–0.70). There was no clinically significant change in the use of therapeutic dose anticoagulants (odds ratio, 1.01; 95% CI, 1.01–1.02). There were no differences in risk-adjusted mortality between hospitals with high rates of repurposed medication use compared with hospitals with low rates of use. CONCLUSIONS AND RELEVANCE:. Hospital variation in the use of repurposed medications varied widely across hospitals early in the pandemic and later converged with the emergence of randomized clinical trials. Platforms developed for rapid activation and enrollment in clinical trials of repurposed medications are needed prior to the next pandemic to expedite effective, evidence-based practice.

IMPORTANCE:. Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES:. To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS:. A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES:. Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS:. Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS:. Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.

Traditionally, the cellular spectrum is allocated to operators (OPs) through auctions, as ideal mechanisms to discover market prices and allocate scarce resources. Even though spectrum is indeed scarce in sub-6 GHz bands, it becomes abundant in millimeter-wave (mmWave) bands. Interestingly, in that context, it is base station (BS) density which is limiting, and thus a critical factor, due to the outage phenomena in urban environments. Facing BS scarcity is one of the main reasons to foster virtualization techniques aimed at improving utilization and lowering costs. We consider a scenario with an infrastructure provider (InP) owner of a number of BSs and a set of OPs with their users (UEs). We propose a three-phase framework to price network infrastructure slices (NISs) and allocate them to OPs and to efficiently associate UEs with those NISs. The framework stages are: 1) an initial association, 2) a distributed auction mechanism across the BSs to allocate resources to Ops, and 3) a re-association process where the OPs can optimize the NISs they are awarded. The auction incentivizes OPs to bid truthfully and the outcome yields both socially optimal NISs and Vickrey-Clarke-Groves (VCG) prices. For the re-association phase, we propose deterministic and stochastic exchange-matching algorithms and demonstrate their convergence to stable matching and stable-optimal matching, respectively.

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.

Abstract Simultaneously achieving high efficiency and high durability in perovskite solar cells is a critical step toward the commercialization of this technology. Inverted perovskite photovoltaic (IP‐PV) cells incorporating robust and low levelized‐cost‐of‐energy (LCOE) buffer layers are supposed to be a promising solution to this target. However, insufficient inventory of materials for back‐electrode buffers substantially limits the development of IP‐PV. Herein, a composite consisting of 1D cation‐doped TiO2 brookite nanorod (NR) embedded by 0D fullerene is investigated as a top modification buffer for IP‐PV. The cathode buffer is constructed by introducing fullerene to fill the interstitial space of the TiO2 NR matrix. Meanwhile, cations of transition metal Co or Fe are doped into the TiO2 NR to further tune the electronic property. Such a top buffer exhibits multifold advantages, including improved film uniformity, enhanced electron extraction and transfer ability, better energy level matching with perovskite, and stronger moisture resistance. Correspondingly, the resultant IP‐PV displays an efficiency exceeding 22% with a 22‐fold prolonged working lifetime. The strategy not only provides an essential addition to the material inventory for top electron buffers by introducing the 0D:1D composite concept, but also opens a new avenue to optimize perovskite PVs with desirable properties.

ObjectiveThe aims of the present study were: 1) to calculate the change of direction (COD) deficit (using a modified version of the 505 test and 10 m sprint time), and (2) to examine the differences in linear sprint, jump and COD performances, as well as COD deficit, between under-13 (U13) and under-15 (U15) male handball players.MethodsOne hundred and nineteen young male handball players (under-13 [U13; n = 82] and under-15 [U15; n = 37]). Tests included anthropometric measurements, countermovement jump (CMJ), triple leg-hop for distance, linear sprint test (5, 10 and 20 m), and a modified version of the 505 COD test.ResultsResults showed moderate to very large differences (P < 0.05) in age, predicted age at peak height velocity (APHV), distance from PHV (DPHV), height, and body mass between the age categories. Moreover, U15 players demonstrated higher performances in all jump tests and lower sprint times in 10- (ES = 0.84) and 20-m (ES = 0.51) and a higher 505 deficit (ES = 0.38) than the U13 players (P < 0.05). However, no significant differences were observed for the 505 COD test between groups (ES = 0.12; P > 0.05).ConclusionsOur results suggest that during the transition from pre- to post-puberty, young handball players should focus on transferring their progressive improvements in strength, speed, and power capacities to COD performance.

