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Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers.Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves.We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated.CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC.

Los organoides son estructuras miniaturizadas, generadas principalmente a partir de células madre pluripotentes inducidas, que se cultivan en el laboratorio conservando sus características innatas o adquiridas. Tienen el potencial de reproducir procesos de desarrollo biológico, modelar procesos patológicos que permitirán el descubrimiento de nuevos fármacos y propicien la medicina regenerativa. Sin embargo, estas experiencias requieren perfeccionamiento constante porque pueden haberse realizado variaciones en la constitución de estos órganos. Por ello, el presente artículo tiene como objetivo revisar la información actualizada sobre organoides y sus procesos experimentales básicos y recientes, empezando por la gastrulación, para tratar de imitar, en lo posible, la formación de las tres capas: ectodermo, mesodermo y endodermo, incluyendo los factores que intervienen en la inducción, diferenciación y maduración en la generación de estos organoides. Asimismo, el diseño y preparación de medios de cultivo altamente especializados que permitan obtener el órgano seleccionado con la mayor precisión y seguridad. Se realizó una búsqueda de artículos originales y de revisión publicados en PubMed, Nature y Science. Los artículos se seleccionaron por sus resúmenes y por su texto completo. Las conclusiones de este articulo destacan las ventajas futuras en el uso y aplicaciones de los organoides.

This research proposal aims at studying the development of social skills among high school students through a multidisciplinary program that incorporates physical education and socialization lessons. The study will pursue a multidisciplinary approach by incorporating physical education classes and sports on the one hand with education for social skills on the other. Are students who are active or even participate in physical education classes more prone to develop their social skills than students who do not take part, or tend to remain passive or in these classes? Social skills include students’ ability to develop social communication, cooperation in a teamwork, self-discipline, assertiveness and social adaptation skills as influenced by their level of activity in physical education and sports classes. Students are also engaged in reflexive sports mediation. Reflexive mediation takes place during or after a sport session, during which students reflect (discuss and analyze) about events that took place during the sports session, and whether the action and reaction could or should have been done differently.

The Association of American Medical Colleges described 13 Core Entrustable Professional Activities (EPAs) that graduating students should be prepared to perform under indirect supervision on day one of residency. Surgery program directors recently recommended entrustability in these Core EPAs for incoming surgery interns. We sought to determine if graduating students intending to enter surgery agreed they had the skills to perform these Core EPAs.Using de-identified, individual-level data collected from and about 2019 Association of American Medical Colleges Graduation Questionnaire respondents, latent profile analysis was used to group respondents based on their self-assessed Core EPAs skills' response patterns. Associations between intended specialty, among other variables, and latent profile analysis group were assessed using independent sample t -tests and chi-square tests and multivariable logistic regression methods.Among 12,308 Graduation Questionnaire respondents, latent profile analysis identified 2 respondent groups: 7,863 (63.9%) in a high skill acquisition agreement (SAA) group and 4,445 (36.1%) in a moderate SAA group. Specialty was associated with SAA group membership (plt; 0.001), with general surgery, orthopaedic surgery, and emergency medicine respondents (among others) overrepresented in the high SAA group. In the multivariable logistic regression models, each of anesthesiology, ophthalmology, pediatrics, psychiatry, and radiology (vs general surgery) specialty intention was associated with a lower odds of high SAA group membership.Graduating students' self-assessed Core EPAs skills were higher for those intending general surgery than for those intending some other specialties. Our findings can inform collaborative efforts to ensure graduates' acquisition of the skills expected of them at the start of residency.

