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This paper reports the results from three targeted searches of Milagro TeV sky maps: two extragalactic point source lists and one pulsar source list. The first extragalactic candidate list consists of 709 candidates selected from the Fermi-LAT 2FGL catalog. The second extragalactic candidate list contains 31 candidates selected from the TeVCat source catalog that have been detected by imaging atmospheric Cherenkov telescopes (IACTs). In both extragalactic candidate lists Mkn 421 was the only source detected by Milagro. This paper presents the Milagro TeV flux for Mkn 421 and flux limits for the brighter Fermi-LAT extragalactic sources and for all TeVCat candidates. The pulsar list extends a previously published Milagro targeted search for Galactic sources. With the 32 new gamma-ray pulsars identified in 2FGL, the number of pulsars that are studied by both Fermi-LAT and Milagro is increased to 52. In this sample, we find that the probability of Milagro detecting a TeV emission coincident with a pulsar increases with the GeV flux observed by the Fermi-LAT in the energy range from 0.1 GeV to 100 GeV. © 2014 Elsevier B.V. All rights reserved.

Background: Despite the connections and clear importance of the cerebellum in motor function, research utilizing cerebellar neuromodulation for treatment of movement disorders is still underdeveloped. Here we conduct a systematic review to investigate non-invasive neurostimulation of the cerebellum and its potential impact on motor systems and its function. Our aim is to give a general review of each neurostimulation study focusing on the cerebellum as a treatment target in the past five years at time of search, in order to update the field on current findings and inspire similar cerebellar neurostimulation research without unnecessary repetition., Methods: Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, our search included articles over the past five years that evaluated neurostimulation of the cerebellum (e.g., transcranial magnetic stimulation, transcranial direct current stimulation, and transcranial alternating current stimulation, etc.). Inclusion criteria included: (1) neurostimulation (repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS)) of the cerebellum; (2) only original articles, and (3) outcomes focused on motor functions. Exclusion criteria included: (1) neurostimulation with the goal of targeting any brain structure other than the cerebellum and (2) reviews and conference abstracts., Results: The search revealed 82 distinct articles relevant to the research question. Included are 17 articles concerning rTMS, 56 articles concerning tDCS, and 9 articles concerning tACS. The majority of the studies are controlled trials of varying types, with 79, with two case studies and one pilot study., Conclusions: Many studies showed significant effects on motor function and circuitry via non-invasive neurostimulation of the cerebellum. Common targets of cerebellar neurostimulation include visuomotor control, stroke rehabilitation for improvements in balance and coordination, and motor skill acquisition. The field is still exploring ideal parameters of neurostimulation for each disorder or function of interest. Future research areas should include the inclusion of individual anatomy, including functional connectivity, and improving stimulation selectivity., (© 2024 The Author(s). Published by IMR Press.)

Introduction: The lingering burden of the COVID-19 pandemic on primary care clinicians and practices poses a public health emergency for the United States. This study uses clinician-reported data to examine changes in primary care demand and capacity., Methods: From March 2020 to March 2022, 36 electronic surveys were fielded among primary care clinicians responding to survey invitations as posted on listservs and identified through social media and crowd sourcing. Quantitative and qualitative analyses were performed on both closed- and open-ended survey questions., Results: An average of 937 respondents per survey represented family medicine, pediatrics, internal medicine, geriatrics, and other specialties. Responses reported increases in patient health burden, including worsening chronic care management and increasing volume and complexity. A higher frequency of dental- and eyesight-related issues was noted by respondents, as was a substantial increase in mental or emotional health needs. Respondents also noted increased demand, "record high" wait times, and struggles to keep up with patient needs and the higher volume of patient questions. Frequent qualitative statements highlighted the mismatch of patient needs with practice capacity. Staffing shortages and the inability to fill open clinical positions impaired clinicians' ability to meet patient needs and a substantial proportion of respondents indicated an intention to leave the profession or knew someone who had., Conclusion: These data signal an urgent need to take action to support the ability of primary care to meet ongoing patient and population health care needs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC., Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured., Results: The non-survival group had increased levels of white blood cells, neutrophils (both p <0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (β=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]., Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Garcia-Flores, Dawid De Vera, Pilo, Rego, Gomez-Casado, Arranz-Salas, Hierro Martín, Alcaide, Torres, Ortega-Gomez, Boughanem and Macias-Gonzalez.)

