Ashford and St Peter's Hospitals NHS Foundation Trust

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Cardiovascular disease is a significant and ever-growing problem in the United Kingdom, accounting for nearly one-third of all deaths and leading to significant morbidity. It is also of particular and pressing interest as developing countries experience a change in lifestyle which introduces novel risk factors for cardiovascular disease, leading to a boom in cardiovascular disease risk throughout the developing world. The burden of cardiovascular disease can be ameliorated by careful risk reduction and, as such, primary prevention is an important priority for all developers of health policy. Strong consensus exists between international guidelines regarding the necessity of smoking cessation, weight optimisation and the importance of exercise, whilst guidelines vary slightly in their approach to hypertension and considerably regarding their approach to optimal lipid profile which remains a contentious issue. Previously fashionable ideas such as the polypill appear devoid of in-vivo efficacy, but there remain areas of future interest such as the benefit of serum urate reduction and utility of reduction of homocysteine levels.

Our population is ageing, and obesity is increasing in the elderly bringing massive and rapidly changing burdens of ill health related to increased body weights and fat as well as the main drivers of poor diet and inactivity. Overweight and obesity, and a static body mass index (BMI) commonly conceal sarcopenia (gain in body fat but loss of muscle mass and functional capacity) in older people, aggravated by inactivity. A systematic computerized literature search using an iterative manipulation process of the keywords: obesity, elderly, weight loss. The following databases were accessed on 20 October 2010: Medline, Cochrane Collaboration, Ovid and Scholar Google. A large number of clinical consequences of overweight and obesity are particularly problematic for elderly individuals, including type 2 diabetes mellitus, arthritis, urinary incontinence and depression. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults has often been misinterpreted that obesity is not as harmful in the elderly. BMI may be a less appropriate index in the elderly. All the medical consequences of obesity are multi-factorial but all are alleviated by modest, achievable weight loss (5-10 kg) with an evidence-based maintenance strategy. Since sarcopenic obesity is common in the elderly, a combination of exercise and modest calorie restriction appears to be the optimal method of reducing fat mass and preserving muscle mass. Reduction in polypharmacy is a valuable target for weight management. Age is not an obstacle to weight management interventions using moderate calorie restriction and exercise, and the currently licensed drug orlistat appears to have no age-related hazards. Overall balance of clinical outcomes has not been evaluated. In older people the risks from bariatric surgery outweigh benefits. Obesity, and specifically sarcopenic obesity, should also be prevented not only from younger age, but also during major life transitions including retirement, to improve better health outcomes and quality of life in later years, with a focus on those in 'obese families', where the main increases in obesity are located. Randomized controlled trials to determine health benefits and risks from long-term weight management in obese elderly are necessary.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

OBJECTIVES: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice. METHODS: A Medline search was performed using the search terms "methotrexate", "folic acid", "folinic acid", "folate" and "homocysteine". Literature relevant to the use of folates as a supplement to MTX in the treatment of RA was reviewed and other papers referred to as references were explored. RESULTS: The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor. CONCLUSIONS: We propose that folic acid supplements be prescribed routinely to all patients receiving MTX for the treatment of RA. We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of MTX administration.

Summary Intravenous lidocaine is used widely for its effect on postoperative pain and recovery but it can be, and has been, fatal when used inappropriately and incorrectly. The risk‐benefit ratio of i.v. lidocaine varies with type of surgery and with patient factors such as comorbidity (including pre‐existing chronic pain). This consensus statement aims to address three questions. First, does i.v. lidocaine effectively reduce postoperative pain and facilitate recovery? Second, is i.v. lidocaine safe? Third, does the fact that i.v. lidocaine is not licensed for this indication affect its use? We suggest that i.v. lidocaine should be regarded as a ‘high‐risk’ medicine. Individual anaesthetists may feel that, in selected patients, i.v. lidocaine may be beneficial as part of a multimodal peri‐operative pain management strategy. This approach should be approved by hospital medication governance systems, and the individual clinical decision should be made with properly informed consent from the patient concerned. If i.v. lidocaine is used, we recommend an initial dose of no more than 1.5 mg.kg ‐1 , calculated using the patient’s ideal body weight and given as an infusion over 10 min. Thereafter, an infusion of no more than 1.5 mg.kg ‐1 .h ‐1 for no longer than 24 h is recommended, subject to review and re‐assessment. Intravenous lidocaine should not be used at the same time as, or within the period of action of, other local anaesthetic interventions. This includes not starting i.v. lidocaine within 4 h after any nerve block, and not performing any nerve block until 4 h after discontinuing an i.v. lidocaine infusion.

