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Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

IntroductionAtaxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease.MethodsWe enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls.ResultsWe observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation.DiscussionWe identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.

Graphitic carbon nitride (g-C3N4) is a metal-free photocatalyst active under visible light but exhibits low photocatalytic activity due to its low specific surface area and fast recombination rates. However, it is possible to enhance its effectiveness and performance can be significantly improved by preparing composites of g-C3N4 with activated carbon (AC). In this manuscript, agave bagasse was employed as a precursor for activated carbon ranging from relatively low, medium and high porosity. The ability of the g-C3N4/activated carbon composite to degrade isobutanol as a model odorous VOC was evaluated under visible light. Different activation/deactivation phenomena were observed at different operation times. It was found that materials with higher porosity presented a higher level of degradation of the model VOC. However, synergy between the materials was demonstrated for the dynamic removal of isobutanol. These results demonstrate the synthesis of a composite with photocatalytic and adsorption properties based on g-C3N4 supported on activated carbon obtained from agave bagasse, which could contribute to the development of green photocatalytic materials and serve as an alternative for managing waste from the tequila industry.

Background and Aims: Hypoalbuminemia, as defined by serum albumin (SA) levels ≤35 g/L, is associated to venous and arterial thrombosis in general population and in patients at risk of cardiovascular disease. It is unknown if SA ≤35 g/L is also associated to portal vein thrombosis (PVT) in cirrhosis. Methods: Cirrhotic patients enrolled in the Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry (PRO-LIVER) study (n = 753), were followed-up for 2 years to assess the risk of PVT, that was diagnosed by Doppler ultrasonography. Child-Pugh classes, Model for End-Stage Liver Disease score, presence of hepatocellular carcinoma and laboratory variables including SA, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline. Results: SA ≤35 g/L was detected in 52% of patients. A logistic multivariate regression analysis showed that higher Child-Pugh class, hepatocellular carcinoma and thrombocytopenia were significantly associated to SA ≤35 g/L. In a subgroup of patients where data regarding hs-CRP and D-dimer were available, SA ≤35 g/L was inversely associated with hs-CRP and D-dimer. During the follow-up, a total of 61 patients experienced PVT. A Kaplan Meier survival analysis showed SA ≤35 g/L was associated to increased risk of PVT compared to SA >35 g/L (P = .005). A multivariate Cox proportional hazards regression analysis showed that male sex, lower platelet count, and SA ≤35 g/L remained associated to PVT after adjusting for confounding factors. Conclusion: Cirrhotic patients with SA ≤35 g/L are at higher risk of experiencing PVT compared to those with SA >35 g/L and could be considered as potential candidates to anticoagulant prophylaxis for PVT prevention.

To date, the effect of blinatumomab and donor lymphocyte infusion association as a salvage treatment for acute lymphoblastic leukemia (ALL) relapse after allogeneic transplant procedure is still unknown. Here, we report a case report of a patient with early relapse of ALL after allogeneic hematopoietic stem cell transplant successfully treated with a combination of blinatumomab and DLI.

ABSTRACTBackground The Michigan State College of Human Medicine began as an experiment to teach medical students in community-based settings and to create a primary care workforce for the state. Decades later, CHM faced internal and external challenges that spurred creation of a new curriculum – the Share Discovery Curriculum – founded on learning by doing and other learning theories.Methods A curricular design group (CDG) developed guiding principles for reform. Based on this, pedagogies and structures were selected to achieve this vision and developed into a curricular structure. Components of the first-year curriculum were piloted with a group of students and faculty members.Results Six guiding principles were endorsed, grounded in learning theories such as Dewey’s Learning by Doing. Based upon these, several key features of the new curriculum emerged: learning communities; one-on-one coaches for students; symptom-based presentations for content; simulation, authentic clinical tasks, flipped classrooms, and modified practice-based learning as primary teaching modalities; early, integrated clinical and scientific learning; milestones as course learning objectives; and a multidimensional, competency-based assessment system.Discussion The process and outcomes described here are intended as an exemplar for schools undertaking curricular change. Early stakeholder engagement, faculty development, sustainable administrative systems, and managing complexity are core to the success of such endeavors.

