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DICER1 gene encodes an RNaseIII endoribonuclease essential for the cleavage of pre-microRNA to mature microRNA. Germline DICER1 mutation results in DICER syndrome, a cancer predisposition syndrome which manifests in the thyroid gland as early-onset multinodular goiter and increased risk for differentiated thyroid carcinoma. Recently, somatic DICER1 mutations were described in various thyroid neoplasms, including follicular adenoma, papillary thyroid carcinoma, follicular carcinoma, and poorly differentiated thyroid carcinoma. In this study, we identified and described 14 cases (1.7%) with somatic DICER1 mutations from a cohort of 829 patients with thyroid follicular cell-derived thyroid carcinomas which were sequenced using MSK-IMPACT targeted next-generation sequencing platform. We expanded the histologic spectrum of thyroid carcinomas with somatic DICER1 mutations to include Hurthle cell carcinoma, high-grade differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. All patients were adults with a median age of diagnosis of 59 years (range: 22-82). Although rare, a subset of thyroid cancers, including the aggressive subtypes, display somatic DICER1 mutations, some of which have oncogenic potential., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative genetic disorder characterized by impaired intracellular transport of cholesterol and other lipids. The Niemann-Pick Disease, type C1 Severity Scale (NPC-SS) was developed to quantify neurological progression of NPC; it is used to monitor the natural history of disease progression and assess response to treatment. The objective of the study was to examine the interrater reliability of the NPC-SS in a phase 2/3 trial., Methods: Study data were from a multicenter, prospective, randomized, double-blind trial of adrabetadex in 56 subjects with NPC1. Clinical data recorded at each study site were distributed to two independent blinded central raters to generate a severity score. A composite four-item score was utilized as the primary clinical study end point, whereas a five-item focused score has been utilized in other NPC1 trials. Interrater reliability was assessed using two-way mixed models for instrument stability, Cohen kappa, weighted kappa, and percent agreement for the four- and five-item scores., Results: The frequency distribution and mean (S.D.) of the NPC-SS domain assessments by the raters were almost identical. Evaluation at the patient visit level showed wide variability between visits; however, weighted kappa calculation provided a lower variability between visits. The average kappa coefficients ranged between 0.69 and 0.89, indicating good to very good agreement between raters., Conclusions: These results support the NPC-SS, including derived four- and five-item composite scores, as reliable measures for use in a clinical trial setting., (Copyright © 2021. Published by Elsevier Inc.)

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody 1 . Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab 2 , S2X259 3 and S2H97 4 . The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: We aimed to assess and compare autonomic function in Parkinson's disease (PD) associated with the leucine-rich repeat kinase (LRRK2) G2019S mutation (LRRK2-PD) and non-LRRK2 PD, by the study of heart rate variability (HRV) and sympathetic skin responses (SSR)., Methods: In a cross-sectional three-year study, fifty LRRK2-PD and fifty clinically matched non-LRRK2 PD patients were included. Cardiac parasympathetic functions were assessed using heart rate variation to deep breathing (HR-DB), to the Valsalva maneuver (HR-V) and to standing (HR-S) and the sympathetic autonomic system by sympathetic skin responses (SSR)., Results: Neurophysiological, parasympathetic and sympathetic dysautonomia were found in 78%, 69% and 37% of all PD patients respectively. Rates of dysautonomia in the LRRK2-PD and non-LRRK2 PD patient subgroups were 76% vs 80% (p = 0.405) for neurophysiological, 62% vs 76% (p = 0.123) for parasympathetic and 38% vs 36% (p = 0.500) for sympathetic dysautonomia. HR-S was the most frequently altered parameter in both groups, and was significantly associated with the tremor-dominant (TD) motor phenotype of PD in the total cohort (p = 0.004) and in LRRK2-PD (p = 0.015). In LRRK2-PD patients, female gender was associated with parasympathetic dysfunction (p = 0.024), and with altered HR-DB (p = 0.022). Early-onset parkinsonism was also significantly associated with preserved neurophysiological autonomic functions (p = 0.044) in LRRK2-PD. In non-LRRK2 PD patients, male gender was associated with early parasympathetic (p = 0.043) and sympathetic dysfunction (p = 0.007)., Conclusion: Our study showed a roughly similar neurophysiological autonomic profile in non-LRRK2 PD and LRRK2-PD. The latter had some peculiarities with more marked parasympathetic dysfunction and more altered HR-DB in females, more altered HR-S in the TD-motor phenotype, and preserved autonomic functions in early-onset parkinsonism. These preliminary findings would require further investigations on larger genetically homogeneous cohorts to explore the multiple facets of autonomic dysfunction in PD., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Systematic reviews provide a structured framework for summarizing the available evidence in a comprehensive, objective, and transparent manner. They inform evidence-based guidelines in medicine, public policy, and more recently, in environmental health and toxicology. Many regulatory agencies have extended and adapted the well-established systematic review methods, initially developed for clinical studies, for their assessment needs. The use of systematic reviews to summarize evidence from existing human, animal, and mechanistic studies can reduce reliance on animal test data in risk assessment and can help avoid unnecessary duplication of animal experiments that have already been conducted. As alternative test methods can be expected to play an increasing role in human health risk assessment in the future, systematic reviews can be particularly helpful in validating these alternatives. The field of evidence-based toxicology has undergone extensive development since its first meeting in 2007 as a result of collaborative efforts among international experts and public health agencies, particularly with respect to the use of mechanistic data and evidence integration. The continued development and wider adoption of systematic review methodology can lead to better 3R implementation. As undertaking a systematic review can be a complex and lengthy process, it is important to understand the main steps involved. Key steps, along with current best practices, are described with references to guidance from organizations with expertise in evidence synthesis. Applications of systematic reviews in clinical, observational, and experimental studies are presented. Finally, software tools available to facilitate and increase the efficiency of completing a systematic review are described.