OBJECTIVES: To investigate the prospects of newly available benchtop sequencers to provide rapid whole-genome data in routine clinical practice. Next-generation sequencing has the potential to resolve uncertainties surrounding the route and timing of person-to-person transmission of healthcare-associated infection, which has been a major impediment to optimal management. DESIGN: The authors used Illumina MiSeq benchtop sequencing to undertake case studies investigating potential outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. SETTING: Isolates were obtained from potential outbreaks associated with three UK hospitals. PARTICIPANTS: Isolates were sequenced from a cluster of eight MRSA carriers and an associated bacteraemia case in an intensive care unit, another MRSA cluster of six cases and two clusters of C difficile. Additionally, all C difficile isolates from cases over 6 weeks in a single hospital were rapidly sequenced and compared with local strain sequences obtained in the preceding 3 years. MAIN OUTCOME MEASURE: Whole-genome genetic relatedness of the isolates within each epidemiological cluster. RESULTS: Twenty-six MRSA and 15 C difficile isolates were successfully sequenced and analysed within 5 days of culture. Both MRSA clusters were identified as outbreaks, with most sequences in each cluster indistinguishable and all within three single nucleotide variants (SNVs). Epidemiologically unrelated isolates of the same spa-type were genetically distinct (≥21 SNVs). In both C difficile clusters, closely epidemiologically linked cases (in one case sharing the same strain type) were shown to be genetically distinct (≥144 SNVs). A reconstruction applying rapid sequencing in C difficile surveillance provided early outbreak detection and identified previously undetected probable community transmission. CONCLUSIONS: This benchtop sequencing technology is widely generalisable to human bacterial pathogens. The findings provide several good examples of how rapid and precise sequencing could transform identification of transmission of healthcare-associated infection and therefore improve hospital infection control and patient outcomes in routine clinical practice.

OBJECTIVE: The aim of this study was to compare the diagnostic performance of clinical vaginal examination with that of transvaginal sonography (TVS) in the presurgical diagnosis of deep infiltrating endometriosis. METHODS: One-hundred and fifty-five women with symptoms suggestive of endometriosis were included. One-hundred and twenty-nine patients met the inclusion criteria and were prospectively and independently assessed by vaginal examination and TVS prior to a diagnostic laparoscopy and, where appropriate, radical resection and histological confirmation of endometriosis was performed. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and positive and negative likelihood ratios (LR+ and LR-) were calculated for each test method. RESULTS: In total, 83 (64%) women had histological confirmation of endometriosis, 52 (40%) of whom had deep infiltrating endometriosis. The prevalence of endometriosis on the uterosacral ligaments, pouch of Douglas, vagina, bladder, rectovaginal space and rectosigmoid was 23.3%, 16.3%, 8.5%, 3.1%, 6.9% and 24%. PPV, NPV, LR+ and LR- for vaginal examination were 92%, 87%, 41.56 and 0.60 for ovarian endometriosis; 43%, 84%, 2.48 and 0.63 for uterosacral ligament disease; 64%, 95%, 9.14 and 0.26 for involvement of the pouch of Douglas; 80%, 97%, 42.91 and 0.28 for vaginal endometriosis; 78%, 98%, 46.67 and 0.23 for endometriosis of the rectovaginal space; 100%, 98%, 75.60 and 0.75 for bladder involvement; 86%, 84%, 18.97 and 0.63 for rectosigmoidal endometriosis. Values for TVS were similar with regard to vaginal and rectovaginal space endometriosis, but were clearly superior to vaginal examination in cases of ovarian (87%, 99%, 24.56 and 0.04), uterosacral ligament (91%, 90%, 31.35 and 0.37) and rectosigmoidal (97%, 97%, 88.51 and 0.1) endometriosis. CONCLUSIONS: TVS is a more useful test than is vaginal examination in detecting endometriosis in the ovaries and rectosigmoid.

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture - healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884-91.

BACKGROUND: In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure. OBJECTIVES: To assess the effects of different pharmacological interventions in people with acute pancreatitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model. MAIN RESULTS: We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. SOURCE OF FUNDING: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials.Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. AUTHORS' CONCLUSIONS: Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).

