ALSUntangled #77: Psilocybin.

ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation.

Glepaglutide, a Long-acting Glucagon-like Peptide-2 Analog, Reduces Parenteral Support in Patients with Short Bowel Syndrome: a Phase 3, Randomized, Controlled Trial.

Background And Aims: Glepaglutide is a long-acting GLP-2 analog developed to improve intestinal absorption in short bowel syndrome (SBS) patients. We conducted a trial to establish efficacy and safety of glepaglutide in reducing parenteral support (PS) needs in SBS patients with intestinal failure (IF).

Methods: In an international, placebo-controlled, randomized, parallel-group, double-blind, phase 3 trial, SBS-IF patients requiring PS ≥3 days/week were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice-weekly (TW) or once-weekly (OW), or placebo.

Sleep spindle variation in patients with Parkinson's disease on first nights of sub-optimal deep brain stimulation.

Objective: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is a common treatment for motor symptoms of Parkinson's disease but its influence on non-motor symptoms is less clear. Sleep spindles are known to be reduced in patients with Parkinson's disease, but the effect of STN DBS is unknown. The objective of our study was to address this knowledge gap.

A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies.

The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models.

HiCrayon reveals distinct layers of multi-state 3D chromatin organization.

Chromatin contact maps are often shown as 2D heatmaps and visually compared to 1D genomic data by simple juxtaposition. While common, this strategy is imprecise, placing the onus on the reader to align features with each other. To remedy this, we developed HiCrayon, an interactive tool that facilitates the integration of 3D chromatin organization maps and 1D datasets.

Bedside Small Bowel Follow-Through: The Role in the Management of Adhesive Small Bowel Obstruction.

Background:  Adhesive small bowel obstruction (ASBO) accounts for the majority of hospitalizations related to SBO following abdominal surgery. Delays in the management of ASBO are associated with longer hospital stays and increased mortality rates, making it imperative to establish an efficient way of determining which patients need surgical intervention.

Purpose: To evaluate the contribution of bedside small bowel follow-through (BSBFT) in the management of suspected ASBO.

Cutaneous Findings as a Harbinger of Disseminated Fungal Infection.

is a dimorphic fungus that causes pulmonary, disseminated, or, rarely, primary cutaneous disease. Primary cutaneous histoplasmosis presents with non-specific skin lesions, which can lead to poor patient outcomes due to diagnostic challenges and delays in diagnosis. A 62-year-old male on immunosuppressive medications for lupus nephritis presented to the emergency department with 24 hours of altered mental status.

Mixed-methods multicenter assessment of healthcare workers' knowledge, perceptions, and practices related to blood culture utilization in hospitalized adults.

Objective: To understand healthcare workers' (HCWs) beliefs and practices toward blood culture (BCx) use.

Design: Cross-sectional electronic survey and semi-structured interviews.

Setting: Academic hospitals in the United States.

Rhabdoid Tumor of the Kidney and Soft Tissues: Results from National Wilms Tumor Study-5 and Children's Oncology Group Study AREN0321.

Purpose: National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT).

Patients And Methods: Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1).

Carbohydrate-mediated interactions between chloroviruses and the immune system.

Understanding the molecular mechanisms which drive and modulate host-pathogen interactions are essential when designing effective therapeutic and diagnostic approaches aimed at controlling infectious diseases. Certain large and giant viruses have recently been discovered as components of the human virome, yet little is known about their interactions with the host immune system. We have dissected the role of viral N-linked glycans during the interaction between the glycoproteins from six chloroviruses (belonging to three chlorovirus classes: NC64A, SAG, and Osy viruses) and the representative carbohydrate-binding receptors of the innate immune system.

Prolonged Immunomodulator Delivery Boosts Monocyte Exosome Secretion and Elevates Cathelicidin/LL-37 Content.

Human cathelicidin LL-37 offers significant benefits to the immune system and in treating various diseases, but its therapeutic potential is hindered by low activity and instability in physiological environments. Here, we introduce a strategy to boost LL-37 levels in exosomes derived from THP-1 monocytes by incubating cells with electrospun nanofibers containing immunomodulators (e.g.

Prenatal Tobacco Exposure, Brain Subcortical Volumes, and Gray-White Matter Contrast.

Importance: Maternal tobacco use during pregnancy (MTDP) remains a major public health challenge. However, the complete spectrum of effects of MTDP is not fully understood.

Objectives: To examine the longitudinal associations of MTDP and children's brain morphometric subcortical volume and gray-white matter contrast (GWC) development.

Treatment-induced ripple effect: a systematic review exploring the abscopal phenomenon in Glioblastoma multiforme.

Purpose: This systematic review aimed to collate and synthesize the available literature on the abscopal effect in Glioblastoma multiforme (GBM) neoplasms, focusing on the reported biochemical mechanisms driving the abscopal effect.

Methods: A systematic search was conducted in PubMed, Cochrane Database of Systematic Reviews, and Epistemonikos from inception to May 1, 2023. Studies exploring the abscopal effect in GBM were included.

Planning a Phased Guideline Implementation Strategy Across the Multicenter Ventilation Liberation for Kids (VentLib4Kids) Collaborative.

Objectives: To evaluate contextual factors relevant to implementing pediatric ventilator liberation guidelines and to develop an implementation strategy for a multicenter collaborative.