With the increasing need for the incorporation of computer science (CS) concepts into elementary and secondary education, it is imperative that the teaching workforce is adequately prepared to ensure that instruction in CS is robust, relevant, and aligned with appropriate learning standards, where appropriate. This paper shares results from a recent survey administered to current computer science educators across the K-12 space in the state of New Jersey. Using these results and recent literature, the research distills actionable, assessed needs to guide the provision of professional learning to ensure that educators have the necessary tools and knowledge to ensure robust and equitable implementation of computer science education. Results point towards a need to expand the present understanding of computer science by effectively differentiating CS from technology-based instruction and addressing an overrepresentation of analytical content domains, reaffirm a commitment to equity by acknowledging the persistent gaps in participation of marginalized student groups, and critically examining when and where the use of technology is necessary for delivering CS instruction.

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí

IMPORTANCE: The administration of a fourth BNT162b2 COVID-19 vaccine dose was approved in Israel in December 2021 for individuals 60 years or older who were vaccinated with a third dose 4 months previously or earlier to control the substantial surge of the SARS-CoV-2 Omicron variant. Nonetheless, the association between receipt of the fourth dose and protection against infection remains elusive. OBJECTIVE: To determine the association of the fourth BNT162b2 dose with protection against SARS-CoV-2–related infections, hospitalizations, and deaths during the Omicron surge in long-term care facility (LTCF) residents. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted in Israel between January 10 and March 31, 2022 and included LTCF residents 60 years or older. EXPOSURES: Vaccination with the fourth dose of BNT162b2 vs 3 doses that were administered 4 months previously or earlier. MAIN OUTCOMES AND MEASURES: Cumulative incidences of SARS-CoV-2 infections, hospitalizations, and deaths during the Omicron surge. The follow-up was initiated more than 7 days after receipt of the fourth dose, which was matched to the follow-up initiation date of those who had received 3 doses of vaccine in each facility. We obtained hazard ratios and 95% confidence intervals from multivariable Cox regression models. RESULTS: The data of 43 775 residents (mean [SD] age, 80.1 [9.4] years; 29 679 women [67.8%]) were analyzed, of whom 24 088 (55.0%) and 19 687 (45.0%) received the fourth and third dose (4 months previously or earlier), respectively. The median follow-up time was 73 days (4-dose group: IQR, 6 days; 3-dose group: IQR, 56 days). More than 7 days postvaccination with the fourth dose, SARS-CoV-2 infection was detected among 4058 fourth-dose vs 4370 third-dose recipients (cumulative incidence, 17.6% vs 24.9%). The corresponding incidences of hospitalizations for mild-to-moderate COVID-19, severe illness, and mortality were 0.9% and 2.8%, 0.5% and 1.5%, and 0.2% and 0.5%, respectively. The adjusted protections were 34% (95% CI, 30%-37%), 64% (95% CI, 56%-71%), and 67% (95% CI, 57%-75%) against overall infection, hospitalizations for mild-to-moderate illness, and severe illness, respectively, and 72% (95% CI, 57%-83%) against related deaths. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that receipt of a fourth BNT162b2 dose conferred high protection against COVID-19 hospitalizations and deaths among LTCF residents during a substantial Omicron variant surge, but protection was modest against infection. These findings are relevant to the control of COVID-19 pandemic globally, especially among the population of LTCFs.

We present efficient analytical gradients of property-based diabatic states and couplings using a Lagrangian formalism. Unlike previous formulations, the method achieves a computational scaling that is independent of the number of adiabatic states used to construct the diabats. The approach is generalizable to other property-based diabatization schemes and electronic structure methods as long as analytical energy gradients are available and integral derivatives with the property operator can be formed. We also introduce a scheme to phase and reorder diabats to ensure their continuity between molecular configurations. We demonstrate this for the specific case of Boys diabatic states obtained from state-averaged complete active space self-consistent field electronic structure calculations with GPU acceleration in the TeraChem package. The method is used to test the Condon approximation for the hole transfer in an explicitly solvated model DNA oligomer.