Background: Obesity represents a major global health challenge with important clinical implications. Despite its recognized importance, the global disease burden attributable to high body mass index (BMI) remains less well understood. Methods: for individuals aged ≥20 years. The Socio-Demographic Index (SDI) was used as a composite measure to assess the level of socio-economic development across different regions. Subgroup analyses considered age, sex, year, geographical location, and SDI. Findings: From 1990 to 2021, the global deaths and DALYs attributable to high BMI increased more than 2.5-fold for females and males. However, the age-standardized death rates remained stable for females and increased by 15.0% for males. Similarly, the age-standardized DALY rates increased by 21.7% for females and 31.2% for males. In 2021, the six leading causes of high BMI-attributable DALYs were diabetes mellitus, ischemic heart disease, hypertensive heart disease, chronic kidney disease, low back pain and stroke. From 1990 to 2021, low-middle SDI countries exhibited the highest annual percentage changes in age-standardized DALY rates, whereas high SDI countries showed the lowest. Interpretation: The worldwide health burden attributable to high BMI has grown significantly between 1990 and 2021. The increasing global rates of high BMI and the associated disease burden highlight the urgent need for regular surveillance and monitoring of BMI. Funding: National Natural Science Foundation of China and National Key R&D Program of China.

Significance Statement National and international guidelines recommend supportive approaches to AKI management, but organizational strategies to improve delivery of AKI care have not previously been tested in multicenter randomized studies. The authors describe a pragmatic, multicenter, cluster randomized trial across five United Kingdom hospitals of an intervention comprising an AKI detection and e-alert system, an AKI care bundle, and an educational program for health care workers. Although the intervention did not alter the primary outcome of 30-day mortality, it was associated with reductions in length of hospital stay as well as an increase in AKI incidence that likely reflected improved recognition. These results combined with previous evidence show that strategies to improve the systematic delivery of supportive AKI care can lead to improvements in patient outcomes. Background Variable standards of care may contribute to poor outcomes associated with AKI. We evaluated whether a multifaceted intervention (AKI e-alerts, an AKI care bundle, and an education program) would improve delivery of care and patient outcomes at an organizational level. Methods A multicenter, pragmatic, stepped-wedge cluster randomized trial was performed in five UK hospitals, involving patients with AKI aged ≥18 years. The intervention was introduced sequentially across fixed three-month periods according to a randomly determined schedule until all hospitals were exposed. The primary outcome was 30-day mortality, with pre-specified secondary endpoints and a nested evaluation of care process delivery. The nature of the intervention precluded blinding, but data collection and analysis were independent of project delivery teams. Results We studied 24,059 AKI episodes, finding an overall 30-day mortality of 24.5%, with no difference between control and intervention periods. Hospital length of stay was reduced with the intervention (decreases of 0.7, 1.1, and 1.3 days at the 0.5, 0.6, and 0.7 quantiles, respectively). AKI incidence increased and was mirrored by an increase in the proportion of patients with a coded diagnosis of AKI. Our assessment of process measures in 1048 patients showed improvements in several metrics including AKI recognition, medication optimization, and fluid assessment. Conclusions A complex, hospital-wide intervention to reduce harm associated with AKI did not reduce 30-day AKI mortality but did result in reductions in hospital length of stay, accompanied by improvements in in quality of care. An increase in AKI incidence likely reflected improved recognition.

This study aimed to explore how individuals recovered and adapted following surgical resection of their rectal cancer and the syndrome that occurs as a consequence of this operation. This syndrome, 'anterior resection syndrome', consists of frequency, urgency, fragmentation and incontinence of faeces, and is thought to occur in 90% of patients who have received this type of surgery. Little qualitative research has been undertaken in this area, and this study adds to current quality of life data and explores supportive care strategies that nurses could use to assist patients. This study uses a grounded theory approach and in-depth interviews to explore patient's experiences. Participants were recruited from a cancer unit within the UK. Participants were recruited from a total population sample of 27 patients who had received surgery from 2001 to 2002. Following eligibility criteria to exclude those who had disease progression, seven patients were identified 1 year following surgery. Interviews were used to explore the experience of the syndrome. Three categories were identified: adapting to the physical changes, psychological adaptation and stigma. A secondary theme, running throughout all these categories, was the feeling of confidence and normality. Although the physical changes were expected as a consequence of surgery, most participants described the difficulty in controlling and managing symptoms in their period of recovery. Developing a philosophical stance was important in managing the lack of control and returning to perceived normality, despite the social stigma of bowel problems. Information on a range of strategies to manage physical symptoms is helpful in providing supportive care. Understanding that patients often rely on inappropriate strategies for management and are reluctant to discuss symptoms is important. The specialist nurse has a role in providing supportive care in managing chronic symptoms following cancer treatment.

