Are all hamstring injuries equal? A retrospective analysis of time to return to full training following BAMIC type 'c' and T-junction injuries in professional men's rugby union.

We aimed to determine whether the anatomical location (intramuscular tendon or T-Junction) of hamstring muscle injuries in professional men's rugby union associates with a prolonged time to return to full training and a higher rate of re-injury/subsequent injury. We reviewed the medical records of an Irish professional rugby union club to identify hamstring muscle injuries incurred across five seasons. Clinicians and players were not blinded to MRI results at the time of rehabilitation. A blinded musculoskeletal radiologist re-classified all included injuries (n = 91) according to the British Athletics Muscle Injury Classification framework. Players who sustained an injury with intramuscular tendon involvement required a longer time to return to full training compared to players who sustained an injury without intramuscular tendon involvement (78 days vs. 24 days). Players who sustained a biceps femoris injury with T-junction involvement did not require a longer time to return to full training compared to players who sustained a biceps femoris injury without T-junction involvement (29 days vs. 27 days). Injuries with either intramuscular tendon or T-junction involvement were not associated with an increased rate of re-injury/subsequent injury to the same limb (intramuscular tendon involvement - odds ratio = 0.96, T-junction involvement - odds ratio = 1.03). When a hamstring muscle injury involves the intramuscular tendon, the injured player and stakeholders should be made aware that a longer time to return to full training is likely required. T-junction involvement does not alter the expected clinical course of biceps femoris injuries.

Synthetically accessible de novo design using reaction vectors: Application to PARP1 inhibitors.

De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction-based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand-coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction-based de novo design to the design of synthetically accessible and biologically active compounds as proof-of-concept of our reaction vector-based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible.

Intramuscular Tendon Injuries of the Hamstring Muscles: A More Severe Variant? A Narrative Review.

Hamstring strain injuries (HSI) are one of the most common sport-related injuries. They have a high injury burden and a high recurrence rate. The development of novel muscle injury grading systems has provided new insights into the possible impact of injury location on the time to return to play (TTRTP) and re-injury following HSI. In particular, injuries to the intramuscular tendon (IMT) may be present in up to 41% of all HSI and have been described as a 'serious thigh muscle strain'. Re-injury rates as high as 60% have been described in elite track and field athletes, as well as prolonged TTRTP. A systematic search was carried out using appropriate keywords to identify articles reporting on HSI involving the IMT in athletes. The primary aim was to determine whether IMT injuries warrant being classified as a distinct clinical entity with different expected outcomes to other hamstring muscle injuries. This narrative review summarises the existing evidence on: (1) the anatomy of the IMT and its response to injury; (2) the role of MRI and novel grading scales in IMT injury management (3) clinical assessment of IMT injuries, (4) TTRTP and re-injury rates across sports following IMT, (5) conservative rehabilitation and the role of specific 'IMT-oriented' strategies, and (6) indications for and approaches to surgery. The review found that important clinical outcomes such as re-injury rates and TTRTP vary across populations, cohorts and sports which suggest that outcomes are specific to the sporting context. Bespoke rehabilitation, tailored to IMT injury, has been shown to significantly reduce re-injuries in elite track and field athletes, without compromising TTRTP. Continued prospective studies across other sports and cohorts, are warranted to further establish relevant clinical findings, indications for surgical intervention and outcomes across other sporting cohorts.

The forgotten people: Hepatitis B virus (HBV) infection as a priority for the inclusion health agenda.

Hepatitis B virus (HBV) infection represents a significant global health threat, accounting for 300 million chronic infections and up to 1 million deaths each year. HBV disproportionately affects people who are under-served by health systems due to social exclusion, and can further amplify inequities through its impact on physical and mental health, relationship with stigma and discrimination, and economic costs. The 'inclusion health' agenda focuses on excluded and vulnerable populations, who often experience barriers to accessing healthcare, and are under-represented by research, resources, interventions, advocacy, and policy. In this article, we assimilate evidence to establish HBV on the inclusion health agenda, and consider how this view can inform provision of better approaches to diagnosis, treatment, and prevention. We suggest approaches to redress the unmet need for HBV interventions among excluded populations as an imperative to progress the global goal for the elimination of viral hepatitis as a public health threat.

Discovery of BAY-390, a Selective CNS Penetrant Chemical Probe as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonist.

Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy. Consequently, there is an increasing interest in TRPA1 inhibitors as potential analgesics. Herein, we report the identification of a fragment-like hit from a high-throughput screening (HTS) campaign and subsequent optimization to provide a novel and brain-penetrant TRPA1 inhibitor (compound 18, BAY-390), which is now being made available to the research community as an open-source in vivo probe.

Modified trauma assessment clinic: A rapid, scalable model.

