The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.

Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with , and independent confirmatory evidence has recently been published for four more.

Outcomes in Ankle Replacement Study (OARS).

Aims: The aim of this study was to capture 12-month outcomes from a representative multicentre cohort of patients undergoing total ankle arthroplasty (TAA), describe the pattern of patient-reported outcome measures (PROMs) at 12 months, and identify predictors of these outcome measures.

Methods: Patients listed for a primary TAA at 19 NHS hospitals between February 2016 and October 2017 were eligible. PROMs data were collected preoperatively and at six and 12 months including: Manchester-Oxford Foot and Ankle Questionnaire (MOXFQ (foot and ankle)) and the EuroQol five-dimension five-level questionnaire (EQ-5D-5L).

Why the trial researcher matters: Day-to-day work viewed through the lens of normalization process theory.

Researchers working in the field, the places where research-relevant activity happens, are essential to recruitment and data collection in randomised controlled trials (RCTs). This study aimed to understand the nature of this often invisible work. Data were generated through an RCT of a pharmacist-led medication management service for older people in care homes.

Evaluation of effectiveness and safety of pharmacist independent prescribers in care homes: cluster randomised controlled trial.

Objective: To estimate the effectiveness, cost effectiveness (to be reported elsewhere), and safety of pharmacy independent prescribers in care homes.

Design: Cluster randomised controlled trial, with clusters based on triads of a pharmacist independent prescriber, a general practice, and one to three associated care homes.

Setting: Care homes across England, Scotland, and Northern Ireland, their associated general practices, and pharmacy independent prescribers, formed into triads.

English care home staff morale and preparedness during the COVID pandemic: A longitudinal analysis.

Background: Staff actions to prevent infection introduction and transmission in long-term care facilities (LTCFs) were key to reducing morbidity and mortality from COVID-19. Implementing infection control measures (ICMs) requires training, adherence and complex decision making while trying to deliver high quality care. We surveyed LTCF staff in England about their preparedness and morale at 3 timepoints during the COVID-19 epidemic.

Effects of interactions between anthropogenic stressors and recurring perturbations on ecosystem resilience and collapse.

Insights into declines in ecosystem resilience and their causes and effects can inform preemptive action to avoid ecosystem collapse and loss of biodiversity, ecosystem services, and human well-being. Empirical studies of ecosystem collapse are rare and hampered by ecosystem complexity, nonlinear and lagged responses, and interactions across scales. We investigated how an anthropogenic stressor could diminish ecosystem resilience to a recurring perturbation by altering a critical ecosystem driver.

Neuropathic-like Pain in Fibrous Dysplasia/McCune-Albright Syndrome.

Context: Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard analgesics (nonsteroidal anti-inflammatory drugs and opiates) is unpredictable. No studies have explored whether the type of pain is variable in this patient group.

Objective: To determine the frequency of neuropathic-like pain in patients with FD/MAS.

Awakening Canadians to ageism: a study protocol.

Background: Making fun of growing older is considered socially acceptable, yet ageist humour reinforces negative stereotypes that growing old is linked with physical and mental deterioration, dependence, and less social value. Such stereotypes and discrimination affect the wellbeing of older people, the largest demographic of Canadians. While ageism extends throughout professions and social institutions, we expect nurses-the largest and most trusted group of healthcare professionals-to provide non-ageist care to older people.

Clinical and biomechanical factors associated with falls and rheumatoid arthritis: baseline cohort with longitudinal nested case-control study.

Objective: To identify the clinical and biomechanical characteristics associated with falls in people with RA.

Methods: A total of 436 people ≥60 years of age with RA completed a 1 year prospective survey of falls in the UK. At baseline, questionnaires recorded data including personal and medical history, pain and fatigue scores, health-related quality of life (HRQoL), physical activity and medication history.

Rare musculoskeletal diseases in adults: a research priority setting partnership with the James Lind Alliance.

Background: Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients.

