Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation.

Mutations in GBA (glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by GBA mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a Drosophila model of GCase deficiency.

Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and β-lactam antibiotics.

Unlabelled: The inoculum effect has been observed for nearly all antibiotics and bacterial species. However, explanations accounting for its occurrence and strength are lacking. Previous work found that the relationship between [ATP] and growth rate can account for the strength and occurrence of the inoculum effect for bactericidal antibiotics.

Cost-Effectiveness of an Extended-Role General Practitioner Clinic for Persistent Physical Symptoms: Results From the Multiple Symptoms Study 3 Pragmatic Randomized Controlled Trial.

Objectives: This study aimed to evaluate the cost-effectiveness of an extended-role general practitioner symptoms clinic (SC), added to usual care (UC) for patients with multiple persistent physical symptoms (sometimes known as medically unexplained symptoms).

Methods: This was a 52-week within-trial cost-utility analysis of a pragmatic multicenter randomized controlled trial comparing SC + UC (n = 178) with UC alone (n = 176), conducted from the primary perspective of the UK National Health Service and personal and social services (PSS). Base-case quality-adjusted life-years (QALYs) were measured using EQ-5D-5L.

Second generation lethality in RNAseH2a knockout zebrafish.

Removal of ribonucleotides from DNA by RNaseH2 is essential for genome stability, and its impacted function causes the neurodegenerative disease, Aicardi Goutières Syndrome. We have created a zebrafish rnaseh2a mutant to model this process. Surprisingly, RNaseH2a knockouts show little phenotypic abnormality at adulthood in the first generation, unlike mouse knockout models, which are early embryonic lethal.

Community contexts and knowledge: accountability, leadership and meaningful involvement of communities in Programme Science.

Introduction: A Programme Science approach that prioritizes populations who will benefit most and ensuring resources are allocated to programmes that meet the needs of those populations will bring an equity focus to research. Gay men and other men who have sex with men, people who use drugs, sex workers of all genders, and trans and gender-diverse people, defined by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) as key populations, have been disproportionately impacted since the start of the HIV pandemic. Through documenting community experiences from global key population-led networks, the authors explore the potential value and impact of community-led organizations and service delivery as critical components in effective HIV and Sexually Transmitted infections (STI) programmes.

Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial.

Background: People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only.

Methods: The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023.

A model for mechanistic investigation of tau protein spread.

Unlabelled: Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another.

Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and β-lactam antibiotics.

The inoculum effect has been observed for nearly all antibiotics and bacterial species. However, explanations accounting for its occurrence and strength are lacking. We previously found that growth productivity, which captures the relationship between [ATP] and growth, can account for the strength of the inoculum effect for bactericidal antibiotics.

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation.

Mutations in (), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a model of GCase deficiency.

Characterizing dengue transmission in rural areas: A systematic review.

Dengue has historically been considered an urban disease associated with dense human populations and the built environment. Recently, studies suggest increasing dengue virus (DENV) transmission in rural populations. It is unclear whether these reports reflect recent spread into rural areas or ongoing transmission that was previously unnoticed, and what mechanisms are driving this rural transmission.

Study protocol for the Multiple Symptoms Study 3: a pragmatic, randomised controlled trial of a clinic for patients with persistent (medically unexplained) physical symptoms.

Introduction: Persistent physical symptoms (which cannot be adequately attributed to physical disease) affect around 1 million people (2% of adults) in the UK. They affect patients' quality of life and account for at least one third of referrals from General Practitioners (GPs) to specialists. These referrals give patients little benefit but have a real cost to health services time and diagnostic resources.

Cost-utility analysis of shockwave lithotripsy vs ureteroscopic stone treatment in adults.

Objectives: To assess the cost-effectiveness, resource use implications, quality-adjusted life-years (QALYs) and cost per QALY of care pathways starting with either extracorporeal shockwave lithotripsy (SWL) or with ureteroscopic retrieval (ureteroscopy [URS]) for the management of ureteric stones.

Patients And Methods: Data on quality of life and resource use for 613 patients, collected prospectively in the Therapeutic Interventions for Stones of the Ureter (TISU) randomized controlled trial (ISRCTN 92289221), were used to assess the cost-effectiveness of two care pathways, SWL and URS. A health provider (UK National Health Service) perspective was adopted to estimate the costs of the interventions and subsequent resource use.