Purpose: To perform a scoping review to determine what is known about emotional intelligence (EI) in undergraduate medical education (UME). Two main questions were asked: (1) What medical student characteristics are associated with EI? Are there correlations with demographic or other factors?; and (2) What research studies have been done on EI in UME? For example, is there evidence EI changes over time as a result of personal experiences? Should EI be used as an admission criterion? Can EI improve as a result of experiences or deliberate interventions? Method: The authors searched four databases (PubMed, PsycInfo, Education Resources Information Center, and Web of Science) for all papers published up to and including December 2020. Two reviewers independently screened articles to determine if they met inclusion criteria. All authors extracted and analyzed data. Results: A set of 1520 papers on the topic of emotional intelligence was identified, with 119 papers meeting inclusion criteria. Most studies were done at international locations with only 17 done at US medical schools. Seventy-five were cohort or cross-sectional studies. Study populations were mixed among the studies, with year of medical study, inclusion of other healthcare students, and participation rates among the inter-study differences noted. Conclusions: Numerous gaps in the literature on EI exist with several points being clear: (1) there is disagreement on the definition of EI; (2) it is undetermined whether EI is a trait or an ability; and (3) there is marked variability among the instruments used to measure EI. It is also becoming apparent that using EI determination may be helpful as a component of the admission process, higher EI is likely related to improved clinical reasoning, and higher EI contributes to more effective stress management.

Abstract Background Headache is among the most frequent symptoms of acute COVID-19 infection. Its mechanisms remain obscure, but due to its migraine-like characteristics, the activation of the trigeminal system could account for its underlying pathophysiology. Methods Our aim was to compare the serum levels of CGRP, as a theoretical marker of trigemino-vascular activation, in 25 COVID-19 inpatients with lung involvement experiencing headache, against 15 COVID-19 inpatients without headache and with those of 25 matched healthy controls with no headache history. Results Morning serum alpha-CGRP levels, as measured by ELISA (Abbexa, UK), were increased in COVID-19 patients with headache (55.2±34.3 pg/mL) vs. controls (33.9±14.0 pg/mL) (p

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

In this study, molecular typing using Randomly Amplified Polymorphic DNA (RAPD-PCR) was conducted on 16 original isolates of Metarhizium acridum obtained from locusts (Schistocerca piceifrons ssp. piceifrons.) in Mexico (MX). The analysis included reference strains of the genus Metarhizium sourced from various geographical regions. The isolates were identified by phenotypic (macro and micromorphology) and genotypic methods (RAPD-PCR and Amplified Fragment Length Polymorphisms (AFLP), through a multidimensional analysis of principal coordinates (PCoA) and a minimum spanning network (MST). Subsequently, Sequences-Characterized Amplified Region (SCAR) markers were developed for the molecular detection of M. acridum, these markers were chosen from polymorphic patterns obtained with 14 primers via RAPD-PCR. Phenotypic and genotypic characterization identified the MX isolates as M. acridum. Of all the polymorphic patterns obtained, only OPA04 and OPA05 were chosen, which presented species-specific bands for M. acridum, and further utilized to create SCAR markers through cloning and sequencing of the specific bands. The specificity of these two markers was confirmed via Southern hybridization. The SCAR markers (Ma-160OPA-05 and Ma-151OPA-04) exhibit remarkable sensitivity, detecting down to less than 0.1 ng, as well as high specificity, as evidenced by their inability to cross-amplify or generate amplification with DNAs from other strains of Metarhizium (as Metarhizium anisopliae) or different genera of entomopathogenic fungi (Cordyceps fumosorosea and Akanthomyces lecanii). These SCAR markers yield readily detectable results, showcasing high reproducibility. They serve as a valuable tool, especially in field applications.

Background and aimsWiskott–Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data.MethodsHerein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed.ResultsThe patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by WAS gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP− population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT.ConclusionHere, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients.