Significant technical challenges exist when measuring synaptic connections between neurons in living brain tissue. The patch clamping technique, when used to probe for synaptic connections, is manually laborious and time-consuming. To improve its efficiency, we pursued another approach: instead of retracting all patch clamping electrodes after each recording attempt, we cleaned just one of them and reused it to obtain another recording while maintaining the others. With one new patch clamp recording attempt, many new connections can be probed. By placing one pipette in front of the others in this way, one can "walk" across the tissue, termed "patch-walking." We performed 136 patch clamp attempts for two pipettes, achieving 71 successful whole cell recordings (52.2%). Of these, we probed 29 pairs (i.e., 58 bidirectional probed connections) averaging 91 μ m intersomatic distance, finding 3 connections. Patch-walking yields 80-92% more probed connections, for experiments with 10-100 cells than the traditional synaptic connection searching method., Competing Interests: 5.2.Declaration of Interests I.K., W.M.S, and C.R.F. are co-inventors on a patent describing pipette cleaning that is licensed by Sensapex.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials. We emphasise the importance of establishing a European approach for risk and sustainability governance of advanced materials as soon as possible to keep up with the pace of innovation and to manage uncertainty among regulators, industry, SMEs and the public, regarding potential risks and impacts of advanced materials. Coordination of safe and sustainable advanced material research efforts, and data management according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles will enhance the generation of regulatory-relevant knowledge. This knowledge is crucial to identify whether current regulatory standardised and harmonised test methods are adequate to assess advanced materials. At the same time, there is urgent need for responsible innovation beyond regulatory compliance which can be promoted through the Safe and Sustainable Innovation Approach. that combines the Safe and Sustainable by Design concept with Regulatory Preparedness, supported by a trusted environment. We further recommend consolidating all efforts and networks related to the risk and sustainability governance of advanced materials in a single, easy-to-use digital portal. Given the anticipated complexity and tremendous efforts required, we identified the need of establishing an organisational structure dedicated to aligning the fast technological developments in advanced materials with proper risk and sustainability governance. Involvement of multiple stakeholders in a trusted environment ensures a coordinated effort towards the safe and sustainable development, production, and use of advanced materials. The existing infrastructures and network of experts involved in the governance of nanomaterials would form a solid foundation for such an organisational structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9'-norharmane dimer (nHo-dimer), which belongs to the β-carboline (βC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.

Goal: This study was developed to explicate underlying organizational factors contributing to the deterioration of primary care clinicians' mental health during the COVID-19 pandemic., Methods: Using data from the Larry A. Green Center for the Advancement of Primary Health Care for the Public Good's national survey of primary care clinicians from March 2020 to March 2022, a multidisciplinary team analyzed more than 11,150 open-ended comments. Phase 1 of the analysis happened in real-time as surveys were returned, using deductive and inductive coding. Phase 2 used grounded theory to identify emergent themes. Qualitative findings were triangulated with the survey's quantitative data., Principal Findings: The clinicians shifted from feelings of anxiety and uncertainty at the start of the pandemic to isolation, lack of fulfillment, moral injury, and plans to leave the profession. The frequency with which they spoke of depression, burnout, and moral injury was striking. The contributors to this distress included crushing workloads, worsening staff shortages, and insufficient reimbursement. Consequences, both felt and anticipated, included fatigue and demoralization from the inability to manage escalating workloads. Survey findings identified responses that could alleviate the mental health crisis, namely: (1) measuring and customizing workloads based on work capacity; (2) quantifying resources needed to return to sufficient staffing levels; (3) promoting state and federal support for sustainable practice infrastructures with less administrative burden; and (4) creating patient visits of different lengths to rebuild relationships and trust and facilitate more accurate diagnoses., Practical Applications: Attention to clinicians' mental health should be rapidly directed to on-demand, confidential mental health support so they can receive the care they need and not worry about any stigma or loss of license for accepting that help. Interventions that address work-life balance, workload, and resources can improve care, support retention of the critically important primary care workforce, and attract more trainees to primary care careers., (Copyright © 2024 Foundation of the American College of Healthcare Executives.)

Background and Objectives: In a hospital radiopharmacy with 2a operational level, including the preparation of radiopharmaceuticals from prepared and approved reagent kits, it is common to have a single activimeter or dose calibrator for labeling and fractionation, and to perform the quality controls of the 99m Tc-radiopharmaceuticals. In certain cases, the accumulation of radioactive material or accidental contamination of the work area causes the background to exceed the limits to carry out the radiochemical purity analyses and it is necessary to look for viable alternatives. In this work, a Geiger Müller detector (equipped with a probe for measuring surface contamination) frequently used for radioprotection purposes, was validated as an alternative and its performance was compared against the activimeter for 99m Tc-radiopharmaceuticals., Materials and Methods: Using [ 99m Tc]pertechnetate, systematic studies of error analyses and detector response to activity concentration, activity and measurement time were carried out in liquid matrices and in paper. The results were compared against an activimeter calibrated for [ 99m Tc]Tc., Results: The developed method was used to determine the radiochemical purity of the compounds [ 99m Tc]Tc-MDP and [ 99m Tc]Tc-MIBI by ascending paper chromatography tests, obtaining comparable values to those measured with an activimeter in the same system (within 1% uncertainty) and using the method of vial partitioning in a dedicated equipment., Conclusions: This work demonstrates that a Geiger Müller detector with a probe for measuring surface contamination can be adequately used to replace other equipment in the control of radiochemical purity in the hospital radiopharmacy., (Copyright © 2024 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: The objective of this study is to describe the facilitators and barriers of telemedicine during the COVID-19 pandemic for primary care clinicians in safety-net settings., Methods: We selected 5 surveys fielded between September 2020 and March 2023 from the national "Quick COVID-19 Primary Care Survey" by the Larry A. Green Center, with the Primary Care Collaborative. We used an explanatory sequential mixed method approach. We compared safety-net practices (free & charitable organization, federally qualified health center (FQHC), clinics with a 50% or greater Medicaid) to all other settings. We discuss: 1) telemedicine services provided; 2) clinician motivations; 3) and telemedicine access., Results: All clinicians were similarly motivated to implement telemedicine. Safety-net clinicians were more likely to report use of phone visits. These clinicians felt less "confident in my use of telemedicine" (covariate-adjusted OR = 0.611, 95% CI 0.43 - 0.87) and were more likely to report struggles with televisits in March 2023 (covariate-adjusted OR = 1.73, 95% CI 1.16 - 2.57), particularly with physical examinations. Safety-net clinicians were more likely to endorse reductions in no-shows (covariate-adjusted OR = 1.77, 95% CI 1.17 - 2.68). Telemedicine increased access and new patient-facing demands including portal communications., Conclusions: This study enhances our understanding of the use of telemedicine within the safety-net setting. Clinician perceptions are important for identifying barriers to telemedicine following the end of the Federal COVID-19 Public Health Emergency. Clinicians highlighted significant limitations to its use including clinical appropriateness, quality of physical examinations, and added patient-facing workload., Competing Interests: Conflict of interest: The authors have no conflicts of interests to declare., (© Copyright 2024 by the American Board of Family Medicine.)