BACKGROUND: Patient-controlled analgesia is a widely used and effective method of controlling pain after THA. This method is associated with substantial undesirable side effects. Local infiltration has been introduced in an attempt to reduce opioid requirements postoperatively, but its ability to reduce pain without complications is still questioned. QUESTIONS/PURPOSES: We evaluated patient-controlled analgesia use, pain and satisfaction scores, complication rates, and ropivacaine levels associated with the use of periarticular multimodal drug infiltration in THA. PATIENTS AND METHODS: We randomized 64 patients undergoing THA to receive a periarticular intraoperative multimodal drug injection or to receive no injection. All patients received patient-controlled analgesia for 24 hours after surgery. The final assessment was at 6 weeks. RESULTS: Patients receiving the periarticular injection used less patient-controlled analgesia 6 hours postoperatively. The 24-hour patient-controlled analgesia requirement postsurgery also was less. The visual analog scale score for pain on activity in the postanesthetic care unit was less for patients who received an injection. The visual analog scale satisfaction score was similar in the two groups throughout the followup period. Recorded unbound ropivacaine levels were 2.5 times lower than toxic levels. CONCLUSIONS: Periarticular intraoperative injection with multimodal drugs can reduce postoperative patient-controlled analgesia requirements and pain on activity in patients undergoing THA with no apparent increase in risk. LEVEL OF EVIDENCE: Level I, therapeutic study. See the guidelines online for a complete description of level of evidence.

Background: Postoperative analgesia with the use of parenteral opioids or epidural analgesia can be associated with troublesome side effects. Good perioperative analgesia facilitates rehabilitation, improves patient satisfaction, and may reduce the hospital stay. We investigated the analgesic effect of locally injected drugs around a total knee prosthesis. Methods: Sixty-four patients undergoing total knee arthroplasty were randomized either to receive a periarticular intraoperative injection containing ropivacaine, ketorolac, epimorphine, and epinephrine or to receive no injection. The perioperative analgesic regimen was standardized. All patients in both groups received patient-controlled analgesia for twenty-four hours after the surgery, and this was followed by standard analgesia. Visual analog scores for pain, during activity and at rest, and for patient satisfaction were recorded preoperatively and postoperatively and at the six-week follow-up examination. The consumption of patient-controlled analgesia at specific postoperative time-points and the overall analgesic requirement were measured. Results: The patients who had received the injection used significantly less patient-controlled analgesia at six hours, at twelve hours, and over the first twenty-four hours after the surgery. In addition, they had higher visual analog scores for patient satisfaction and lower visual analog scores for pain during activity in the post-anesthetic-care unit and four hours after the operation. No cardiac or central nervous system toxicity was observed. Conclusions: Intraoperative periarticular injection with multimodal drugs can significantly reduce the requirements for patient-controlled analgesia and improve patient satisfaction, with no apparent risks, following total knee arthroplasty. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

CONTEXT: Secondary hypogonadism is common in aging men; its natural history and predisposing factors are unclear. OBJECTIVES: The objectives were 1) to identify factors that predispose eugonadal men (T ≥ 10.5 nmol/L) to develop biochemical secondary hypogonadism (T < 10.5 nmol/L; LH ≤ 9.4 U/L) and secondary hypogonadal men to recover to eugonadism; and 2) to characterize clinical features associated with these transitions. DESIGN: The study was designed as a prospective observational general population cohort survey. SETTING: The setting was clinical research centers. PARTICIPANTS: The participants were 3369 community-dwelling men aged 40-79 years in eight European centers. INTERVENTION: Interventions included observational follow-up of 4.3 years. MAIN OUTCOME MEASURE: Subjects were categorized according to change/no change in biochemical gonadal status during follow-up as follows: persistent eugonadal (n = 1909), incident secondary hypogonadal (n = 140), persistent secondary hypogonadal (n = 123), and recovered from secondary hypogonadism to eugonadism (n = 96). Baseline predictors and changes in clinical features associated with incident secondary hypogonadism and recovery from secondary hypogonadism were analyzed by regression models. RESULTS: The incidence of secondary hypogonadism was 155.9/10 000/year, whereas 42.9% of men with secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by obesity (body mass index ≥ 30 kg/m(2); odds ratio [OR] = 2.86 [95% confidence interval, 1.67; 4.90]; P < .0001), weight gain (OR = 1.79 [1.15; 2.80]; P = .011), and increased waist circumference (OR = 1.73 [1.07; 2.81], P = .026; and OR = 2.64 [1.66; 4.21], P < .0001, for waist circumference 94-102 and ≥102 cm, respectively). Incident secondary hypogonadal men experienced new/worsening sexual symptoms (low libido, erectile dysfunction, and infrequent spontaneous erections). Recovery from secondary hypogonadism was predicted by nonobesity (OR = 2.28 [1.21; 4.31]; P = .011), weight loss (OR = 2.24 [1.04; 4.85]; P = .042), normal waist circumference (OR = 1.93 [1.01; 3.70]; P = .048), younger age (< 60 y; OR = 2.32 [1.12; 4.82]; P = .024), and higher education (OR = 2.11 [1.05; 4.26]; P = .037), but symptoms did not show significant concurrent improvement. CONCLUSION: Obesity-related metabolic and lifestyle factors predispose older men to the development of secondary hypogonadism, which is frequently reversible with weight loss.