Purpose: Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects., Methods: Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses., Results: CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity., Conclusions: CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC., Competing Interests: RM, SR, PD, and KP are stockholder of Micregen Ltd, this relationship had no effect on study design, analysis, or interpretation of results, and this does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declared they had no conflict of interest.

p16 is the most useful diagnostic marker for human papillomavirus (HPV)-associated anogenital lesions. In the cervix, the pattern of p16 immunoreactivity generally correlates with lesion severity. p16 expression in anal intraepithelial neoplasia (AIN) is far less studied. Whether such correlation holds true has to be determined. We correlated the degree and pattern of p16 immunohistochemistry (IHC) results with morphologic diagnoses of 1000 anal squamous and transitional zone biopsy specimens. Using the Lower Anogenital Squamous Terminology criteria, p16 IHC results were classified as block staining, partial staining, or negative. Among 150 samples without morphologic evidence of AIN, p16 was negative in 85% and partial staining in 15%. AIN 1 (n=400) revealed diverse results: 28% negative, 35% partial, and 37% block staining. Among AIN 2 (n=298), 89% were block, 9% partial staining, and 2% negative. AIN 3 (n=152) revealed block (95%) or partial staining (5%). For the detection of AIN 2/3, p16 block staining yielded 91% sensitivity, 73% specificity, 80% positive predictive value, 91% negative predictive value, and a Youden Index of 0.64. Combining block staining and partial staining slightly increased sensitivity (99%) and negative predictive value (98%), but significantly decreased specificity (43%), positive predictive value (59%) and Youden Index (0.42, P<0.001). As with the cervix, p16 immunoreactivity correlates with morphologic diagnoses of AIN. Block staining offers the optimal diagnostic value for AIN 2/3. Caution is required since AIN 1 frequently exhibits block staining; the prognostic value of p16 warrants further investigation., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The involvement of traditional risk factors and combined genetic markers of recurrent arterial ischemic stroke (AIS) in adults remains unclear., Objective: This study aims to determine significant clinical and genetic factors of AIS recurrence, and to investigate the combined effect of genotypes on the occurrence of a second cerebral ischemic attack., Methods: We investigated a cohort study of AIS patients (18-50 years old) followed in the neurology department over 5 years. Traditional and genetic risk factors were carried through a multivariable logistic regression model. We used a Cox proportional hazard model for identifying predictors of recurrence., Results: Two hundred and seventy patients were enrolled in our study. The risk of AIS recurrence was 36.2% within 5 years. The potential risk of recurrence of AIS increased with traditional and genetic risk factors such as hypertension, diabetes mellitus, heart failure, and family history of cerebrovascular diseases. This risk increased with increasing number of genetic factors. The hazard ratio (HR) was 0.66 (95% confidence interval [CI] 0.97-2.67) for the subject with one genetic factor, 1.61 (95% CI 0.97-2.25) for combined methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and 2.57 (95% CI 1.32-4.99) for combined factor V Leiden (FVL) and MTHFR polymorphisms (677 or 1298). The HR for the three polymorphisms combined was 6.04 (95% CI 2.40-15.16)., Conclusions: Our findings suggest that cumulative effect of both traditional and common genetic risk factors was associated with recurrence of ischemic stroke. We demonstrated for the first time that a combined genotype FVL/MTHFR profile increase the risk of a second cerebral ischemic attack., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Estrogen receptors (ERs) relate to cardio-protection in adults, but their role in younger patients is not known. We aimed to assess the myocardial expression of ERα- and ERβ- mRNA in young patients with congenital cardiac disease and to analyze their putative protective role. Patients and Methods: Twenty children and young adults (seven females and 13 males) with a median age of 13.8 years (interquartile range: 12.3 years) were enrolled in this prospective study. The myocardial expression of ER-mRNA and genes involved in inflammation, growth, and stress response was assessed by real-time PCR and was correlated to post-operative (po) outcome. Results: ER-mRNA was detected in the myocardium of all patients, independently of gender and age. The expression of ER-mRNA correlated with that of mRNA coding for brain natriuretic peptide and for all cytokines tested. A higher ERα-mRNA expression correlated with lower troponin T concentrations at 24 h po ( p = 0.032), higher PaO 2 /FiO 2 ratio at 4 h po ( p = 0.059), lower fluid retention at 4 h po ( p = 0.048), and lower aspartate aminotransferase (AST) levels at 24 h po ( p = 0.047). A higher ERβ-mRNA expression was also correlated with lower fluid retention at 24 h po ( p = 0.048). Patients in whom the levels of ERα- and ERβ-mRNA were >P50 had lower troponin T ( p = 0.003, respectively) and lower AST concentrations at 24 h po ( p = 0.043, respectively) than the others. Conclusions: The expression of ERα- and ERβ-mRNA is present in the myocardium of children and young adults with congenital cardiac defect and is associated with lower markers of po organ damage. This suggests that ERs may provide perioperative organ protection in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rouatbi, Farhat, Heying, Vazquez-Jimenez, Parent and Seghaye.)

