Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis.

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L.

Age- and Sex-Specific Myocardial Blood Flow Values in Patients Without Coronary Atherosclerosis on Rb-82 PET Myocardial Perfusion Imaging.

Background: Quantitative myocardial blood flow (MBF) on positron-emission tomography myocardial perfusion imaging is a measure of the overall health of the coronary circulation. The ability to adequately augment blood flow, measured by myocardial blood flow reserve (MBFR), is associated with lower major adverse cardiovascular events and all-cause mortality. The age-specific ranges of MBFR in patients without demonstrable coronary artery disease have not been well established.

Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAF-mutant resectable melanoma: the randomized phase 2 NeoTrio trial.

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF-mutant melanoma.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group.

Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions.

Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion.

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.

Clinical characteristics and outcomes of patients requiring prolonged mechanical circulatory support after high-risk percutaneous coronary intervention.

Background: There are limited data on the clinical characteristics and outcomes of patients who require prolonged mechanical circulatory support (MCS) after Impella-supported high-risk percutaneous coronary intervention (HR-PCI).

Aims: The aim of this study is to describe the contemporary clinical characteristics, outcomes, and predictors associated with prolonged MCS support after assisted HR-PCI.

Methods: Patients enrolled in the prospective, multicentre, clinical endpoint-adjudicated PROTECT III study who had undergone HR-PCI using Impella were evaluated.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.

Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.

Results: We found high heritability for two ancestry backgrounds.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group.

Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions.

Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.

Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30.

White Matter Integrity and Chronic Poststroke Upper Limb Function: An ENIGMA Stroke Recovery Analysis.

Background: Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following stroke. However, when structurally compromised, other tracts may become relevant for compensation or recovery of function.

Methods: We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more severe (laterality index of CST fractional anisotropy ≥0.

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8 T cells, serves as a common genetic link between these conditions.

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics.

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M muscarinic acetylcholine receptor (M mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders.

A systematic review with evidence mapping of supportive care interventions for melanoma patients and caregivers.

Aim: We conducted a systematic review and evidence gap mapping to explore the existing supportive care interventions and their impact on well-being outcomes for melanoma patients and caregivers.

Methods: We searched MEDLINE, Embase, Web of Science Index Medicus, CINAHL, Lilacs, CENTRAL (Cochrane Library) and PsycINFO in December 2022, including interventional studies assessing the effectiveness of any supportive care intervention among melanoma patients and/or their caregivers.

Findings: Twenty studies were included in this review.

Transplantation Referral Patterns for Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia at Academic and Community Sites in the Connect® Myeloid Disease Registry: Potential Barriers to Care.

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral.

Interactions between the lipidome and genetic and environmental factors in autism.

Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for example, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis (n = 8), sleep disturbances (n = 20) and cognitive function (n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

Background And Objectives: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance.