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Abstract: In collaboration with recruiting and background check firms, we gave a customized application form designed to both deter and enhance detection of deception to 27 real-life candidates. A total of 269 elements common to both the customized form and their usual free-form resumes were verified. Inaccuracies were reduced from 23% on the resumes to 11% on the customized forms ( p < .001). Furthermore, candidates who did not provide contact information for past professional experiences to facilitate our verifications were less likely to submit fully accurate information about the experience, compared to those who did provide contact information (39% and 77%, respectively, p = .007). This novel method thus appears to be a cost-effective way to address resume fraud.

PURPOSE: Older adults have unique risk factors for poor outcomes after hematopoietic stem-cell transplant (HSCT). We sought to determine the impact of our multidisciplinary supportive care program, Enhanced Recovery after stem-cell transplant (ER-SCT), on survival outcomes in patients age 65 years and older who underwent HSCT. PATIENTS AND METHODS: In this retrospective study, clinicodemographic data, nonrelapse mortality (NRM), overall survival (OS), and relapse were compared between 64 patients age 65 years and older who underwent allogeneic stem-cell transplant during ER-SCT program's first year, October 2017 through September 2018, and 140 historical controls age 65 years and older who underwent allogeneic HSCT, January 2015 through September 2017. RESULTS: In the ER-SCT cohort, 41% (26 of 64) of patients were women, and the median (range) age was 68 (65-74) years; in the control cohort, 38% (53 of 140) of patients were women, and the median (range) age was 67 (65-79) years. Hematopoietic cell transplant comorbidity index and donor type/cell source were similar between cohorts. The ER-SCT cohort had a lower 1-year NRM rate (13% v 26%, P = .03) and higher 1-year OS rate (74% v 53%, P = .007). Relapse rate did not differ significantly between cohorts. In multivariate analyses, ER-SCT was associated with improved 1-year NRM (hazard ratio, 0.4; 95% CI, 0.2 to 0.9; P = .02) and improved 1-year OS (hazard ratio, 0.5; 95% CI, 0.3 to 0.9; P = .03). CONCLUSION: A multidisciplinary supportive care program may improve NRM and OS in older patients undergoing allogeneic HSCT. Randomized studies are warranted to confirm this benefit and explore which program components most contribute to the improved outcomes.

Background: Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods: This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n= 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results: The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions: Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food. Citation Format: Alice Bellicha, Gaëlle Wendeu-Foyet, Xavier Coumoul, Meriem Koual, Fabrice Pierre, Françoise Guéraud, Laurent Zelek, Charlotte Debras, Bernard Srour, Laury Sellem, Emmanuelle Kesse-Guyot, Chantal Julia, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-03.

Purpose and scopeThe aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist.Methods of statement developmentA multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022.Results and conclusionsChromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.

Chimeric antigen receptor (CAR) T-cell therapy is the new standard treatment for various indications in patients with advanced hematologic malignancies. Despite the several preclinical and early phase clinical trials, the overall clinical experience has been disappointing when applying this innovative therapy in solid tumors. The failure of CAR T-cell therapy and its limited antitumor activity in solid tumors have been attributed to several mechanisms, including tumor antigen heterogeneity, the hostile tumor microenvironment and poor trafficking of CAR T cells into tumor sites, and the unacceptable toxicities in some settings, among others. However, remarkable improvements have been made in understanding many of these failure mechanisms for which several emerging novel approaches are being applied to overcome these challenges. In this review, after a brief historic background for immunotherapy in solid tumors, we highlight the recent developments achieved in CAR T-cell designs, summarize completed clinical trials, and discuss current challenges facing CAR T-cell therapy and the suggested strategies to overcome these barriers.

This study illustrates how user-generated content, posted in the form of heritage site reviews on social media, can serve to reveal the relationship between the cocreated interpretation of World Heritage Sites (WHSs)—in terms of values, tangible and intangible attributes, as well as site visit logistics—and the emotional experience of the site. Two WHSs are taken as a case study. More than 2,000 reviews were retrieved from TripAdvisor and analyzed through the application of a mixed method that integrates qualitative digital ethnography and machine learning. Results show that TripAdvisor reviews capture tourists' emotional reactions from personal encounters with heritage and provide insights into the range of values—including the social, historic, and aesthetical values—that visitors experience when engaging with aspects of the past to associate meanings for the present. Results also show that the relation between experiences gained at WHSs and contextual aspects is not linear; instead, it is a complex one that results from the interaction of different factors and their associated sentiments. We discuss our results by reflecting on their theoretical and practical implications.

