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This report describes the case of a frail 36-year-old patient who underwent an endovascular treatment of a right subclavian artery pseudoaneurysm (SAP) associated with an arteriovenous fistula secondary to a traumatic central venous catheter insertion. The deployment of a covered stent from the innominate to the right common carotid artery combined with coiling of the SAP and the internal mammary artery was performed. Two additional covered stents were deployed from the vertebral artery to the distal subclavian artery to preserve right upper extremity circulation. This case highlights the feasibility of an endovascular treatment of a complex SAP in a candidate unsuitable for open surgery.

Background: Certified peer recovery specialists (CPRS) and licensed clinical social workers (LCSWs) can facilitate substance use disorder (SUD) treatment engagement for emergency department (ED) patients at risk for overdose. Predictors of treatment engagement after such behavioral services are unknown. Methods: This secondary analysis included Rhode Island ED patients at high risk for opioid overdose participating in a randomized controlled trial comparing the effectiveness of CPRS and LCSWs services (2018–2021). SUD treatment engagement within 90 days post-discharge was identified using statewide administrative data. Potential predictors were obtained from baseline questionnaires. Classification and regression trees (CART) were used to identify predictors of treatment engagement. Results: In the ED, 323 and 325 participants received CPRS and LCSWs services, respectively, among whom 141 (43.7 %) and 137 (42.2 %) engaged in SUD treatment within 90 days post-discharge. For the CPRS group, predictors of treatment engagement included unhealthy alcohol use, prescription opioid or benzodiazepine use in past 6 months, and lifetime history of: unstable housing, barriers to treatment, bipolar disorder diagnosis, addiction treatment, and recovery services. In the LCSW group, predictors included health insurance, current pain, opioid overdose in past year, and lifetime history of anxiety disorder diagnosis and mental illness treatment. However, CART had low predictive accuracy (CPRS: 60.9 %, LCSW: 54.8 %). Conclusions: Among ED patients at high risk of opioid overdose receiving behavioral services, 90-day SUD treatment engagement was high. Sociobehavioral and clinical patient characteristics did not accurately predict treatment engagement. Behavioral services should be offered to all ED patients at high risk of opioid overdose.

Introduction: The use of race in clinical risk prediction tools may exacerbate racial disparities in healthcare access and outcomes. This study quantified the number of individuals reclassified for primary prevention of cardiovascular disease owing to a change in their race alone on the basis of a commonly used risk prediction tool. Methods: This is a cross-sectional analysis of individuals aged 40–75 years without a history of cardiovascular events, diabetes, or other high-risk features using the 2005–2018 National Health and Nutritional Examination Survey. Authors compared atherosclerotic cardiovascular disease risk scores using the American Heart Association/American College of Cardiology equation recommended for White individuals or individuals of other races with that recommended for Black individuals. Results: A total of 2,946 White individuals; 1,361 Black individuals; and 2,495 individuals of other races were included in the analysis. Using the American Heart Association/American College of Cardiology equation, the mean 10-year atherosclerotic cardiovascular disease risk was 5.80% (95% CI=5.54, 6.06) for White individuals, 7.04% (956% CI=6.69, 7.39) for Black individuals, and 4.93% (95% CI=4.61, 5.24) for individuals of other races. When using the American Heart Association/American College of Cardiology equation designated for the opposite race (White/other race versus Black), the mean atherosclerotic cardiovascular disease risk score increased by 1.02% (95% CI=0.90, 1.13) for White individuals, decreased by 1.82% (95% CI= −1.67, −1.96) for Black individuals, and increased by 0.98% (95% CI=0.85, 1.10) for individuals of other races. When using clinical atherosclerotic cardiovascular disease categories of 10%, 16.93% of all individuals were reclassified when using the American Heart Association/American College of Cardiology's equation designated for the opposite race. Conclusions: Changing race within a commonly used cardiovascular risk prediction tool results in significant changes in risk classification among eligible White and Black individuals in the U.S.

Summary: Mesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis, encompassing cross-presentation assays and molecular profiling, among other cellular investigations, elucidated A1’s impact on endosomal escape, reactive oxygen species production, and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma, we observe significant therapeutic potency, particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall, this study introduces a strong target for developing an antigen-adaptable vaccination platform, capable of synergizing with immune checkpoint blockers to trigger tumor regression, supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine.

Background: Oil and gas exploitation can release several contaminants in the environment, including trace elements, with potentially deleterious effects on exposed pregnant individuals and their developing fetus. Currently, there is limited data on pregnant individuals’ exposure to contaminants associated with oil and gas activity. Objectives: We aimed to 1) measure concentrations of trace elements in biological and tap water samples collected from pregnant individuals participating in the EXPERIVA study; 2) compare with reference populations and health-based guidance values; 3) assess correlations across matrices; and 4) evaluate associations with the density/proximity of oil and gas wells. Methods: We collected tap water, hair, nails, and repeated urine samples from 85 pregnant individuals, and measured concentrations of 21 trace elements. We calculated oil and gas well density/proximity (Inverse Distance Weighting [IDW]) for 4 buffer sizes (2.5 km, 5 km, 10 km, no buffer). We performed Spearman’s rank correlation analyses to assess the correlations across elements and matrices. We used multiple linear regression models to evaluate the associations between IDWs and concentrations. Results: Some study participants had urinary trace element concentrations exceeding the 95th percentile of reference values; 75% of participants for V, 29% for Co, 22% for Ba, and 20% for Mn. For a given trace element, correlation coefficients ranged from −0.23 to 0.65 across matrices; correlations with tap water concentrations were strongest for hair, followed by nails, and urine. Positive (e.g., Cu, Cr, Sr, U, Ga, Ba, Al, Cd) and negative (e.g., Fe) associations were observed between IDW metrics and the concentrations of certain trace elements in water, hair, and nails. Significance: Our results suggest that pregnant individuals living in an area of oil and gas activity may be more exposed to certain trace elements (e.g., Mn, Sr, Co, Ba) than the general population. Association with density/proximity of wells remains unclear.

Conservation initiatives led by Indigenous peoples are a relatively recent phenomenon gaining momentum around the world. Initiatives to establish Indigenous protected areas are also taking root in Canada. We studied the Akumunan Biodiversity Reserve (ABR) in the province of Quebec to assess (1) the approach followed by the Essipit Innu First Nation (EIFN) Band Council to implement the ABR; (2) the EIFN’s vision that led to the creation of the ABR; and (3) the role the EIFN would like to play in the governance of the ABR. Six focus groups conducted with 22 community members have shown that the process which led to the creation of the ABR was fraught with challenges. The EIFN’s vision for the ABR is holistic — “everything” must be protected to respect the memory of the Elders and ensure natural resource sustainability. To ensure the respect of this vision, the community wants to play a leading role in governing the ABR. The EIFN faced many challenges, notably administrative hurdles, opposition due to cultural and value differences, lack of long-term funding, and disregard for the relationship that Indigenous people have with the land. Respecting EIFN’s vision also demands that traditional activities on the land be allowed to continue in protected areas, in order to guarantee that the identity, culture, health, and well-being of current and future generations will be maintained. The community management model developed by the EIFN Band Council provides useful insights on the process leading to the acknowledgement of the Indigenous Protected and Conserved Area status. Moreover, it could be a source of inspiration for other Indigenous conservation projects.