Pseudomonas aeruginosa (P. aeruginosa) displays high drug resistance and biofilm-mediated adaptability, which makes its infections difficult to treat. Alternative intervention methods and targets have made such infections treatment manageable. One of the biofilm components, functional amyloids of Pseudomonas (Fap) is correlated positively with virulence and mucoidy phenotype found in infection in cystic fibrosis (CF) patients. Extracellular accessibility, conservation across P. aeruginosa isolates and linkage with lung infections phenotype in CF patients, makes Fap a promising intervention target. Furthermore, the reported effect of bacterial amyloid on neuronal function and immune response makes it a targetable candidate. In the current study, Fap C protein and its immediate interactions were explored to extract antigenic T-cell and B-cell epitopes. A combination of epitopes and peptide adjuvants has been linked to derive vaccine candidate structures. The vaccine candidates were validated for antigenicity, allergenicity, physiochemical properties, stability and interactions with TLRs and MHC alleles. Immunosimulation studies have demonstrated that vaccines elicit Th1 dominated response, which can assist in good prognosis of infection in CF patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Plants native to extreme habitats often face changes in environmental conditions such as salinity level and water availability. In response, plants have evolved efficient mechanisms allowing them to survive or recover. In the present work, effects of high salinity and salt-stress release were studied on the halophyte Cakile maritima. Four week-old plants were either cultivated at 0 mM NaCl or 200 mM NaCl. After one month of treatment, plants were further irrigated at either 0 mM NaCl, 200 mM NaCl, or rewatered to 0 mM NaCl (stress release). Upon salt stress, C. maritima plants exhibited reduced biomass production and shoot hydration which were associated with a decrease in the amount of chlorophyll a and b. However, under the same stressful conditions a significant increase of anthocyanin and malonyldialdehyde concentrations was noticed. Salt-stressed plants were able to maintain stable protein complexes of thylakoid membranes. Measurement of chlorophyll fluorescence and P700 redox state showed that PSI was more susceptible for damage by salinity than PSII. PSII machinery was significantly enhanced under saline conditions. All measured parameters were partially restored under salt-stress release conditions. Photoinhibition of PSI was also reversible and C. maritima was able to successfully re-establish PSI machinery indicating the high contribution of chloroplasts in salt tolerance mechanisms of C. maritima. Overall, to overcome high salinity stress, C. maritima sets a cascade of physio-biochemical and molecular pathways. Chloroplasts seem to act as metabolic centers as part of this adaptive process enabling growth restoration in this halophyte following salt stress release., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: The COVID-19 pandemic has exacerbated disparities in poverty and illness for people in vulnerable circumstances in ethnocultural communities. We sought to understand the evolving impacts of COVID-19 on ethnocultural communities to inform intersectoral advocacy and community action., Methods: The Illuminate Project used participatory action research, with cultural health brokers as peer researchers, from Sept. 21 to Dec. 31, 2020, in Edmonton, Alberta. Twenty-one peer researchers collected narratives from members of ethnocultural communities and self-interpreted them as they entered the narratives into the SenseMaker platform, a mixed-method data collection tool. The entire research team analyzed real-time, aggregate, quantitative and qualitative data to identify emerging thematic domains, then visualized these domains with social network analysis., Results: Brokers serving diverse communities collected 773 narratives. Identified domains illuminate the evolving and entangled impacts of COVID-19 including the following: COVID-19 prevention and management; care of acute, chronic and serious illnesses other than COVID-19; maternal care; mental health and triggers of past trauma; financial insecurity; impact on children and youth and seniors; and legal concerns. We identified that community social capital and cultural brokering are key assets that facilitate access to formal health and social system supports., Interpretation: The Illuminate Project has illustrated the entangled, systemic issues that result in poor health among vulnerable members of ethnocultural communities, and the exacerbating effects of COVID-19, which also increased barriers to mitigation. Cultural brokering and community social capital are key supports for people during the COVID-19 pandemic. These findings can inform policy to reduce harm and support community resiliency., Competing Interests: Competing interests: Denise Campbell-Scherer reports participating on the Pfizer advisory panel on obesity, outside the submitted work. Yvonne Chiu is the executive director of the Multicultural Health Brokers Cooperative (MHBC) and acknowledges that MHBC relies on government grants for its operations and program delivery. Ali Mahdi, Aline Gayawira, Fransiska Awasis, Funke Olokude, Hannah Goa, Hina Syed, Judy Sillito, Lydia Yip, Lyn Belle, Mawien Akot, Monique Nutter, Nadia Farhat, Yan Wang, Niga Jalal, Saida Khalif, Shiva Chapagain, Stephanie Fernandez, Susan Azarcon, Zhewar Hama are employees of the MHBC. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