Background & Aims: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis., Methods: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4 + T-cell-induced murine colitis models., Results: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r -/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs., Conclusions: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4 + T-cell-driven chronic intestinal inflammation., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The incidence of Crohn's disease (CD) continues to increase worldwide. The contribution of CD4 + cell populations remains to be elucidated. We aimed to provide an in-depth transcriptional assessment of CD4 + T cells driving chronic inflammation in CD., Methods: We performed single-cell RNA-sequencing in CD4 + T cells isolated from ileal biopsies of patients with CD compared with healthy individuals. Cells underwent clustering analysis, followed by analysis of gene signaling networks. We overlapped our differentially expressed genes with publicly available microarray data sets and performed functional in vitro studies, including an in vitro suppression assay and organoid systems, to model gene expression changes observed in CD regulatory T (Treg) cells and to test predicted therapeutics., Results: We identified 5 distinct FOXP3 + regulatory Treg subpopulations. Tregs isolated from healthy controls represent the origin of pseudotemporal development into inflammation-associated subtypes. These proinflammatory Tregs displayed a unique responsiveness to tumor necrosis factor-α signaling with impaired suppressive activity in vitro and an elevated cytokine response in an organoid coculture system. As predicted in silico, the histone deacetylase inhibitor vorinostat normalized gene expression patterns, rescuing the suppressive function of FOXP3 + cells in vitro., Conclusions: We identified a novel, proinflammatory FOXP3 + T cell subpopulation in patients with CD and developed a pipeline to specifically target these cells using the US Food and Drug Administration-approved drug vorinostat., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic non-communicable diseases (NCDs) are predominantly related to modifiable health behaviors and account for 74% of global deaths at present. Behavior modification through self-management is a strategy to prevent NCDs. Chronic Disease Self-Management Programs (CDSMPs) have demonstrated improvements in health behaviors, health status, and use of healthcare., Objective: We evaluated the effects of a 6-week CDSMP on self-efficacy, health behaviors, mental health, health-related quality of life (HR-QoL), and health responsibilities among vulnerable populations with chronic disease in Europe., Methods: A prospective cohort study with a 6-month pre-post single-group design was conducted in five European countries. The intervention targeted adults with chronic conditions and low socioeconomic status, as well as their caregivers. The intervention was a 6-week community-based CDSMP in a group setting. Outcomes were measured per self-report questionnaire at baseline and 6-month follow-up: self-efficacy, health behaviors, mental health, HR-QoL, and health responsibilities., Results: Of 1,844 participants, 1,248 (67.7%) completed follow-up and attended ≥4 sessions. For the chronic condition group, the following outcome measures at follow-up significantly improved compared with baseline (all P < 0.002): self-efficacy (SEMCD-6 6.7 vs. 6.4), mental health (PHQ-8 6.3 vs. 7.0), HR-QoL (SF-12 PCS 42.3 vs. 40.2, SF-12 MCS 42.8 vs. 41.4), health utility (EQ-5D-5L 0.88 vs. 0.86), self-rated health (EQ-5D-5L 67.2 vs. 63.9), communication with healthcare providers (2.28 vs. 2.11), understanding information (3.10 vs. 3.02), number of doctor visits (3.61 vs. 4.97), accident and emergency department visits (0.25 vs. 0.48), total nights in a hospital (0.65 vs. 1.13), and perceived medical errors (19.6 vs. 28.7%). No significant changes were detected in dietary habits, physical activity, substance use, and sleep and fatigue. For caregivers without a chronic condition, only doctor visits significantly decreased (1.54 vs. 2.25, P < 0.001)., Discussion: This CDSMP was associated with improvement in self-efficacy, depression, HR-QoL, and health responsibilities over 6 months in a diverse European population with a chronic condition. However, additional interventions targeting lifestyle risk factors are needed to improve health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Korenhof, Rouwet, Elstgeest, Fierloos, Tan, Pisano-Gonzalez, Boone, Pers, Pilotto, López-Ventoso, Diez Valcarce, Zhang and Raat.)

