Coexistent HCN4 and GATA5 rare variants and Atrial Fibrillation in a large Spanish Family.

BACKGROUND: Familial association of atrial fibrillation (AF) can involve single gene variants related to known arrhythmogenic mechanisms; however, genome-wide association studies often disclose complex genetic variants in familial and non-familial AF, making it difficult to relate to known pathogenetic mechanisms. METHODS: The finding of 4 siblings with AF led to studying 47 members of a family. Long-term Holter monitoring (298 hours average) ruled out silent AFWhole-exome sequencing was performed and variants shared by the index cases were filtered and prioritized according to current recommendations. HCN4 currents (IHCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H and/or native Hcn4 channels using the patch-clamp technique and topologically associated domain analysis of GATA5 variant carriers were performed. RESULTS: The clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H, HCN4 variant, 14 the intronic 20,61040536,G,A GATA5 rare variant, and 9 carried both variants (HCN4+GATA5). Five of the 6 AF cases (onset age ranging 33-70 years) carried both variants and one the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly and independently increased AF risk [OR=32.740 (1.812-591.408)] and not age, hypertension or overweight. Functional testing showed that IHcn4 generated by heterozygous p.P1163H were normal. Topologically associating domain analysis suggested that GATA5 could affect the expression of many genes, including those encoding microRNA-1. CONCLUSION: The coincidence of two rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanism(s) involved.

Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

Valoración de un nuevo apósito para úlceras por presión: a propósito de un caso / Assessment for a new dressing for pressure ulcers: regarding a case

El objetivo de este estudio fue valorar la aplicación de un nuevo apósito superabsorbente a propósito de un caso clínico de un paciente con una úlcera por presión (UPP) con alto nivel exudativo, maceración de la piel perilesional, molestias y dolor. El paciente presentaba múltiples comorbilidades, estaba institucionalizado, desorientado, y presentaba una UPP grado IV. Accedió a comenzar un tratamiento con un apósito superabsorbente de nueva implementación en la institución. Se realizó una valoración en conjunto con su enfermera de la residencia según las Necesidades de Virginia Henderson. Según los resultados de dicha valoración se enunció un plan de cuidados con Diagnósticos NANDA, Resultados NOC con sus indicadores e Intervenciones NIC con sus actividades. Se priorizaron cuatro diagnósticos enfermeros: [00032] Patrón respiratorio ineficaz, [00129] Confusión crónica, [00312] Lesión por presión en el adulto y [00132] Dolor agudo. Los resultados NOC enunciados fueron [0402] Estado respiratorio: intercambio gaseoso, [0912] Estado neurológico: consciencia, [1101] Integridad tisular: piel y membranas mucosas, [110123] Necrosis, [1103] Curación de la herida: por segunda intención, [1004] Estado nutricional y [2109] Nivel de malestar. El plan de cuidados fue eficaz en el alcance de la puntuación diana de todos los indicadores excepto el indicador [110115] Lesiones cutáneas, cuya puntuación al alta se mantuvo igual que al ingreso, en 1 “grave”. El nuevo apósito disminuyó el exudado de la úlcera, redujo el tejido necrotizado y mejoró los bordes perilesionales. Esto mejoró a su vez el malestar del paciente al disminuir la frecuencia de cura de tres veces al día a una.(AU)

The objective of this study was to assess the application of a new super absorbent dressing, regarding the clinical case of a patient with one pressure ulcer (PU) with high levels of exudate, maceration of the perilesional skin, discomfort and pain. The patient presented multiple comorbidities; he was institutionalized, disoriented, and presented a Grade IV PU. The patient agreed to initiate treatment with a super absorbent dressing newly implemented at the institution. There was joint assessment with his nurse at the elderly home, according to Virginia Henderson’s Needs. Based on the results of said assessment, a plan of care was stated with NANDA diagnoses, NOC outcomes with their indicators, and NIC interventions with their activities. Four nursing diagnoses were prioritized: [00032] Ineffective breathing pattern, [00129] Chronic confusion, [00312] Pressure lesion in adults, and [00132] Acute pain. The NOC outcomes stated were [0402] Respiratory Status: Gas Exchange, [0912] Neurological status: Consciousness; [1101] Tissue Integrity: Skin and mucous membranes, [110123] Necrosis, [1103] Wound healing: Second intention, [1004] Nutritional status, and [2109] Discomfort level. The plan of care was effective at reaching the target score in all indicators except for [110115] Skin lesions with high score that stays the same than at admission, at 1 “severe”. The new dressing reduced the ulcer exudate and the necrotic tissue, and improved the perilesional edges. At the same time, there was an improvement in discomfort for the patient by reducing the frequency of cures from three times to once a day.(AU)