Background: Substance use patterns are diverse, and multiple substances are often involved in fatal and nonfatal overdoses. Additionally, polysubstance use is associated with greater difficulty accessing and remaining in substance use disorder (SUD) treatment. The aim of this study was to identify substance use patterns and determine their association with SUD treatment engagement among emergency department (ED) patients at risk of opioid overdose. Methods: This was a sub-analysis of a randomized controlled trial comparing two behavioral interventions for individuals at two EDs in Rhode Island from 2018 to 2021. Past six-month substance use frequency for eight substances plus injection drug use was self-reported at trial enrollment, and SUD treatment engagement within 90 days after enrollment was obtained using administrative data linkages. Latent class analysis identified substance use patterns and multivariable log-binomial models estimated the association with SUD treatment engagement. Results: Among 607 participants, there were four substance use patterns: 1) low reported use (n = 295), 2) frequent injection and heroin use (n = 131), 3) high frequency broad polysubstance use (n = 62), and 4) low frequency broad polysubstance use (n = 119). Compared to participants with the low reported use pattern, those with the frequent injection and heroin pattern had a greater likelihood of SUD treatment engagement (adjusted risk ratio = 1.28; 95% confidence interval = 1.02–1.61). Conclusions: Distinct and meaningful polysubstance use patterns showed differential SUD treatment engagement after ED discharge. Nuanced relationships between substance use patterns and treatment highlight the necessity for tailored harm reduction, treatment, and recovery services.

Introduction: The cardiometabolic health status of Inuit in Nunavik has worsened in the last thirty years. The high concentrations of perfluoroalkyl acids (PFAAs) may be contributing to this since PFAAs have been linked with hypercholesterolemia, diabetes, and high blood pressure. The aim of this study was to examine the association between a PFAAs mixture and lipid profiles, Type II diabetes, prediabetes, and high blood pressure in this Inuit population. Methods: We included 1212 participants of the Qanuilirpitaa? 2017 survey aged 16–80 years. Two mixture models (quantile g-computation and Bayesian Kernel Machine Regression (BKMR)) were used to investigate the associations between six PFAAs (PFHxS, PFOS, PFOA and three long-chain PFAAs (PFNA, PFDA and PFUnDA)) with five lipid profiles and three cardiometabolic outcomes. Non-linearity and interaction between PFAAs were further assessed. Results: An IQR increase in all PFAAs congeners resulted in an increase in total cholesterol (β 0.15, 95% confidence interval (CI) 0.06, 0.24), low-density lipoprotein cholesterol (LDL) (β 0.08, 95% CI 0.01, 0.16), high-density lipoprotein cholesterol (HDL) (β 0.04, 95% CI 0.002, 0.08), apolipoprotein B-100 (β 0.03, 95% CI 0.004, 0.05), and prediabetes (OR 1.80, 95% CI 1.11, 2.91). There was no association between PFAAs and triglycerides, diabetes, or high blood pressure. Long-chain PFAAs congeners were the main contributors driving the associations. Associations were largely linear, and there was no evidence of interaction between the PFAAs congeners. Conclusions: Our study provides further evidence of increasing circulating lipids with increased exposure to PFAAs. The increased risk of prediabetes points to the influence of PFAAs on potential clinical outcomes. International regulation of PFAAs is essential to curb PFAAs exposure and related health effects in Arctic communities.

Objectives: Our objective is to determine if specific sociodemographic characteristics were associated with perceived drug-related discrimination among people who use drugs (PWUD) presenting for care in the emergency department (ED). Methods: We conducted a secondary analysis of data from the Navigator trial, a randomized control trial of two behavioral interventions in the ED for people at risk of an opioid overdose. Participants included adult patients presenting to two Rhode Island EDs. Eligible participants included those high risk for an opioid overdose, resided or received most of their healthcare in Rhode Island, and were able to provide consent. The primary outcome of this analysis was self-reported feelings of drug-related discrimination by the medical community. The independent variables of interest included race/ethnicity, gender identity, and sexual orientation. Log-binomial multivariable regression models were constructed with all three independent variables of interest and a selection of sociodemographic covariates. Results: Of 620 eligible participants, 251 (40.5%) reported ever experiencing drug-related discrimination in their lifetime. In the adjusted model, participants who identified as women and participants who identified as LGBQIA+ were more likely to report experiencing drug-related discrimination from the medical community in EDs. Racial/ethnic minority groups were less likely than White (non-Hispanic) participants to report drug-related discrimination. Discussion: In this study population, White participants reported more drug-related discrimination than their minority counterparts, although female and LGBQIA+ patients reported more discrimination. Future studies should further assess the significance of these intersecting identities on self-reported discrimination. This knowledge could improve ED-based interventions, policies, and services for PWUD.

The use of transcatheter edge-to-edge mitral valve repair (TEER) in symptomatic patients with severe mitral regurgitation (MR) has dramatically increased over the last few years. Current guidelines consider TEER as a reasonable option in symptomatic patients with primary or chronic secondary severe MR with high or prohibitive surgical risk and favorable anatomy. However, several anatomical and morphological mitral features have restricted the use of this mini-invasive technique in its early experience. The latest fourth generation (G4) of the MitraClip system has been recently introduced and includes the possibility of independent leaflet grasping and 4 different sizes. This technical update offers the possibility of selecting and combining multiple devices for complex mitral valve anatomies and challenging procedures, which helps expand the applications of TEER. The present review describes the potential advantages and the help of the MitraClip G4 devices to overcome various anatomic and morphologic issues in challenging cases with complex primary and secondary MR procedures.

In the immersive environment of an online serious video game designed to depict social norms about excessive alcohol consumption, this study examines the effects of real-world and virtual-world social norms on alcohol use outcomes, centering on the persuasive elements of the One Shot game and its social psychological effects. This study implements a one-group, pretest-posttest, quasi-experimental design. Using a national sample of young adults aged 21–25 (N = 550) who reported recent binge drinking, OLS regression analyses documented that virtual-world norms were more predictive of alcohol-related outcomes than real-world norms. Specifically, virtual-world descriptive norms paired with severe consequences of hazardous drinking predicted improvements from pre-game to post-game in drinking refusal self-efficacy and attitudes toward drinking. Likewise, virtual-world social disapproval had a similar effect on drinking refusal self-efficacy, but not on attitudes toward drinking. Neither measure of virtual-world social norms had a significant effect on changes in intention to drink less from pre-game to post-game. Real-world descriptive norms and social disapproval had no significant effects on any of the alcohol use outcomes. Each of the three alcohol use outcomes improved significantly from pre-game to post-game. Implications for norms-based research and online serious video games are discussed.

