Are hip joint imaging findings associated with symptoms and early hip osteoarthritis features in elite male Australian Football League draftees?

1) describe intra-articular features (prevalence and severity) and bony hip morphology (prevalence and size) in elite male Australia Football League (AFL) draftees; 2) examine the relationship between bony hip morphology (cam and pincer morphology) and intra-articular features (cartilage defects and labral tears); and 3) examine the relationship between intra-articular features, bony hip morphology, and the Copenhagen Hip and Groin Outcome Score (HAGOS). Cross-sectional study. 58 male AFL draftees underwent 3-tesla hip MRI. Alpha angle determined cam morphology and acetabular depth defined pincer morphology. For each hip, intra-articular features were scored semi-quantitatively. All players completed the HAGOS to determine hip/groin symptoms and sports function. Logistic regression determined whether bony hip morphology was associated with labral tears and cartilage defects. Mann-Whitney U tests evaluated the difference in HAGOS subscale scores between football players with and without intra-articular features and bony hip morphology. Cam and pincer morphology were evident in 20% and 19% of hips, respectively. Nearly half of hips (41%) had a labral tear, with only 14% having a cartilage defect. Greater alpha angle was associated with the presence of labral tears (OR 1.14, 95%CI 1.07 to 1.21, p < 0.001) but not cartilage defects. Hip imaging findings were not associated with lower (worse) HAGOS scores. Hip joint imaging findings were common in elite male AFL draftees but not associated with worse pain, symptoms, or sport function. Cam morphology may contribute to the development of labral tears in male AFL draftees.

FlowAtlas: an interactive tool for high-dimensional immunophenotyping analysis bridging FlowJo with computational tools in Julia.

As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise. New population discovery and detection of rare populations in FlowAtlas is intuitive and rapid. We demonstrate the capabilities of FlowAtlas using a human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings. FlowAtlas is available at https://github.com/gszep/FlowAtlas.jl.git.

Visual outcomes and prognostic factors in ischaemic retinal vasculitis.

PURPOSE: Our aim was to describe the visual outcomes and determine the clinical factors in ischaemic retinal vasculitis (IRV) that were predictive of a poor visual prognosis or infectious aetiology. METHODS: Retrospective cohort study of consecutive presentations of IRV to Auckland District Health Board from 2009 to 2022. RESULTS: The median age at presentation was 39.2 years and 108 (53.7%) were women. The total median follow-up was 4.8 years. Infectious aetiology was present in 151 eyes (52.1%). Moderate visual loss (20/50 to 20/200) occurred in 20 eyes (6.9%) and severe visual loss (≤20/200) occurred in 41 eyes (14.1%). Median visual acuity was 20/30 (IQR 20/25 to 20/100) on presentation and 20/25 (IQR 20/20 to 20/50) at final follow-up. Retinitis (HR 4.675 p=0.048) and cystoid macular oedema (CME) (HR 7.265 p<0.001) were significantly associated with vision loss. There was concurrent macular ischaemia in 26 eyes (19.4%) and CME in 52 eyes (17.9%). Retinitis was predictive of infectious aetiology (p=0.006) and cotton wool spots for non-infectious aetiology (p<0.001). Retinal haemorrhage (HR 5.580 p=0.001), retinal vein occlusion (HR 5.071 p=0.001) and quadrants of ischaemia (HR 2.222 p=0.025) were significantly associated with vitreous haemorrhage. CONCLUSION: In patients with IRV, 21% of affected individuals sustained moderate-to-severe vision loss over 5 years. Ultra-widefield fluorescein angiography can be used to quantify the risk of neovascular complications and guide treatment.

Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates Mtb infection outcomes in people living with HIV (PLWH). Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. Here, we investigated the immune responses elicited by BCG administered via intravenous (IV) or intradermal (ID) routes in Simian Immunodeficiency Virus (SIV)-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of Mtb challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic molecules, and key transcription factors. Our results showed that IV BCG induces a robust and sustained immune response, including tissue-resident memory T (TRM) cells in lungs, polyfunctional CD4+ and CD8αß+ T cells expressing multiple cytokines, and CD8αß+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of IV BCG-vaccinated MCM. Although IV BCG vaccination resulted in an influx of TRM cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>105 copies/mL) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on IV BCG-induced protection against Mtb.

