Muscle Fibre Typology as a Novel Risk Factor for Hamstring Strain Injuries in Professional Football (Soccer): A Prospective Cohort Study.

BACKGROUND: Hamstring strain injuries (HSI) are prevalent in team sports and occur frequently in the later phase of matches. In the search for interindividual factors that determine muscle fatigue and possibly injury risk, muscle fibre typology is a likely candidate. OBJECTIVE: The aim of the study was to determine whether muscle fibre typology is a risk factor for HSI. METHODS: A prospective cohort study was conducted over three seasons in professional football players competing in the Belgian Jupiler Pro League (n = 118) and in the English Premier League (n = 47). A total of 27 HSI were sustained during this period. Muscle fibre typology was non-invasively estimated using proton magnetic resonance spectroscopy and was characterized as a fast, slow, or intermediate typology based on the carnosine concentration in the soleus. A multivariate Cox model was used to identify risk factors for HSI. RESULTS: Football players exhibited a wide variety of muscle typologies (slow 44.9%, intermediate 39.8%, fast 15.3%). In the combined cohort, players with a fast typology displayed a 5.3-fold (95% confidence interval [CI] 1.92-14.8; P = 0.001) higher risk of sustaining an index HSI than slow typology players. This was also independently observed in both leagues separately as, respectively, a 6.7-fold (95% CI 1.3-34.1; P = 0.023) and a 5.1-fold (95% CI 1.2-20.4; P = 0.023) higher chance was found in fast typology players than in slow typology players of the Jupiler Pro League and the Premier League cohort. CONCLUSION: We identified muscle fibre typology as a novel and potent risk factor for HSI in team sports.

CORP: quantification of human skeletal muscle carnosine concentration by proton magnetic resonance spectroscopy.

Noninvasive techniques to quantify metabolites in skeletal muscle provide unique insight into human physiology and enable the translation of research into practice. Proton magnetic resonance spectroscopy (1H-MRS) permits the assessment of several abundant muscle metabolites in vivo, including carnosine, a dipeptide composed of the amino acids histidine and beta-alanine. Muscle carnosine loading, accomplished by chronic oral beta-alanine supplementation, improves muscle function and exercise capacity and has pathophysiological relevance in multiple diseases. Moreover, the marked difference in carnosine content between fast-twitch and slow-twitch muscle fibers has rendered carnosine an attractive candidate to estimate human muscle fiber type composition. However, the quantification of carnosine with 1H-MRS requires technical expertise to obtain accurate and reproducible data. In this review, we describe the technical and physiological factors that impact the detection, analysis, and quantification of carnosine in muscle with 1H-MRS. We discuss potential sources of error during the acquisition and preprocessing of the 1H-MRS spectra and present best practices to enable the accurate, reliable, and reproducible application of this technique.

A randomised controlled trial of energetic activity for depression in young people (READY): a multi-site feasibility trial protocol.

BACKGROUND: Prevalence of depression is increasing in young people, and there is a need to develop and evaluate behavioural interventions which may provide benefits equal to or greater than talking therapies or pharmacological alternatives. Exercise could be beneficial for young people living with depression, but robust, large-scale trials of effectiveness and the impact of exercise intensity are lacking. This study aims to test whether a randomised controlled trial (RCT) of an intervention targeting young people living with depression is feasible by determining whether it is possible to recruit and retain young people, develop and deliver the intervention as planned, and evaluate training and delivery. METHODS: The design is a three-arm cluster randomised controlled feasibility trial with embedded process evaluation. Participants will be help-seeking young people, aged 13-17 years experiencing mild to moderate low mood or depression, referred from three counties in England. The intervention will be delivered by registered exercise professionals, supported by mental health support workers, twice a week for 12 weeks. The three arms will be high-intensity exercise, low-intensity exercise, and a social activity control. All arms will receive a 'healthy living' behaviour change session prior to each exercise session and the two exercise groups are energy matched. The outcomes are referral, recruitment, and retention rates; attendance at exercise sessions; adherence to and ability to reach intensity during exercise sessions; proportions of missing data; adverse events, all measured at baseline, 3, and 6 months; resource use; and reach and representativeness. DISCUSSION: UK National Health Service (NHS) policy is to provide young people with advice about using exercise to help depression but there is no evidence-based exercise intervention to either complement or as an alternative to medication or talking therapies. UK National Institute for Health and Care Excellence (NICE) guidelines suggest that exercise can be an effective treatment, but the evidence base is relatively weak. This feasibility trial will provide evidence about whether it is feasible to recruit and retain young people to a full RCT to assess the effectiveness and cost-effectiveness of an exercise intervention for depression. TRIAL REGISTRATION: ISRCTN, ISRCTN66452702 . Registered 9 April 2020.