IntroductionMiller Fisher syndrome (MFS) is considered a rare variant of Guillain-Barré syndrome (GBS), a group of acute-onset immune-mediated neuropathies characterized by the classic triad of ataxia, areflexia, and ophthalmoparesis. The present review aimed to provide a detailed and updated profile of all aspects of the syndrome through a collection of published articles on the subject, ranging from the initial description to recent developments related to COVID-19.MethodsWe searched PubMed, Scopus, EMBASE, and Web of Science databases and gray literature, including references from the identified studies, review studies, and conference abstracts on this topic. We used all MeSH terms pertaining to “Miller Fisher syndrome,” “Miller Fisher,” “Fisher syndrome,” and “anti-GQ1b antibody.”ResultsAn extensive bibliography was researched and summarized in the review from an initial profile of MFS since its description to the recent accounts of diagnosis in COVID-19 patients. MFS is an immune-mediated disease with onset most frequently following infection. Anti-ganglioside GQ1b antibodies, detected in ~85% of patients, play a role in the pathogenesis of the syndrome. There are usually no abnormalities in MFS through routine neuroimaging. In rare cases, neuroimaging shows nerve root enhancement and signs of the involvement of the central nervous system. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. Although MFS is generally self-limited and has excellent prognosis, rare recurrent forms have been documented.ConclusionThis article gives an updated narrative review of MFS with special emphasis on clinical characteristics, neurophysiology, treatment, and prognosis of MFS patients.

Resumen: Introducción: El trastorno por estrés postraumático (TEPT) se ha postulado como un factor de cronificación de la migraña. Nuestro objetivo fue investigar la frecuencia del TEPT y los eventos vitales traumáticos (ET) en pacientes con migraña episódica (ME) y crónica (MC) y su impacto sobre parámetros clínicos, otras comorbilidades y biomarcadores de migraña. Material y métodos: Se reclutó a pacientes con ME y MC según CIC-3β en una Unidad de Cefaleas y un centro de Atención Primaria. Se utilizaron cuestionarios validados para investigar TEPT, ET, síntomas autonómicos craneales, comorbilidades (depresión, ansiedad, fatiga), discapacidad, impacto de la migraña y calidad de vida. Se determinaron los niveles séricos basales de CGRP, VIP y PACAP por ELISA. Resultados: Ciento dieciséis pacientes fueron incluidos: 35 ME y 81 MC; 19 sufrían migraña refractaria (MR). Se detectó TEPT en 23 casos (19,8%): 20 MC y 3 ME (χ2 p = 0,046; T de Fisher p = 0,073). La frecuencia de ningún ET ni el número de ET por paciente fue diferente entre MC y ME; 5/19 MR habían sufrido violación (vs. 2/97 no MR; p = 0,002). El TEPT se asoció con más síntomas autonómicos, mayor puntuación en escalas de ansiedad, depresión y fatiga, y menor calidad de vida, y no modificó los niveles de neuropéptidos. Conclusiones: Este estudio sugiere que el TEPT es frecuente en pacientes con migraña, especialmente MC, también en nuestro medio, y que particularmente el antecedente de violencia sexual es frecuente en MR. El TEPT impacta negativamente sobre la migraña, asociando más comorbilidades y peor calidad de vida, por lo que es preciso investigarlo en estos pacientes. Abstract: Introduction: Post-traumatic stress disorder (PTSD) has been proposed as a risk factor for migraine chronification. The aim of this study was to investigate the frequency of PTSD and traumatic life events (TE) in patients with episodic migraine (EM) and chronic migraine (CM) and their impact on clinical parameters, other comorbidities, and migraine biomarkers. Material and methods: Patients with EM and CM ICHD-3Beta according to the International Classification of Headache Disorders (third edition; beta version) were recruited at a headache unit and a primary care centre. We used validated questionnaires to investigate PTSD, TE, cranial autonomic symptoms, comorbidities (depression, anxiety, and fatigue), disability, migraine impact, and quality of life. Baseline serum levels of CGRP, VIP, and PACAP were determined by ELISA. Results: The study included 116 patients: 35 with EM and 81 with CM. Nineteen presented refractory migraine (RM). PTSD was detected in 23 patients (19.8%): 20 with CM and 3 with EM (chi-square: P=.046; Fisher T: P=.073). Neither the frequency of any TE nor the number of TEs per patient were different between CM and EM. A total of 5/19 patients with RM had experienced sexual violence (vs 2/97 with non-RM; P=.002). PTSD was associated with more autonomic symptoms; higher scores on anxiety, depression, and fatigue scales; and poorer quality of life; and it did not change neuropeptide levels. Conclusions: Our results suggest that PTSD is frequent in patients with migraine, and especially CM, in our setting; history of sexual violence is particularly frequent in patients with RM. PTSD has a negative impact on migraine, with higher numbers of comorbidities and poorer quality of life; therefore, further research is needed in this patient group.