INTRODUCTION: Trauma Assessment Clinic (TAC) has become a very useful tool in managing busy trauma clinics and reducing attendances. There is good evidence of safety and efficacy. Extension of pre-existing TAC during the COVID pandemic has proven successful. Rapid start-up models for establishing TACs are not well described in the literature. This study aimed to prove that a modified TAC has similar efficacy and can be initiated in rapid start-up manner with minimal cost. METHODS: A new electronic pathway of referral with a template was created between the Emergency Department (ED) and the Orthopaedic department. RESULTS: Following introduction of our modified TAC 32% of patients referred to the TAC did not require in-person review thereby avoiding any additional hospital visit. Average time to first in-person review appointment was 15 days. Combining these, the projected reduction in all fracture clinic attendance was 48%. CONCLUSION: This paper describes the process of how a major teaching and tertiary referral orthopaedic unit developed an accelerated establishment process for a Trauma Assessment Clinic as an alternative to the traditional "Glasgow model". This can be instituted quickly, safely, and is scalable for use in a large hospital. The template provided can be used as a guide or "blueprint" should other orthopaedic departments require a rapid start-up of a Trauma Assessment Clinic.

A real-time measurement of general practice workload in the Republic of Ireland: a prospective study.

BACKGROUND: Demand for GP services in the Republic of Ireland (RoI) is increasing, and the resultant escalation in workload demands is an issue of growing concern. Accordingly, the accurate measurement and description of GP workload is essential to inform future healthcare planning. AIM: To provide a real-time measurement of GP workload with respect to hours worked and of proportional time expenditure on typical workload activities. DESIGN AND SETTING: A prospective study among GPs in the RoI that took place from January 2019 to March 2019. METHOD: Participants were invited to enrol in the study by direct email invitation and via notifications posted within GP-specific monthly journals; online forums; and a social media platform. Participants used a time-management software program to self-record workload activity in real time over 6 weeks. RESULTS: In total, 123 GPs were included for final analyses with a total of 8930 hours of activity recorded. The mean duration of a two-session day (excluding break-time) was 9.9 hours (95% confidence interval [CI] = 9.7 to 10.0; interquartile range [IQR] 7.9 to 13.9). Of this time, 64% was spent on clinical consultations. In total, 25.4% of activity was recorded outside the hours of 9.00 am and 5.00 pm. An average of 12.4 face-to-face consultations were completed per session of activity. The mean duration of a 10-session week was greatest for the partner (50.8 hours; 95% CI = 49.8 to 51.9) and >55-year-old (50.8 hours; 95% CI = 49.3 to 52.2) demographics, relative to their respective colleagues. CONCLUSION: To the authors' knowledge, this is the first study to provide an objective, accurate, and granular real-time measurement of GP workload in the RoI, demonstrating the significant volume and variety of work undertaken by GPs in the RoI.

Case finding and therapy for chronic viral hepatitis in primary care (HepFREE): a cluster-randomised controlled trial.

BACKGROUND: The prevalence of viral hepatitis (hepatitis B virus and hepatitis C virus) in migrants is higher than among the general population in many high-income countries. We aimed to determine whether incentivising and supporting primary-care physicians in areas with a high density of migrants increases the numbers of adult migrants screened for viral hepatitis. METHODS: HepFREE was a multicentre, open, cluster-randomised controlled trial in general practices in areas of the UK with a high density of migrants (Bradford, Yorkshire, and northeast and southeast London). Participants were adult patients (aged 18 years or older) in primary care, who had been identified as a first or second generation migrant from a high-risk country. General practices were randomly assigned (1:2:2:2:2) to an opportunistic screening (control) group or to one of four targeted screening (interventional) groups: standard (ie, hospital-based) care and a standard invitation letter; standard care and an enhanced invitation letter; community care and a standard invitation letter; or community care and an enhanced invitation letter. In control screening, general practitioners (GPs) were given a teaching session on viral hepatitis and were asked to test all registered migrants. In the intervention, GPs were paid a nominal sum for setting up searches of records, reimbursed for signed consent forms, and supported by a dedicated clinician. Patients who were eligible for testing and tested positive for viral hepatitis in the intervention groups were eligible to enrol in a second embedded trial of community versus hospital based care. The primary outcomes were the proportion of patients eligible for screening, the proportion of those eligible who were sent an invitation letter in the intervention groups, the uptake of viral hepatitis screening (in the intention-to-treat population), the proportion of patients who tested positive for viral hepatitis, the proportion who complied with treatment, and the cost-effectiveness of the intervention. This trial is registered with ISRCTN, number ISRCTN54828633. FINDINGS: Recruitment and testing ran from Oct 31, 2013, to Feb 4, 2017, and each practice recruited for 18 consecutive calendar months. We approached 70 general practices in three areas with a high density of migrants, of which 63 general practices agreed to participate. Five practices withdrew and 58 practices were randomly assigned: eight to control and 50 to an intervention. In control practices, 26 046 (38·4%) of 67 820 patients who were initially registered were eligible for testing, as were 152 321 (43·3%) of 351 710 patients in the interventional groups in London and Bradford. Of 51 773 randomly selected eligible patients in the intervention groups in London and Bradford, letters were sent to 43 585 (84·2%) patients. In the eight control general practices, screening was taken up by 543 (1·7%) of 31 738 eligible participants, which included 5692 newly registered patients. However, in the 50 general practices that used the intervention, screening was taken up by 11 386 (19·5%) of 58 512 eligible participants (including 6739 newly registered patients; incidence rate ratio 3·70, 95% CI 1·30-10·51; p=0·014) and this intervention was cost-effective. 720 (4·5%) of 15 844 patients who received a standard letter versus 1032 (3·7%) of 28 095 patients who received the enhanced letter were tested (0·70, 0·38-1·31; p=0·26). In the control group, 17 patients tested positive for viral hepatitis, as did 220 patients (one with a co-infection) in the intervention groups. In the embedded study, 220 patients were randomly assigned to either hospital-based care or community care; 80 (87·9%) of 91 patients in the hospital setting complied with treatment versus 105 (81·4%) of 129 patients in the community setting. The intervention was cost-effective at willingness to pay thresholds in excess of £8540. One serious adverse event (thyroiditis) was noted. INTERPRETATION: Screening migrants for viral hepatitis in primary care is effective if doctors are incentivised and supported. Community care is expensive and there is no evidence that this offers benefits in this setting or that bespoke invitation letters add value. We suggest that bespoke invitation letters should not be used, and we suggest that outreach, community-based services for migrants should not be developed. FUNDING: National Institute for Health Research.