Prefabricated contoured foot orthoses to reduce pain and increase physical activity in people with hip osteoarthritis: A randomised feasibility trial.

BACKGROUND: Hip osteoarthritis (OA) is a prevalent and burdensome condition that leads to impaired quality of life and a substantial economic burden. Encouraging physical activity, particularly walking, is crucial for OA management, but many individuals with hip OA fail to meet recommended activity levels. Prefabricated contoured foot orthoses have shown promise in improving hip muscle efficiency during walking in laboratory settings, but their real-world feasibility and efficacy remain uncertain. OBJECTIVE: The aim of this study was to assess the feasibility of conducting a fully powered randomised controlled trial (RCT) to evaluate the effectiveness of prefabricated contoured foot orthoses, prescribed via telehealth, in people with hip OA. METHODS: This feasibility trial randomised 27 participants with hip OA into two groups: prefabricated contoured foot orthoses or flat shoe inserts. Feasibility outcomes were assessed, including recruitment rate, adherence, logbook completion, and dropout rate. Patient-reported outcomes and accelerometer-measured physical activity were collected as secondary outcomes. RESULTS: While the recruitment rate was low (0.88 people/week), adherence to the intervention (59%), logbook completion (93%), and dropout rates (7%) met or exceeded our predefined feasibility parameters. Participants found the intervention acceptable, and practicality was demonstrated with minor adverse events. Preliminary efficacy testing indicated that prefabricated contoured foot orthoses positively affected physical activity (adjusted mean difference = 2590 [260 to 4920] steps/day), with comparable outcomes for hip-related quality of life and pain. CONCLUSION: This trial supports proceeding to a fully powered RCT to assess the effect of teleheath prescribed prefabricated contoured foot orthoses on physical activity in people with hip OA. STUDY REGISTRATION NUMBER: National Institutes of Health Trial Registry (NCT05138380).

Attitudes toward and preparedness for lung transplantation among individuals with cystic fibrosis in the era of highly effective modulators.

BACKGROUND: Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era. METHODS: All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record. RESULTS: There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV1) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions. CONCLUSIONS: Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care.

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Femoroacetabular impingement syndrome in middle-aged individuals is strongly associated with the development of hip osteoarthritis within 10-year follow-up: a prospective cohort study (CHECK).

OBJECTIVE: The objective is to determine the association and absolute risk of femoroacetabular impingement syndrome (FAIS) for the development of radiographic hip osteoarthritis (RHOA). METHODS: This is a nationwide, multicentre prospective cohort study (Cohort Hip and Cohort Knee) with 1002 individuals aged between 45 and 65 years. Hips without definitive RHOA (Kellgren-Lawrence (KL) grade≤1) at baseline and with anteroposterior pelvic radiographs at baseline and 10-year follow-up available (n=1386 hips) were included. FAIS was defined by the baseline presence of a painful hip, limited internal hip rotation≤25° and cam morphology defined by an alpha angle>60°. The outcomes were incident RHOA (KL grade≥2 or total hip replacement (THR)) and incident end-stage RHOA (KL≥3 or THR) within 10 years. RESULTS: Of the 1386 included hips (80% women; mean age 55.7±5.2 years), 21 hips fulfilled criteria for FAIS and 563 hips did not fulfil any of the FAIS criteria (reference group; no symptoms, no signs, no cam morphology). Within 10-year follow-up, 221 hips (38%) developed incident RHOA and 15 hips (3%) developed end-stage RHOA (including 9 hips with THR). Adjusted for sex, age and body mass index, FAIS with cam morphology resulted in an OR of 6.85 (95% CI 2.10 to 22.35) for incident RHOA and 47.82 (95% CI 12.51 to 182.76) for incident end-stage RHOA, compared with hips not having any FAIS criteria. The absolute risk of FAIS was 81% for incident RHOA and 33% for incident end-stage RHOA. CONCLUSION: FAIS was strongly associated with the development of RHOA within 10 years. Although the baseline prevalence of FAIS was low, the high absolute risk of FAIS for RHOA warrants further studies to determine preventive strategies.