Randomised controlled trial comparing the clinical and cost-effectiveness of various washout policies versus no washout policy in preventing catheter associated complications in adults living with long-term catheters: study protocol for the CATHETER II study.

Background: Various washout policies are widely used in adults living with long-term catheters (LTC). There is currently insufficient evidence on the benefits and potential harms of prophylactic LTC washout policies in the prevention of blockages and other LTC-related adverse events, such as urinary tract infections. CATHETER II tests the hypothesis that weekly prophylactic LTC washouts (normal saline or citric acid) in addition to standard LTC care reduce the incidence of catheter blockage requiring intervention compared to standard LTC care only in adults living with LTC.

Shockwave lithotripsy compared with ureteroscopic stone treatment for adults with ureteric stones: the TISU non-inferiority RCT.

Background: Urinary stone disease affects 2-3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient's quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention.

Addressing epistemic injustice in HIV research: a call for reporting guidelines on meaningful community engagement.

Introduction: Despite the widely recognized ethical and practical benefits of community engagement in HIV research, epistemic injustice persists within the field. Namely, the knowledge held by communities disproportionately affected by HIV is systematically afforded less credibility than that of more privileged academic researchers. In order to illustrate what this looks like in practice, we synthesized the extent of reporting on community engagement within recent high-impact HIV intervention research papers.

Peer- and community-led responses to HIV: A scoping review.

Introduction: In June 2021, United Nations (UN) Member States committed to ambitious targets for scaling up community-led responses by 2025 toward meeting the goals of ending the AIDS epidemic by 2030. These targets build on UN Member States 2016 commitments to ensure that 30% of HIV testing and treatment programmes are community-led by 2030. At its current pace, the world is not likely to meet these nor other global HIV targets, as evidenced by current epidemiologic trends.

The effect of patient-centered communication on medication intake: an experimental study.

It is not only crucial to provide patients with information, but also to communicate this information in a way to enable patient participation in health decisions. Experimental studies investigating the association between the communication style of health professionals and patients' health decisions are rare, which limits causal conclusions. This study investigated the effect of a doctor's patient-centered communication style on the likelihood to take a medication.

Shockwave Lithotripsy Versus Ureteroscopic Treatment as Therapeutic Interventions for Stones of the Ureter (TISU): A Multicentre Randomised Controlled Non-inferiority Trial.

Background: Renal stone disease is common and can cause emergency presentation with acute pain due to ureteric colic. International guidelines have stated the need for a multicentre randomised controlled trial (RCT) to determine whether a non-invasive outpatient (shockwave lithotripsy [SWL]) or surgical (ureteroscopy [URS]) intervention should be the first-line treatment for those needing active intervention. This has implications for shaping clinical pathways.

Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles.

Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson's disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression.

Tdp1 protects from topoisomerase 1-mediated chromosomal breaks in adult zebrafish but is dispensable during larval development.

Deficiency in the DNA end-processing enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), causes progressive neurodegeneration in humans. Here, we generated a knockout zebrafish and confirmed the lack of TDP1 activity. In adulthood, homozygotes exhibit hypersensitivity to topoisomerase 1 (Top1) poisons and a very mild locomotion defect.

Slowed Protein Turnover in Aging Drosophila Reflects a Shift in Cellular Priorities.

The accumulation of protein aggregates and dysfunctional organelles as organisms age has led to the hypothesis that aging involves general breakdown of protein quality control. We tested this hypothesis using a proteomic and informatic approach in the fruit fly Drosophila melanogaster. Turnover of most proteins was markedly slower in old flies.

The clinical and cost effectiveness of surgical interventions for stones in the lower pole of the kidney: the percutaneous nephrolithotomy, flexible ureterorenoscopy and extracorporeal shockwave lithotripsy for lower pole kidney stones randomised controlled trial (PUrE RCT) protocol.

Introduction: Renal stones are common, with a lifetime prevalence of 10% in adults. Global incidence is increasing due to increases in obesity and diabetes, with these patient populations being more likely to suffer renal stone disease. Flank pain from stones (renal colic) is the most common cause of emergency admission to UK urology departments.