OBJECTIVE The deleterious effects of trans fatty acids (TFAs) on cardiovascular health are well established; however, their impact on type 2 diabetes remains poorly understood. In particular, little is known about the impact of specific TFA types on type 2 diabetes etiology. We aimed to explore the associations between different types of TFAs (total, ruminant, industry produced [iTFAs], and corresponding specific isomers) and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 105,551 participants age >18 years from the French NutriNet-Santé cohort (2009–2021) were included (mean baseline age 42.7 years; SD 14.6 years); 79.2% were women. Dietary intake data, including usual TFA intake, were collected using repeated 24-h dietary records (n = 5.7; SD 3.1). Associations between sex-specific quartile of dietary TFAs and diabetes risk were assessed using multivariable Cox models. RESULTS Total TFA intake was associated with higher type 2 diabetes risk (hazard ratio [HR]quartile 4 vs. 1 1.38; 95% CI 1.11–1.73; Ptrend < 0.001; n = 969 incident cases). This association, specifically observed for iTFAs (HR 1.45; 95% CI 1.15–1.83; Ptrend < 0.001), was mainly driven by elaidic acid (HR 1.37; 95% CI 1.09–1.72; Ptrend < 0.001) and linolelaidic acid (HR 1.29; 95% CI 1.04–1.58; Ptrend = 0.07). In contrast, ruminant TFAs were not significantly associated with risk of type 2 diabetes. CONCLUSIONS In this large prospective cohort, higher intakes of total and iTFAs were associated with increased type 2 diabetes risk. These findings support the World Health Organization’s recommendation to eliminate iTFAs from the food supply worldwide. Consumers should be advised to limit the consumption of food products containing partially hydrogenated oils (main vector of iTFAs). This may contribute to lowering the substantial global burden of type 2 diabetes.

Transient diaphragm dysfunction is common during the first week after cardiac surgery; however, the precise incidence, risk factors, and outcomes of persistent diaphragm dysfunction are not well described.In a single-centre prospective cohort study, we included all consecutive patients over 18 yr who underwent elective cardiac surgery. Diaphragm function was evaluated with ultrasound (M-mode) by recording the excursion of both hemidiaphragms at two different time points: preoperatively and after the seventh postoperative day in patients breathing without assistance. Significant diaphragm dysfunction after the seventh day of the index cardiac surgery was defined as a decrease in diaphragm excursion below the lower limit of normal: at rest,9 mm for women and10 mm for men; after a sniff test,16 mm for women and18 mm for men.Overall, 122 patients were included in the analysis. The median [interquartile range (IQR)] age was 69 [59-74] years and 96/122 (79%) were men. Ten (8%) patients had diaphragm dysfunction after the seventh postoperative day. We did not identify risk factors for persistent diaphragm dysfunction. Persistent diaphragm dysfunction was associated with a longer median [IQR] duration of noninvasive (8 [0-34] vs 0 [0-0] hr; difference in medians, 8 hr; 95% confidence interval [CI], 0 to 22; P0.001) and invasive mechanical ventilation (5 [3-257] vs 3[2-4] hr; difference in medians, 2 hr; 95% CI, 0.5 to 41; P = 0.008); a higher reintubation rate (4/10, 40% vs 1/112, 0.9%; relative risk, 45; 95% CI, 7.1 to 278; P0.0001), a higher incidence of pneumonia (4/10 [40%] vs 7/112 [6%]; relative risk, 6; 95% CI, 2 to 16; P0.001), and longer median [IQR] length of stay in the intensive care unit (8 [5-29] vs 4 [2-6] days; difference in medians, 4 days; 95% CI, 2 to 12; P = 0.002).The incidence of persistent diaphragm dysfunction was 8% in patients undergoing elective cardiac surgery and was associated with adverse respiratory outcomes.ClinicalTrials.gov (NCT04276844); prospectively registered 19 February 2020.RéSUMé: CONTEXTE: Un dysfonctionnement transitoire du diaphragme est fréquent au cours de la première semaine après une chirurgie cardiaque. Toutefois, l’incidence précise, les facteurs de risque et les devenirs liés à un dysfonctionnement persistant du diaphragme ne sont pas bien décrits. MéTHODE: Dans une étude de cohorte prospective monocentrique, nous avons inclus tous les patients consécutifs de plus de 18 ans qui ont bénéficié d’une chirurgie cardiaque non urgente. La fonction du diaphragme a été évaluée à l’échographie (mode M) en enregistrant l’excursion des deux hémidiaphragmes à deux moments différents : avant l’opération et après le septième jour postopératoire chez les patients respirant sans assistance. Un dysfonctionnement significatif du diaphragme après le septième jour de la chirurgie cardiaque initiale a été défini comme une diminution de l’excursion diaphragmatique en dessous de la limite inférieure de la normale, soit : au repos,9 mm pour les femmes et10 mm pour les hommes; après un test de reniflement,16 mm pour les femmes et18 mm pour les hommes. RéSULTATS: Au total, 122 patients ont été inclus dans l’analyse. L’âge médian des patients (écart interquartile [ÉIQ]) était de 69 ans [59-74] ans et 96/122 (79 %) étaient des hommes. Dix (8 %) patients ont présenté un dysfonctionnement du diaphragme après le septième jour postopératoire. Nous n’avons pas identifié de facteurs de risque de dysfonctionnement persistant du diaphragme. Un dysfonctionnement persistant du diaphragme était associé à : une durée médiane [ÉIQ] de ventilation non invasive (8 [0–34] vs 0 [0–0] h; différence dans les médianes, 8 heures; intervalle de confiance [IC] à 95 %, 0 à 22; P0,001) et de ventilation mécanique invasive (5 [3–257] vs 3[2–4] h; différence dans les médianes, 2 heures; IC 95 %, 0,5 à 41; P = 0,008) plus longues, un taux de réintubation plus élevé (4/10, 40 % vs 1/112, 0,9 %; risque relatif, 45; IC 95 %, 7,1 à 278; P0,0001), une incidence plus élevée de pneumonie (4/10 [40 %] vs 7/112 [6 %]; risque relatif, 6; IC 95 %, de 2 à 16; P0,001), et une durée de séjour médiane [ÉIQ] plus longue à l’unité de soins intensifs (8 [5-29] vs 4 [2–6] jours; différence en médianes, 4 jours; IC 95 %, 2 à 12; P = 0,002). CONCLUSION: L’incidence de dysfonctionnement persistant du diaphragme était de 8 % chez les patients bénéficiant d’une chirurgie cardiaque non urgente et était associée à des issues respiratoires indésirables. ENREGISTREMENT DE L’éTUDE: ClinicalTrials.gov (NCT04276844); enregistrée prospectivement le 19 février 2020.