Introduction: Testicular adrenal rest tumors (TARTs) predominantly occur in patients with congenital adrenal hyperplasia (CAH) and may interfere with the function of the testicles., Objective: This study aimed to identify the factors that contribute to the occurrence of TARTs in patients with CAH and influence their volume., Study Design: This was a comparative cross-sectional study. Male patients aged 0-16 years with CAH were included. Weight, height, bone age determination, biochemical and androgenic profiles, and testicular ultrasound were performed. Patients were divided into those with and without TARTs and the between-group differences were assessed using the Mann-Whitey U test and Fisher's exact test. A ROC curve was created for serum ACTH levels to identify the cut-off point to diagnose TARTs. Variables that influenced the volume of the TARTs were identified using Spearman's correlation coefficient., Results: TARTs were observed in seven (19.4%) of 36 male children with CAH. Of the patients with TARTs, 85.7% were pubertal. Serum concentrations of adrenocorticotropic hormone (ACTH) levels were significantly higher in patients with TARTs than in those without (309.0 pg/mL vs. 45.2 pg/mL; p = 0.006). ACTH levels >200 pg/mL were found to predict the presence of TARTs (sensitivity 85.7%; specificity 86.2%) (Figure). The factors found to correlate with TARTs volume were ACTH levels (coefficient 0.004; p = 0.009) and the three-year average of serum testosterone levels (coefficient 9.64; p = 0.003).] DISCUSSION: The main limitation of this study was the small sample size. However, an ACTH cut-off point to predict insufficient hormonal treatment and consequently the presence of TART had not been described., Conclusions: High ACTH (>200 pg/mL) was found to be predictive insufficient hormonal treatment in patients with CAH. The three-year average of serum testosterone levels and ACTH concentrations were correlated with the volume of TARTs., Competing Interests: Conflicts of interest Nothing to declare., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: During the COVID-19 pandemic, telemedicine emerged as an important tool in primary care. Technology and policy-related challenges, however, revealed barriers to adoption and implementation. This report describes the findings from weekly and monthly surveys of primary care clinicians regarding telemedicine during the first 2 years of the pandemic., Methods: From March 2020 to March 2022, we conducted electronic surveys using convenience samples obtained through social networking and crowdsourcing. Unique tokens were used to confidentially track respondents over time. A multidisciplinary team conducted quantitative and qualitative analyses to identify key concepts and trends., Results: A total of 36 surveys resulted in an average of 937 respondents per survey, representing clinicians from all 50 states and multiple specialties. Initial responses indicated general difficulties in implementing telemedicine due to poor infrastructure and reimbursement mechanisms. Over time, attitudes toward telemedicine improved and respondents considered video and telephone-based care important tools for their practice, though not a replacement for in-person care., Conclusions: The implementation of telemedicine during COVID-19 identified barriers and opportunities for technology adoption and highlighted steps that could support primary care clinics' ability to learn, adapt, and implement technology., (© 2023 Annals of Family Medicine, Inc.)

Background: There are major shortfalls in the identification and screening of at-risk migrant groups. This study aims to evaluate the effectiveness of a new digital tool (IS-MiHealth) integrated into the electronic patient record system of primary care centres in detecting prevalent migrant infections. IS-MiHealth provides targeted recommendations to health professionals for screening multiple infections, including human immunodeficiency virus (HIV), hepatitis B and C, active tuberculosis (TB), Chagas disease, strongyloidiasis and schistosomiasis, based on patient characteristics (including variables of country of origin, age and sex)., Methods: A pragmatic pilot cluster-randomized-controlled trial was deployed from March to December 2018. Eight primary care centres in Catalonia, Spain, were randomly allocated 1:1 to use of the digital tool for screening, or to routine care. The primary outcome was the monthly diagnostic yield of all aggregated infections. Intervention and control sites were compared before and after implementation with respect to their monthly diagnostic yield using regression models. This study is registered on international standard randomised controlled trial number (ISRCTN) (ISRCTN14795012)., Results: A total of 15 780 migrants registered across the eight centres had at least one visit during the intervention period (March-December 2018), of which 14 598 (92.51%) fulfilled the criteria to be screened for at least one infection. There were 210 (2.57%) individuals from the intervention group with new diagnoses compared with 113 (1.49%) from the control group [odds ratio: 2.08, 95% confidence interval (CI) 1.63-2.64, P < 0.001]. The intervention centres raised their overall monthly diagnosis rate to 5.80 (95% CI 1.23-10.38, P = 0.013) extra diagnoses compared with the control centres. This monthly increase in diagnosis in intervention centres was also observed if we consider all cases together of HIV, hepatitis B and C, and active TB cases [2.72 (95% CI 0.43-5.00); P = 0.02] and was observed as well for the parasitic infections' group (Chagas disease, strongyloidiasis and schistosomiasis) 2.58 (95% CI 1.60-3.57; P < 0.001)., Conclusions: The IS-MiHealth increased screening rate and diagnostic yield for key infections in migrants in a population-based primary care setting. Further testing and development of this new tool is warranted in larger trials and in other countries., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine.)