Defining a core breath profile for healthy, non-human primates.

Non-human primates remain the most useful and reliable pre-clinical model for many human diseases. Primate breath profiles have previously distinguished healthy animals from diseased, including non-human primates. Breath collection is relatively non-invasive, so this motivated us to define a healthy baseline breath profile that could be used in studies evaluating disease, therapies, and vaccines in non-human primates. A pilot study, which enrolled 30 healthy macaques, was conducted. Macaque breath molecules were sampled into a Tedlar bag, concentrated onto a thermal desorption tube, then desorbed and analyzed by comprehensive two-dimensional gas chromatography-time of flight mass spectrometry. These breath samples contained 2,017 features, of which 113 molecules were present in all breath samples. The core breathprint was dominated by aliphatic hydrocarbons, aromatic compounds, and carbonyl compounds. The data were internally validated with additional breath samples from a subset of 19 of these non-human primates. A critical core consisting of 23 highly abundant and invariant molecules was identified as a pragmatic breathprint set, useful for future validation studies in healthy primates.

The mechanism of mammalian proton-coupled peptide transporters.

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into different conformational states of two mammalian POTs, SLC15A1, and SLC15A2. Nevertheless, these studies leave open important questions regarding the mechanism of proton and substrate coupling, while simultaneously providing a unique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employ extensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and its thermodynamic driving forces. By computing conformational free energy landscapes in different protonation states and in the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps that drive inward-directed alternating access. These simulations identify key differences in the extracellular gate between mammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results from constant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. This study provides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave the way to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organ bioavailability.

The cells in our body are sealed by a surrounding membrane that allows them to control which molecules can enter or leave. Desired molecules are often imported via transport proteins that require a source of energy. One way that transporter proteins achieve this is by simultaneously moving positively charged particles called protons across the membrane. Proteins called POTs (short for proton-coupled oligopeptide transporters) use this mechanism to import small peptides and drugsin to the cells of the kidney and small intestine. Sitting in the centre of these transporters is a pocket that binds to the imported peptide which has a gate on either side: an outer gate that opens towards the outside of the cell, and an inner gate that opens towards the cell's interior. The movement of protons from the outer to the inner gate is thought to shift the shape of the transporter from an outwards to an inwards-facing state. However, the molecular details of this energetic coupling are not well understood. To explore this, Lichtinger et al. used computer simulations to pinpoint where protons bind on POTs to trigger the gates to open. The simulations proposed that two sites together make up the outward-facing gate, which opens upon proton binding. Lichtinger et al. then validated these sites experimentally in cultured human cells that produce mutant POTs. After the desired peptide/drug has attached to the binding pocket, the protons then move to two more sites further down the transporter. This triggers the inner gate to open, which ultimately allows the small molecule to move into the cell. These findings represent a significant step towards understanding how POTs transport their cargo. Since POTs can transport a range of drugs from the digestive tract into the body, these results could help researchers design molecules that are better absorbed. This could lead to more orally available medications, making it easier for patients to adhere to their treatment regimen.

Cardiovascular and Metabolic Risk Incidence Among Adult Allogeneic Stem Cell Transplant Recipients: A Narrative Review.