For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

Biliary atresia (BA) is a progressive inflammatory process of the biliary tree resulting in biliary obstruction. No single known genetic or environmental factor has been established to cause BA. Cystic fibrosis (CF) is a rare cause of neonatal cholestasis, and it has never been described in familial BA cases. Here, we investigate two siblings of first-degree consanguineous parents presenting with neonatal BA. Shortly after the Kasai operation, the proband developed severe respiratory symptoms attributable to a missed CF diagnosis. This was discovered after re-investigating the family history, which revealed a first-degree cousin with CF who did not manifest BA. Afterwards, we identified a pathogenic variant (DeltaF508) in CFTR in both BA-affected siblings along with their cousin. This intrigued us to study the molecular etiology behind the familial BA presentations, which exclusively contributed to BA-pathogenesis in BA-CF-affected siblings and not in their CF-only affected cousin. We applied a multistep approach to investigate the variant profile of both siblings' and their cousin's exomes. We curated the genes whose variants were shared by the BA-CF siblings but absent or heterozygous in their CF-only-affected cousin. Consequently, we identified three candidate genes (SNAPC4, UCK1, and ZHX2) besides CFTR. We propose that these genes act cumulatively or individually in inducing BA-pathogenesis-either by aggravating the biliary damage in the context of CF or increasing the susceptibility of BA as a separate CF-comorbidity. To our knowledge, this is the first report of DeltaF508 in CFTR with familial neonatal BA cases.

Acrylamide is classified as a probable human carcinogen by the International Agency for Research on Cancer but epidemiologic evidence on the carcinogenicity of acrylamide from dietary sources is limited.This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort, accounting for menopausal and hormone receptor status.This prospective cohort study included 80,597 French females (mean ± SD age at baseline: 40.8 ± 14 y) during a mean ± SD follow-up of 8.8 ± 2.3 y. Acrylamide intake was evaluated using repeated 24-h dietary records (n ± SD = 5.5 ± 3.0), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal, and postmenopausal) were assessed by Cox hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors).The mean ± SD dietary acrylamide intake was 30.1 ± 21.9 µg/d (main contributors: coffee, potato fries and chips, pastries, cakes, bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between dietary acrylamide exposure and breast cancer risk overall (HR for quartile 4 compared with 1: 1.21; 95% CI: 1.00, 1.47) and a positive association was observed with premenopausal cancer (HRQ4vs.Q1: 1.40; 95% CI: 1.04, 1.88). Restricted cubic spline analyses suggested evidence for nonlinearity of these associations, with higher HRs for intermediate (quartile 2) and high (quartile 4) exposures. Receptor-specific analyses revealed positive associations with estrogen receptor-positive breast cancer (total and premenopausal). Acrylamide intake was not associated with postmenopausal breast cancer.Results from this large prospective cohort study suggest a positive association between dietary acrylamide and breast cancer risk, especially in premenopausal females, and provide new insights that support continued mitigation strategies to reduce the content of acrylamide in food.This trial was registered at clinicaltrials.gov as NCT03335644.