The field of nanomedicine has significantly influenced research areas such as drug delivery, diagnostics, theranostics, and regenerative medicine; however, the further development of this field will face significant challenges at the regulatory level if related guidance remains unclear and unconsolidated. This review describes those features and pathways crucial to the clinical translation of nanomedicine and highlights considerations for early-stage product development. These include identifying those critical quality attributes of the drug product essential for activity and safety, appropriate analytical methods (physical, chemical, biological) for characterization, important process parameters, and adequate pre-clinical models. Additional concerns include the evaluation of batch-to-batch consistency and considerations regarding scaling up that will ensure a successful reproducible manufacturing process. Furthermore, we advise close collaboration with regulatory agencies from the early stages of development to assure an aligned position to accelerate the development of future nanomedicines., (© 2021. The Author(s).)

In this work, a model has been formulated to describe the complex process of LiCoO 2 leaching through the participation of competing reactions in acid media including the effect of H 2 O 2 as reducing agent. The model presented here describes the extraction of Li and Co in the presence and absence of H 2 O 2 , and it takes into account the different phenomena affecting the controlling mechanisms. In this context, the model predicts the swift from kinetic control to diffusion control. The model has been implemented and solved to simulate the leaching process. To validate the model and to estimate the model parameters, a set of 12 (in triplicate) extraction experiments were carried out varying the concentration of hydrochloric acid (within the range of 0.5-2.5 M) and hydrogen peroxide (range 0-0.6%v/v). The simulation results match fairly well with the experimental data for a wide range of conditions. Furthermore, the model can be used to predict results with different solid-liquid ratios as well as different acid and oxygen peroxide concentrations. This model could be used to design or optimize a LiCoO 2 extraction process facilitating the corresponding economical balance of the treatment., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prepregnancy body mass index (BMI) and gestational weight gain (GWG) are the most investigated indicators of maternal nutritional status, which is a modifiable factor that plays a vital role in maternal and infant health. This study describes prepregnancy BMI and GWG of 840,243 women with 2,087,765 weight observations in the Brazilian Food and Nutrition Surveillance System from 2008 to 2018. Prepregnancy BMI was classified according to the World Health Organization cut-offs. Total GWG was calculated from weight measurements taken after 36 weeks of pregnancy and classified according to the Institute of Medicine guidelines. Temporal trends in prepregnancy BMI status were examined, and maps were used to evaluate changes in excessive GWG in each Brazilian federation unit. On overall, prepregnancy overweight and obesity increased from 22.6% to 28.8% and from 9.8% to 19.8%, respectively, between 2008 and 2018. The prevalence of excessive GWG rose from 34.2% to 38.7% during the same period and in 11 of the 27 Brazilian federation units between 2008 and 2016. Women with underweight showed the highest values for mean total GWG for all the compared years (overall variation from 12.3 to 13.1 kg), followed by those with normal weight (11.9 to 12.5 kg), overweight (10.1 to 10.9 kg) and obesity (from 8.2 to 8.9 kg). Within each BMI group, values remained fairly stable throughout the studied period for first- and second-trimester GWG and total GWG. These results help to fill a significant gap in understanding the distribution of prepregnancy BMI and GWG in Brazilian women., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Purpose: To examine the psychometric properties and scores of the Person-Centered Primary Care Measure (PCPCM) in 28 languages and 35 Organisation for Economic Co-operation and Development (OECD) countries., Methods: Using a paid online sampling service, we requested age- and sex-representative samples of 360 adults in each country. We administered the Person-Centered Primary Care Measure-a previously validated 11-item, patient-reported measure that was developed using what patients and clinicians said is most important about primary care. We also assessed construct validity through associations with demographics, the Patient-Enablement Instrument, number of years the person had been with their primary care physician and practice, whether the patient thought the doctor knowing the results would improve their care, and whether it was hard to complete the survey. We assessed the psychometric properties of the PCPCM in each country and report the summative and item-specific PCPCM scores for each country., Results: The PCPCM exhibited solid psychometric properties across all languages and countries, with Cronbach's alphas ranging from 0.88 to 0.95, and corrected item-total correlations ranging from 0.47 to 0.81, with the vast majority of countries ranging from the low 0.50s to the high 0.70s. Multiple analyses showed strong evidence of concurrent validity. With a potential range from a low of 1 to a high of 4, the overall mean score was 2.74, with a standard deviation of 0.19. Mean PCPCM scores ranged from the lowest in Sweden (2.28) to the highest in Turkey (3.08), with Germany ranking second (3.01), and the United States third (2.99)., Conclusion: The internal consistency and concurrent validity of the PCPCM across multiple countries provides strong evidence of the coherence of the breadth of primary care functions that patients and clinicians say are important. The diversity of total and item-specific scores across countries provokes interesting hypotheses about the influence of each different country's policies, practices, demographics, and culture on primary care, and provides a strong impetus for further ecological and individual data analyses using the Person-Centered Primary Care Measure. Annals "Online First" article ., (© 2021 Annals of Family Medicine, Inc.)