Rare earth elements (REEs) play a crucial role in manufacturing high-tech products and developing various technologies, including those related to the transition to clean energy. Consequently, there has been a significant increase in REE production, which has the potential to contribute to the contamination of groundwater systems that are highly susceptible to industrial pollution. Groundwater REE contamination, specifically in coastal aquifer systems, could affect large populations that rely on that water for drinking and domestic use. In this study, we conducted column transport experiments using five representative coastal aquifer materials to understand better the mechanisms that control REE mobility and retention in coastal aquifers. These experiments were conducted by adding humic acid (HA) to the REE solution under fresh and brackish water conditions. The REEs were shown to be most mobile in sand samples, followed by two types of low-calcareous sandstone and one type of high-calcareous sandstone, and least mobile in red loamy sand. The mobility of REEs, found in solution primarily as REE-HA complexes, was controlled mainly by the retention of HA, which increases with ionic strength. Furthermore, it was found that the presence of carbonate and clay minerals reduces REE mobility due to enhanced surface interactions. The enrichment of middle-REE (Nd-Gd) was observed in the sand samples, while heavy-REE (Tb-Lu) enrichment was observed in the calcareous sandstones and the red loamy sand. This change in REE pattern likely originates from the release of carbonate ions from the carbonate minerals that stabilize heavy-REEs compared to middle-REEs.

Objectives: Defining how pregnant women respond to SARS-CoV-2 infection and vaccination is critical to optimize vaccination strategies that protect mother and infant at the epidemic. This study aimed to compare Anti-SARS-CoV-2-spike IgG of vaccinated vs. infected women and to determine the optimal timing of maternal vaccination during pregnancy at the time of epidemic. Study design: We collected maternal/cord blood at delivery (October 2021-March 2022) and measured Anti-SARS-CoV-2-spike-IgG geometric mean concentrations (IgG-GMC), using a quantitative immunoassay. We compared groups according to timing and number of doses and correlated maternal and fetal IgG levels. We described the proportion of women with IgG-levels above the 150 AU/ml positivity threshold according to the timing of infection/vaccination and performed a sub-analysis for maternal IgG-GMC levels pre and during the Omicron wave. Results: We included 238 vaccinated women, 125 who received two doses and 113 three; and 48 unvaccinated infected women. All groups infected/vaccinated in the second or third-trimester had an IgG-GMC above the positivity threshold. Third-trimester vaccination (second/third dose) resulted in higher maternal and cord-blood IgG-GMC compared to the second-trimester (maternal-IgG:10232 vs. 4325 AU/mL,ptwo doses and their newborns had IgG-levels above the positivity threshold at all time points. In vaccinated-women, there were higher maternal IgG-GMC levels during the Omicron wave than pre-Omicron. Conclusions: At the time of epidemic, receiving an additional COVID-19 vaccine dose in the third-trimester resulted in a higher IgG-GMC compared to the second-trimester. Relatively higher levels of maternal and cord IgG-GMC were achieved following vaccination than infection. Women infected during or before the first-trimester might benefit from an additional third-trimester dose to prevent peripartum infection and to passively immunize their newborn. The higher levels of maternal IgG-GMC in the Omicron period are suggestive of hybrid immunity.

BackgroundWe aimed to determine vaccine hesitancy and the main barriers associated with the 2019 novel coronavirus, SARS-CoV-2 (COVID-19) vaccination among families of children diagnosed with food/drug/environmental allergies.MethodsBetween May and June 2021, we approached 146 families seen at the outpatient allergy clinic at the Montreal Children's Hospital and a community allergy practice were invited to complete an anonymous online survey on COVID-19 and vaccination attitudes and behaviour. Uni and multivariable logistic regressions were compared to estimate factors associated with vaccine hesitancy.ResultsAmong all patients, 24.1% reported vaccine hesitancy. The large majority of parents (95.2%) believed that vaccines work. The most common barrier to vaccination was fear of adverse side effects (57.0%). One-third of participants (31.5%) reported that a history of food, venom and drug allergy was a contraindication for COVID-19 vaccination. Fifty-nine (60.8%) participants stated that the dissemination of additional information would increase their willingness to be vaccinated. Most (96.9%) parents reported that their children's vaccinations were up to date. Hesitant families were more likely to be parents of children aged 6–10 years, be of Asian descent, report that mRNA vaccines are riskier than traditional vaccines, and report that the vaccine should not be given if the child has a history of allergic reaction to vaccines.ConclusionVaccine hesitancy exists mainly among certain ethnic groups and families with young children. Allergies to food, venom and drug allergy are commonly perceived as contraindications for COVID-19 vaccination. Knowledge translation activities addressing parental concerns will help increase vaccination rates.