International audience; Iron−sulfur (Fe−S) clusters are prosthetic groups of proteins biosynthesized on scaffold proteins by highly conserved multi-protein machineries. Biosynthesis of Fe−S clusters into the ISCU scaffold protein is initiated by ferrous iron insertion, followed by sulfur acquisition, via a still elusive mechanism. Notably, whether iron initially binds to the ISCU cysteine-rich assembly site or to a cysteine-less auxiliary site via N/O ligands remains unclear. We show here by SEC, circular dichroism (CD), and Mossbauer spectroscopies that iron binds to the assembly site of the monomeric form of prokaryotic and eukaryotic ISCU proteins via either one or two cysteines, referred to the 1-Cys and 2-Cys forms, respectively. The latter predominated at pH 8.0 and correlated with the Fe−S cluster assembly activity, whereas the former increased at a more acidic pH, together with free iron, suggesting that it constitutes an intermediate of the iron insertion process. Iron not binding to the assembly site was non-specifically bound to the aggregated ISCU, ruling out the existence of a structurally defined auxiliary site in ISCU. Characterization of the 2-Cys form by site-directed mutagenesis, CD, NMR, X-ray absorption, Mossbauer, and electron paramagnetic resonance spectroscopies showed that the iron center is coordinated by four strictly conserved amino acids of the assembly site, Cys35, Asp37, Cys61, and His103, in a tetrahedral geometry. The sulfur receptor Cys104 was at a very close distance and apparently bound to the iron center when His103 was missing, which may enable iron-dependent sulfur acquisition. Altogether, these data provide the structural basis to elucidate the Fe−S cluster assembly process and establish that the initiation of Fe−S cluster biosynthesis by insertion of a ferrous iron in the assembly site of ISCU is a conserved mechanism.

Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A

Endoscopic thoracoscopic sympathectomy (ETS) is the gold standard therapy for primary focal palmar hyperhidrosis (PFPH), resulting in high patient satisfaction rates. The most common side effect of ETS is compensatory hyperhidrosis (CH). Previous studies followed patients' satisfaction degree of surgery and the incidence of CH during a limited follow-up period of 1 to 3 years. The purpose of this study was to investigate the long-term outcomes and patient satisfaction after ETS.After approval of our institutional review board, we conducted a retrospective review of all consecutive patients who underwent ETS for PFPH at our institution between 1998 and 2019. Electronic medical records were reviewed for short-term outcomes. Long-term outcomes were collected through telephone questionnaires. Primary outcome was the resolution of PFPH. Secondary outcomes were CH and long-term patient satisfaction.During the study period, 256 patients underwent ETS to treat primary focal palmar hyperhidrosis at our institution between the years 1998-2019. One-hundred and fifty (58.6%) patients agreed to participate in the study and were included in the final analysis. The mean age was 23.8 (17 to 58) years, 56% were females. The mean follow-up time was 11±6.1 (1 to 22) years. Ninety-four percent reported resolution of PFPH; however, CH was reported by 90% of participants. CH decreased mean patient satisfaction score from 4.8±0.5 to 3.8±2 ( P =0.009). This effect was more pronounced in patients with CH of the head and neck ( P =0.009). Patients' satisfaction decreased over time from a mean of 4.8±0.4 in the first year after surgery to a mean of 3.7±1.4 12 years or more after surgery ( P0.001). Despite this, 79% of patients reported they would recommend ETS to other patients.ETS for PFPH is highly effective and results in high patient satisfaction rates even after long-term follow-up. Despite high rates of postoperative CH, nearly 80% of patients would still recommend the procedure to fellow patients, justifying its reputation as the gold standard treatment for PFPH.