A system of 5020 robotic fiber positioners was installed in 2019 on the Mayall Telescope, at Kitt Peak National Observatory. The robots automatically retarget their optical fibers every 10–20 minutes, each to a precision of several microns, with a reconfiguration time of fewer than 2 minutes. Over the next 5 yr, they will enable the newly constructed Dark Energy Spectroscopic Instrument (DESI) to measure the spectra of 35 million galaxies and quasars. DESI will produce the largest 3D map of the universe to date and measure the expansion history of the cosmos. In addition to the 5020 robotic positioners and optical fibers, DESI’s Focal Plane System includes six guide cameras, four wave front cameras, 123 fiducial point sources, and a metrology camera mounted at the primary mirror. The system also includes associated structural, thermal, and electrical systems. In all, it contains over 675,000 individual parts. We discuss the design, construction, quality control, and integration of all these components. We include a summary of the key requirements, the review and acceptance process, on-sky validations of requirements, and lessons learned for future multiobject, fiber-fed spectrographs.

Abstract Migraine is a common and burdensome neurological condition which affects mainly female patients during their childbearing years. Valproate has been widely used for the prophylaxis of migraine attacks and is also included in the main European Guidelines. Previous (2014) European recommendations on limiting the use of valproate in women of childbearing age did not achieve their objective in terms of limiting the use of valproate in women of childbearing age and raising awareness regarding the hazardous effect of valproate to children exposed in utero. The teratogenic and foetotoxic effects of valproate are well documented, and more recent studies show that there is an even greater neurodevelopmental risk to children exposed to valproate in the womb. The latest 2018 European review from the European Medicines Agency, with the active participation of the European Headache Federation, concluded that not enough has been done to mitigate the risks associated with in utero exposure to valproate. The review called for more extensive restrictions to the conditions for prescribing, better public awareness, and a more effective education campaign in migrainous women.

From 2016 to 2018, Hidalgo County observed the emergence of Zika virus (ZIKV) infections along with sporadic cases of Dengue virus (DENV) and West Nile virus (WNV). Due to the emergence of ZIKV and the historical presence of other mosquito-borne illnesses, Hidalgo County obtained funding to enhance mosquito surveillance and educate residents on arboviruses and travel risks. During this time period, Hidalgo County mosquito surveillance efforts increased by 1.275%. This increase resulted in >8000 mosquitoes collected, and 28 mosquito species identified. Aedes aegypti, Ae albopictus and Culex quinquefasciatus made up approximately two-thirds of the mosquitoes collected in 2018 (4122/6171). Spatiotemporal shifts in vector species composition were observed as the collection period progressed. Significantly, temperature variations (p < 0.05) accounted for associated variations in vector abundance, whereas all other climate variables were not significant.

El objetivo de la investigación consistió en realizar una selección y adaptación fenotípica de tres variedades élites de caña de azúcar (Saccharum officinarum L.) para la producción de panela granulada en la provincia de Bongará. Para ello, se eligió un factorial en DBCA, y el esquema seguido en campo fue mediante el uso de nueve variedades, entres diferentes edades de corte, y en cuatro bloques, formando un total de 27 tratamientos. De las variedades elegidas, tres fueron autóctonas de la zona, y seis introducidas del ámbito nacional e internacional. El área experimental fue instalada en el anexo de Cocachimba a una altitud de 1721 m.s.n.m. Las variedades evaluadas fueron Mex73-523, Amarilla (PR10-59), Carriza (POJ29-61), V74-7, Mex73-1240, Colcamar (CO-421), Mex79-431, H32-8560 y Mex69-290.Las variables que se tuvieron en cuenta para la selección y la administración de los tratamientos fueron: “rendimiento de grados brix(°Bx)”, “biomasa(Tn/Ha)”, y “rendimiento de jugo (Kg jugo / 100 Kg d ecaña)”. Se obtuvieron diferencias significativas entre las medias de los tratamientos, para los rendimientos de grados brix(p = 0,000 < 0,05), biomasa (p = 0,000 < 0,05), y jugo (p = 0,000 < 0,05), a través de pruebas de análisis de varianza (PruebaANOVA).