We determined whether COVID-19 vaccination was associated with Quality of Life (QoL) changes among individuals previously infected with SARS-CoV-2 in Israel. Using a validated questionnaire, we collected information about socio-demographics, SARS-CoV-2 infection, COVID-19 vaccination and QoL (using the EQ-5D-5L tool) 3–18 months post-infection among adults tested for SARS-CoV-2 by polymerase chain reaction in Northern Israel between March 2020-June 2022. We compared post-COVID QoL between those vaccinated against COVID-19 at the time of infection and those not, using an adjusted linear regression model, stratified by time elapsed since infection. Of 951 participants, mean EQ-5D Utility Index (EQ-5D UI) was 0·82 (SD = 0·26) and 0·83 (SD = 0·25) among the 227 double and 250 triple vaccinated respectively, compared to 0·76 (SD = 0·33) among those who received 0 dose (n = 243). In the adjusted model, previously infected individuals vaccinated with two or more doses reported a 0·05 increase in QoL score post- infection (CI = 0·01–0·10, p = 0·02) compared with those unvaccinated when infected. No association between vaccination and QoL was detected beyond 12 months post-infection. Vaccination with two or more doses of COVID19 vaccine, or at least the BNT162b2 vaccine, may partly mitigate QoL losses associated with post-acute COVID-19 symptoms, at least in the first 12 months post-infection.

Effective leaders in healthcare settings create a motivating work environment, initiate changes in practice, and facilitate interdisciplinary collaboration to advance patient-centered care. Health professionals in cancer education need leadership development to meet the continued rise in cancer cases and to keep up with the rapid biomedical and technological advances in global cancer care. In addition, leadership development in cancer education supports interprofessional collaboration, optimizes patient engagement, and provides mentorship opportunities necessary for career advancement and skill development. The identified benefits from leadership development in cancer education led to the creation of an interactive pilot leadership workshop titled "Essential Skills in Cancer Education: Leadership, Leading, and Influencing Change in Cancer Education," held at the International Cancer Education Conference in October 2020. The workshop was led by global leaders in cancer education and utilized lectures, mentorship opportunities, interactive case studies, and individual learning projects to develop leadership skills in multidisciplinary oncology professionals. Fifteen attendees from diverse educational backgrounds and levels of experience participated in the virtual leadership workshop and mentorship program. Following the workshop, participants reported an increase in knowledge regarding how to use different leadership styles, initiate changes in practice, and apply leadership skills in their career development and at their institutions. The feedback received from participants through post-workshop evaluations was overall positive and demonstrated an interest for more leadership development opportunities in cancer education. This pilot workshop shows that leadership is a valuable and teachable skill that will benefit both healthcare professionals and patients in the field of cancer education.