Serial tests of T-cell function predict long-term survival in an elderly cohort from a Scottish general practice.

INTRODUCTION The care of the elderly presents serious challenges to general practice. In 1979, the first author took over the care of a general practice in Scotland where 21% of registered patients were elderly. This resulted in a high workload and prompted research into how this might be mitigated. AIM To measure serial tests of T-cell function in these individuals in order to identify those whose immune response was impaired and assess the effect of this in a long term follow up. METHODS This research comprised two phases. In the assessment phase (1979-82), patients were invited to have a 3-monthly visit from a research nurse where clinical measurements were made and blood taken for immunological tests of lymphocyte proliferation after culture with phytohaemagglutinin (PHA). For each patient, all records were surveyed and problems identified. In the follow-up phase (post 1982), all deaths were assessed with complete life-long follow up. RESULTS Of 405 people originally invited to participate in this research, 314 (78%) agreed and 246 (153 female, 93 male) entered the follow-up phase and were followed for 36.5 years. Factors significantly associated with lower survival were age, male sex, diastolic blood pressure, current smoking and poor immune function, as demonstrated by the percentage of negative responses in at least six PHA tests. Considered in four groups by percentage of failing tests, the lowest group had a life span 4 years shorter than the highest (P<0.01). The four groups did not differ significantly in general practitioner workload, diagnosed problems or causes of death. DISCUSSION Poor cellular immune function was associated with poor survival over lifetime follow up of >30 years. A sensitive, specific and longitudinally consistent measure of T-cell function is required to predict who may be at risk of poorer survival within our practices.

The impact of HPV cervical screening on negative large loop excision of the transformation zone (LLETZ): A comparative cohort study.

OBJECTIVE: To determine the incidence and predictors of negative large loop excision of the transformation zone (LLETZ) following the introduction of Human Papillomavirus (HPV) cervical screening. METHOD: A retrospective cohort study. Two independent cohorts, who attended for a LLETZ procedure, before and after the introduction of HPV cervical screening were compared. For each cohort, 401 individuals were randomly selected from a colposcopy database. Clinical and colposcopic variables were extracted. The incidence of negative LLETZ was estimated in each cohort. Regression analysis was used to adjust for potential confounders and explore predictors of negative LLETZ. RESULTS: Eighty women (19.9%) from the pre-HPV testing cohort and 54 women (13.4%) from the post-HPV cohort were negative for cervical intraepithelial neoplasia (RR 0.75, CI: 0.55 to 0.93). In the post-HPV testing cohort, independent predictors of negative LLETZ were low grade cytology (RR 3.60, CI: 2.18-5.97) and a type 3 transformation zone (TZ) (RR 2.88, CI: 1.76-4.72). Women with both low grade cytology and a TZ type 3 were 10.4 times more likely to have a negative LLETZ (absolute risk 40%, 95% CI: 27-54%). CONCLUSIONS: Despite a 25% reduction in negative LLETZ following the introduction of HPV cervical screening, the incidence is still high. These results highlight the importance of continuing to improve the specificity of cervical intraepithelial neoplasia screening; this should include the use of biomarkers that detect HPV-transforming infections and techniques that sample an entirely endocervical transformation zone.

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

γδT cells regulate chronic airway inflammation and development of airway remodelling.

BACKGROUND: γδT cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, γδT cells promote resolution of acute inflammation. However, their contribution to inflammation-associated airway remodelling remains unexplored. Here we investigate the effects of γδT cell blockade on established allergic airway inflammation and development of remodelling. METHODS: Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCRδ antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined. RESULTS: Therapeutic blockade of γδT cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition. CONCLUSIONS: These results demonstrate a unique role for γδT cells in constraining allergen-induced airway remodelling. Manipulating the γδT cell compartment may therefore contribute to strategies to prevent and treat remodelling.

The role of cytological follow-up after radical vaginal trachelectomy for early-stage cervical cancer.

OBJECTIVES: To identify whether recurrences were picked up by cytology alone after radical vaginal trachelectomy and to determine the false-positive rate of abnormal cytology. METHODS: Retrospective collection of patients from the cancer registry since radical vaginal trachelectomy was first performed in Bristol in 1999. All cytology results were collated and re-reviewed by a senior consultant cellular pathologist at the cytopathology centre in Southmead Hospital, Bristol. Cytology results and pathology and survival data are discussed, and any downgrading or upgrading of reports is reviewed. RESULTS: Eighteen women were identified and 80 isthmic cytology samples were reviewed. Only one recurrence has occurred. Lower uterine segment sampling was apparent in 25 samples and other endometrial cells in 21 samples: thus 58% showed endometrial cell sampling. Odd metaplastic cells from the newly formed transformation zone were found in 25 samples (31%). Fifteen (19%) showed significant inflammation, two with actinomyces. After cytology review, seven of 80 reports were changed: two between negative and inadequate, two borderline changes in endocervical cells and one mild dyskaryosis were downgraded to negative, and two cases reported as ?glandular neoplasia were changed to squamous cell carcinoma and negative, respectively. CONCLUSIONS: Cytology reporting may be challenging after trachelectomy. Cytology in our series did not add to the diagnosis of recurrence in the one case in which it occurred. We propose a pragmatic follow-up regime, and discuss the importance of the centralization of cytology reporting in these patients.