The effectiveness of a multidisciplinary intervention strategy for the treatment of symptomatic joint hypermobility in childhood: a randomised, single Centre parallel group trial (The Bendy Study).

Introduction: Joint hypermobility is common in childhood and can be associated with musculoskeletal pain and dysfunction. Current management is delivered by a multidisciplinary team, but evidence of effectiveness is limited. This clinical trial aimed to determine whether a structured multidisciplinary, multisite intervention resulted in improved clinical outcomes compared with standard care.

The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis.

Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.

Isothiocyanates are detected in human synovial fluid following broccoli consumption and can affect the tissues of the knee joint.

Osteoarthritis is a major cause of disability and there is no current pharmaceutical treatment which can prevent the disease or slow its progression. Dietary advice or supplementation is clearly an attractive option since it has low toxicity and ease of implementation on a population level. We have previously demonstrated that sulforaphane, a dietary isothiocyanate derived from its glucosinolate precursor which is found in broccoli, can prevent cartilage destruction in cells, in in vitro and in vivo models of osteoarthritis.

The RUDY study: using digital technologies to enable a research partnership.

Patients have extensive experience of their disease that can enhance the design and execution of research leading to significant innovations and efficiencies in the research process. The research community on the whole have been slow to adopt practices that enable patients to become active partners in research. Digital technologies are providing the means to do this more easily and so are increasingly being used to interact with patients and involve them in the design and execution of research.

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations.

We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E).

Health-related quality of life and a cost-utility simulation of adults in the UK with osteogenesis imperfecta, X-linked hypophosphatemia and fibrous dysplasia.

Background: Health-related quality of life of adults with osteogenesis imperfecta (OI), fibrous dysplasia (FD) and X-linked hypophosphatemia (XLH) remains poorly described. The aim of this study was to describe the HRQoL of adults with osteogenesis imperfecta, fibrous dysplasia and X-linked hypophophataemia and perform a cost-utility simulation to calculate the maximum cost that a health care system would be willing to pay for a hypothetical treatment of a rare bone disease.

Results: Participants completed the EQ-5D-5 L questionnaire between September 2014 and March 2016.

Chiari malformation, syringomyelia and bulbar palsy in X linked hypophosphataemia.

X linked hypophosphataemia (XLH) is a rare condition with numerous musculoskeletal complications. It may mimic other more familiar conditions, such as vitamin D deficiency, ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. We describe two cases with Chiari type 1 malformations and syringomyelia, neither of which is well recognised in XLH.

Inhibition of the thioesterase activity of human fatty acid synthase by 1,4- and 9,10-diones.

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo.

Patient experiences of participation in a medical student teaching workshop.

Objectives: To investigate the motivations for and experiences of patients who actively participate in a workshop to teach medical students about chronic disease.

Design: Descriptive study using structured telephone or e-mail-based questionnaire exploring the views of 'patient tutors' who participate in a 'living with chronic disease' workshop.

Participants: 'Patient tutors' with a chronic medical condition who had participated in at least one 'living with chronic disease' workshop for medical students at Oxford University Medical School.

Venous thromboembolism (VTE) risk assessment and prophylaxis in acute orthopaedic admissions: improving compliance with national guidelines.

"Each year over 25,000 people die from Venous Thromboembolism (VTE) contracted in hospital. This is more than the combined total of deaths from breast cancer, AIDS and traffic accidents". (1) Orthopaedic patients are at particular risk of VTE.

Now I know what I don't know: how to reform the foundation years to fit 21st-century medicine.

The two-year Foundation Programme was introduced in the UK as a structured way to deal with the lack of training, support and difficulties with career progression associated with the old senior house office (SHO) grade. Although it provides a clear curriculum and structure for career progression, there is growing dissatisfaction among participants about the difference between the aspirations of the Foundation Programme and the realities of working as a foundation doctor. In particular, the erosion of the traditional team structure, difficulties with the system of assessment and a feeling that the career structure is now too rigid has led to a situation where doctors are being forced to choose their specialty training too early and often with little experience in the specialty.