To evaluate the associations of peri-operative neutrophil-to-lymphocyte ratio (NLR) and change in NLR with survival after radical cystectomy.We retrospectively reviewed a multicentre cohort of patients with bladder cancer who underwent radical cystectomy between 2010 and 2020. Preoperative NLR, postoperative NLR, delta-NLR (postoperative minus preoperative NLR) and NLR change (postoperative divided by preoperative NLR) were calculated. Patients were stratified based on elevation of preoperative and/ or postoperative NLR above the median values. Multivariable Cox regression models were used to evaluate the associations of peri-operative NLR and NLR change with survival.The study cohort included 346 patients with a median age of 69 years. The median (interquartile range) preoperative NLR, postoperative NLR, delta-NLR and NLR change were 2.55 (1.83, 3.90), 3.33 (2.21, 5.20), 0.43 (-0.50, 2.08) and 1.2 (0.82, 1.96), respectively. Both preoperative and postoperative NLR were elevated in 110 patients (32%), 126 patients (36%) had an elevated preoperative or postoperative NLR, and 110 patients (32%) did not have an elevated NLR. On multivariable analysis, increased preoperative and postoperative NLR were significantly associated with decreased survival. While delta-NLR and NLR change were not associated with outcome, patients with elevations in both preoperative and postoperative NLR had the worst overall (hazard ratio [HR] 2.97, 95% confidence interval [CI] 1.78, 4.95; P 0.001) and cancer-specific survival rates (HR 2.41, 95% CI 1.3, 4.4; P = 0.004).Preoperative and postoperative NLR are significant predictors of survival after radical cystectomy; patients in whom both NLR measures were elevated had the worst outcomes. Future studies should evaluate whether an increase in NLR during long-term follow-up may precede disease recurrence.

Nucleus accumbens (NAc) neurons integrate excitatory inputs from cortical and limbic structures, contributing to critical cognitive functions, including decision-making. As these afferents mature from adolescence through adulthood, incoming signals to the NAc may summate differently between age groups. Decision-making evaluates both reward and risk before action selection, suggesting an interplay between reward- and risk-related circuits. Medial orbitofrontal cortex (MO)-NAc circuits permit risk assessment behaviors and likely underlie risk information incorporation. As adolescents make reward-centric choices regardless of risk, we hypothesized the impact of MO activity alters reward-related NAc circuits in an age-dependent manner. To test this hypothesis, we used single-unit electrophysiology to measure MO train stimulation’s effect on reward-related pathways, specifically the basolateral amygdala (BLA)-NAc circuit, in adult and adolescent rats. MO train stimulation altered the strength but not the timing of BLA–NAc interactions in a frequency-dependent manner. In adults, MO train stimulation produced a frequency-dependent, bidirectional effect on BLA-evoked NAc AP probability. Contrastingly, MO train stimulation uniformly attenuated BLA-NAc interactions in adolescents. While the mature MO can govern reward-related circuits in an activity-dependent manner, perhaps to adapt to positive or negative decision-making outcomes, the adolescent MO may be less able to bidirectionally impact reward-related pathways resulting in biased decision-making.

INTRODUCTION: Hypoglycaemia is a significant burden to people living with diabetes and an impediment to achieving optimal glycaemic outcomes. The use of continuous glucose monitoring (CGM) has improved the capacity to assess duration and level of hypoglycaemia. The personal impact of sensor-detected hypoglycaemia (SDH) is unclear. Hypo-METRICS is an observational study designed to define the threshold and duration of sensor glucose that provides the optimal sensitivity and specificity for events that people living with diabetes experience as hypoglycaemia. METHODS: We will recruit 600 participants: 350 with insulin-treated type 2 diabetes, 200 with type 1 diabetes and awareness of hypoglycaemia and 50 with type 1 diabetes and impaired awareness of hypoglycaemia who have recent experience of hypoglycaemia. Participants will wear a blinded CGM device and an actigraphy monitor to differentiate awake and sleep times for 10 weeks. Participants will be asked to complete three short surveys each day using a bespoke mobile phone app, a technique known as ecological momentary assessment. Participants will also record all episodes of self-detected hypoglycaemia on the mobile app. We will use particle Markov chain Monte Carlo optimization to identify the optimal threshold and duration of SDH that have optimum sensitivity and specificity for detecting patient-reported hypoglycaemia. Key secondary objectives include measuring the impact of symptomatic and asymptomatic SDH on daily functioning and health economic outcomes. ETHICS AND DISSEMINATION: The protocol was approved by local ethical boards in all participating centres. Study results will be shared with participants, in peer-reviewed journal publications and conference presentations., Hypo-RESOLVE has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777460