INTRODUCTION: Parkinson's disease (PD) is managed primarily by dopamine agonists and physiotherapy while virtual reality (VR) has emerged recently as a complementary method. The present study reviewed the effectiveness of VR in rehabilitation of patients with PD. METHODS: Literature search up to June 2019 identified ten studies (n = 343 participants) suitable for meta-analysis and 27 studies (n = 688 participants) for systematic review. Standard mean difference (SMD) and 95% confidence intervals (CI) were calculated using a random effects model. RESULTS: In meta-analysis, compared with active rehabilitation intervention, VR training led to greater improvement of stride length, SMD = 0.70 (95%CI = 0.32-1.08, p = 0.0003), and was as effective for gait speed, balance and co-ordination, cognitive function and mental health, quality of life and activities of daily living. Compared with passive rehabilitation intervention, VR had greater effects on balance: SMD = 1.02 (95%CI = 0.38-1.65, p = 0.002). Results from single randomised controlled trials showed that VR training was better than passive rehabilitation intervention for improving gait speed SMD = 1.43 (95%CI = 0.51-2.34, p = 0.002), stride length SMD = 1.27 (95%CI = 0.38-2.16, p = 0.005) and activities of daily living SMD = 0.96 (95%CI = 0.02-1.89). Systematic review showed that VR training significantly (p < 0.05) improved motor function, balance and co-ordination, cognitive function and mental health, and quality of life and activities of daily living. CONCLUSION: VR used in rehabilitation for patients with PD improves a number of outcomes and may be considered for routine use in rehabilitation.

OBJECTIVES: To describe incidence and prevalence of cardiovascular disease (CVD), its risk factors, medication prescribed to treat CVD and predictors of CVD within a nationally representative dataset. DESIGN: Cross-sectional study of adults with and without CVD. SETTING: The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is an English primary care sentinel network. RCGP RSC is over 50 years old and one of the oldest in Europe. Practices receive feedback about data quality. This database is primarily used to conduct surveillance and research into influenza, infections and vaccine effectiveness but is also a rich resource for the study of non-communicable disease (NCD). The RCGP RSC network comprised 164 practices at the time of study. RESULTS: Data were extracted from the records of 1 275 174 adults. Approximately a fifth (21.3%; 95% CI 21.2% to 21.4%) had CVD (myocardial infarction (MI), angina, atrial fibrillation (AF), peripheral arterial disease, stroke/transient ischaemic attack (TIA), congestive cardiac failure) or hypertension. Smoking, unsafe alcohol consumption and obesity were more common among people with CVD. Angiotensin system modulating drugs, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors (statins) and calcium channel blockers were the most commonly prescribed CVD medications. Age-adjusted and gender-adjusted annual incidence for AF was 28.2/10 000 (95% CI 27.8 to 28.7); stroke/TIA 17.1/10 000 (95% CI 16.8 to 17.5) and MI 9.8/10 000 (95% CI 9.5 to 10.0). Logistic regression analyses confirmed established CVD risk factors were associated with CVD in the RCGP RSC network dataset. CONCLUSIONS: The RCGP RSC database provides comprehensive information on risk factors, medical diagnosis, physiological measurements and prescription history that could be used in CVD research or pharmacoepidemiology. With the exception of MI, the prevalence of CVDs was higher than in other national data, possibly reflecting data quality. RCGP RSC is an underused resource for research into NCDs and their management and welcomes collaborative opportunities.