Desalination technology based on Reverse Osmosis (RO) membrane filtration has been resorted to provide high-quality drinking water. RO produced drinking water is characterized by a low bacterial cell concentration. Monitoring microbial quality and ensuring membrane-treated water safety has taken advantage of the rapid development of DNA-based techniques. However, the DNA extraction process from RO-based drinking water samples needs to be evaluated regarding the biomass amount (filtration volume) and residual disinfectant such as chlorine, as it can affect the DNA yield. We assessed the DNA recovery applied in drinking water microbiome studies as a function of (i) different filtration volumes, (ii) presence and absence of residual chlorine, and (iii) the addition of a known Escherichia coli concentration into the (sterile and non-sterile, chlorinated and dechlorinated) tap water prior filtration, and directly onto the (0.2 μm pore size, 47 mm diameter) mixed ester cellulose membrane filters without and after tap water filtration. Our findings demonstrated that the co-occurrence of residual chlorine and low biomass/cell density water samples (RO-treated water with a total cell concentration ranging between 2.47 × 102-1.5 × 103 cells/mL) failed to provide sufficient DNA quantity (below the threshold concentration required for sequencing-based procedures) irrespective of filtration volumes used (4, 20, 40, 60 L) and even after performing dechlorination. After exposure to tap water containing residual chlorine (0.2 mg/L), we observed a significant reduction of E. coli cell concentration and the degradation of its DNA (DNA yield was below detection limit) at a lower disinfectant level compared to what was previously reported, indicating that free-living bacteria and their DNA present in the drinking water are subject to the same conditions. The membrane spiking experiment confirmed no significant impact from any potential inhibitors (e.g. organic/inorganic components) present in the drinking water matrix on DNA extraction yield. We found that very low DNA content is likely to be the norm in chlorinated drinking water that gives hindsight to its limitation in providing robust results for any downstream molecular analyses for microbiome surveys. We advise that measurement of DNA yield is a necessary first step in chlorinated drinking water distribution systems (DWDSs) before conducting any downstream omics analyses such as amplicon sequencing to avoid inaccurate interpretations of results based on very low DNA content. This study expands a substantial source of bias in using DNA-based methods for low biomass samples typical in chlorinated DWDSs. Suggestions are provided for DNA-based research in drinking water with residual disinfectant., Competing Interests: The authors have declared that no competing interests exist.

Objective: To examine the frequency of specific learning disorder among primary school children., Methods: The cross-sectional study was conducted from January to July 2018 in Sarai Alamgir, Gujrat, Pakistan, and comprised children studying in 3rd and 4th grades of six local public and private primary schools. Data was collected using structured clinical diagnostic interviews based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Data was analysed using SPSS 16., Results: Of the 837 subjects, 413(49.3%) were from private schools and 424(50.7%) from public schools. A total of 174(20.7%) children were found vulnerable to specific learning disorders, while 13(7.5%) of them were diagnosed as suffering from different specific learning disorders. Of these 13 subjects, 1(7.7%) child had reading impairment, 3(23.1%) had mathematics impairment, 4(30.8%) had multiple impairment in mathematics and writing, 1(7.7%) had multiple impairment in mathematics and reading, 1(7.7%) had multiple impairment in reading and writing, and 3(23.1%) had multiple impairment in mathematics, reading and writing., Conclusions: Specific learning disorder was found to be prevailing in public and private school children.

Non-alcoholic fatty liver disease is the accumulation of triglycerides in liver. In its malignant form, it can proceed to steatohepatitis, fibrosis, cirrhosis, cancer and ultimately liver impairment, leading to liver transplantation. In a previous study, ultrasound-induced thermal strain imaging (US-TSI) was used to distinguish between excised fatty livers from obese mice and non-fatty livers from control mice. In this study, US-TSI was used to quantify lipid composition of fatty livers in ob/ob mice (n = 28) at various steatosis stages. A strong correlation coefficient was observed (R 2  = 0.85) between lipid composition measured with US-TSI and hepatic triglyceride content. Hepatic triglyceride content is used to quantify adipose tissue in liver. The ob/ob mice were divided into three groups based on the degree of steatosis that is used in clinics: none, mild and moderate. A non-parametric Kruskal-Wallis test was conducted to determine if US-TSI can potentially differentiate among the steatosis grades in non-alcoholic fatty liver disease., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Context: After primary infection, varicella zoster virus (VZV) becomes latent in ganglionic neurons. If immunity declines, VZV is reactivated and can spread to the dermatome depending from this ganglion and in some cases to the spinal cord. Myelopathy is rare and may develop in the absence of skin rash making the diagnosis very difficult., Findings: From 1994 to 2014, we collected five observations of clinically and laboratory confirmed zoster myelopathy. The age of our patients ranged from 14 to 78. They did not have any significant past medical history. Four patients had a history of radicular rash. After 3 weeks (4-45 days), patients presented paraparesis, sensory loss, and sphincter dysfunction. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level (5/5cases) and pleocytosis (2/5 cases). Spinal cord magnetic resonance imaging (MRI) demonstrated T2 hyper intense lesions with swelling and contrast enhancement. The diagnosis was supported by laboratory evidence, including the detection of VZV antibodies in the CSF. All patients received intravenous acyclovir and two patients received IV methylprednisolone. A marked improvement was observed in most of the patients within 2 months., Conclusion /clinical Relevance: Based on our patients and on previous reports, we highlight the possibility of the occurrence of VZV myelopathy in immunocompetent subjects. The diagnosis must be evoked even in the absence of typical skin lesions. In this case, spinal cord MRI and virological tests are useful tools for the diagnosis. We also emphasize on the importance of accurate diagnosis to enable the specific treatment and ameliorate the outcome.