Antimigration versus conventional fully covered metal stents in the endoscopic treatment of anastomotic biliary strictures after deceased-donor liver transplantation.

INTRODUCTION: Migration of fully covered metal stents (FCMS) remains a limitation of the endoscopic treatment of anastomotic biliary strictures (ABS) following orthotopic liver transplantation (OLT). The use of antimigration FCMS (A-FCMS) might enhance endoscopic treatment outcomes for ABS. METHODS: Single center retrospective study. Consecutive patients with ABS following OLT who underwent ERCP with FCMS placement between January 2005 and December 2020 were eligible. Subjects were grouped into conventional-FCMS (C-FCMS) and A-FCMS. The primary outcome was stent migration rates. Secondary outcomes were stricture resolution, adverse event, and recurrence rates. RESULTS: A total of 102 (40 C-FCMS; 62 A-FCMS) patients were included. Stent migration was identified at the first revision in 24 C-FCMS patients (63.2%) and in 21 A-FCMS patients (36.2%) (p = 0.01). The overall migration rate, including the first and subsequent endoscopic revisions, was 65.8% in C-FCMS and 37.3% in A-FCMS (p = 0.006). The stricture resolution rate at the first endoscopic revision was similar in both groups (60.0 vs 61.3%, p = 0.87). Final stricture resolution was achieved in 95 patients (93.1%), with no difference across groups (92.5 vs 93.5%; p = 0.84). Adverse events were identified in 13 patients (12.1%) with no difference across groups. At a median follow-up of 52 (IQR: 19-85.5) months after stricture resolution, 25 patients (24.5%) developed recurrences, with no difference across groups (C-FCMS 30% vs A-FCMS 21%; p = 0.28). CONCLUSIONS: The use of A-FCMS during ERCP for ABS following OLT results in significantly lower stent migration rates compared to C-FCMS. However, the clinical benefit of reduced stent migration is unclear. Larger studies focusing on stricture resolution and recurrence rates are needed.

Reassessment of the electrical connection between the pulmonary veins and the left atrium: A study to determine the different contributions of myocardial fibers along the standard ablation circumference.

Background: Circumferential ablation around the ipsilateral pulmonary veins (PVs) is the standard strategy for atrial fibrillation ablation. The present study seeks to assess which regions of the standard ablation circumference are the main contributors to the venoatrial electrical connection. Methods: A total of 41 patients were included under a specific atrial fibrillation ablation protocol in which the anterior and posterior segments of the standard circumference, between the equatorial line of the superior and the inferior ipsilateral PVs, were ablated first. If PV isolation was not achieved, ablation was extended superiorly or inferiorly, on the basis of the earliest atrial activation recorded during pacing from inside the PV. Complete PV isolation and the length of the areas not requiring ablation (ANRA) at the time of electrical isolation were evaluated. Results: Ablation of the anterior and posterior segments of the standard circumference led to the isolation of 77% left-PV pairs and 51% right-PV pairs (p = 0,015). A superior extension was required in 23% left-PV pairs and in 46% right-PV pairs, while an inferior extension was required only in 10% left-PV pairs and in 11% right-PV pairs. PV isolation was achieved before completing the standard ablation circumference in 97% left-PV pairs and in 94% right-PV pairs, with a median ANRA of 36.9 (IQR: 30.9-42.1) mm in the left PVs [16.0 (IQR: 12.0-19.0) mm superior and 18.8 (IQR: 16.1-24.9) mm inferior, p < 0.01] and 36.9 (IQR: 30.2-41.0) mm in the right PVs [15.1 (IQR: 10.7-19.1) mm superior and 20.6 (IQR: 16.9-23.3) mm inferior, p < 0.01]. Conclusions: The myocardial fibers along the anterior and posterior regions of the standard ablation circumference are the main contributors to the electrical connection between the pulmonary veins and the left atrium. Ablation of these regions results in PV isolation in the majority of patients.