Summary: Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer’s disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders. : Microglia play a key role in neuroinflammation and neurodegeneration in different neurodegenerative diseases, but little is known about the epigenetic modifying enzymes regulating their inflammatory response. Carrillo-Jimenez et al. identify TET2 as a major regulator of the microglia proinflammatory response and suggest that, by targeting this protein, microglial activation could be impaired. Keywords: microglia, epigenetics, TET2, metabolism, TLR-4, neuroinflammation

Several infertile patients, who may even represent around 40% of the infertile cohort, may respond “suboptimally” (4–9 oocytes retrieved) following IVF, despite being predicted as normal responders. The aim of our longitudinal study was to evaluate the ovarian response of suboptimal responders in terms of the number of oocytes retrieved, following their second IVF cycle, evaluating exclusively patients who had the same stimulation protocol and used the same or higher initial dose of the same type of gonadotropin compared to their previous failed IVF attempt. Overall, our analysis included 160 patients treated with a fixed antagonist protocol in their second cycle with the same [53 (33.1%)] or higher [107 (66.9%)] starting dose of rFSH. The number of oocytes retrieved was significantly higher in the second IVF cycle [6 (5–8) vs. 9 (6–12), p < 0.001]. According to our results, a dose increment of rFSH remained the only significant predictor of the number of oocytes retrieved in the subsequent IVF cycle (coefficient 0.02, p-value = 0.007) after conducting GEE multivariate regression, while adjusting for relevant confounders. A regression coefficient of 0.02 for the starting dose implies that an increase of 50 IU of the initial rFSH dose would lead to 1 more oocyte.

In India, a practice of "Batch in vitro fertilization (IVF)" has evolved in many infertility centers in an effort to align infertility management with logistics. A "Batch IVF" is an approach where the menstrual cycles of multiple women are programmed, such that they can undergo all the processes; from stimulation until embryo transfer about the same time. In "Batch IVF", the day for initiating stimulation is calculated retrospectively from the day the visiting embryologist is available at the clinic (day of ovum pick-up). Aligning the cycles of multiple women with steroids followed by down regulation with long gonadotropin-releasing hormone agonist (GnRH-A) is one of the currently employed methods for batching. There is sufficient evidence on scheduling cycles with steroids in GnRH-An protocol without compromising on the outcome. The objective of this paper is to provide evidence-based clinical concept on scheduling cycles in "Batch IVF" setup with GnRH-An protocol through literature review.

The ongoing deployment of smart meters and different commercial devices has made electricity disaggregation feasible in buildings and households, based on a single measure of the current and, sometimes, of the voltage. Energy disaggregation is intended to separate the total power consumption into specific appliance loads, which can be achieved by applying Non-Intrusive Load Monitoring (NILM) techniques with a minimum invasion of privacy. NILM techniques are becoming more and more widespread in recent years, as a consequence of the interest companies and consumers have in efficient energy consumption and management. This work presents a detailed review of NILM methods, focusing particularly on recent proposals and their applications, particularly in the areas of Home Energy Management Systems (HEMS) and Ambient Assisted Living (AAL), where the ability to determine the on/off status of certain devices can provide key information for making further decisions. As well as complementing previous reviews on the NILM field and providing a discussion of the applications of NILM in HEMS and AAL, this paper provides guidelines for future research in these topics.

This study examines how companies can achieve high performance through certain organizational behaviors (open-mindedness and social networks) and innovation. The impact of open-mindedness in defiance of basic assumptions and processes could motivate the use of internal and external networks. These social networks are the cornerstone for the creation of knowledge and the construction of radical innovations, which in turn trigger the transformation new knowledge into organizational performance. We use structural equation modelling (SEM) to test our research model and hypotheses in a sample of 324 companies from the Brazilian industrial sector. Data were collected by a regular mail survey. The study brings a proper understanding that radical innovations play a crucial role for organizational performance in emerging economies. Results also show that open-mindedness is associated with both internal networks and external social networks. In addition, the external social network mediates the effects of open-mindedness on the internal social network. Finally, external social networks have an indirect influence on radical innovations, through internal social networks, and a direct effect on organizational performance.