Purpose: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease. Amniotic fluid stem cells (AFSC) improve NEC injury but human translation remains difficult. We aimed to evaluate the use of extracellular vesicles (EV) derived from human AFSC., Methods: Human AFSC (hAFSC) were cultured according to the protocol (Celprogen Inc., California, U.S.A.). Conditioned medium was obtained, ultra-centrifuged, and EV were suspended in phosphate-buffered saline (PBS). C57BL/6 pups were grouped into: (1) breast-fed (Control, n = 11); (2) NEC + placebo (NEC + PBS; n = 10); and (3) NEC + treatment (NEC + EV; n = 11). NEC was induced post-natal days P5-9 by (A) gavage feeding hyperosmolar formula; (B) hypoxia for 10 min; and (C) lipopolysaccharide. Intra-peritoneal injections of PBS or hAFSC-EV were given on P6-7. All animals were sacrificed on P9 and terminal ileum harvested., Results: hAFSC-EV administration reduced intestinal injury (p = 0.0048), NEC incidence (score ≥ 2), and intestinal inflammation (IL-6 p < 0.0001; TNF-α p < 0.0001). Intestinal stem cell expression (Lgr5 +) and cellular proliferation (Ki67) were enhanced above control levels following hAFSC-EV administration (Lgr5 p = 0.0003; Ki67 p < 0.0001)., Conclusion: hAFSC-EV administration reduced intestinal NEC injury and inflammation while increasing stem cell expression and cellular proliferation. hAFSC-EV administration may induce similar beneficial effects to exogenous stem cells.

Electromagnetic simulations are an important tool for the safety assessment of RF coils. They are a useful resource for MRI RF coil designers, especially when complemented with experimental measurements and testing using physical phantoms. Regular-shaped (spherical/cylindrical) homogeneous phantoms are the MRI standard for RF testing but are somewhat inaccurate when compared with anthropomorphic anatomies, especially at high frequencies. In this work, using a recently developed anthropomorphic heterogeneous human head phantom, studies were performed to analyze the scattering parameters (S-parameters) and the electric and magnetic field distributions using (1) the B 1 + field mapping method on a 7 T human MRI scanner and (2) numerical full-wave electromagnetic simulations. All studies used the following: a recently developed six-compartment refillable 3D-printed anthropomorphic head phantom (developed from MRI scans obtained in vivo), where the phantom itself is filled in its entirety with either heterogeneous loading, or homogeneous brain or water loading, in vivo imaging, and a commercial homogeneous spherical water phantom. Our results determined that the calculated S-parameters for all the anthropomorphic head phantom models were comparable to the model that is based on the volunteer (within 17% difference of the reflection coefficient value) but differed for the commercial homogeneous spherical water phantom (within 45% difference). The experimentally measured B 1 + field maps of the anthropomorphic heterogeneous and homogeneous brain head phantoms were most comparable to the in vivo measured values. The numerical simulations also show that both the anthropomorphic homogeneous water and brain phantom models were less accurate in terms of electric field intensities/distributions when compared with the segmented in-vivo-based head model and the anthropomorphic heterogeneous head phantom model. The presented data highlights the differences between the physical phantoms/phantom models, and the in vivo measurements/segmented in-vivo-based head model. The results demonstrate the usefulness of 3D-printed anthropomorphic phantoms for RF coil evaluation and testing., (© 2020 John Wiley & Sons, Ltd.)