Extremely high HIV-1 viral load in a patient with undiagnosed clinical indicator disease for HIV infection.

We report a case of a new diagnosis of HIV with an extremely high viral load presenting with HIV encephalopathy, in a 54-year-old woman who had been treated with 2 years of extended high-dose immunosuppressant therapy for a recalcitrant pruritic rash before diagnosis.

The effect of tenofovir on renal function in HIV-positive pregnant women.

INTRODUCTION: Tenofovir is a commonly used component of antiretroviral therapy (ART) to reduce vertical transmission of HIV. Although systematic review of tenofovir use in pregnancy concluded it to be low risk for foetal abnormalities (1), data is limited on its impact on renal function in pregnant women. A recent South African study (2) concluded that renal dysfunction in HIV-infected pregnant women is significantly less common than in other HIV-infected adults, however there is currently no UK data. We aimed to investigate the effect of tenofovir on renal function in HIV-1 positive pregnant women in a UK clinic. METHODS: We retrospectively analyzed data on renal function in pregnancy from a cohort of women attending a busy inner city London antenatal clinic. All women were screened for renal function throughout pregnancy via serum creatinine and estimated glomerular filtration rate (eGFR) calculated using modification of diet in renal disease (MDRD) and corrected for ethnicity. RESULTS: Ninety-seven HIV-1 positive women were registered at Homerton Hospital antenatal service of a total of 105 pregnancies between January 2010 and September 2013. Tenofovir was prescribed in 71/105 pregnancies (67.6%). Of the 71 pregnancies, 41 were prescribed tenofovir pre-conception (57.7%). Of the pregnant women who started tenofovir in pregnancy, 21/31 (67.7%) were initiated before week 24 of pregnancy, in line with British HIV association (BHIVA) guidelines (3). There was no deterioration in median serum creatinine or decline in eGFR in women prescribed tenofovir during pregnancy. At six weeks after delivery, in the 42 women who continued tenofovir therapy and had eGFR measured, one woman had eGFR=60, all others eGFR >90 (Table 1). CONCLUSIONS: Consistent with current guidelines and experience, this study shows tenofovir did not cause decline in renal function in pregnancy in our cohort of HIV-1 positive women, whether started during pre-conception or during pregnancy. More evidence should be prospectively collected looking at effects of tenofovir on other measures of tubular renal function in pregnancy such as proteinuria and protein-creatinine ratio.

Simeprevir for the treatment of hepatitis C and HIV/hepatitis C co-infection.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis in 170 million people worldwide and can progress to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, a disease process accelerated in HIV co-infection. Approximately 25% of HIV infected people are co-infected with HCV (worldwide prevalence 4-5 million) and up to 16.7% of deaths in this population are attributable to HCV co-infection. Previous treatment options for HCV were limited to pegylated interferon and ribavirin (PEG-IFN/RBV), a combination that demonstrated lower successful cure rates in genotype 1 HCV mono-infection and HIV/HCV co-infection, and is also associated with a considerable adverse side-effect profile. The development of directly acting antivirals (DAAs) offers the first class of drug to achieve good viral suppression in previously hard-to-treat patient groups. We review the benefits, tolerability and drug interactions with concomitant drugs of the DAA simeprevir for patients who have HCV mono-infection and hep C/HIV co-infection.

Medium ring synthesis by radical ipso-substitution.

A new approach to eight and nine membered ring synthesis is described in which a radical ipso-substitution reaction features as a key step.