Background: The blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in some cardiovascular and lung diseases. Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with increased inflammation. Although PAH exhibits a higher prevalence among women, men have a poorer prognosis. We investigated the NLR as an independent predictor of transplant-free survival in PAH. Methods: We performed a retrospective analysis of 78 PAH patients from the Quebec PAHBiobank (71% female). We used univariate and multivariate (adjusted for age, sex, renal function, and disease severity) Cox regression analyses to assess the relationship between the NLR and transplant-free survival, in the whole sample, and according to sex. The NLR was categorized as high (≥ 4.8) or low (

Two types of early childhood hyperkalemia had been recognized, according to the presence or absence of urinary salt wasting. This condition was attributed to a maturation disorder of aldosterone receptors and is characterized by sustained hyperkalemia, hyperchloremic metabolic acidosis (MA) due to reduced ammonium urinary excretion and bicarbonate loss, and normal creatinine with growth delay. We present 3 patients of the type without salt wasting, which we will call transient early-childhood hyperkalemia (TECHH) without salt wasting, and discuss its physiopathology according to new insights into sodium and potassium handling by the aldosterone in distal nephron. In 3 children from 30 to 120-day-old admitted with bronchiolitis and growth delay hyperkalemia was found in routine laboratory. Further studies revealed a normal creatinine with inappropriately normal or low fractional excretion (FE) of potassium, accompanied by inadequately normal serum aldosterone and plasma renin activity for their higher plasma potassium levels, but without urine salt wasting. They also presented hyperchloremic MA with FE of bicarbonate 0.58%–2.2%, positive urinary anion gap during MA and normal ability to acidify the urine. Based on these findings a diagnosis of TECHH without salt wasting was made and they were treated sodium bicarbonate and hydrochlorothiazide with favorable response. The condition was transient in all cases leading to treatment discontinuation. Given that TECCH without salt wasting is a tubular disorder of transient nature with mild symptoms; it must be keep in mind in the differential diagnosis of hyperkalemia in young children. Resumen: Se reconocen dos variedades de hiperpotasemia temprana de la infancia (del inglés Early childhood hyperkalemia) según la presencia o no de pérdida salina urinaria. Se trata de una entidad atribuida a un desorden madurativo en los receptores de aldosterona caracterizada por hiperpotasemia, acidosis metabólica (AM) hiperclorémica por diminución de la eliminación de amonio y bicarbonaturia, y creatinina normal con retraso de crecimiento. Presentamos 3 pacientes de la forma con ausencia de pérdida salina, a la que denominaremos hiperpotasemia transitoria del lactante (HTL) sin pérdida salina, y discutimos su fisiopatología en relación a los nuevos conocimientos en el manejo tubular del sodio y el potasio por la aldosterona. En 3 pacientes de entre 30 y 120 días de edad con bronquiolitis y retraso de crecimiento se encontró hiperpotasemia en laboratorio de rutina. Presentaban creatinina normal, excreción fraccionada (EF) de potasio disminuida o inapropiadamente normal junto a niveles de aldosterona y renina plasmática inadecuadamente normales para el estado de hiperpotasemia, pero sin pérdida salina. También cursaban con AM hiperclorémica con bicarbonaturia (EF bicarbonato 0,58%–2,2%), anión restante urinario positivo durante AM y capacidad normal para acidificar la orina. En base a estos hallazgos se diagnosticó HTL sin pérdida salina y se trataron con bicarbonato de sodio e hidroclorotiazida con buena respuesta. El cuadro fue transitorio permitiendo la suspensión del tratamiento. Dado que el HTL sin pérdida salina es un desorden tubular transitorio con síntomas leves debe tenerse presente en el diagnóstico diferencial de hiperpotasemia en niños pequeños.

Resumen: Se reconocen 2 variedades de hiperpotasemia temprana de la infancia (del inglés Early childhood hyperkalemia) según la presencia o no de pérdida salina urinaria. Se trata de una entidad atribuida a un desorden madurativo en los receptores de aldosterona caracterizada por hiperpotasemia, acidosis metabólica hiperclorémica por diminución de la eliminación de amonio y bicarbonaturia, y creatinina normal con retraso de crecimiento. Presentamos 3 pacientes de la forma con ausencia de pérdida salina, a la que denominaremos hiperpotasemia transitoria del lactante sin pérdida salina, y discutimos su fisiopatología con relación a los nuevos conocimientos en el manejo tubular del sodio y el potasio por la aldosterona. En 3 pacientes de entre 30 y 120 días de edad con bronquiolitis y retraso de crecimiento se encontró hiperpotasemia en laboratorio de rutina. Presentaban creatinina normal, excreción fraccionada de potasio disminuida o inapropiadamente normal junto a niveles de aldosterona y renina plasmática inadecuadamente normales para el estado de hiperpotasemia, pero sin pérdida salina. También cursaban con acidosis metabólica hiperclorémica con bicarbonaturia (excreción fraccionada de bicarbonato 0,58-2,2%), anión restante urinario positivo durante acidosis metabólica y capacidad normal para acidificar la orina. En base a estos hallazgos se diagnosticó hiperpotasemia transitoria del lactante sin pérdida salina y se trataron con bicarbonato de sodio e hidroclorotiazida con buena respuesta. El cuadro fue transitorio permitiendo la suspensión del tratamiento. Dado que la hiperpotasemia transitoria del lactante sin pérdida salina es un desorden tubular transitorio con síntomas leves debe tenerse presente en el diagnóstico diferencial de hiperpotasemia en niños pequeños. Abstract: Two types of early-childhood hyperkalemia had been recognized, according to the presence or absence of urinary salt wasting. This condition was attributed to a maturation disorder of aldosterone receptors and is characterized by sustained hyperkalemia, hyperchloremic metabolic acidosis due to reduced ammonium urinary excretion and bicarbonate loss, and normal creatinine with growth delay. We present three patients of the type without salt wasting, which we will call transient early-childhood hyperkalemia without salt wasting, and discuss its physiopathology according to new insights into sodium and potassium handling by the aldosterone in distal nephron. In three children from 30 to 120-day-old admitted with bronchiolitis and growth delay hyperkalemia was found in routine laboratory. Further studies revealed a normal creatinine with inappropriately normal or low fractional excretion of potassium, accompanied by inadequately normal serum aldosterone and plasma renin activity for their higher plasma potassium levels, but without urine salt wasting. They also presented hyperchloremic metabolic acidosis with fractional excretion of bicarbonate 0.58–2.2%, positive urinary anion gap during metabolic acidosis and normal ability to acidify the urine. Based on these findings a diagnosis of transient early-childhood hyperkalemia without salt wasting was made and they were treated sodium bicarbonate and hydrochlorothiazide with favorable response. The condition was transient in all cases leading to treatment discontinuation. Given that transient early-childhood hyperkalemia without salt wasting is a tubular disorder of transient nature with mild symptoms; it must be keep in mind in the differential diagnosis of hyperkalemia in young children.

It is currently unknown how quantitative diffusion and myelin MRI designs affect the results of a longitudinal study. We used two independent datasets containing 6 monthly MRI measurements from 20 healthy controls and 20 relapsing-remitting multiple sclerosis (RR-MS) patients. Six designs were tested, including 3 MRI acquisitions, either over 6 months or over a shorter study duration, with balanced (same interval) or unbalanced (different interval) time intervals between MRI acquisitions. First, we show that in RR-MS patients, the brain changes over time obtained with 3 MRI acquisitions were similar to those observed with 5 MRI acquisitions and that designs with an unbalanced time interval showed the highest similarity, regardless of study duration. No significant brain changes were found in the healthy controls over the same periods. Second, the study duration affects the sample size in the RR-MS dataset; a longer study requires more subjects and vice versa. Third, the number of follow-up acquisitions and study duration affect the sensitivity and specificity of the associations with clinical parameters, and these depend on the white matter bundle and MRI measure considered. Together, this suggests that the optimal design depends on the assumption of the dynamics of change in the target population and the accuracy required to capture these dynamics. Thus, this work provides a better understanding of key factors to consider in a longitudinal study and provides clues for better strategies in clinical trial design.