The impact of obesity on postoperative complications and short-term survival after liver transplantation.

BACKGROUND AND AIMS: Obesity is considered a risk factor for perioperative complications, but its effect on patients undergoing liver transplantation (LT) remains unclear. This study was conducted to analyze the impact of obesity on early morbidity and mortality risk following LT. METHODS: A multicenter study of outcomes in patients submitted to LT between 2009 and 2019 was conducted. Recipients were stratified into obese (BMI ≥ 30 kg/m2) and nonobese patients (BMI < 30 kg/m2). Early postoperative complications were compared and 30-day and 1-year patient and graft survival were assessed by Kaplan-Meier method. Primary graft nonfunction (PGNF) was defined as the presence of total bilirubin > 10 mg/dl, INR > 1.6 or ALT > 2000 U/l within the first week after LT. RESULTS: A total of 1608 patients were included after applying exclusion criteria, nonobese (1149, 71.46%) and obese patients (459, 28.54%). There were no significant differences in age, sex, Model for End-stage Liver Disease, Charlson comorbidity score, ethnicity, waiting list time and ischemia time. There were significantly higher rates of vascular (17.58% vs 23.53%, P = 0.021) and biliary complications (27.68% vs 35.73%, P = 0.006) and PGNF (11.40% vs 12.20%, P = 0.021) in obese patients. There was a significantly increased risk for long-term graft failure; however, there was no significant difference in patient survival after LT. CONCLUSION: Obese patients have significantly increased morbidity in terms of vascular and biliary complications and PGNF after LT. They have a higher risk for worse 1-year graft survival in comparison to controls.

Esophageal necrosis secondary to thoracic aortic aneurysm.

We present the case of a 78-year-old man with dyslipidemia with ongoing treatment with statins. He was admitted for a history of 3-month dysphagia and weight loss. The physical exam was unremarkable. Blood tests revealed anemia (hemoglobin 11,5 g/dL). Gastroscopy showed a partially stenotic bulging ulcer in the middle esophagus, with a fibrinous base and residual clot Histopathology ruled out any malignancy and confirmed the presence of transmural necrosis with infiltration of inflammatory cells. Computed tomography (CT) revealed a 11x11x12 cm thoracic aortic aneurysm, with an intramural 4 cm thrombus in the anterolateral wall. The patient was referred for urgent Vascular Surgery, but unfortunately, he presented massive hematemesis with cardiorespiratory arrest, and despite cardiopulmonary resuscitation, he died.

Prevalence and prognosis of anxiety, insomnia, and type D personality in patients with myocardial infarction: A Spanish cohort.

BACKGROUND: It has been suggested that patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) have more psycho-emotional disorders than patients with obstructive coronary artery disease (MICAD). The aim of this study is to compare the prevalence of anxiety, insomnia, and type D personality between MINOCA and MICAD and their impact on prognosis. METHODS: Patients with myocardial infarction undergoing coronary angiography were prospectively enrolled. Psychological questionnaires were completed by each patient during admission. RESULTS: Among a total of 533 patients, 56 had MINOCA and 477 had MICAD. There were no differences in the prevalence of anxiety and insomnia between both groups: trait anxiety median value (M) MINOCA = 18 (11-34) vs. MICAD M = 19 (12-27), p = 0.8; state anxiety MINOCA M = 19 (11-29) vs. MICAD M = 19 (12.2-26), p = 0.6; and insomnia MINOCA M = 7 (3-11) vs. MICAD M = 7 (3-12), p = 0.95. More MINOCA patients had type D personality (45.0% vs. 28.5%, p = 0.03). At 3-year follow-up, there were no differences in mortality between MINOCA and MICAD (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.28-2.17) in major adverse cerebral or cardiovascular events (MACCE) (HR 0.71, 95% CI 0.38-1.31). Scores of trait anxiety and negative affectivity were significantly associated with MACCE (HR 1.65, 95% CI [1.05-2.57]; HR 1.75, 95% CI [1.11-2.77], respectively). High insomnia levels were associated with greater mortality (HR 2.72, 95% CI [1.12-6.61]). CONCLUSIONS: Anxiety and insomnia levels were similar between patients with MINOCA and those with MICAD, whilst the prevalence of type D personality was higher in the MINOCA than in the MICAD group. Higher scores in trait anxiety, insomnia, and negative affectivity were related to a worse prognosis at 3-year follow-up.

