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Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.
No full text20.500.12530/87909Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, -40.3 (32.7) mmHg; Valsalva, -55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): -562 (-1162.5, -209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up
Suicide mortality in Spain during the COVID-19 pandemic: Longitudinal analysis of sociodemographic factors.
No full text20.500.12530/87857The COVID-19 pandemic has compromised public health response across the globe. Several countries reported increasing number of suicides during the pandemic. This study aimed to analyze the suicide mortality series in Spain (2000-2021), with a particular interest in depicting longitudinal trends during the COVID-19 pandemic. Moreover, it intended to identify sociodemographic groups with a higher increase in suicide victims during the pandemic. To do so, suicide cases from the National death index data were used. Weighted annual mortality rate was compared between pre-pandemic and pandemic years. Poisson time series models were used to analyze the trend in suicide mortality, considering sociodemographic variables (sex, age, migration status, marital status, and urbanicity). As a result, weighted mortality rate for 2020 was 8.92 (CI95 = [8.29, 9.57]) and 9.21 for 2021 (CI95 = [8.56, 9.88]). Annual mortality from the pandemic years was significantly higher than mortality from the prepandemic ones (p 1.02, across series). A significantly increased number of suicides was also observed for mid-age adults, large urban areas, and single people (RR > 1.05, across series). To sum up, our study supports an increasing number of suicide victims in Spain during the pandemic. We show that the COVID-19 influence on suicide risk factors (e.g., lack of social support networks) plays a critical role in the increasing trend of specific sociodemographic groups
Agresiones sexuales agudas con penetración en pediatría ¿son frecuentes las infecciones de transmisión sexual?
No full textTrends in the association between meeting the physical activity guidelines and risk of mortality in US adults.
No full text20.500.12530/87857To examine the trends in the association between meeting the physical activity (PA) guidelines and mortality in adults. We included seventeen annual representative samples of US adults 1998-2014 (n = 482,756) and all-cause and cause-specific mortality ascertained through December 2019. Participants were grouped according to PA Guidelines: 150 or more min/week in aerobic PA and muscle-strengthening activities 2 or more times/week. To provide further context, we also examined the trends in mortality risk associated with other modifiable health factors. Meeting the PA guidelines was associated with lower 5-year mortality risk (HR = 0.59, 95%CI, 0.55, 0.63) based on the pooled analyses. We consistently observed an inverse association in all years, but there was a nonsignificant trend association (P for trend = 0.305) between meeting PA guidelines and 5-year mortality across the seventeen annual surveys. Meeting aerobic (HR = 0.58, 95%CI, 0.56, 0.61) and muscle-strengthening (HR = 0.86, 95%CI, 0.81, 0.90) guidelines were independently associated with 5-year mortality risk in pooled analyses, without any evidence for trends in the associations. Similar results were found with cause-specific mortality and 10-year mortality risk. In pooled analyses, attaining a high educational level, body mass index Meeting PA guidelines lower mortality risk and this association does not seem to have varied over time. Encouraging adults to meet the PA guidelines may provide substantial health benefits, despite social, demographic and lifestyle changes, as well as the advances in medical technology and pharmacological treatments
CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation.
No full text20.500.12530/87908The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-valu
Review: Risk Stratification of Patients With Ulcerative Colitis for Treatment With Tofacitinib.
No full textReal-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain.
No full text20.500.12530/87908Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile
European reference network for rare inherited congenital anomalies (ERNICA) evidence based guideline on the management of gastroschisis.
No full text20.500.12530/87857The European Reference Network for rare Inherited Congenital Anomalies, ERNICA, guidelines for gastroschisis cover perinatal period to help teams to improve care. A systematic literature search including 136 publications was conducted. Research findings were assessed following the GRADE methodology. The evidence to decision framework was used to determine the strength and direction of recommendations. The mode or timing of delivery do not impact neonatal mortality, risk of NEC or time on parenteral nutrition (PN). Intra or extra abdominal bowel dilatation predict complex gastroschisis and longer length of hospital stay but not increased perinatal mortality. Outcomes after Bianchi procedure and primary fascia closure under anesthesia are similar. Sutureless closure decreases the rate of surgical site infections and duration of ventilation compared to surgical closure. Silo-staged closure with or without intubation results in similar outcomes. Outcomes of complex gastroschisis (CG) undergoing early or delayed surgical repair are similar. Early enteral feeds starting within 14 days is associated with lower risk of surgical site infection. The panel suggests vaginal birth between 37 and 39 w in cases of uncomplicated gastroschisis. Bianchi's approach is an option in simple gastroschisis. Sutureless closure is suggested when general anesthesia can be avoided, sutured closure. If anesthesia is required. Silo treatment without ventilation and general anesthesia can be considered. In CG with atresia primary intestinal repair can be attempted if the condition of patient and intestine allows. Enteral feeds for simple gastroschisis should start within 14 days
CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.
No full text20.500.12530/87912Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes
Non-suppressible viraemia during HIV-1 therapy: a challenge for clinicians.
No full textIn individuals receiving antiretroviral therapy (ART), persistent low-level viraemia not attributed to suboptimal ART adherence, detrimental pharmacological interactions, or drug resistance is referred to as non-suppressible viraemia (NSV). This Review presents recent findings in the virological characterisation of NSV, revealing that it consists of one or a few identical populations of plasma viruses without signs of evolution. This finding suggests that NSV originates from virus production by expanded HIV-infected cell clones, reflecting the persistence of the HIV reservoir despite ART. We discuss knowledge gaps regarding the management and the clinical consequences of NSV. The prevalence of NSV remains to be precisely determined and there is very little understanding of its effects on virological failure, HIV transmission, secondary inflammation, morbidity, and mortality. This issue, along with the absence of specific recommendations for the management of NSV in HIV clinical guidelines, underscores the complexities involved in treating individuals with NSV