Objectives:  The aim of the present in vitro study is to compare the remineralization brushing effect of three toothpastes and Aloe vera (AV) gel., Materials and Methods:  Forty sound extracted teeth were placed in a demineralizing solution for 4 days and randomly assigned to four groups: group A: 1,450-ppm fluoride toothpaste; group B: AV nonfluoridated toothpaste; group C: AV 1,000-ppm fluoridated toothpaste; and group D: AV gel. A 3-minute pH cycling was performed twice a day for each group for 12 days. Specimens were analyzed before and after by scanning electron microscope-energy dispersive X-ray., Statistical Analysis:  The outcomes were analyzed by Kolmogorov-Smirnov's tests, repeated-measures analyses of variance followed by univariate analyses, and Bonferroni's multiple comparisons tests to compare the calcium-to-phosphorus (Ca:P) ratio within time among toothpaste groups., Results:  Following remineralization, the Ca:P ratio increased in all groups. The difference of the Ca:P ratio was not significant between groups C, D, and A. The mean ratio was significantly lower in group B ( p -value = 0.026)., Conclusions:  The AV gel demonstrated a remineralization capacity equal to that of the 1,450-ppm fluoride toothpaste. In contrast, fluoride-free AV toothpaste showed a lower remineralization efficiency. Further studies are required to understand its mechanism., Competing Interests: None declared., (European Journal of Dentistry. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes organ dysfunction, including cerebral vasculopathy and neurological complications. Hippocampal segmentation with newer and advanced 7 Tesla (7T) MRI protocols has revealed atrophy in specific subregions in other neurodegenerative and neuroinflammatory diseases, however, there is limited evidence of hippocampal involvement in SCD. Thus, we explored whether SCD may be also associated with abnormalities in hippocampal subregions. We conducted 7T MRI imaging in individuals with SCD, including the HbSS, HbSC and HbS/beta thalassemia genotypes (n = 53), and healthy race and age-matched controls (n = 47), using a customized head coil. Both T1- and T2-weighted images were used for automatic segmentation of the hippocampal subfields. Individuals with SCD had, on average, significantly smaller volume of the region including the Dentate Gyrus and Cornu Ammonis (CA) 2 and 3 as compared to the control group. Other hippocampal subregions also showed a trend towards smaller volumes in the SCD group. These findings support and extend previous reports of reduced volume in the temporal lobe in SCD patients. Further studies are necessary to investigate the mechanisms that lead to structural changes in the hippocampus subfields and their relationship with cognitive performance in SCD patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Antibiotic resistance has become a global concern for healthcare workers and physicians. Efflux pumps are one of the major mechanisms of resistance. Hence, we describe examples of natural efflux pump inhibitors used to combat antibiotic resistance., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The rapid emergence of carbapenemase producing Gram-negative bacterial strains exhibit broad-spectrum β-lactam resistance, especially New Delhi metallo-β-lactamase (NDM-1). It is a major public health threat as it catalyses the hydrolysis of a vast variety of β-lactam antibiotics, including carbapenems, which is the last choice for physicians to treat infections. NDM-1 and its variants are continuously spreading worldwide, in spite of constant efforts to control. Its clinical treatment remains challenging due to continuous evolution of new variants. A thorough structural study of all variants is required to develop new and effective inhibitors. This review focuses on the dissemination, position of substitution and carbapenemases activity of all the 28 NDM variants so far reported., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally., Objective: To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1., Design, Setting, and Participants: Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019., Exposures: Oral miglustat at baseline and at follow-up., Main Outcomes and Measures: Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively., Results: Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29)., Conclusions and Relevance: These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.

Objectives: The objective of this study was to compare ICDAS and DMFT/S in the evaluation of caries status of the first permanent molar in 200 children aged 7 to 13 years., Methods: This was a cross-sectional design study. Participants were selected from two private schools in Lebanon. The examinations were performed by two trained and calibrated examiners using a dental mirror and a WHO probe. The number of decayed (D), missing (M) and filled (F) teeth was recorded in DMFT/S form, and the numbers related to D, M and F were then added to record the DMFT/S value (D1MFT/S, D2MFT/S and D3MFT/S). In the ICDAS, the assessment of caries associated with restorations and sealant was recorded. Student t tests/and Mann-Whitney tests were used to compare the continuous variables. Chi-square tests and Fisher exact tests were used to compare the categorical variables., Results: The average age of the participants was 9.21 ± 1.927 (7-13 years old). No significant difference was found between the mean time to score DMFT, DMFS and ICDAS indices (-p-value > 0.05). The prevalence of caries with D1MFS, D2MFS and D3MFS was 80.5%, 54% and 30.5%, respectively. However, the prevalence of caries with ICDAS II was 77.5%., Conclusion: The DMF index is an international user-friendly system that shows the carious history of teeth. However, the ICDAS assesses the different stages of caries and describes the restorative status of the tooth, promoting new preventive approaches and curative needs. More studies should be done to confirm these findings., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: Solitary bone plasmacytoma (SBP) are rare lesions, accounting for less than 5% of all plasma cell proliferations. We describe a case of a 21-year-old female with Trisomy 21 presenting with cauda equina compression from an SBP. Findings: Solitary bone plasmacytoma (SBP) is a rare primary bone tumor. It is characterized by monoclonal proliferation of malignant plasma cells localized to a bone segment, without signs of systemic invasion. The vertebral location is the most common. It preferentially affects men during their 5th or 6th decade. Clinical relevance: We report the first association between solitary bone plasmacytoma and Trisomy 21.