Advances in allogeneic hematopoietic stem cell transplantation (alloHSCT) and supportive care over the past decade have reduced transplant and relapse-related mortality, leading to a greater number of long-term survivors. However, transplant-related late effects, such as cardiovascular disease (CVD) and metabolic diseases, are becoming significant concerns for this group. This review aims to address several key questions regarding cardiovascular late effects in alloHSCT recipients, including the long-term incidence of CVD-related events, the prevalence of risk factors, screening and management recommendations, and evidence for screening and prevention strategies. A literature search was conducted in PubMed Central using the National Library of Medicine search engine, covering all relevant research from inception to 2023. The initial search identified 751 research records, of which 41 were shortlisted based on specific criteria (≥18 years of age at the time of transplant, allogeneic transplant, and inclusion of more than 30 patients). Our review highlights published evidence confirming the increased CVD risk among alloHSCT recipients. This risk is especially pronounced among individuals who have developed traditional and modifiable risk factors or have been exposed to transplant-specific risk factors. Evidence of the use of traditional cardiac risk factor calculators in the alloHSCT population is limited, in addition, there is emerging evidence that general population calculators potentially underestimate CVD risk given the increased risk of CVD in the allogeneic group as a whole. Studies that develop and validate transplant recipient-specific CVD risk stratification tools appear to be severely lacking and the field's focus needs to be shifted here in the coming years. To improve patient engagement and adherence to CVD risk factor measures, we recommend that a multidisciplinary model involving both specialists and primary care physicians is crucial in ensuring regular follow-up in the community and to potentially improve adherence.

TET1 displays catalytic and non-catalytic functions in the adult mouse cortex.

TET1/2/3 dioxygenases iteratively demethylate 5-methylcytosine, beginning with the formation of 5-hydroxymethylcytosine (5hmC). The post-mitotic brain maintains higher levels of 5hmC than most peripheral tissues, and TET1 ablation studies have underscored the critical role of TET1 in brain physiology. However, deletion of Tet1 precludes the disentangling of the catalytic and non-catalytic functions of TET1. Here, we dissect these functions of TET1 by comparing adult cortex of Tet1 wildtype (Tet1 WT), a novel Tet1 catalytically dead mutant (Tet1 HxD), and Tet1 knockout (Tet1 KO) mice. Using DNA methylation array, we uncover that Tet1 HxD and KO mutations perturb the methylation status of distinct subsets of CpG sites. Gene ontology (GO) analysis on specific differential 5hmC regions indicates that TET1's catalytic activity is linked to neuronal-specific functions. RNA-Seq further shows that Tet1 mutations predominantly impact the genes that are associated with alternative splicing. Lastly, we performed High-performance Liquid Chromatography Mass-Spectrometry lipidomics on WT and mutant cortices and uncover accumulation of lysophospholipids lysophosphatidylethanolamine and lysophosphatidylcholine in Tet1 HxD cortex. In summary, we show that Tet1 HxD does not completely phenocopy Tet1 KO, providing evidence that TET1 modulates distinct cortical functions through its catalytic and non-catalytic roles.

Ancient genomes reveal over two thousand years of dingo population structure.

Dingoes are culturally and ecologically important free-living canids whose ancestors arrived in Australia over 3,000 B.P., likely transported by seafaring people. However, the early history of dingoes in Australia-including the number of founding populations and their routes of introduction-remains uncertain. This uncertainty arises partly from the complex and poorly understood relationship between modern dingoes and New Guinea singing dogs, and suspicions that post-Colonial hybridization has introduced recent domestic dog ancestry into the genomes of many wild dingo populations. In this study, we analyzed genome-wide data from nine ancient dingo specimens ranging in age from 400 to 2,746 y old, predating the introduction of domestic dogs to Australia by European colonists. We uncovered evidence that the continent-wide population structure observed in modern dingo populations had already emerged several thousand years ago. We also detected excess allele sharing between New Guinea singing dogs and ancient dingoes from coastal New South Wales (NSW) compared to ancient dingoes from southern Australia, irrespective of any post-Colonial hybrid ancestry in the genomes of modern individuals. Our results are consistent with several demographic scenarios, including a scenario where the ancestry of dingoes from the east coast of Australia results from at least two waves of migration from source populations with varying affinities to New Guinea singing dogs. We also contribute to the growing body of evidence that modern dingoes derive little genomic ancestry from post-Colonial hybridization with other domestic dog lineages, instead descending primarily from ancient canids introduced to Sahul thousands of years ago.

Pathophysiology of Preeclampsia-Induced Vascular Dysfunction and Implications for Subclinical Myocardial Damage and Heart Failure.

