Trophic relationship between Salix flowers, Orthosia moths and the western barbastelle.

We present the results of a study which describes the relationship between the western barbastelle Barbastella barbastellus a highly specialised moth predator, and its prey-moths of the genus Orthosia, another selective animal known to converge around a dominant producer of pollen and nectar in early spring-willow trees Salix sp. In order to describe this trophic relationship, we conducted acoustic recordings at five paired sites (willow/control tree) in proximity to known barbastelle hibernation sites (Natura 2000: PLH080003 and PLH200014) beginning in mid-March 2022 after the first willow blossom sighting. Our study confirms a relationship between willow trees and barbastelles during early spring, as their activity around them was significantly higher than control sites. We also explore the activity of barbastelles over time, finding that activity levels around willows significantly decrease from the night of the first recorded bat, while the abundance of non-moth specialist bats remains consistent. Short-time importance (directly after hibernation) of willows for a moth specialist bat is probably due to other species blossom, attracting alternative prey, and in consequence-the bat. This newly described relationship should influence current conservation measures aimed at barbastelles.

Overcoming barriers to HIV pre-exposure prophylaxis (PrEP) coverage in Australia among Medicare-ineligible people at risk of HIV: results from the MI-EPIC clinical trial.

Background Overseas-born people who are ineligible for government-subsidised health care experience barriers to accessing HIV pre-exposure prophylaxis (PrEP) in Australia. This study aimed to assess a program providing free PrEP to overseas-born adults at risk of acquiring HIV. Methods Medicare-Ineligible Expanded Implementation in Communities (MI-EPIC) was a single-arm, open-label trial of daily tenofovir disoproxil fumarate/emtricitabine as PrEP. Six clinics recruited Medicare-ineligible adults who met HIV risk criteria in New South Wales, Australia. We recorded data on HIV and sexually transmitted infection (STI) diagnoses, and PrEP dispensing from July 2019 to June 2020. PrEP adherence as a medication possession ratio (MPR) was calculated as pills dispensed divided by days. We administered an optional survey on behaviours and attitudes to PrEP and sexual health. Results The 221 participants (206 men; 93.2%) had a median age of 29years (IQR 26-34). Participants were mostly born in Asia (53.4%), Latin America or the Caribbean (25.3%), or Europe (10.9%). Adherence was high; 190 participants (86.0%) had an MPR of >60%. Of 121 survey participants, 42 (34.7%) completed the survey in a language other than English. Of participants who had not used PrEP in the 6months before enrolment (n=45, 37.2%), the most common reasons were cost (n=22, 48.9%), and lack of knowledge about accessing PrEP (n=20, 44.4%). Conclusions Medicare-ineligible people at risk of HIV demonstrate high adherence when given access to free PrEP and translated information. Increasing PrEP awareness and reducing barriers to accessing PrEP in this high-risk population should be priorities in HIV prevention.

Will virtual multidisciplinary team meetings become the norm for musculoskeletal oncology care following the COVID-19 pandemic? - experience from a tertiary sarcoma centre.

BACKGROUND: Like with all cancers, multidisciplinary team (MDT) meetings are the norm in bone and soft tissue tumour (BST) management too. Problem in attendance of specialists due to geographical location is the one of the key barriers to effective functioning of MDTs. To overcome this problem, virtual MDTs involving videoconferencing or telemedicine have been proposed, but however this has been seldom used and tested. The COVID-19 pandemic forced the implementation of virtual MDTs in the Oxford sarcoma service in order to maintain normal service provision. We conducted a survey among the participants to evaluate its efficacy. METHODS: An online questionnaire comprising of 24 questions organised into 4 sections was circulated among all participants of the MDT after completion of 8 virtual MDTs. Opinions were sought comparing virtual MDTs to the conventional face-to-face MDTs on various aspects. A total of 36 responses were received and were evaluated. RESULTS: 72.8% were satisfied with the depth of discussion in virtual MDTs and 83.3% felt that the decision-making in diagnosis had not changed following the switch from face-to-face MDTs. About 86% reported to have all essential patient data was available to make decisions and 88.9% were satisfied with the time for discussion of patient issues over virtual platform. Three-fourths of the participants were satisfied (36.1% - highly satisfied; 38.9% - moderately satisfied) with virtual MDTs and 55.6% of them were happy to attend MDTs only by the virtual platform in the future. Regarding future, 77.8% of the participants opined that virtual MDTs would be the future of cancer care and an overwhelming majority (91.7%) felt that the present exercise would serve as a precursor to global MDTs involving specialists from abroad in the future. CONCLUSION: Our study shows that the forced switch to virtual MDTs in sarcoma care following the unprecedented COVID-19 pandemic to be a viable and effective alternative to conventional face-to-face MDTs. With effective and efficient software in place, virtual MDTs would also facilitate in forming extended MDTs in seeking opinions on complex cases from specialists abroad and can expand cancer care globally.