Toxoplasmosis is one of the most prevalent and neglected zoonotic global diseases caused by Toxoplasma gondii . The current pharmacological treatments show clinical limitations, and therefore, the search for new drugs is an urgent need in order to eradicate this infection. Due to their intrinsic biological activities, β-carboline (βC) alkaloids might represent a good alternative that deserves further investigations. In this context, the in vitro anti- T. gondii activity of three βCs, harmine ( 1 ), 2-methyl-harminium ( 2 ), and 9-methyl-harmine ( 3 ), was evaluated herein. Briefly, the three alkaloids exerted direct effects on the parasite invasion and/or replication capability. Replication rates of intracellular treated tachyzoites were also affected in a dose-dependent manner, at noncytotoxic concentrations for host cells. Additionally, cell cycle analysis revealed that both methyl-derivatives 2 and 3 induce parasite arrest in S/M phases. Compound 3 showed the highest irreversible parasite growth inhibition, with a half maximal inhibitory concentration (IC50) value of 1.8 ± 0.2 μM and a selectivity index (SI) of 17.2 at 4 days post infection. Due to high replication rates, tachyzoites are frequently subjected to DNA double-strand breaks (DSBs). This highly toxic lesion triggers a series of DNA damage response reactions, starting with a kinase cascade that phosphorylates a large number of substrates, including the histone H2A.X to lead the early DSB marker γH2A.X. Western blot studies showed that basal expression of γH2A.X was reduced in the presence of 3 . Interestingly, the typical increase in γH2A.X levels produced by camptothecin (CPT), a drug that generates DSB, was not observed when CPT was co-administered with 3 . These findings suggest that 3 might disrupt Toxoplasma DNA damage response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alomar, Yañuk, Angel, Gonzalez and Cabrerizo.)

Patch clamp electrophysiology is a common technique used in neuroscience to understand individual neuron behavior, allowing one to record current and voltage changes with superior spatiotemporal resolution compared with most electrophysiology methods. While patch clamp experiments produce high fidelity electrophysiology data, the technique is onerous and labor intensive. Despite the emergence of patch clamp systems that automate key stages in the typical patch clamp procedure, full automation remains elusive. Patch clamp pipettes can miss the target cell during automated experiments because of positioning errors in the robotic manipulators, which can easily exceed the diameter of a neuron. Further, when patching in acute brain slices, the inherent light scattering from non-uniform brain tissue can complicate pipette tip identification. We present a convolutional neural network (CNN), based on ResNet101, to identify and correct pipette positioning errors before each patch clamp attempt, thereby preventing the deleterious effects of and accumulation of positioning errors. This deep-learning-based pipette detection method enabled superior localization of the pipette within 0.62 ± 0.58 μm, resulting in improved cell detection success rate and whole-cell patch clamp success rates by 71% and 59%, respectively, compared with the state-of-the-art cross-correlation method. Furthermore, this technique reduced the average time for pipette correction by 81%. This technique enables real-time correction of pipette position during patch clamp experiments with similar accuracy and quality of recording to manual patch clamp, making notable progress toward full human-out-of-the-loop automation for patch clamp electrophysiology., (Copyright © 2021 Gonzalez et al.)

The whole-cell patch-clamp method is a gold standard for single-cell analysis of electrical activity, cellular morphology, and gene expression. Prior to our discovery that patch-clamp pipettes could be cleaned and reused, experimental throughput and automation were limited by the need to replace pipettes manually after each experiment. This article presents an optimized protocol for pipette cleaning, which enables it to be performed quickly (< 30 s), resulting in a high yield of whole-cell recording success rate (> 90%) for over 100 reuses of a single pipette. For most patch-clamp experiments (< 30 whole-cell recordings per day), this method enables a single pipette to be used for an entire day of experiments. In addition, we describe easily implementable hardware and software as well as troubleshooting tips to help other labs implement this method in their own experiments. Pipette cleaning enables patch-clamp experiments to be performed with higher throughput, whether manually or in an automated fashion, by eliminating the tedious and skillful task of replacing pipettes. From our experience with numerous electrophysiology laboratories, pipette cleaning can be integrated into existing patch-clamp setups in approximately one day using the hardware and software described in this article. Graphic abstract: Rapid enzymatic cleaning for reuse of patch-clamp pipettes., Competing Interests: Competing interestsMCY and IK have consulting agreements with Neuromatic Devices, which manufactures pipette pressure control systems. IK, WAS, and CRF are inventors on U.S. Patent 10,830,758 related to pipette cleaning technology and licensed to Sensapex., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

FOXP3+ Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3+ cells led to systemic inflammation. BMI1-deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17-like proinflammatory cells, a transition relevant to human Crohn's disease associated CD4+ T cells.

Optimizing the well-being of the oncology clinician has never been more important. Well-being is a critical priority for the cancer organization because burnout adversely impacts the quality of care, patient satisfaction, the workforce, and overall practice success. To date, 45% of U.S. ASCO member medical oncologists report experiencing burnout symptoms of emotional exhaustion and depersonalization. As the COVID-19 pandemic remains widespread with periods of outbreaks, recovery, and response with substantial personal and professional consequences for the clinician, it is imperative that the oncologist, team, and organization gain direct access to resources addressing burnout. In response, the Clinician Well-Being Task Force was created to improve the quality, safety, and value of cancer care by enhancing oncology clinician well-being and practice sustainability. Well-being is an integrative concept that characterizes quality of life and encompasses an individual's work- and personal health-related environmental, organizational, and psychosocial factors. These resources can be useful for the cancer organization to develop a well-being blueprint: a detailed start plan with recognized strategies and interventions targeting all oncology stakeholders to support a culture of community in oncology.