Background: The clinical implications of potential interactions between proton pump inhibitors (PPIs) and clopidogrel have been debated for over a decade., Objective: We assessed the association between combined clopidogrel-PPI treatment and the risk of recurrent myocardial infarction (MI) and three secondary outcomes., Patients and Methods: A nested case-control study was conducted within Cerner Corporation's Health Facts ® database. A retrospective cohort of patients who experienced a first MI and started clopidogrel treatment was created. Within this cohort, patients experiencing a second MI (cases) were matched with up to five controls. Logistic regression was used to estimate adjusted odds ratios (aORs). Findings were compared with those obtained from models with three negative control exposure drugs: H 2 receptor antagonists, prasugrel, and ticagrelor., Results: In total, 2890 recurrent MI cases were identified within 12 months following entry into the cohort of clopidogrel users (N = 52,006). aOR for PPI use versus non-use among clopidogrel users was 1.08 [95% confidence interval (CI) 0.95-1.23]. Similar ORs were obtained for secondary endpoints. A positive association between combined use of clopidogrel/PPIs and increased risk of MI was seen in the group aged 80-89 years (aOR 1.26; 95% CI 1.05-1.51). No associations with MI were observed for (1) H2 receptor antagonist use versus non-use among clopidogrel users or (2) PPI use versus non-use among prasugrel users or among ticagrelor users., Conclusions: Overall, our findings do not support a significant adverse clinical impact of concomitant clopidogrel/PPI use by patients with MI. Nonetheless, investigation of the possible association seen in those aged 80-89 years may be warranted.

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular disorders, caused by mutations in the dysferlin gene and characterized by a high degree of clinical variability even though within the same family. This study aims to describe three cases, belonging to a consanguineous Tunisian family, sharing a new splicing mutation in the dysferlin gene and presenting intra-familial variability of dysferlinopathies: Proximal-distal weakness and distal myopathy with anterior tibial onset. We performed the next generation sequencing for mutation screening and reverse transcriptase-PCR for gene expression analysis. Routine muscle histology was used for muscle biopsy processing. The clinical presentation demonstrated heterogeneous phenotypes between the three cases: Two presented intermediate phenotypes of dysferlinopathy with proximal-distal weakness and the third had a distal myopathy with anterior tibial onset. Genetic analysis yielded a homozygous splicing mutation (c.4597-2A>G) in the dysferlin gene, giving rise to the suppression of 28 bp of the exon 43. The splicing mutation found in our family (c.4597-2A>G) is responsible for the suppression of 28 bp of the exon 43 and a wide clinical intra-familial variability.

Context: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing., Objective: The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up., Design: We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care., Methods: All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome., Results: Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain., Conclusion: Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1., Method: Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community., Results: Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry., Conclusion: Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.

Introduction: Screening for anti-aquaporin 4 (anti-AQP4) antibodies, a specific marker of neuromyelitis optica spectrum disorders (NMOSD), is part of the immunological investigation performed in a context of central nervous system (CNS) inflammation with optic neuritis and/or myelitis. The aim of our study was to evaluate the prevalence and the diagnostic value of anti-AQP4 antibodies in Tunisian patients with such inflammatory neurological conditions., Methods: During 3years, 170 consecutive serum samples of Tunisian patients with CNS inflammatory disorders and optico-spinal involvement were tested in our laboratory for anti-AQP4 antibodies using indirect immunofluorescence on transfected cells., Results: The global seroprevalence of anti-AQP4 in our study was 4.1% (7 cases/170). The diagnosis of NMOSD was made for the 7 seropositive patients and for 2 seronegative patients, which leads to a seroprevalence of 77.7% in our NMOSD subgroup. The detection of anti-AQP4 allowed the diagnosis of NMOSD in 4 patients with incomplete clinical presentation and 5 patients with positive antinuclear antibodies. In one case, seropositivity was detected in a second sample, one year after an initial seronegativity., Conclusion: NMOSD seem to represent a rare etiology of optic neuritis and/or myelitis in Tunisian patients. Despite its low global seroprevalence in our study population, anti-AQP4 appears to be a very clinically relevant marker for NMOSD diagnosis. Repeating the screening in case of initial negativity could be interesting in clinical practice., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Aims: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination., Materials and Methods: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group)., Results: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated., Conclusions: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents., (© 2019 John Wiley & Sons Ltd.)

Introduction: cerebrovascular accident (stroke) constitutes a major public health problem due to the number of people affected and to its medical social and economic consequences. This study aims to identify poor vital prognostic factors for survival in patients with acute arterial stroke., Methods: we conducted a prospective study of patients with symptoms suggestive of stroke at the two University Hospitals of Sfax, Tunisia over a period of 4 months. Patients were followed-up for a period of 1 month., Results: we collected data from 200 patients. After one month of follow-up, mortality was 19.9%. Poor prognostic factors were: male sex, consumption of tobacco, a history of stroke, low Glasgow score, high NIHSS, headaches, acute symptomatic epileptic seizures, Babinski's sign, mydriasis, aphasia, combined deviation of the head and the eyes, high PAS, PAD and PAM, hyperthermia, hyperglycaemia, leukocytosis, high concentration of CRP, creatinine, urea and troponin T, haemorrhagic stroke, perilesional oedema, a mass effect, commitment, total middle cerebral artery topography of ischemia, early signs of ischemia, meningeal hemorrhage, ventricular flood, hydrocephalus, the recourse to respiratory support, to anti-edematous treatment and to antihypertensive therapy, hemorrhagic transformation, vascular epilepsy, infectious, metabolic complications, complications of bed sores., Conclusion: the identification of the predictive factors for survival allows for optimisation of therapeutic procedures and better implementation of patient' management. A comparative study will be considered to measure the impact of the corrective measures., Competing Interests: Les auteurs ne déclarent aucun conflit d’intérêts., (© Khadija Sonda Moalla et al.)