AIM/HYPOTHESIS: The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS: A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

Abnormal fear and anxiety can manifest as psychiatric disorders. The bed nucleus of the stria terminalis (BNST) is implicated in sustained responding to, or anticipation of, an aversive event which can be expressed as anticipatory anxiety. The BLA is also active during anticipatory anxiety and sends projections to the BNST. However, little is known about the role for BLA neurons that project to BNST (BLA-BNST) in anticipatory anxiety in rodents. To address this, we tested whether chemogenetic inactivation of the BLA-BNST pathway attenuates sustained conditioned responses produced by anticipation of an aversive stimulus. For comparison, we also assessed BLA-BNST inactivation during social interaction, which is sensitive to unlearned anxiety. We found that BLA-BNST inactivation reduced conditioned sustained freezing and increased social behaviors, but surprisingly, only in males. To determine whether sex differences in BLA-BNST neuronal activity contribute to the differences in behavior, we usedin vivoandex vivoelectrophysiological approaches. In males, BLA-BNST projection neurons were more active and excitable, which coincided with a smaller after-hyperpolarization current (IAHP) compared with other BLA neurons; whereas in females, BLA-BNST neurons were less excitable and had largerIAHPcompared with other BLA neurons. These findings demonstrate that activity of BLA-BNST neurons mediates conditioned anticipatory anxiety-like behavior in males. The lack of a role of BLA-BNST in females in this behavior, possibly because of low excitability of these neurons, also highlights the need for caution when generalizing the role of specific neurocircuits in fear and anxiety.SIGNIFICANCE STATEMENTAnxiety disorders disproportionately affect women. This hints toward sex differences within anxiety neurocircuitry, yet most of our understanding is derived from male rodents. Furthermore, debilitating anticipation of adverse events is among the most severe anxiety symptoms, but little is known about anticipatory anxiety neurocircuitry. Here we demonstrated that BLA-BNST activity is required for anticipatory anxiety to a prolonged aversive cue, but only in males. Moreover, BLA-BNST neurons are hypoactive and less excitable in females. These results uncover BLA-BNST as a key component of anticipatory anxiety circuitry, and cellular differences may explain the sex-dependent role of this circuit. Uncovering this disparity provides evidence that the assumed basic circuitry of an anxiety behavior might not readily transpose from males to females.

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

Both analytical and numerical methods have proven to be suitable for describing radiation transport and interactions. The standard Boltzmann formalism derived from statistical mechanics requires to be specifically re-formulated to account for the interactions with external electromagnetic fields. Verifying the proper implementation of the external electromagnetic field coupling in Monte Carlo simulation codes is a key issue to confirm the feasibility of using such a tool to describe complex applications like image-guided radiotherapy based on integrating magnetic resonance scanner to the radiant field of ionizing radiation along with the subsequent dosimetric effects. The present work reports on the feasibility and reliability of the Monte Carlo FLUKA and PENELOPE main codes to assess electron trajectory in presence of strong magnetic fields. The obtained results confirm the ability of FLUKA and Penelope to model the alterations in the electron trajectories due to external magnetic field effects, also demonstrating an excellent agreement between both codes and with the theoretical-analytical model.