A common electrophysiology technique used in neuroscience is patch clamp: a method in which a glass pipette electrode facilitates single cell electrical recordings from neurons. Typically, patch clamp is done manually in which an electrophysiologist views a brain slice under a microscope, visually selects a neuron to patch, and moves the pipette into close proximity to the cell to break through and seal its membrane. While recent advances in the field of patch clamping have enabled partial automation, the task of detecting a healthy neuronal soma in acute brain tissue slices is still a critical step that is commonly done manually, often presenting challenges for novices in electrophysiology. To overcome this obstacle and progress towards full automation of patch clamp, we combined the differential interference microscopy optical technique with an object detection-based convolutional neural network (CNN) to detect healthy neurons in acute slice. Utilizing the YOLOv3 convolutional neural network architecture, we achieved a 98% reduction in training times to 18 min, compared to previously published attempts. We also compared networks trained on unaltered and enhanced images, achieving up to 77% and 72% mean average precision, respectively. This novel, deep learning-based method accomplishes automated neuronal detection in brain slice at 18 frames per second with a small data set of 1138 annotated neurons, rapid training time, and high precision. Lastly, we verified the health of the identified neurons with a patch clamp experiment where the average access resistance was 29.25 M[Formula: see text] (n = 9). The addition of this technology during live-cell imaging for patch clamp experiments can not only improve manual patch clamping by reducing the neuroscience expertise required to select healthy cells, but also help achieve full automation of patch clamping by nominating cells without human assistance.

This report presents the American Society of Clinical Oncology's (ASCO's) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.

Background: Previous research demonstrated that registries are effective for improving clinical guideline adherence for the care of patients with type 2 diabetes. However, registry implementation has typically relied on intensive support (such as practice facilitators) for practice change and care improvement., Objective: To determine whether a remotely delivered, low-intensity organizational change intervention supports implementation and use of diabetes registries in primary care., Design: Cluster-randomized controlled effectiveness trial of providing limited external support leveraging internal practice resources and problem-solving capacities for driving diabetes registry implementation in 32 practices in Virginia., Intervention: All practices identified local implementation champions who participated in an in-person education session on the value and use of diabetes registries, while intervention practices were also paired with peer mentors and had access to a physician informaticist, who worked remotely to assist practices with implementation., Main Measures: Practice champions reported progress on registry implementation milestone achievement, and reported practice-level organizational capacity by using a modified version of the Assessment of Chronic Illness Care (ACIC)., Key Results: Intervention practices were significantly more likely to have implemented a registry (44% vs 6%, P = .04) and to have achieved more implementation milestones (5.5 vs 2.6, P < .0001) than control practices. Baseline ACIC scores indicated room for organizational improvement with regard to chronic illness care (overall median, 6.4; range, 3.8 to 10.8) and clinical information systems use (median, 6.0; range, 0 to 11) with no significant differences between intervention and control practices., Conclusions: Remotely provided guidance paired with limited in-person assistance can support rapid implementation of diabetes registries in typical primary care practices., Competing Interests: Conflict of interest: The authors declare that they do not have a conflict of interest., (© Copyright 2020 by the American Board of Family Medicine.)

Background and Objectives: Scarce evidence exists in the medical literature describing the attitudes of rural community residents about the impact of losing their local physician. This pilot study explores aspects of access to care, both within and outside of primary care settings, that result from loss of a rural family physician., Methods: We selected study participants through convenience and snowball sampling, and we conducted in-person interviews of up to 60 minutes. We audio recorded and transcribed the interviews (May to August, 2018), then analyzed transcripts using immersion crystallization and managed within Atlas.ti 7.0 software (Berlin, Germany)., Results: We interviewed 18 participants, some of whom interviewed as pairs. Our analysis revealed three significant themes: rurally-specific access to care concerns, relationships valued for being both community and care based, and loss felt specific to the integrated community leadership roles occupied by family physicians. In addition, participants identified social challenges they associated with losing their "country doctor," such as withering community cohesion., Conclusions: Our findings suggest that rural physicians offer tremendous value to their communities, both inside and beyond their clinic walls. Issues of social cohesion and local health leadership affected by physician loss should be addressed by policy makers and educators charged with designing patient-centered solutions to improve health outcomes in rural communities. Current health and medical education reforms would benefit from greater focused attention on these issues.