Hormone replacement therapy after endometrial cancer.

Endometrial cancer is the fourth most common female cancer in the UK and the most common gynaecological cancer. Quality of life and symptom control needs to be considered in women who enter a surgically induced menopause. Hormone replacement in this population has been controversial to date. The current evidence regarding the safety of estrogen only and combined hormone replacement therapy is discussed in this review. The use of topical vaginal therapies, alternate therapies and the current data regarding testosterone use for symptom control is also outlined.

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

OBJECTIVE: To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. METHODS: This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. RESULTS: Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25(th) -75(th) centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. CONCLUSION: Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Delays in treating endometrial cancer in the South West of England.

BACKGROUND: Poor cancer survival rates in the United Kingdom are often blamed on delayed medical care. A local audit of endometrial cancer revealed a variety of preventable delays. We surveyed practice in the South West of England to see if this was an isolated or widespread problem. METHODS: All 15 hospitals in the South West of England collected information prospectively from all women with endometrial cancer over 3 months in the spring of 2009. RESULTS: There were delays in all stages of the uterine cancer pathway. Excluding extraneous cases, 52% of women waited more than a month and 12% waited more than 6 months to see their GP from the onset of symptoms. Almost half the cases said they were unaware that abnormal bleeding was a symptom of cancer. Only a quarter of women had treatment within 31 days from the outpatient visit to first definitive treatment and 18% waited more than the target of 62 days for their treatment. CONCLUSIONS: Significant treatment delays occur because women do not report bleeding. If this is replicated throughout Britain, approximately 1000 women per year will delay presentation for at least 3 months and 600 will wait for more than 6 months.

Proton MR spectroscopy in a 1T open MR imaging system.

(1)H-MR spectroscopy is an established noninvasive MR imaging technique that can be helpful in the diagnosis of brain lesions and in treatment planning. Claustrophobia and body habitus preclude some patients from routine MR imaging in a closed-bore system. The development of (1)H-MR spectroscopy for use in an open MR imaging system would enable a more complete characterization of brain lesions in these patients.

Is small beautiful? Student performance and perceptions of their experience at larger and smaller sites in rural and remote longitudinal integrated clerkships in the Rural Clinical School of Western Australia.

INTRODUCTION: The Rural Clinical School of Western Australia (RCSWA) provides 25% of Western Australia's medical students in their first full clinical year with a longitudinal integrated clerkship in rural and remote areas. They live and work in 10 different sites in groups of 3 to 10 members. This study aimed to discover if students at the smaller sites were disadvantaged by the reduced number of student colleagues, and also by a smaller population catchment area potentially providing a smaller number of clinical presentations. METHOD: Data were collected from 2003 until 2007 from a variety of sources including annual comparisons of end of year results, annual mid-year interviews of all students and staff, and the Dundee Ready Education Environment Measure (DREEM) Survey. RESULTS: There was no difference in end of year results between smaller sites and larger sites and both had slightly higher marks (and statistically significantly better) than their metropolitan colleagues. Mid-year interviews were shown to correlate significantly with the findings from the DREEM questionnaire in terms of student perceptions. Students at small sites were more satisfied with their educational experience than those at the larger sites. CONCLUSION: With good infrastructure, clarity about learning objectives and a structured academic approach to the complexities of the first full clinical year's curriculum, students need not be disadvantaged by being sent in small numbers to small and/or remote sites for their clinical education. This was established both academically in terms of end of year marks, and also by their subjective experiences.

Tolerizing allergic responses in the lung.

The absolute requirement of the pulmonary immune system is to limit the inflammatory consequences of inhaled infectious agents while maintaining tolerance to harmless aeroallergens. This tolerance is maintained by a complex network of cells and molecules interacting with lung stromal cells. However, in some individuals there is a breakdown in tolerance to particles such as pollens, animal dander, or dust, resulting in the development of allergic pathology. Emerging evidence suggests that this breakdown in tolerance is influenced by the genetic background of individuals as well as environmental considerations such as early exposure to respiratory pathogens. Further understanding of the mechanisms used by the pulmonary immune system to maintain tolerance might result in exploitation of novel avenues for therapy to treat the growing number of chronic asthmatic patients.