Aims/hypothesis Problematic hypoglycaemia still complicates insulin therapy for some with type 1 diabetes. This study describes baseline emotional, cognitive and behavioural characteristics in participants in the HARPdoc trial, which evaluates a novel intervention for treatment-resistant problematic hypoglycaemia. Methods We documented a cross-sectional baseline description of 99 adults with type 1 diabetes and problematic hypoglycaemia despite structured education in flexible insulin therapy. The following measures were included: Hypoglycaemia Fear Survey II (HFS-II); Attitudes to Awareness of Hypoglycaemia questionnaire (A2A); Hospital Anxiety and Depression Index; and Problem Areas In Diabetes. k-mean cluster analysis was applied to HFS-II and A2A factors. Data were compared with a peer group without problematic hypoglycaemia, propensity-matched for age, sex and diabetes duration (n = 81). Results The HARPdoc cohort had long-duration diabetes (mean ± SD 35.8 ± 15.4 years), mean ± SD Gold score 5.3 ± 1.2 and a median (IQR) of 5.0 (2.0–12.0) severe hypoglycaemia episodes in the previous year. Most individuals had been offered technology and 49.5% screened positive for anxiety (35.0% for depression and 31.3% for high diabetes distress). The cohort segregated into two clusters: in one (n = 68), people endorsed A2A cognitive barriers to hypoglycaemia avoidance, with low fear on HFS-II factors; in the other (n = 29), A2A factor scores were low and HFS-II high. Anxiety and depression scores were significantly lower in the comparator group. Conclusions/interpretation The HARPdoc protocol successfully recruited people with treatment-resistant problematic hypoglycaemia. The participants had high anxiety and depression. Most of the cohort endorsed unhelpful health beliefs around hypoglycaemia, with low fear of hypoglycaemia, a combination that may contribute to persistence of problematic hypoglycaemia and may be a target for adjunctive psychological therapies. Graphical abstract

Este articulo explora, a través de algunos fragmentos del entramado históricos de los Tupinambá de Olivença, las prácticas de autonomía, las traducciones cosmopolíticos y la producción de una contra-antropología Tupinambá, producidas en la trama de su movimiento indígena a lo largo de la lucha por la demarcación de la Tierra Indígena y la retomada del territorio. Estos fragmentos escapan, sin embargo, de la captura que provocan esas categorías de cuño analítico, conectándose unos a los otros, motivo por el cual uso la metáfora del entramado de un tejido para relatar los entrelazamientos de las relaciones producidas por los parientes Tupinambá. Es por este motivo que a lo largo del texto al hablar de autonomía, el relato nos lleva a entender su curso junto al de las retomadas; por su parte, las retomadas se explica en la autonomía lograda por las relaciones acumuladas en los enfrentamiento cosmopolíticos entre mundos que se anulan en la lucha por el territorio; un enfrentamiento, que a su vez, se materializa en la alteridad que se produce por los espacios vividos donde se garantizan las prácticas autonómicas. Entrelazamientos que formando un entramado de relaciones ubicuas el cual soporta la lucha de los Tupinambá de Olivença.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease that typically affects middle-aged men with ulcerative colitis (UC). However, recent studies point out to epidemiological changes. Our aim was to determine if the epidemiology, clinical course and outcome of patients with PSC followed at a reference hepatology center resemble what is described in the literature.Retrospective search of patients with a diagnosis of PSC treated in our center between 2000 and 2019.Cohort of 55 patients (mean age: 37 years), 44% women. Most were large duct type (79%). Most diagnoses were made after 2011. At time of diagnosis, 63% of patients were asymptomatic. The median time from suspicion to diagnosis was 2 years. After a mean follow-up time of 7 years, one third developed cirrhosis, and 25% required liver transplantation (LT); among these, the disease recurred in almost half. Inflammatory bowel disease (IBD) was present in 45%, especially UC. Although statistical significance was not reached, PSC in women was characterized by higher rate of asymptomatic presentation and more frequent association with UC versus other forms of IBD. Women also had more frequently cirrhosis at diagnosis and required LT more often than men.The epidemiology of PSC is changing. The number of women affected is greater than what was expected from the literature, with a recent increase in incidence. There seems to be differences between sexes in the form of presentation and disease course that should be confirmed in subsequent studies.

