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Orthohantavirus is a genus of globally distributed RNA viruses in the family Hantaviridae. In the Americas, the viruses are hosted by native rodent species within the Cricetidae family (2). Although [...]

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Abstract The synthetic lethal effect observed with the use of PARP inhibitors (PARPi) with tumors characterized by the loss of key players in the homologous recombination (HR) pathway, commonly referred to as “BRCAness”, is maintaining high interest in oncology. While BRCAness is a well-established feature in breast, ovarian, prostate, and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HR deficiency (HRD) from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology 500 HRD (TSO500-HRD) panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM and RAD51C immunohistochemical analysis as part of our “composite biomarker approach” to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

Abstract Background Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). Objectives To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. Methods 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. Results Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p

Objective: To assess FEES findings in defining oral feeding safety in children with suspected dysphagia, comparing them with clinical feeding evaluation results. Methods: This study comprised a case series involving children with suspected dysphagia, referred for evaluation by otolaryngologists and speech-language pathologists (SLPs) at a Brazilian quaternary public university hospital. These children underwent both clinical evaluations and fiberoptic endoscopic evaluation of swallowing (FEES), with a comprehensive collection of demographic and clinical data. Subsequently, the authors performed a comparative analysis of findings from both assessments. Results: Most patients successfully completed the FEES procedure (93.7%), resulting in a final number of 60 cases included in the study. The prevalence of dysphagia was confirmed in a significant 88% of these cases. Suspected aspiration on clinical SLP evaluation was present in 34 patients. Of these, FEES confirmed aspiration or penetration in 28 patients. Among the 35 patients with aspiration or penetration on FEES, 7 (20%) had no suspicion on SLP clinical assessment. All seven patients in whom clinical SLP evaluation failed to predict penetration/aspiration had neurological disorders. The median age of the children was 2.8 years, and 49 (81.6%) had neurological disorders, while 35 (58.3%) had chronic pulmonary disease. The most prevalent complaints were choking (41.6%) and sialorrhea (23.3%). Conclusion: FEES can diagnose structural anomalies of the upper aerodigestive tract and significantly contribute to the detection of aspiration and penetration in this group of patients with suspected dysphagia, identifying moderate and severe dysphagia even in cases where clinical assessment had no suspicion.

The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and the cardio-renal system. The classical RAS, mainly mediated by angiotensin I, angiotensin-converting enzyme, and angiotensin II, has been reported to be altered in critically ill patients, such as those in vasodilatory shock. However, recent research has highlighted the role of some components of the counterregulatory axis of the classical RAS, termed the alternative RAS, such as angiotensin-converting Enzyme 2 (ACE2) and angiotensin-(1-7), or peptidases which can modulate the RAS like dipeptidyl-peptidase 3, in many critical situations. In cases of shock, dipeptidyl-peptidase 3, an enzyme involved in the degradation of angiotensin and opioid peptides, has been associated with acute kidney injury and mortality and preclinical studies have tested its neutralization. Angiotensin-(1-7) has been shown to prevent septic shock development and improve outcomes in experimental models of sepsis. In the context of experimental acute lung injury, ACE2 activity has demonstrated a protective role, and its inactivation has been associated with worsened lung function, leading to the use of active recombinant human ACE2, in preclinical and human studies. Angiotensin-(1-7) has been tested in experimental models of acute lung injury and in a recent randomized controlled trial for patients with COVID-19 related hypoxemia. Overall, the alternative RAS appears to have a role in the pathogenesis of disease in critically ill patients, and modulation of the alternative RAS may improve outcomes. Here, we review the available evidence regarding the methods of analysis of the RAS, pathophysiological disturbances of this system, and discuss how therapeutic manipulation may improve outcomes in the critically ill.

Abstract Background Postoperative atrial fibrillation (POAF) is a common and potentially serious complication post cardiac surgery. Hypomagnesaemia is common after cardiac surgery and recent evidence indicates that supplementation of magnesium may prevent POAF. We aim to investigate the effectiveness of continuous intravenous magnesium sulphate administration in the perioperative period to prevent POAF as compared to placebo. Methods The (POMPAE) trial is a phase 2, single-center, double-blinded randomized superiority clinical study. It aims to assess the impact of perioperative continuous intravenous magnesium administration on the occurrence of cardiac surgery-related POAF. A total of 530 patients will be included. Eligible patients will be randomized in 1:1 ratio to the intervention or placebo group with stratification based on the presence of valvular surgery. The objective of the infusion is to maintain ionized magnesium levels between 1.5 and 2.0 mmol/L. Discussion The primary outcome measure is the incidence of de novo POAF within the first 7 days following surgery, with censoring at hospital discharge. This trial may generate crucial evidence for the prevention of POAF and reduce clinical adverse events in patients following cardiac surgery. Trial registration The POMPAE trial was registered at ClinicalTrials.gov under the following identifier NTC05669417, https://clinicaltrials.gov/ct2/show/NCT05669417 . Registered on December 30, 2022. Protocol version Version 3.3, dated 13–01-2023.