Cardiovascular disease in women: Do we need new diagnostic and therapeutic strategies?

Cardiovascular disease (CVD) is the leading cause of death worldwide affecting both sexes equally. However, in comparison to men, in women, it often is underrecognized and undertreated in both primary and secondary prevention settings. It is clear, that in the healthy population, there are profound differences both anatomically and biochemically between women and men, and this may impact how both groups present when they become ill. Moreover, some diseases affect more frequently women than men such as myocardial ischemia or infarction without obstructive coronary disease, Takotsubo syndrome, some atrial arrhythmias, or heart failure with preserved ejection fraction. Therefore, diagnostic and therapeutic strategies that have been established largely on the basis of clinical studies with a predominantly male population must be adapted before being applied to women. There is a paucity of data regarding cardiovascular disease in women. It is inadequate to only perform a subgroup analysis evaluating a specific treatment or invasive technique when women constitute fifty percent of the population. In this regard, this may affect the time of clinical diagnosis and severity assessments of some valvulopathies. In this review, we will focus on the differences in the diagnosis, management, and outcomes for women with the most frequent cardiovascular pathologies including coronary artery disease, arrhythmia, heart failure, and valvopathies. In addition, we will describe diseases that exclusively affect women that are related to pregnancy, and some of them are life-threatening. Although the lack of research on women plays a role in the poorer outcomes in women, especially in ischemic heart disease, some techniques such as transcatheter aortic valve implantation and transcatheter edge-to-edge therapy seem to have better outcomes in women.

Absence of High Lipoprotein(a) Levels Is an Independent Predictor of Acute Myocardial Infarction without Coronary Lesions.

The pathophysiological mechanisms underlying Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA) are still under debate. Lipoprotein (a) [Lp(a)] has proinflammatory and prothrombotic actions and has been involved in the pathogenesis of atherosclerosis. However, no previous studies have linked Lp(a) levels with the probability of developing MINOCA. Moreover, the relationship between MINOCA and the plasma levels of other proatherogenic and proinflammatory molecules such as Interleukin-18 (IL18) and proprotein convertase subtilisin/kexin type 9 (PCSK9) has not been studied. We conducted a prospective, multicenter study involving 1042 patients with acute myocardial infarction (AMI). Seventy-six patients had no significant coronary lesions. All patients underwent plasma analysis on admission. MINOCA patients were younger (57 (47-68) vs. 61 (52-72) years; p = 0.010), more frequently female (44.7% vs. 21.0%; p < 0.001), and had lower rates of diabetes and of Lp(a) > 60 mg/dL (9.2% vs. 19.8%; p = 0.037) than those with coronary lesions; moreover, High Density Lipoprotein cholesterol (HDL-c) levels were higher in MINOCA patients. The absence of Lp(a) > 60 mg/dL and of diabetes were independent predictors of MINOCA, as well as female sex, high HDL-c levels, and younger age. IL-18 and PCSK9 levels were not predictors of MINOCA. During a follow-up of 5.23 (2.89, 7.37) years, the independent predictors of the primary outcome (acute ischemic events or death) in the whole sample were Lp(a) > 60 mg/dL, older age, low estimated Glomerular Filtration rate (eGFR), hypertension, previous heart failure (HF), coronary artery bypass graft, use of insulin, and no therapy with acetylsalicylic acid. In conclusion, in AMI patients, the absence of high Lp(a) levels, as well high HDL-c levels, were independent predictors of the inexistence of coronary artery disease. High Lp (a) levels were also an independent predictor of ischemic events or death.