Roland Asmar1, Juan Garcia-Puig2, Philippe Gosse3, Yuri A Karpov4, Peter Wilhem De Leeuw5, Dieter Magometschniggs6, Lajos Matos7, Roland Schmieder81Institut Cardiovasculaire, Paris, France; 2Hospital La Paz, Madrid, Spain; 3Hôpital Saint André, Bordeaux, France; 4Russian Academy of Medical Sciences, Moscow, Russia; 5Academisch Ziekenhuis, Maastricht, the Netherlands; 6Institut für Hypertoniker, Vienna, Austria; 7Hungarian Institut of Cardiology, Budapest, Hungary; 8Medizinische FakultÄt, Erlangen GermanyBackground: Ambulatory blood pressure (BP) is more sensitive than office BP and is highly correlated with the left ventricular mass (LVM) of hypertensive patients with left ventricular hypertrophy (LVH). Methods: In this prospectively designed ancillary study of the PICXEL trial, the effects of first-line combination perindopril/indapamide on ambulatory BP were compared with those of monotherapy with enalapril in 127 patients. Hypertensive patients with LVH received once daily either perindopril 2 mg/indapamide 0.625 mg (n = 65) or enalapril 10 mg (n = 62) for 52 weeks. Dose adjustments were allowed for uncontrolled BP. Twenty-four-hour ambulatory BP and echocardiographic parameters were measured at baseline, week 24, and week 52. Results: At study end, both treatments significantly improved ambulatory BP compared with baseline (p ≤ 0.01). Perindopril/indapamide treatment reduced 24-hour and daytime systolic BP (SBP) and pulse pressure (PP) significantly more than enalapril treatment (p < 0.01). No significant between-group differences were noted for diastolic BP (DBP) or for night-time measurements. Trough/peak ratios were higher with perindopril/indapamide than with enalapril (88.5 vs 65.8 for SBP and 86.7 vs 63.9 for DBP, respectively). The global smoothness index was higher with perindopril/indapamide than with enalapril (6.6 vs 5.2 for SBP and 5.6 vs 4.9 for DBP, respectively). With perindopril/indapamide treatment, LVM index was significantly reduced (−9.1 g/m2 from baseline; p vs baseline

Abstract Introduction This video module is an effective and versatile teaching tool that provides comprehensive instruction for intrauterine device (IUD) insertion in any clinical setting or academic situation. This method was created to offer an alternative for IUD insertion training due to the difficulties faced by medical learners, particularly family medicine residents, to obtain the required training. The method is simple to implement, provides easier access than the traditional methods of instruction for learners (i.e., demonstration and instruction in IUD insertion clinics), and reduces time for instruction and evaluation by preceptors. Methods This resource has three components: the video, the written material for instruction, and a validated measurement instrument. The effectiveness of the video module was studied in a group of 39 learners, comparing it with the traditional form of instruction. Results The results showed that the video module is as effective as the traditional method of instruction in providing procedural knowledge instruction. In procedure performance, the video module group performed better than the traditional group. The pretest and the posttest were compared to assess whether the intervention influenced knowledge within the groups. In the traditional instruction group, the participants improved significantly from the beginning to the end of the study, pretest (M = 8.0, SD = 2.52) and posttest (M = 11.3, SD = 1.70, t(18) = 5.64, p < .5). The group exposed to the video-module instruction also demonstrated a significant improvement in knowledge, pretest (M = 9.0, SD = 2.33) and posttest (M =12.3, SD = 1.87, t(19) = 6.92, p < .05). The participants in the video module instruction group obtained higher scores (M = 48.1, SD = 4.89) than the participants in the traditional instruction group (M = 43.8, SD = 6.42, t(37) = 2.37, p < .05). The between groups effect size difference was in favor of video module training with a medium effect size difference compared to the traditional training approach (d = 0.75). Discussion This video-module is an alternative to traditional forms of instruction that aims to overcome the difficulties faced by learners to obtain procedural training in IUD insertion. The video-module is being used at the University of Calgary Family Medicine Department in regular scheduled curricular activities for first-year residents and students, and is being implemented for its use by faculty and community preceptors in clinical urban and rural settings.

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and is caused by polyglutamine expansion in the huntingtin protein. Mutant huntingtin protein and its fragments are resistant to protein degradation and produce a blockade of the ubiquitin proteasome system (UPS). In HD models, the proteasome inhibitor epoxomicin aggravates protein accumulation and the inductor of autophagy, trehalose, diminishes it. We have investigated the effects of epoxomicin and trehalose in skin fibroblasts of control and HD patients. Untreated HD fibroblasts have increased the levels of ubiquitinized proteins and higher levels of reactive oxygen species (ROS), huntingtin and the autophagy marker LAMP2A. Baseline replication rates were higher in HD than in controls fibroblasts but that was reverted after 12 passages. Epoxomicin increases the activated caspase-3, HSP70, huntingtin, ubiquitinated proteins and ROS levels in both HD and controls. Treatment with trehalose counteracts the increase in ROS, ubiquitinated proteins, huntingtin and activated caspase-3 levels induced by epoxomicin, and also increases the LC3 levels more in HD fibroblast than controls. These results suggest that trehalose could revert protein processing abnormalities in patients with Huntington's Disease.