Design: Cross-sectional qualitative analysis of a 2023/2024 survey.

Setting: International, multicenter Ventilation Liberation for Kids (VentLib4Kids) collaborative.

Sex and gender as predictors for allograft and patient-relevant outcomes after kidney transplantation.

Background: Sex, as a biological construct, and gender, defined as the cultural attitudes and behaviours attributed by society, may be associated with allograft loss, death, cancer, and rejection. Other factors, such as recipient age and donor sex, may modify the association between sex/gender and post-transplant outcomes.

Objectives: We sought to evaluate the prognostic effects of recipient sex and, separately, gender as independent predictors of graft loss, death, cancer, and allograft rejection following kidney or simultaneous pancreas-kidney (SPK) transplantation.

Gene therapy for the heart: encapsulated viruses to the rescue.

This commentary provides an in-depth analysis and perspective on the pioneering research article titled 'Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart'. The original study explores the innovative use of extracellular vesicle-encapsulated AAVs (EV-AAV-6 and -9) as a superior gene-delivery approach for cardiomyocytes (CMs), which not only provides increased AAV neutralizing antibody (NAb) resistance but also has implications for increased gene delivery efficacy to ischemic hearts. This study examined the efficacy of EVs isolated from the conditioned medium of AAV-6 and -9 producing HEK293T cells in combinatorial and in systems in comparison to free AAVs in the presence of the NAbs.

ER-LD Membrane Contact Sites: A Budding Area in the Pathogen Survival Strategy.

The endoplasmic reticulum (ER) and lipid droplets (LDs) are essential organelles involved in lipid synthesis, storage, and transport. Physical membrane contacts between the ER and LDs facilitate lipid and protein exchange and thus play a critical role in regulating cellular lipid homeostasis. Recent research has revealed that ER-LD membrane contact sites are targeted by pathogens seeking to exploit host lipid metabolic processes.

Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity.

Nitrogen bisphosphonates, such as zoledronic acid, target the enzyme farnesyl diphosphate synthase (FDPS) in the isoprenoid biosynthetic pathway (IBP), and are the frontline treatment for osteolytic bone diseases. A strong affinity of these agents for bone limits their distribution out of the skeleton. Geranylgeranyl diphosphate synthase (GGDPS) is directly downstream to FDPS in the IBP and novel GGDPS inhibitors such as RAM2061 have been shown to have key drug-like features including prolonged half-life, metabolic stability, and systemic distribution.

Liposuction for Superficialization of Deep Hemodialysis Vascular Access: A Novel Application.

Background: More than 65% of patients with end-stage renal disease (ESRD) use arteriovenous fistulas (AVFs) for hemodialysis. The increasing incidence of comorbid ESRD and obesity (body mass index, >35 kg/m) precludes patients from kidney transplantation, resulting in a need for long-term, durable AVF access. Compared with traditional superficialization techniques for overlying adiposity, liposuction is minimally invasive and well-tolerated, allowing for earlier fistula use with lower complications.

In vitro assessment of effect of initial specimen diversion device on detection of central venous catheter contamination or colonization.

The role of initial specimen diversion devices (ISDDs) in preventing contamination of central venous catheter (CVC) blood cultures is undefined. A model to simulate CVC colonization and contamination compared standard cultures with ISDD technique. ISDD detected 100% of colonized CVCs while decreasing false-positive cultures from 36% to 16%.

Seven versus 14 days of antimicrobial therapy for severe multidrug-resistant Gram-negative bacterial infections in intensive care unit patients (OPTIMISE): a randomised, open-label, non-inferiority clinical trial.

Background: Shorter courses of antimicrobial therapy have been shown to be non-inferior to longer durations for the management of several infections. However, data on critically ill patients with severe infections by multidrug-resistant Gram-negative bacteria (MDR-GNB) are scarce. In the duratiOn of theraPy in severe infecTIons by MultIdrug-reSistant gram-nEgative bacteria (OPTIMISE) trial, we assessed the non-inferiority of 7-day versus 14-day antimicrobial therapy for patients with intensive care unit (ICU)-acquired severe infections by MDR-GNB.

Pulmonary hypertension as a prognostic marker in low-flow low-gradient aortic stenosis: Insights from invasive hemodynamics and post-TAVR outcomes.

Introduction: Pulmonary hypertension (PH) is a common and significant comorbidity in patients with low-flow low-gradient (LF-LG) aortic stenosis, impacting prognosis after transcatheter aortic valve replacement (TAVR). Non-invasive tools often fail to capture PH's full clinical impact due to inherent limitations. This study evaluates the prognostic significance of PH measured invasively and explores its implications on post-TAVR outcomes.

Neuroimaging findings of adolescent depression: A review by the Research Domain Criteria (RDoC) framework.

This review examines neuroimaging studies on adolescent depression (AD) within the Research Domain Criteria (RDoC) framework, focusing on fMRI, DTI, and EEG findings. The research highlights disrupted connectivity in several neural networks-such as the affective, reward processing, cognitive control, and default mode networks-that underpin emotional and cognitive dysfunctions in AD. Notably, hypoconnectivity in the affective and cognitive control networks correlates with deficits in emotional processing and executive functioning, while hyperactivity in the default mode network relates to excessive self-referential thoughts.