This paper describes data from a systematic review and meta-analysis [1] conducted to identify and evaluate published peer reviewed evidence on the association between perineal use of talc powder and risk of ovarian cancer. These data were collected from multiple electronic bibliographic databases, as well as from grey literature sources, without applying time, language or other filters. A meta-analysis was conducted to quantitatively assess the ovarian cancer risk in relation to talc use and other potential risk factors., (© 2020 The Authors.)

Introduction: Myocardial remodeling due to large atrial septum defect (ASD) is macroscopically characterized by dilation of the right-sided cardiac cavities secondary to volume overload, the cellular mechanisms of which are not yet understood. We postulated that inflammation, fibrosis, and cell death are actors of right atrial remodeling secondary to ASD. Patients and Methods: In 12 children with large ASD (median age: 63 months), expression of genes coding for proteins involved in the response to cell stress and -protection, inflammation, growth and angiogenesis, fibrosis, and apoptosis was assessed by RT-PCR in right atrial myocardial biopsies taken during cardiac surgery. The presence of cytokines in myocardial cells was confirmed by immunohistochemistry and effective apoptosis by TUNEL assay. Results: In all patients investigated, a cellular response to early mechanical stress with the initiation of early protective mechanisms, of inflammation (and its control), -growth, and -angiogenesis, of fibrosis and apoptosis was present. The apoptotic index assessed by TUNEL assay averaged 0.3%. Conclusions: In children with large ASD, macroscopic right atrial remodeling relates to cellular mechanisms involving the expression of numerous genes that either still act to protect cells and tissues but that also harm as they initiate and/or sustain inflammation, fibrosis, and cell death by apoptosis. This may contribute to long term morbidity in patients with ASD., (Copyright © 2020 Rouatbi, Farhat, Heying, Gérard, Vazquez-Jimenez and Seghaye.)

CAPN3 gene encodes for calpain-3; this protein is a calcium-dependent intracellular protease. Deficiency of this enzyme leads to weakness of the proximal limb muscles and pelvic and shoulder girdles, the so-called limb-girdle muscular dystrophy type 2A (LGMD2A). Here, we reported the case of a Tunisian patient with LGMD2A associated with a novel missense mutation (c.T1681C/p.Y561H). A 61-year-old man, with consanguineous parents, was referred for gait difficulties and slowly progressive proximal weakness of the four limbs associated with moderate hypertrophy of the calves but his facial muscles were unaffected. Electromyography showed that the profile was myopathic pattern and creatine kinase (CK) level was high. Muscle biopsy processing included routine histological, immunohistochemical, and Western Blot reactions, using a panel of antibodies directed against dystrophin, dysferlin, calpain-3, sarcoglycan α, β, γ, and δ. For mutation analysis, we designed an NGS-based screening. Immunological analyses demonstrated a total deficiency in calpain-3 and δ-sarcoglycan, and a reduced expression of dysferlin. The genetic study yielded a homozygous missense mutation (c.T1681C) of the 13th exon of the CAPN3 gene. The mutation found in our patient (c.T1681C/p.Y561H) has not been previously reported. It is responsible for complete calpain-3 and δ-sarcoglycan deficiency and reduced dysferlin expression. The genetic study is mandatory in such cases with multiple-protein deficiency and ambiguous results of immune-histology and Western Blot studies.

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer., Objectives: To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence., Methodology: We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis., Results: A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20-1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation., Conclusion: Perineal use of talc powder is a possible cause of human ovarian cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Five-word test (5WT) is a memory test to assess the verbal episodic memory. It measures the memory of subjects with memory impairment, in particular within the framework of the diagnosis of Alzheimer's disease, where it is sensitive and specific. The purpose of our study was to evaluate the effect of different sociodemographic parameters on subject's performance, to set standards relevant to Tunisian population and to compare our results to previous studies., Methods: We report 5WT calibration in 315 normal subjects aged 40 to 90 years (169 men, 146 women), divided into four age groups (40-49,50-59,60-69 and 70 years) having three levels of education (I: primary, II:secondary and III:higher). We calculated the mean score (standard deviation) for the different scores: Total Score (TS), Total Weighted Score (TWS), Delayed Free Recall (DFR), Total Delayed Recall (TDR) and Total Free Recall (TFR)., Results: The average age of subjects was 57.29 years (11.02). Performances appeared to be better in youngest and better educated subjects, without any significant difference between the two sexes. Standards were calculated on the basis of age and levels of education., Conclusion: Five-word test allows rapid screening of patients in whom complementary neuropsychological assessment is essential for the diagnosis of cognitive disorders., Competing Interests: Les auteurs ne déclarent aucun conflit d’intérêts., (© Nadia Bouattour et al.)