Private development on shoreline environments has many implications for ecological systems and understanding the social context can help authorities and conservation groups appropriately manage its impacts. This article presents findings from an online non-random sample survey to identify potential factors that may predict individuals’ views on private development on the shorelines of two historic waterways in Ontario: the Rideau Canal (RC) and Trent-Severn Waterway (TSW). Using exploratory multinomial logistic regression analysis, we found that overall perception of environmental threat, perception of shoreline development as a threat, ownership of waterfront property, and type of usage of the waterways are significant predictors of views on private shoreline development in the RC and TSW among respondents to the survey. Authorities and conservation groups can use these results to better anticipate the reactions of individuals and groups to private development projects and tailor engagement programs with property owners and other stakeholders.

Summary: HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more “open” conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4+ T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4+ T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC.

Summary: Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

Abstract Background Phase contrast (PC) cardiovascular magnetic resonance (CMR) in the ascending aorta (AAo) is widely used to calculate left ventricular (LV) stroke volume (SV). The accuracy of PC CMR may be altered by turbulent flow. Measurement of SV at another site is suggested in the presence of aortic stenosis, but very few data validates the accuracy or inaccuracy of PC in that setting. Our objective is to compare flow measurements obtained in the AAo and LV outflow tract (LVOT) in patients with aortic stenosis. Methods Retrospective analysis of patients with aortic stenosis who had CMR and echocardiography. Patients with mitral regurgitation were excluded. PC in the AAo and LVOT were acquired to derive SV. LV SV from end-systolic and end-diastolic tracings was used as the reference measure. A difference ≥ 10% between the volumetric method and PC derived SVs was considered discordant. Metrics of turbulence and jet eccentricity were assessed to explore the predictors of discordant measurements. Results We included 88 patients, 41% with bicuspid aortic valve. LVOT SV was concordant with the volumetric method in 79 (90%) patients vs 52 (59%) patients for AAo SV (p = 0.015). In multivariate analysis, aortic stenosis flow jet angle was a strong predictor of discordant measurement in the AAo (p = 0.003). Mathematical correction for the jet angle improved the concordance from 59 to 91%. Concordance was comparable in patients with bicuspid and trileaflet valves (57% and 62% concordance respectively; p = 0.11). Accuracy of SV measured in the LVOT was not influenced by jet eccentricity. For aortic regurgitation quantification, PC in the AAo had better correlation to volumetric assessments than LVOT PC. Conclusion LVOT PC SV in patients with aortic stenosis and eccentric jet might be more accurate compared to the AAo SV. Mathematical correction for the jet angle in the AAo might be another alternative to improve accuracy.

Background: Transcatheter valve-in-valve replacement (ViV-TAVR) has emerged as an alternative to redo-surgical aortic valve replacement (Redo-SAVR) for the treatment of failed surgical aortic bioprostheses. However, the benefit of ViV-TAVR compared with Redo-SAVR remains debated with regard to short-term hemodynamic results and short- and long-term clinical outcomes. Objective: This study aimed to compare short-term hemodynamic performance and long-term clinical outcomes of ViV-TAVR vs. Redo-SAVR in patients treated for surgical aortic bioprosthetic valve failure. Methods: We retrospectively analyzed the data prospectively collected in 184 patients who underwent Redo-SAVR or ViV-TAVR. Transthoracic echocardiography was performed before and after the procedure and analyzed in an echocardiography core laboratory using the new Valve Academic Research Consortium-3 criteria. An inverse probability of treatment weighting was used to compare the outcomes between both procedures. Results: ViV-TAVR showed lower rate of intended hemodynamic performance (39.2% vs. 67.7%, p < 0.001) at 30 days, which was essentially driven by a higher rate (56.2% vs. 28.8%, p = 0.001) of high residual gradient (mean transvalvular gradient ≥20 mm Hg). Despite a trend for higher 30-day mortality in the Redo-SAVR vs. ViV-TAVR group (8.7% vs. 2.5%, odds ratio [95% CI]: 3.70 [0.77-17.6]; p = 0.10), the long-term mortality was significantly lower (24.2% vs. 50.1% at 8 years; hazard ratio [95% CI]: 0.48 [0.26-0.91]; p = 0.03) in the Redo-SAVR group. After inverse probability of treatment weighting analysis, Redo-SAVR remained significantly associated with reduced long-term mortality compared with ViV-TAVR (hazard ratio [95% CI]: 0.32 [0.22-0.46]; p < 0.001). Conclusions: ViV-TAVR was associated with a lower rate of intended hemodynamic performance and numerically lower mortality at 30 days but higher rates of long-term mortality compared with Redo-SAVR.

Summary: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.

Summary: Although SARS-CoV-2 mRNA vaccination has been shown to be safe and effective in the general population, immunocompromised solid organ transplant recipients (SOTRs) were reported to have impaired immune responses after one or two doses of vaccine. In this study, we examined humoral responses induced after the second and the third dose of mRNA vaccine in different SOTR (kidney, liver, lung, and heart). Compared to a cohort of SARS-CoV-2 naïve immunocompetent health care workers (HCWs), the second dose induced weak humoral responses in SOTRs, except for the liver recipients. The third dose boosted these responses but they did not reach the same level as in HCW. Interestingly, although the neutralizing activity against Delta and Omicron variants remained very low after the third dose, Fc-mediated effector functions in SOTR reached similar levels as in the HCW cohort. Whether these responses will suffice to protect SOTR from severe outcome remains to be determined.

Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19–76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition.

Sarcoidosis is an inflammatory multisystemic disease of unknown etiology characterized by the formation of noncaseating epithelioid cell granulomas. Cardiac sarcoidosis might be life-threatening and its diagnosis and treatment remain a challenge nowadays. The aim of this review is to provide an updated overview of cardiac sarcoidosis and, through 10 practical clinical questions and real-life challenging case scenarios, summarize the main clinical presentation, diagnostic criteria, imaging findings, and contemporary treatment. Résumé: La sarcoïdose est une maladie inflammatoire multisystémique de cause inconnue, caractérisée par la formation de granulomes non caséeux composés de cellules épithélioïdes. La sarcoïdose cardiaque est une pathologie potentiellement mortelle qui demeure, à ce jour, difficile à diagnostiquer et à traiter. L'objectif de cet article est de présenter les données les plus à jour concernant la sarcoïdose cardiaque et de résumer, à l'aide de 10 questions cliniques et de cas réels, la présentation clinique, les critères diagnostiques, les trouvailles à l'imagerie et le traitement contemporain.