Augmenting endogenous repair of soft tissues with nanofibre scaffolds.

As our ability to engineer nanoscale materials has developed we can now influence endogenous cellular processes with increasing precision. Consequently, the use of biomaterials to induce and guide the repair and regeneration of tissues is a rapidly developing area. This review focuses on soft tissue engineering, it will discuss the types of biomaterial scaffolds available before exploring physical, chemical and biological modifications to synthetic scaffolds. We will consider how these properties, in combination, can provide a precise design process, with the potential to meet the requirements of the injured and diseased soft tissue niche. Finally, we frame our discussions within clinical trial design and the regulatory framework, the consideration of which is fundamental to the successful translation of new biomaterials.

United Kingdom Frozen Shoulder Trial (UK FROST), multi-centre, randomised, 12 month, parallel group, superiority study to compare the clinical and cost-effectiveness of Early Structured Physiotherapy versus manipulation under anaesthesia versus arthroscopic capsular release for patients referred to secondary care with a primary frozen shoulder: study protocol for a randomised controlled trial.

BACKGROUND: Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy. METHODS: We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods. DISCUSSION: The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014.

Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy.

CONTEXT: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response. OBJECTIVE: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol. DESIGN: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy. SETTING: Hospital antenatal clinics. PARTICIPANTS: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks. INTERVENTIONS: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery. MAIN OUTCOME MEASURE: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison). RESULTS: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (ß = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (ß = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (ß = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (ß = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation. CONCLUSIONS: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.

Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.

BACKGROUND: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research.

Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards.

There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.

Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks' follow-up.

BACKGROUND: A comprehensive assessment of initial HIV-1 treatment success may inform study design and treatment guidelines. METHODS: Group-based, systematic review and meta-analysis of initial antiretroviral therapy studies, in adults, of ≥ 48 weeks duration, reported through December 31, 2012. Size-weighted, intention-to-treat efficacy was calculated. Parameters of study design/eligibility, participant and treatment characteristics were abstracted. Multivariable, random effects, linear regression models with backwards, stepwise selection were then used to identify variables associated with efficacy. OUTCOME MEASURES: Antiviral efficacy (undetectable plasma viral load) and premature cessation of therapy. RESULTS: 114 studies were included (216 treatment groups; 40,124 participants; mean CD4 count 248 cells/µL [SD 81]; mean HIV-1 plasma viral load log10 4.9 [SD 0.2]). Mean efficacy across all groups was 60% (SD 16) over a mean 82 weeks' follow-up (SD 38). Efficacy declined over time: 66% (SD 16) at 48 weeks, 60% (SD 16) at 96 weeks, 52% (SD 18) at 144 weeks. The most common reason for treatment cessation was participant decision (11%, SD 6.6). Efficacy was higher with 'Preferred' than 'Alternative' regimens (as defined by 2013 United States antiretroviral guidelines): 75% vs. 65%, respectively, difference 10%; 95%CI 7.6 to 15.4; p<0.001. In 98 groups (45%) reporting efficacy stratified by pre-treatment viral load (< or ≥100,000 copies/mL), efficacy was greater for the lower stratum (70% vs. 62%, respectively, difference 8.4%; 95%CI 6.0 to 10.9; p<0.001). This difference persisted within 'Preferred' regimens. Greatest efficacy was associated with use of tenofovir-emtricitabine (vs. other nucleoside analogue backbones) and integrase strand transfer inhibitors (vs. other third drug classes). CONCLUSION: Initial antiretroviral treatments for HIV-1 to date appear to have suboptimal long-term efficacy, but are more effective when commenced at plasma viral loads <100,000 copies/mL. Rising viral load should be considered an indication for starting treatment. Integrase inhibitors offer a treatment advantage (vs. other third drug classes).

Why does my shoulder hurt? A review of the neuroanatomical and biochemical basis of shoulder pain.

If a patient asks 'why does my shoulder hurt?' the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or 'nociception', (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.

Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate.

OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.