Access to genetic testing in the field of cancer is becoming increasingly important as discoveries are made in basic, translational, and clinical research. It has thus been possible to demonstrate that common cancers whose diagnosis was based essentially on anatomical location and anatomical pathology in the past, were in fact a collection of rare diseases defined by molecular alterations. These alterations, such as mutations, amplification, or fusion, require the use of sophisticated tools such as Next Generation Sequencing (NGS). Beyond a better characterisation of diseases, this molecular analysis allows the definition of targets accessible to specific drugs, which constitutes the basis of personalised medicine in cancerology. Even if the clinical evaluation of certain molecules has not always been successful, the improved survival of lung cancer patients, for example, confirms the validity of this concept. The problem is now access to these tests, which are not covered by effective specific mechanisms as are expensive molecules or implantable devices, which leads to inequalities in the treatment of cancers on French territory, posing a real ethical problem., L’accès aux tests génétiques dans le domaine de la cancérologie prend de plus en plus d’importance au fur et à mesure des découvertes de la recherche fondamentale, translationnelle et clinique. Il a ainsi été possible de démontrer que des cancers fréquents dont le diagnostic reposait essentiellement sur la localisation anatomique et l’examen anatomopathologique étaient en fait une collection de maladies plus rares définies par des altérations moléculaires. Ces altérations de type mutations, amplification, ou fusion nécessitent le recours à des outils sophistiqués tels que le next generation sequencing (NGS). Au-delà d’une caractérisation meilleure des maladies, cette analyse moléculaire permet la définition de cibles accessibles à des médicaments spécifiques ce qui constitue la base de la médecine personnalisée en cancérologie. Même si l’évaluation clinique des certaines molécules n’a pas toujours été couronnée de succès, l’amélioration de la survie des patients ayant un cancer du poumon par exemple confirme tout le bien-fondé de ce concept. Le problème est donc maintenant l’accès à ces tests qui ne sont pas pris en charge par des mécanismes précis efficaces comme le sont les molécules onéreuses ou les dispositifs implantables ce qui aboutit à des inégalités de prise en charge des cancers sur le territoire français posant un véritable problème éthique.

Resumen Introduccion y objetivos La colangitis esclerosante primaria (CEP) es una enfermedad hepatica colestasica rara, que tipicamente afecta a varones de mediana edad con colitis ulcerosa (CU). No obstante, estudios recientes apuntan a cambios epidemiologicos. Nuestro objetivo es determinar si la epidemiologia, presentacion clinica y curso evolutivo de pacientes con CEP seguidos en un centro de referencia se asemejan a lo descrito en la literatura. Pacientes y metodos Busqueda retrospectiva de pacientes con diagnostico de CEP atendidos en nuestro centro entre los anos 2000 y 2019. Resultados Cohorte de 55 pacientes (media de edad: 37 anos), el 44% mujeres, afectos de CEP, el 79% de ducto grande. Casi dos tercios fueron diagnosticados a partir de 2011. En el momento del diagnostico, un 63% de los pacientes se encontraba asintomatico. La mediana de tiempo desde la sospecha hasta el diagnostico fue de 2 anos. Un 34% desarrollo cirrosis en el seguimiento, y un 25% requirio trasplante hepatico (TH) tras una media de tiempo de 7 anos; entre estos, la enfermedad recurrio en un 46%. Un 45% presentaba una enfermedad inflamatoria intestinal (EII), sobre todo CU. Si bien no se alcanzo significacion estadistica, la CEP en mujeres se caracterizo por mayor tasa de presentacion asintomatica, mayor asociacion con CU frente a otras formas de EII, asi como cirrosis al diagnostico y necesidad de TH con mayor frecuencia que los varones. Conclusiones La epidemiologia de la CEP esta cambiando. El numero de mujeres afectas es mayor al descrito previamente, objetivandose un aumento reciente de la incidencia. Podrian existir diferencias entre sexos en la forma de presentacion y evolucion que deberan confirmarse en estudios posteriores.

International audience; Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.