Background: Fulminant viral myocarditis (FVM) is a rare cause of cardiogenic shock associated with high morbidity and mortality rates. An inappropriately activated immune system results in severe myocardial inflammation. Acute immunosuppressive therapy for FVM therefore gained in popularity and was described in numerous retrospective studies. Methods: We conducted an extensive review of the literature and compared it with our single-centre retrospective review of all cases of FVM from 2009-2019 to evaluate the possible effect of acute immunosuppression with intravenous immunoglobulins and/or high dose corticosteroids in patients with FVM. Results: We report on 17 patients with a mean age of 46 ± 15 years with a mean left ventricular ejection fraction (LVEF) of 15 ± 9% at admission. Fourteen (82%) of our patients had acute LVEF recovery to ≥ 45% after a mean time from immunosuppression of 74 ± 49 hours (3.1 days). Extracorporeal membrane oxygenation (ECMO) was required in 35% (6/17) of our patients for an average support of 126 ± 37 hours. Overall mortality was 12% (2/17). No patient needed a long-term left ventricular assist device or heart transplant. All surviving patients achieved complete long-term LVEF recovery. Conclusions: Our cohort of 17 severely ill patients received acute immunosuppressive therapy and showed a rapid LVEF recovery, short duration of ECMO support, and low mortality rate. Our suggested scheme of investigation and treatment is presented. These results bring more cases of successfully treated FVM with immunosuppression and ECMO to the literature, which might stimulate further prospective trials or a registry. Résumé: Contexte: La myocardite virale fulminante (MVF) est une cause rare de choc cardiogénique, un état associé à des taux élevés de morbidité et de mortalité. L’activation inappropriée du système immunitaire entraîne une inflammation grave du myocarde. Le recours à un traitement immunosuppresseur aigu en cas de MVF a donc gagné en popularité et a fait l’objet de nombreuses études rétrospectives. Méthodologie: Nous avons effectué une revue exhaustive de la littérature et comparé nos observations avec les résultats de notre examen rétrospectif de tous les cas de MVF traités dans un même centre entre 2009 et 2019, afin d’évaluer l’effet possible d’une immunosuppression aiguë par des immunoglobulines administrées par voie intraveineuse et/ou par une corticothérapie à forte dose chez les patients présentant une MVF. Résultats: Nous rapportons les cas de 17 patients dont l’âge moyen était de 46 ± 15 ans et qui avaient une fraction d’éjection ventriculaire gauche (FEVG) moyenne de 15 ± 9 % à l’admission. Chez 14 (82 %) d’entre eux, la FEVG aiguë s’est rétablie à une valeur ≥ 45 % dans les 74 ± 49 heures (3,1 jours) en moyenne après l’administration d’un traitement immunosuppresseur. Un soutien par oxygénation extracorporelle par membrane (ECMO) a dû être administré à 35 % (6/17) des patients, pendant 126 ± 37 heures en moyenne. Le taux global de mortalité s’établissait à 12 % (2/17). Aucun patient n’a eu besoin d’assistance ventriculaire gauche de façon prolongée ni d’une transplantation cardiaque. La FEVG a fini par se rétablir complètement chez tous les patients qui ont survécu. Conclusions: Les 17 patients gravement malades de notre cohorte qui ont reçu un traitement immunosuppresseur aigu ont vu leur FEVG se rétablir rapidement, n’ont eu besoin d’ECMO que pendant une courte période et ont affiché un faible taux de mortalité. Nous présentons notre algorithme d’investigation et de traitement. Nos résultats s’ajoutent à ceux d’autres études témoignant de l’efficacité du traitement de la MVF par immunosuppression et ECMO, ce qui pourrait stimuler la réalisation de nouveaux essais prospectifs ou l’établissement d’un registre.

Viruses often encode proteins that mimic host proteins in order to facilitate infection. Little work has been done to understand the potential mimicry of the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, particularly the receptor-binding motifs, which could be important in determining tropism and druggability of the virus. Peptide and epitope motifs have been detected on coronavirus spike proteins using sequence homology approaches; however, comparing the three-dimensional shape of the protein has been shown as more informative in predicting mimicry than sequence-based comparisons. Here, we use structural bioinformatics software to characterize potential mimicry of the three coronavirus spike protein receptor-binding motifs. We utilize sequence-independent alignment tools to compare structurally known protein models with the receptor-binding motifs and verify potential mimicked interactions with protein docking simulations. Both human and non-human proteins were returned for all three receptor-binding motifs. For example, all three were similar to several proteins containing EGF-like domains: some of which are endogenous to humans, such as thrombomodulin, and others exogenous, such as Plasmodium falciparum MSP-1. Similarity to human proteins may reveal which pathways the spike protein is co-opting, while analogous non-human proteins may indicate shared host interaction partners and overlapping antibody cross-reactivity. These findings can help guide experimental efforts to further understand potential interactions between human and coronavirus proteins.

The next breakthrough for protein therapeutics is effective intracellular delivery and accumulation within target cells. Nuclear localization signal (NLS)-tagged therapeutics have been hindered by the lack of efficient nuclear localization due to endosome entrapment. Although development of strategies for tagging therapeutics with technologies capable of increased membrane penetration has resulted in proportional increased potency, nonspecific membrane penetration limits target specificity and, hence, widespread clinical success. There is a long-standing idea that nuclear localization of NLS-tagged agents occurs exclusively via classical nuclear transport. In the present study, we modified the antibody-drug conjugate trastuzumab-emtansine (T-DM1) with a classical NLS linked to cholic acid (cell accumulator [Accum]) that enables modified antibodies to escape endosome entrapment and increase nuclear localization efficiency without abrogating receptor targeting. In parallel, we developed a proteomics-based method to evaluate nuclear transport. Accum-modified T-DM1 significantly enhanced cytotoxic efficacy in the human epidermal growth factor receptor 2 (HER2)-positive SKBR3 breast cancer system. We discovered that efficacy was dependent on the nonclassical importin-7. Our evaluation reveals that when multiple classical NLS tagging occurs, cationic charge build-up as opposed to sequence dominates and becomes a substrate for importin-7. This study results in an effective target cell-specific NLS therapeutic and a general approach to guide future NLS-based development initiatives.

The magnitude of environmental challenges we are facing today requires the involvement of a diversity of stakeholders and collaborators to develop socially, culturally, and economically robust sustainability practices. Living labs catalyse the development of user-centric solutions for complex environmental issues by exploring, co-creating, testing, and evaluating innovations within real-world contexts. The living lab approach is relatively new in the environmental and agricultural sectors but is quite well established in many areas such as information and communication technology. For living labs to play a greater role in environmental sustainability, we present a research agenda related to the evaluation and effectiveness of living labs in the context of environmental and agricultural sustainability. We refer to evaluation as the act of assessing the process and outcomes of a living lab, and effectiveness as the level to which a living lab is successful in achieving a certain desirable process or outcome. Our research agenda is based on empirical research using an adapted Delphi method – a process to iteratively gather input from a panel of experts – involving a total of 44 researchers and experts in the domains of living labs, evaluation methods, and agro-environmental issues. The resulting integrated research agenda identifies important gaps in both research and practice to improve the impact of living labs. Our findings highlight the need to better understand effective use of this collaborative, open innovation approach in research and management focused on environmental and agricultural sustainability. Future research should investigate the knowledge gaps for we have identified in terms of diversity of stakeholders, key dimensions of evaluation and how to enable effectiveness of living labs.