Tragically, preeclampsia is a leading cause of pregnancy-related complications and is linked to a heightened risk for morbid and fatal cardiovascular disease (CVD) outcomes. Although the mechanism connecting preeclampsia to CVD risk has yet to be fully elucidated, evidence suggests distinct pathways of early and late preeclampsia with shared CV risk factors but with profound differences in perinatal and postpartum risk to the mother and infant. In early preeclampsia, <34 weeks of gestation, systemic vascular dysfunction contributes to near-term subclinical myocardial damage. Hypertrophy and diastolic abnormalities persist postpartum and contribute to early onset heart failure (HF). This HF risk remains elevated decades later and contributes to premature death. Black women are at the highest risk of preeclampsia and HF. These findings support closer monitoring of women postpartum, especially for those with early and severe preeclampsia to control chronic hypertension and reduce the potentially preventable sequelae of heightened CVD and HF risk.

Nutrition as a military capability to deliver human advantage: more people, more ready, more of the time.

Soldiers must achieve high-level mission-preparedness to endure extended periods of physical and cognitive activity, with unpredictable recovery, in all environments. Nutrition provides the foundation for health and performance. Militaries have not maximised the strategic and financial value that considering nutrition as a military capability could deliver. A whole system approach to military nutrition, based on the prepare-perform-recover human capability cycle phases, is presented. Trainee nutrition requirements, through to very-high-readiness forces undertaking arduous roles at reach, must be specifically addressed. Promoting military performance diets in the prepare phase, through practitioner-supported nutrition education and food provision, will ensure mission readiness and mitigate ill health. Delivering nutrition in field settings in the perform phase-through smaller/lighter, nutritionally optimised rations and smart packaging technologies-will improve utility and minimise waste. Strategic dietary supplement use can provide a mission performance-enhancing adjunct to a food-first philosophy. Impact value chain analysis of military nutrition capability investments could support cost-benefit measurement.

Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status.

BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response. RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. CONCLUSION: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.

Distributable, metabolic PET reporting of tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

First-line treatment for femoroacetabular impingement syndrome and hip-related quality of life: study protocol for a multicentre randomised controlled trial comparing a 6-month supervised strength exercise intervention to usual care (the Better Hip Trial).

INTRODUCTION: Femoroacetabular impingement syndrome (FAIS) is a motion-related and position-related clinical condition of the hip associated with pain, reduced physical function and hip-related quality of life (QoL). Interestingly, higher maximal muscle strength is associated with less pain, better physical function and improved QoL in people with FAIS. Furthermore, preliminary evidence suggests that a proportion of patients with FAIS respond positively to strength exercise as first-line treatment. Nonetheless, there is little evidence supporting a specific exercise intervention offered as a first-line treatment. We will conduct a randomised controlled trial investigating the clinical effectiveness and cost-effectiveness of a 6-month strength exercise intervention compared with usual care as first-line treatment in patients with FAIS. METHODS AND ANALYSIS: This is a multicentre randomised controlled trial that will be conducted at hospitals and physiotherapy clinics across Denmark and Australia. A total of 120 patients with FAIS will be randomised (1:1) to 6 months of supervised strength exercise or usual care. The primary outcome is the change in hip-related QoL measured using the International Hip and Outcome Tool 33 (iHOT-33) from baseline to the end of intervention. A health economic evaluation will be conducted from a societal and healthcare perspective based on the data collection over a 12-month period starting at baseline. The analysis will calculate incremental cost-effectiveness ratios using quality-adjusted life-years and iHOT-33 scores while estimating costs using microcosting and cost questionnaires. Secondary outcomes include objectively measured physical function at baseline and after 6 months and patient-reported outcomes measured at baseline, 3-month, 6-month and 12-month follow-up. ETHICS AND DISSEMINATION: The trial has been approved by the Committee on Health Research Ethics in the Central Denmark Region (journal no 1-10-72-45-23) and La Trobe University Human Ethics Committee (HEC24042) and is registered at the Central Denmark Region List of Research Projects (journal no 1-16-02-115-23). Informed consent will be obtained from each participant before randomisation. Results will be published in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05927935.