Global Perspectives on Returning Genetic Research Results in Parkinson Disease.

Background And Objectives: In the era of precision medicine, genetic test results have become increasingly relevant in the care of patients with Parkinson disease (PD). While large research consortia are performing widespread research genetic testing to accelerate discoveries, debate continues about whether, and to what extent, the results should be returned to patients. Ethically, it is imperative to keep participants informed, especially when findings are potentially actionable.

The PANDEM-2 Simulation Exercise: Training the Coordinated Response to a Large-Scale Pandemic in 2 European Public Health Emergency Operations Centers.

Objective: In the course of the EU funded Pandemic Preparedness and Response (PANDEM-2) project, a functional exercise (FX) was conducted to train the coordinated response to a large-scale pandemic event in Europe by using new IT solutions developed by the project. This report provides an overview of the steps involved in planning, conducting, and evaluating the FX.

Methods: The FX design was based on the European Centre for Disease Prevention and Control (ECDC) simulation exercise cycle for public health settings and was carried out over 2 days in the German and Dutch national public health institutes (PHI), with support from other consortium PHIs.

Freeze-dried plasma: Hemostasis and biophysical analyses for damage control resuscitation.

Background: Effective hemorrhage protocols prioritize immediate hemostatic resuscitation to manage hemorrhagic shock. Prehospital resuscitation using blood products, such as whole blood or alternatively dried plasma in its absence, has the potential to improve outcomes in hemorrhagic shock patients. However, integrating blood products into prehospital care poses substantial logistical challenges due to issues with storage, transport, and administration in field environments.

Effect of probiotic extracellular vesicles and their applications on health and disease.

Probiotics have been established to exert a positive impact on the treatment of various diseases. Indeed, these active microorganisms have garnered significant attention in recent years for their potential to prevent and treat illnesses. Their beneficial effects have been hypothesized to be linked to their released extracellular vesicles.

Incidence of cancer-related lymphoedema: a protocol for a living systematic review with meta-analysis.

Introduction: Given the projected rise in the incidence of cancer treatment-related conditions, such as lymphoedema, and the limited research on lymphoedema in cancers with poor prognoses, there is a need for a better understanding of cancer-related lymphoedema incidence and associated risk factors across all types of cancers. The objectives of this review are (1) to produce a resource on an open-access platform that facilitates continuous update of incidence estimates and risk factors as evidence emerges, (2) to provide the most up-to-date estimate of the incidence of cancer-related lymphoedema and (3) to evaluate the strength and consistency of the association between lymphoedema and cancer treatment and non-treatment-related risk factors.

Methods And Analysis: A living systematic and grey literature search will be conducted to identify studies reporting the incidence, prevalence of lymphoedema or associated risk factors in individuals who have undergone treatment for any type of cancer.

Trends in Immunotherapy (IO) Use and Survival Among Patients With High-Incidence Stage IV Cancers Across the United States.

Background And Objectives: IO has transformed cancer management, but its adoption in advanced cancer patients varies by tumor type. With more Stage IV patients undergoing surgery, understanding site-specific outcomes in these challenging patients is essential. We aimed to evaluate IO use and survival trends for Stage IV cancer patients across high-incidence cancers in the US.

Fragmenstein: predicting protein-ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding-based methodology.

Current strategies centred on either merging or linking initial hits from fragment-based drug design (FBDD) crystallographic screens generally do not fully leaverage 3D structural information. We show that an algorithmic approach (Fragmenstein) that 'stitches' the ligand atoms from this structural information together can provide more accurate and reliable predictions for protein-ligand complex conformation than general methods such as pharmacophore-constrained docking. This approach works under the assumption of conserved binding: when a larger molecule is designed containing the initial fragment hit, the common substructure between the two will adopt the same binding mode.

Early initiation of ceftaroline-based combination therapy for methicillin-resistant Staphylococcus aureus bacteremia.

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B.

Dry eye post-cataract surgery: a systematic review and meta-analysis.

Significance: Cataract surgery is one of the most performed surgical procedures worldwide. As a potential complication following cataract surgery, dry eye has the potential to impact visual outcomes, lower patient satisfaction, and be detrimental to quality of life.

Purpose: To evaluate the effect of cataract surgery on dry eye outcomes postoperatively.

Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.

Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96 years.

Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

Review of Impact of Risk Reduction Sessions on Sexual Behaviors in HIV Prevention Trials: Insights from Africa.

Over the past two decades, numerous HIV prevention trials have targeted thousands of young African women, aiming not only to reduce transmissions through biomedical interventions but also to promote safe sexual practices through intensive risk reduction sessions. The primary objective of this study was to review the impact of risk reduction sessions in HIV prevention trials conducted in Africa. We assessed changes in sexual behaviors among women enrolled in various biomedical intervention trials across the African region using both visual and quantitative evaluations.

Artificial intelligence in clinical genetics.

Artificial intelligence (AI) has been growing more powerful and accessible, and will increasingly impact many areas, including virtually all aspects of medicine and biomedical research. This review focuses on previous, current, and especially emerging applications of AI in clinical genetics. Topics covered include a brief explanation of different general categories of AI, including machine learning, deep learning, and generative AI.

NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.

Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates.

Measurement Properties of the Friedreich Ataxia Rating Scale in Patients with Spinocerebellar Ataxia.

Introduction: The Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) is a valid, highly utilized measure for assessing ADL impacts in patients with Friedreich ataxia. We provide evidence of the psychometric validity of the FARS-ADL in two cohorts of patients with spinocerebellar ataxia (SCA).

Methods: Using data from a cohort of real-world subjects with SCA (recruited at Massachusetts General Hospital [MGH]; n = 33) and a phase 3 trial of troriluzole in adults with SCA (NCT03701399 [Study 206]; n = 217), comprising a subset of patients with the SCA3 genotype (n = 89), the psychometric measurement properties and minimal change thresholds of the FARS-ADL were examined.

A cell-free biosensor signal amplification circuit with polymerase strand recycling.

Cell-free systems are powerful synthetic biology technologies that can recapitulate gene expression and sensing without the complications of living cells. Cell-free systems can perform more advanced functions when genetic circuits are incorporated. Here we expand cell-free biosensing by engineering a highly specific isothermal amplification circuit called polymerase strand recycling (PSR), which leverages T7 RNA polymerase off-target transcription to recycle nucleic acid inputs within DNA strand displacement circuits.

Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection.

Protein aggregates are associated with numerous diseases. Here we report a platform for the rapid phenotypic selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli based on phage-assisted continuous evolution (PACE). We developed a new PACE-compatible selection for protein aggregation inhibition and used it to identify cyclic peptides that suppress amyloid-β42 and human islet amyloid polypeptide aggregation.

Transforming an ATP-dependent enzyme into a dissipative, self-assembling system.

Nucleoside triphosphate (NTP)-dependent protein assemblies such as microtubules and actin filaments have inspired the development of diverse chemically fueled molecular machines and active materials but their functional sophistication has yet to be matched by design. Given this challenge, we asked whether it is possible to transform a natural adenosine 5'-triphosphate (ATP)-dependent enzyme into a dissipative self-assembling system, thereby altering the structural and functional mode in which chemical energy is used. Here we report that FtsH (filamentous temperature-sensitive protease H), a hexameric ATPase involved in membrane protein degradation, can be readily engineered to form one-dimensional helical nanotubes.

Endothelial Gsα deficiency promotes ferroptosis and exacerbates atherosclerosis in apolipoprotein E-deficient mice via the inhibition of NRF2 signaling.

The importance of ferroptosis in the occurrence and progression of atherosclerosis is gradually being recognized. The stimulatory G protein α subunit (Gsα) plays a crucial role in the physiology of endothelial cells (ECs). Our previous study showed that endothelial Gsα could regulate angiogenesis and preserve endothelial permeability.

Titin fragment is a sensitive biomarker in Duchenne muscular dystrophy model mice carrying full-length human dystrophin gene on human artificial chromosome.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations of the dystrophin gene, which spans 2.4 Mb on the X chromosome. Creatine kinase (CK) activity in blood and titin fragment levels in urine have been identified as biomarkers in DMD to monitor disease progression and evaluate therapeutic intervention.

Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental osteosarcoma.

Osteosarcoma (OS) is the most common primary bone malignancy. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has been implicated in bone destruction, tumor survival and metastases during OS. We examined the role of Dkk-1 in OS disease progression and explored strategies for targeting its activity.

Robust collection and processing for label-free single voxel proteomics.

With advanced mass spectrometry (MS)-based proteomics, genome-scale proteome coverage can be achieved from bulk tissues. However, such bulk measurement lacks spatial resolution and obscures tissue heterogeneity, precluding proteome mapping of tissue microenvironment. Here we report an integrated wet collection of single microscale tissue voxels and Surfactant-assisted One-Pot voxel processing method termed wcSOP for robust label-free single voxel proteomics.

Accuracy of pathogen diagnostic codes for acute hematogenous musculoskeletal infections in children.

Administrative databases are powerful tools for pediatric research but lack patient-level microbiology results. This study aimed to determine the accuracy of pathogen discharge diagnosis codes for children hospitalized with acute hematogenous musculoskeletal infections (MSKIs). Medical records for 244 children hospitalized with acute hematogenous MSKIs were manually reviewed to determine which bacterial pathogen, if any, was identified for each MSKI based on microbiology results obtained during the hospitalization.

Structural Determinants of Health Literacy Among Formerly Incarcerated Individuals: Insights From the Survey of Racism and Public Health.

Background: Formerly incarcerated individuals (FIIs) encounter difficulties with covering the cost of dental and medical care, adhering to medication regimens, and receiving fair treatment from health care providers. Yet, no published research has examined modifiable pathways to increase FIIs' health literacy (HL), which is essential for addressing the health needs of this vulnerable population.

Objective: The aim of this article is to examine neighborhood characteristics (neighborhood deprivation, racial and economic polarization, and residential segregation) and public assistance program enrollment as structural determinants of limited health literacy (LHL) among FIIs.