Background: Optimal timing for intervention remains uncertain in asymptomatic patients with primary mitral regurgitation (MR). We aimed to assess the prognostic value of a new cardiac damage staging classification in patients with asymptomatic moderate or severe primary MR. Methods: Clinical, Doppler-echocardiographic, and outcome data prospectively collected in 338 asymptomatic patients (64 ± 15 years, 68% men) with at least moderate primary MR were retrospectively analyzed. Patients were hierarchically classified as per the following staging classification: no cardiac damage (stage 0), mild left ventricular or left atrial damage (stage 1), moderate or severe left ventricular or left atrial damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), or right ventricular damage (stage 4). Results: There was a stepwise increase in 10-year mortality rates as per cardiac damage stage: 20.0% in stage 0, 25.6% in stage 1, 31.5% in stage 2, and 61.3% in stage 3-4 (p < 0.001). The staging classification was significantly associated with increased risk of mortality (hazard ratio = 1.41 per one-stage increase, 95% confidence interval: 1.07-1.85, p = 0.015) and the composite of cardiovascular mortality or hospitalization (hazard ratio = 1.51 per one-stage increase, 95% confidence interval: 1.07-2.15, p = 0.020) in multivariable analysis adjusted for EuroSCORE II, mitral valve intervention as a time-dependent variable, and other risk factors. The proposed scheme showed incremental value over several clinical variables (net reclassification index = 0.40, p = 0.03). Conclusions: The new staging classification provides independent and incremental prognostic value in patients with asymptomatic moderate or severe MR.

Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood. Methods: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response. Results: Of note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states. Conclusions: Together, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens.

Background: Studies from high-income countries (HIC) support restrictive blood transfusion thresholds in medical patients. In low- and middle-income countries (LMIC), the etiologies of anemia and baseline health states differ greatly; optimal transfusion thresholds are unknown. This study evaluated the association of packed red blood cell (PRBC) transfusion with mortality outcomes across hemoglobin levels amongst emergency center (EC) patients presenting with medical pathology in Kigali, Rwanda. Methods: This retrospective cohort study was performed using a random sample of patients presenting to the EC at the University Teaching Hospital of Kigali. Patients ≥15 years of age, treated for medical emergencies during 2013–16, with EC hemoglobin measurements were included. The relationship between EC PRBC transfusion and patient mortality was evaluated using logistic regression, with stratified analyses performed at hemoglobin levels of 7 mg/dL and 5 mg/dL. Results: Of 3609 cases sampled, 1116 met inclusion. The median age was 42 years (IQR 29, 60) and 45.2% were female. Transfusion occurred in 12.1% of patients. Hematologic (24.4%) and gastrointestinal pathologies (20.7%) were the primary diagnoses of those transfused. Proportional mortality was higher amongst those receiving transfusions, although not statistically significant (23.7% vs 17.0%, p = 0.06). No significant difference in adjusted odds of overall mortality by PRBC transfusion was found. In stratified analysis, patients receiving EC transfusions with a hemoglobin >5.0 mg/dL, had 2.21 times the odds of mortality (95% CI 1.51–3.21) as compared to those ≤5.0 mg/dL. Conclusions: No association between PRBC transfusion and odds of mortality was observed amongst EC patients in this LMIC setting. An increased mortality association was found for patients receiving PRBC transfusions with an initial hemoglobin >5 mg/dL. Results suggest benefits from PRBC transfusion are limited as compared to HIC. Further research evaluating emergent transfusion thresholds for medical pathologies should be performed in LMICs to guide practice.

Summary: Antibodies can engage specific receptors at the surface of effector cells and mediate several functions beyond viral neutralization. Increasing evidence suggests that Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), have an important role in protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We engineered a cell line stably expressing a GFP-tagged SARS-CoV-2 spike to measure ADCC. This protocol provides an optimized way of measuring ADCC activity mediated by anti-SARS-CoV-2 Spike monoclonal antibodies or plasma from previously infected or vaccinated individuals.For complete details on the use and execution of this protocol, please refer to Anand et al. (2021b).

A finite element framework is developed to resolve the intragranular fields of incompatible deformation generated intrinsically in response to applied deformation, through linear elasticity complemented by the theory of continuous distribution of dislocations and experimental grain-scale observations. Discrete grain-averaged lattice strains, characterized along with grain orientations via X-ray diffraction microscopy, enable high fidelity continuous solutions anchored to measured response and satisfy boundary conditions, mechanical equilibrium, and strain compatibility within a finite element model. A continuous distribution of strain fields in a nickel-based superalloy, evaluated periodically during R = 0 cyclic loading, exposes the fundamental heterogeneity in polycrystalline response which creates locations of high stress gradients and potential sites of failure. Incompatibility is shown to be an effective measure driving the spatial concentration of stress with loading, particularly at twin and high angle grain boundaries. Furthermore, incompatible deformation is shown, through both specific examples and statistically, to be predominantly preserved upon elastic recovery improving our understanding of the history dependence of residual stresses. Positive correlation between residual stress & incompatible deformation and saturation of material response or shakedown in response to cyclic loading is revealed. The scalability of the framework with experiments at multiple length scales are discussed.

Background: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning. Methods: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma. Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD. Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted.

An air embolism (AE) is a rare but dreaded complication during endovascular procedures. Current guidance recommends hyperbaric oxygen therapy and aspiration for the management of a venous AE. However, the management of an arterial AE is much less described. We report a case of a 79-year-old man with symptomatic mitral regurgitation who underwent a MitraClip procedure. During the intervention, a massive AE was detected in the ascending aorta on transesophageal echocardiography. The AE was successfully aspirated while the patient remained hemodynamically stable. This report demonstrates the efficacy of an arterial AE’s aspiration with a real-time echocardiography recording of the technique. Résumé: Une embolie gazeuse (EG) est une complication rare mais redoutée lors des interventions endovasculaires. Les directives actuelles recommandent l'oxygénothérapie hyperbare et l'aspiration pour la prise en charge d'une EG veineuse. Cependant, la prise en charge d'une EG artérielle est beaucoup moins bien décrite. Nous rapportons le cas d'un homme de 79 ans présentant une insuffisance mitrale symptomatique et ayant subi une procédure MitraClip. Au cours de l'intervention, une EG massive a été détectée dans l'aorte ascendante à l'échocardiographie transoesophagienne. L'EG a été aspirée avec succès alors que le patient est resté stable sur le plan hémodynamique. Ce rapport démontre l'efficacité de l'aspiration d'une EG artérielle avec un enregistrement en temps réel de la technique par échocardiographie.

Summary: Age is a major risk factor for neurodegenerative diseases like Parkinson’s disease, but few studies have explored the contribution of key hallmarks of aging, namely DNA methylation changes and heterochromatin destructuration, in the neurodegenerative process. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in DNA demethylation, in the mouse midbrain. Gadd45b overexpression induced global and stable changes in DNA methylation, particularly in introns of genes related to neuronal functions, as well as on LINE-1 transposable elements. This was paralleled by disorganized heterochromatin, increased DNA damage, and vulnerability to oxidative stress. LINE-1 de-repression, a potential source of DNA damage, preceded Gadd45b-induced neurodegeneration, whereas prolonged Gadd45b expression deregulated expression of genes related to heterochromatin maintenance, DNA methylation, or Parkinson’s disease. Our data indicates that aging-related alterations contribute to dopaminergic neuron degeneration with potential implications for Parkinson’s disease.

Summary: With the recent approval of highly effective coronavirus disease 2019 (COVID-19) vaccines, functional and lasting immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently under investigation as antibody levels in plasma were shown to decline during convalescence. Since the absence of antibodies does not equate to absence of immune memory, we evaluate the presence of SARS-CoV-2-specific memory B cells in convalescent individuals. Here, we report a longitudinal assessment of humoral immune responses on 32 donors up to 8 months post-symptom onset. Our observations indicate that anti-Spike and anti-receptor binding domain (RBD) immunoglobulin M (IgM) in plasma decay rapidly, whereas the reduction of IgG is less prominent. Neutralizing activity also declines rapidly when compared to Fc-effector functions. Concomitantly, the frequencies of RBD-specific IgM+ B cells wane significantly when compared to RBD-specific IgG+ B cells, which remain stable. Our results add to the current understanding of immune memory following SARS-CoV-2 infection, which is critical for secondary infection prevention and vaccine efficacy.

Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction with nonobstructive coronary arteries. We describe a case of SCAD in a 39-year-old postpartum woman who presented with acute anterior myocardial infarction, no coronary occlusion but a suspicious coronary angiography. A coronary computed tomography angiogram demonstrated a left anterior descending intramural hematoma confirming the diagnosis. Teaching points emerging from this case are that SCAD and other causes of myocardial infarction with nonobstructive coronary arteries should be investigated, especially because the outcome is not benign. Also, coronary computed tomography angiogram should be considered as a part of the workup and follow-up for SCAD. Résumé: La dissection spontanée de l’artère coronaire (DSAC) est une cause d’infarctus du myocarde en l’absence d’artère coronaire obstruée. Nous présentons un cas de DSAC survenu après un accouchement chez une femme de 39 ans; la patiente présentait un infarctus aigu du myocarde antérieur sans occlusion coronarienne, mais les résultats de la coronarographie ont tout de même éveillé des soupçons. De fait, l’angiogramme coronaire obtenu par tomodensitométrie a révélé un hématome intramural dans l’artère interventriculaire antérieure, ce qui a confirmé le diagnostic de DSAC. Ce cas fait ressortir des points d'enseignement importants, notamment qu’il faut rechercher les signes de DSAC et investiguer les autres étiologies d'infarctus associées à des artères coronaires non obstruées, en particulier parce que les conséquences de telles affections ne sont pas bénignes. La réalisation d’une coronarographie par tomodensitométrie devrait aussi être considérée dans le bilan et le suivi après une DSAC.

Background: Perfluoroalkyl substances (PFASs) are found in several consumer goods. Exposure to PFASs in children has been associated with alteration in thyroid hormones, which have critical roles in brain function. Objective: In 2015, 198 children and youth (3–19 y) were recruited as part of the pilot project Jeunes, Environnement et Santé/Youth, Environment and Health (JES!-YEH!), realized in collaboration with four First Nation communities in Quebec. We aimed to evaluate serum concentrations of PFASs in relation to concentrations of thyroid-stimulating hormone (TSH), free thyroxine (T4) and thyroglobulin while adjusting for relevant confounders. Methods: PFASs (PFOS, PFOA, PFHxS, PFNA), 2,2′,4,4′-Tetrabromodiphenyl ether (PBDE-47) thyroid parameters (TSH, free T4, and thyroglobulin) were measured in serum samples of 186 participants. Iodine, creatinine, and cotinine were measured in urine samples. Serum levels of PFASs were compared to those measured in the general Canadian population and elsewhere. Multivariate regression analyses were performed to determine associations between PFASs and TSH, free T4 and thyroglobulin. Results: PFOS, PFOA and PFHxS serum concentrations were low. However, PFNA concentrations among participants aged 12 to 19 years old from Anishinabe communities were three times higher than those measured in the Canadian Health Measures Survey (2009–2011) for the same age group (Geometric Means: 3.01 μg/L and 0.71 μg/L, respectively) and were particularly higher in the Anishinabe participants aged 6 to 11 years old (GM: 9.44 μg/L). Few participants had levels of TSH, free T4, and thyroglobulin outside age-specific paediatric ranges. When adjusted for relevant covariates and other contaminants, PFNA serum concentrations were positively associated with free T4 levels (Adjusted β = 0.36; p = 0.0014), but not with TSH and thyroglobulin levels. No association was observed between the other PFAS and thyroid hormones parameters. Conclusion: This pilot project reveals among the highest exposure to PFNA in children reported until today, and suggests effects of PFNA as an endocrine disruptor, highlighting the importance of investigating the sources and effects of disproportionate exposure to emerging contaminants in some indigenous communities and ban all PFAS at the international scale. Keywords: Perfluoroalkyl substances, Perfluorononanoic acid, Thyroid hormones, Indigenous communities

Olfactory dysfunction is observed in several neurological disorders, including Huntington disease (HD), and correlates with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the underlying mechanisms are unknown. In order to determine if alterations in the olfactory bulb (OB) are observed in HD we assessed OB weight or area from 3 to 12 months of age in the BACHD transgenic lines (TG5 and TG9). A significant decrease in the OB was observed at 6 and 12 months of age compared to WT. We also detected increased mRNA and protein expression of mutant huntingtin (mHTT) in the OB of TG5 compared to TG9 at specific ages. Despite the higher expression of mHTT in the TG5 OBs, there was increased nuclear accumulation of mHTT in the OB of TG9 compared to WT and TG5 rats. As we observed atrophy of the OB in the BACHD rats we assessed for caspase activation, a known mechanism underlying the cell death observed in HD. We characterized caspase-3, −6, −8 and − 9 mRNA and protein expression levels in the OB of the BACHD transgenic lines at 3, 6 and 12 months of age. Alterations in caspase mRNA and protein expression were detected in the TG5 and TG9 lines. However, the changes observed in the mRNA and protein levels are in some cases discordant, suggesting that the caspase protein modifications detected may be more attributable to post-translational modifications. The caspase activation studies support that cell death may be increased in the rodent HD OB and further our understanding of the olfactory dysfunction and the role of caspases in the pathogenesis of HD.

Soil data and soil mapping are indispensable tools in sustainable forest management. In northern boreal ecosystems, paludification is defined as the accumulation of partially decomposed organic matter over saturated mineral soils, a process that reduces tree regeneration and forest growth. Given this negative effect on forest productivity, spatial prediction of paludification in black spruce stands is important in forest management. This paper provides a description of the soil database to predict organic layer thickness (OLT) as a proxy of paludification in northeastern Canada. The database contains 13,944 OLT measurements (in cm) and their respective GPS coordinates. We collected OLT measurements from georeferenced ground plots and transects from several previous projects. Despite the variety of sources, the sampling design for each dataset was similar, consisting of manual measurements of OLT with a hand probe. OLT measurements were variable across the study area, with a mean ± standard deviation of 21 ± 24 cm (ranging from a minimum of 0 cm to a maximum of 150 cm), and the distribution tended toward positive skewing, with a large number of low OLT values and fewer high OLT values. The dataset has been used to perform OLT mapping at 30-m resolution and predict the risk of paludification in northeastern Canada (Mansuy et al., 2018) [1]. The spatially explicit and continuous database is also available to support national and international efforts in digital soil mapping.