BACKGROUND: Lumbar decompression can result in postsurgical instability and spondylolisthesis in patients with lumbar spinal stenosis (LSS). While pedicle screw (PS) constructs improve stability and support fusion, their use can lead to adjacent level degeneration due to rigidity and resultant overload of anatomical structures. The FFX device is a facet spacer designed to be a less invasive alternative for obtaining fusion compared with PS. OBJECTIVE: The present study aimed to compare biomechanical performance of the FFX device to different lumbar spine procedures using the finite element (FE) method. STUDY DESIGN: Comparative biomechanical study by FE method. METHODS: An FE model for the lumbar spine was developed and validated to assess vertebral displacement and stress variations in the facet joints and discs following surgery. Modeled scenarios included a healthy spine as a reference model, laminectomy (LAM), and prior to/following L4-L5 fusion for LAM + FFX and LAM + PS. RESULTS: LAM increased displacement compared with the healthy spine and both instrumented spine procedures. Facet joint stress at adjacent levels for LAM + PS was significantly higher than with LAM + FFX prior to fusion (+13.5% for L3-L4; +15.7% for L5-S1). Adjacent level disc stress at L5-S1 was 7.7% higher for LAM + PS vs LAM + FFX. Adjacent level facet joint and disc stresses for LAM + FFX were equivalent to LAM + PS once fusion occurred. CONCLUSIONS: Instrumented spine fixation prevents the risk of lumbar instability associated with LAM alone. Compared with PS, the FFX device is a less invasive alternative for the treatment of LSS, which potentially lowers the risk of adjacent segment degeneration prior to fusion that provides equivalent stability once fusion is achieved. LEVEL OF EVIDENCE: 5.

Introduction: Inhaled pulmonary vasodilators (IPVD) have been previously studied in patients with non-coronavirus disease-19 (COVID-19) related acute respiratory distress syndrome (ARDS). The use of IPVD has been shown to improve the partial pressure of oxygen in arterial blood (PaO2), reduce fraction of inspired oxygen (FiO2) requirements, and ultimately increase PaO2/FiO2 (P/F) ratios in ARDS patients. However, the role of IPVD in COVID-19 ARDS is still unclear. Therefore, we performed this meta-analysis to evaluate the role of IPVD in COVID-19 patients. Methods: Comprehensive literature search of PubMed, Embase, Web of Science and Cochrane Library databases from inception through April 22, 2022 was performed for all published studies that utilized IPVD in COVID-19 ARDS patients. The single arm studies and case series were combined for a 1-arm meta-analysis, and the 2-arm studies were combined for a 2-arm meta-analysis. Primary outcomes for the 1-arm and 2-arm meta-analyzes were change in pre- and post-IPVD P/F ratios and mortality, respectively. Secondary outcomes for the 1-arm meta-analysis were change in pre- and post-IPVD positive end-expiratory pressure (PEEP) and lung compliance, and for the 2-arm meta-analysis the secondary outcomes were need for endotracheal intubation and hospital length of stay (LOS). Results: 13 single arm retrospective studies and 5 case series involving 613 patients were included in the 1-arm meta-analysis. 3 studies involving 640 patients were included in the 2-arm meta-analysis. The pre-IPVD P/F ratios were significantly lower compared to post-IPVD, but there was no significant difference between pre- and post-IPVD PEEP and lung compliance. The mortality rates, need for endotracheal intubation, and hospital LOS were similar between the IPVD and standard therapy groups. Conclusion: Although IPVD may improve oxygenation, our investigation showed no benefits in terms of mortality compared to standard therapy alone. However, randomized controlled trials are warranted to validate our findings.

Background There was an immense need for studies evaluating the oral health status of Syrian children with congenital heart disease (CHD) and its impact on their quality of life. No contemporary data are available. The objective of this study was to investigate oral manifestations and oral health-related quality of life (OHRQoL) of children with CHD and compare them with healthy controls aged 4–12 years. Methods A case-control study was undertaken. A total of 200 patients with CHD and 100 healthy children belonging to the same patient’s family were included. Decayed, missed, and filled permanent teeth index (DMFT) and decayed, missed, and filled primary teeth index (dmft), Oral Hygiene Index (OHI), Papillary Marginal Gingivitis Index (PMGI), and dental abnormalities were recorded. The Arabic version of the Child Oral Health-Related Quality of Life Questionnaire (COHRQoL, 36-item) which was divided into 4 different domains (Oral Symptoms, Functional Limitations, Emotional Well-Being, Social Well-Being) were studied. Chi-square test and independent- t-test were used to perform statistical analysis. Results CHD patients experienced more periodontitis, dental caries, poor oral health, and enamel defects. The dmft mean was significantly higher in CHD patients than in healthy children (5.245 vs. 2.660, P P = 0.731). There was a significant difference between CHD patients and healthy children in the mean of the OHI (5.954 vs. 1.871, P P Conclusions Evidence about the oral health and COHRQoL of children with CHD was provided. Further preventive measures are still required to improve the health and quality of life of this vulnerable group of children.

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p p p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7 , a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1–mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1–induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.