A symbolic Neanderthal accumulation of large herbivore crania.

This work examines the possible behaviour of Neanderthal groups at the Cueva Des-Cubierta (central Spain) via the analysis of the latter's archaeological assemblage. Alongside evidence of Mousterian lithic industry, Level 3 of the cave infill was found to contain an assemblage of mammalian bone remains dominated by the crania of large ungulates, some associated with small hearths. The scarcity of post-cranial elements, teeth, mandibles and maxillae, along with evidence of anthropogenic modification of the crania (cut and percussion marks), indicates that the carcasses of the corresponding animals were initially processed outside the cave, and the crania were later brought inside. A second round of processing then took place, possibly related to the removal of the brain. The continued presence of crania throughout Level 3 indicates that this behaviour was recurrent during this level's formation. This behaviour seems to have no subsistence-related purpose but to be more symbolic in its intent.

DRESS syndrome secondary to carbamazepine.

DRESS syndrome is a multisystem disorder that appears in the context of an adverse drug reaction, characterized by fever, rash and peripheral eosinophilia with involvement of other organs such as the liver. The typical liver involvement is acute toxic hepatitis (DILI), showing improvement and a tendency to resolution when corticotherapy is started. We must not forget this manifestation in the clinical context of a DRESS syndrome.

Severity of new-onset type 1 diabetes in children and adolescents during the coronavirus-19 disease pandemic.

INTRODUCTION: ß-pancreatic cells are susceptible to SARS-CoV-2 infection and replication; this could lead to infection-related diabetes or precipitate the onset of type 1 diabetes. This study aimed to determine the severity at diagnosis, analyzing clinical and epidemiological features at debut in children under 16 years of age in the context of the SARS-CoV-2 pandemic. MATERIAL AND METHODS: A retrospective observational multicenter study was carried out in 7 hospitals of the public health network located in the south of our community. The severity at debut is compared with that of the two previous years (2018 and 2019). The level of statistical significance is set at p<0.05. RESULTS: In 2020, 61 patients debuted at the 7 hospital centres. The mean age was 10.1 years (SD: 2.6), 50.8% older than 10 years. The clinical profile at diagnosis was ketoacidosis in 52.5% compared to 39.5% and 26.5% in the previous two years (p<0.01). The mean pH (7.24 vs 7.30/7.30) and excess of bases (-11.9 vs -7.43/-7.9) was lower than in the previous two years, and the glycated haemoglobin higher (11.9 vs 11/10.6), p<0.05. At least 10% of the patients had a positive history of SARS-CoV-2 infection. CONCLUSIONS: There has been an increase in the frequency of diabetic ketoacidosis in type 1 diabetes onset during the first year of the COVID-19 pandemic.

Impact of Pain Neuroscience Education Program in Community Physiotherapy Context on Pain Perception and Psychosocial Variables Associated with It in Elderly Persons: A Ranzomized Controlled Trial.

This study investigated the long-term effect (six-months) of a Pain Neuroscience Education (PNE) program on pain perception, quality of life, kinesiophobia and catastrophism in older adults with multimorbidity and chronic pain. Fifty participants (n = 50) were randomly assigned to the pain education therapy group (PET; n = 24) and control group (CG; n = 26). The PET group received six sessions (i.e., once a week, 50 min) about neurophysiology of pain while the CG carried on with their usual life. Perception of pain through the visual analogue scale (VAS), quality of life (EQ-5D questionnaire), kinesiophobia (TSK-11) and catastrophism (PCS) were assessed after six months since the last PNE session. Statistically significant differences on VAS (t(48) = 44, p = 0.01, ES = 0.42 [0.13, 0.65]) was found in favor to PET group. No other statistically significant differences were found. This study found that the application of a PNE intervention in an isolated form was able to significantly reduce pain perception with low effect size in the long-term (six months after intervention) in elderly people with chronic pain.