Background: Perfluoroalkyl acids (PFAAs) are persistent and ubiquitous environmental contaminants that potentially disrupt endocrine system functions. While some PFAAs (perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA)) are regulated, currently used fluorotelomer alcohols (FTOHs) can be transported to the Arctic and are degraded in a number of PFAAs which biomagnify in Arctic wildlife (e.g. perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUdA)). Objectives: From 2004 to 2017, 279 pregnant Inuit women were recruited as part of biomonitoring projects in Nunavik. Our goal was to evaluate: (i) time-trends in plasma/serum PFAAs levels in pregnant Nunavimmiut women between 2004 and 2017; (ii) compare plasma/serum PFAAs levels in Nunavimmiut women in 2016–2017 to those measured in women of childbearing age in the Canadian Health Measure Survey (CHMS); and (iii) evaluate the associations of PFAAs levels with the consumption of country foods and pregnancy and maternal characteristics during pregnancy in the 97 participants recruited in 2016–2017. Methods: Individual blood sample were collected for serum or plasma PFAAs (PFOS, PFOA, pentafluorobenzoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorobutanesulfonic acid (PFBS), perfluorohexane-1-sulfonic acid (PFHxS), PFNA, PFDA, PFUdA) analyses. Socio-demographic data, pregnancy and maternal characteristics and country foods consumption were documented using a questionnaire. Omega-3 and −6 polyunsaturated fatty acids (PUFA) were measured in red blood cell membranes and their ratio used as a biomarker of marine country foods consumption. Time-trends in PFAAs levels were evaluated using ANCOVA models adjusted for relevant co-variables. Serum/plasma levels of PFAAs in the 97 pregnant women aged 16 to 40 years old and recruited in 2016–2017 were compared to those measured in women aged 18 to 40 years old from the CHMS cycle 5 (2016–2017) using the geometric means (GM) and 95% confidence intervals (95% CI). Multivariate regression analyses were performed to examine associations between concentrations of PFAAs and country foods consumption data. Results: Statistically-significant downward time trends were noted for concentrations of PFOS, PFOA and PFHxS in pregnant Nunavik women between 2004 and 2017. Conversely, between 2011 and 2016–2017, PFNA, PFDA and PFUdA maternal serum levels increased by 19, 13 and 21% respectively. Among participants in 2016–2017, mean concentrations for PFNA (GM: 2.4 μg/L), PFDA (0.53 μg/L) and PFUdA (0.61 μg/L) were higher than those measured in women aged 18–40 years old in the Cycle 5 (2016–2017) of the CHMS. PFOA (0.53 μg/L) and PFHxS (0.26 μg/L) were lower than in CHMS, whereas PFBA, PFHxA and PFBS were not detected in 2016–2017. Ratios of serum/plasma levels of PFNA/PFOA, PFNA/PFOS, PFNA/PFHxS and PFUdA/PFDA were significantly higher in the 97 pregnant women from Nunavik recruited in 2016–2017 compared to CHMS, highlighting their distinct exposure profile. In multivariate models, PFHxS, PFOS, PFNA, PFDA and PFUdA levels in 2016–2017 were strongly associated with the omega-3/omega-6 PUFA ratio, indicating a positive association between marine country foods consumption and higher exposure to PFAAs. Conclusions: The exposure of pregnant women to long-chain PFAAs (PFNA, PFDA and PFUdA) increased from 2004 to 2017 in Nunavik. Associations noted between PFAAs levels and the omega-3/omega-6 ratio highlights the importance of implementing additional strict regulations on PFAAs and their precursors to protect the high nutritional quality and cultural importance of country foods in Nunavik.

Summary: SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoproteins of SARS-CoV-2 mediate viral entry and are the main targets for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic, and public health interventions. Here, we perform a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. Most infected individuals elicit anti-Spike antibodies within 2 weeks of the onset of symptoms. The levels of receptor binding domain (RBD)-specific immunoglobulin G (IgG) persist over time, and the levels of anti-RBD IgM decrease after symptom resolution. Although most individuals develop neutralizing antibodies within 2 weeks of infection, the level of neutralizing activity is significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection.

The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or “ecstasy”), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.

Summary: Several studies have reported an association between the farnesoid X receptor alpha (FXRα) and estrogenic signaling pathways. Fxrα could thus be involved in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). To test this hypothesis, mice were exposed to BPA and/or stigmasterol (S), an FXRα antagonist. Following the exposure to both molecules, wild-type animals showed impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. The crosstalk between BPA and FXRα is further supported by the lower impact of BPA in mice genetically ablated for Fxrα and the fact that BPA counteracted the effects of FXRα agonists. These effects might result from the downregulation of Fxrα expression following BPA exposure. BPA and S act additively in human testis. Our data demonstrate that FXRα activity modulates the impact of BPA on male gonads and on undifferentiated germ cell population. : In this article, Dr Volle and colleagues show that Fxrα participate in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). The present study shows that modulation of FXRa signaling pathway by the FXRα antagonist, namely stigmasterol, acts additively with BPA, leading to impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. In addition these additive effects were also observed in human testis. Keywords: testis, germ cell, FXRα, bisphenol-A, fertility

In this paper, we introduce a new ranking system where the data are preferences resulting from paired comparisons. When direct preferences are missing or unclear, then preferences are determined through indirect comparisons. Given that a ranking of n subjects implies (2n) paired preferences, the resultant computational problem is the determination of an optimal ranking where the agreement between the implied preferences via the ranking and the data preferences is maximized. Comparisons are carried out via simulation studies where the proposed rankings outperform Bradley–Terry in a particular predictive comparison. Keywords: Nonparametric methods, NCAA basketball, Ranking, Simulated annealing, Statistical computing

Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxrα−/− mice, we describe unexpected roles of FXRα on germ cell physiology independent of its effects on somatic cells. FXRα helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRα regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRα controls the expression of the pluripotency marker Lin28 in the germ cells.

Summary: Dorsal raphe (DR) serotonin neurons provide a major input to the ventral tegmental area (VTA). Here, we show that DR serotonin transporter (SERT) neurons establish both asymmetric and symmetric synapses on VTA dopamine neurons, but most of these synapses are asymmetric. Moreover, the DR-SERT terminals making asymmetric synapses on VTA dopamine neurons coexpress vesicular glutamate transporter 3 (VGluT3; transporter for accumulation of glutamate for its synaptic release), suggesting the excitatory nature of these synapses. VTA photoactivation of DR-SERT fibers promotes conditioned place preference, elicits excitatory currents on mesoaccumbens dopamine neurons, increases their firing, and evokes dopamine release in nucleus accumbens. These effects are blocked by VTA inactivation of glutamate and serotonin receptors, supporting the idea of glutamate release in VTA from dual DR SERT-VGluT3 inputs. Our findings suggest a path-specific input from DR serotonergic neurons to VTA that promotes reward by the release of glutamate and activation of mesoaccumbens dopamine neurons. : Wang et al. identify the ultrastructural and molecular characteristics of synaptic connectivity between DR serotonin neurons and VTA dopamine neurons and determined the role of these connections in behavior. Their results indicate that the DR→VTA serotonergic neurons promote reward by the co-release of glutamate and activation of mesoaccumbens dopamine neurons. Keywords: dorsal raphe nucleus, ventral tegmental area, serotonin, VGluT3, reward

Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress, and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed1 heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks, and protects dopaminergic neurons against apoptosis.