Introduction: More than 70% of world mortality is due to chronic conditions. Furthermore, it has been proven that social determinants have an enormous impact on both health-related behaviour and on the received attention from healthcare services. These determinants cause health inequalities. The objective of this study is to reduce the burden of chronic diseases in five European regions, hereby focusing on vulnerable populations, and to increase the sustainability of health systems by implementing a chronic disease self-management programme (CDSMP)., Methods and Analysis: 2000 people with chronic conditions or informal caregivers belonging to vulnerable populations, will be enrolled in the CDSMP in Spain, Italy, the UK, France and the Netherlands. Inclusion of patients will be based on geographical, socioeconomic and clinical stratification processes. The programme will be evaluated in terms of self-efficacy, quality of life and cost-effectiveness using a combination of validated questionnaires at baseline and 6 months from baseline., Ethics and Dissemination: This study will follow the directives of the Helsinki Declaration and will adhere to the European Union General Data Protection Regulation. The project's activities, progress and outcomes will be disseminated via promotional materials, the use of mass media, online activities, presentations at events and scientific publications., Trial Registration Number: ISRCTN70517103; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Age-related health, brain, and cognitive impairment is a great challenge in current society. Cognitive training, aerobic exercise and their combination have been shown to benefit health, brain, cognition and psychological status in healthy older adults. Inconsistent results across studies may be related to several variables. We need to better identify cognitive changes, individual variables that may predict the effect of these interventions, and changes in structural and functional brain outcomes as well as physiological molecular correlates that may be mediating these effects. Projecte Moviment is a multi-domain randomized trial examining the effect of these interventions applied 5 days per week for 3 months compared to a passive control group. The aim of this paper is to describe the sample, procedures and planned analyses., Methods: One hundred and forty healthy physically inactive older adults will be randomly assigned to computerized cognitive training (CCT), aerobic exercise (AE), combined training (COMB), or a control group. The intervention consists of a 3 month home-based program 5 days per week in sessions of 45 min. Data from cognitive, physical, and psychological tests, cardiovascular risk factors, structural and functional brain scans, and blood samples will be obtained before and after the intervention., Results: Effects of the interventions on cognitive outcomes will be described in intention-to-treat and per protocol analyses. We will also analyze potential genetic, demographic, brain, and physiological molecular correlates that may predict the effects of intervention, as well as the association between cognitive effects and changes in these variables using the per protocol sample., Discussion: Projecte Moviment is a multi-domain intervention trial based on prior evidence that aims to understand the effects of CCT, AE, and COMB on cognitive and psychological outcomes compared to a passive control group, and to determine related biological correlates and predictors of the intervention effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03123900.

Purpose: To develop and evaluate a concise measure of primary care that is grounded in the experience of patients, clinicians, and health care payers., Methods: We asked crowd-sourced samples of 412 patients, 525 primary care clinicians, and 85 health care payers to describe what provides value in primary care, then asked 70 primary care and health services experts in a 2½ day international conference to provide additional insights. A multidisciplinary team conducted a qualitative analysis of the combined data to develop a parsimonious set of patient-reported items. We evaluated items using factor analysis, Rasch modeling, and association analyses among 2 online samples and 4 clinical samples from diverse patient populations., Results: The resulting person-centered primary care measure parsimoniously represents the broad scope of primary care, with 11 domains each represented by a single item: accessibility, advocacy, community context, comprehensiveness, continuity, coordination, family context, goal-oriented care, health promotion, integration, and relationship. Principal axes factor analysis identified a single factor. Factor loadings and corrected item-total correlations were >0.6 in online samples (n = 2,229) and >0.5 in clinical samples (n = 323). Factor scores were fairly normally distributed in online patient samples, and skewed toward higher ratings in point-of-care patient samples. Rasch models showed a broad spread of person and item scores, acceptable item-fit statistics, and little item redundancy. Preliminary concurrent validity analyses supported hypothesized associations., Conclusions: The person-centered primary care measure reliably, comprehensively, and parsimoniously assesses the aspects of care thought to represent high-value primary care by patients, clinicians, and payers. The measure is ready for further validation and outcome analyses, and for use in focusing attention on what matters about primary care, while reducing measurement burden., (© 2019 Annals of Family Medicine, Inc.)

We developed a prospective observational study, obtaining clinical and analytical data of patients admitted to the intensive care unit of the Hospital Reina Sofía, who required noninvasive ventilation, from January 1, 2013 to December 31, 2015. The main objective was to determine the 90-day mortality in these patients and conditions, who required noninvasive ventilation as treatment for acute respiratory failure and who developed acute kidney injury. Acute renal failure was defined as an increase in serum creatinine > 0.3 mg/dl at 48 hours with respect to the baseline. The patients were followed for 90 days. We analyzed 221 patients, 65 (29.4%) presented acute kidney injury and 156 (70.6%) normal renal function. Overall mortality at 90 days was 44 (19.9%). In the group of acute kidneys injury, it was 33 (51.6%), being 11 (7.1%) in patients without acute kidney injury (RR 7.340, 95% CI: 3.974-13.559, p < 0.001). Hospital stay in days was 24.2 ± 24.1 with acute kidney injury vs. 21.5 ± 0.7, p = 0.429; stay in the intensive care unit in days was 10.9 ± 14.4 with acute kidney injury vs. 7.3 ± 9.6, p = 0.357, and days of non-invasive ventilation 3.4 ± 3.0 with acute kidney injury vs. 2.7 ± 1.9, p = 0.569, in those patients not affected by the presence of acute kidney injury. In conclusion, the presence of acute kidney injury is an independent factor of mortality in patients with acute respiratory failure requiring noninvasive ventilation.