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Introduction: In-hospital hip fractures follow falls during unrelated admissions. Little data in the Irish setting is available on this vulnerable subset of hip fracture patients. Our objective is to review the incidence of in-hospital hip fractures, identify risk factors, and evaluate outcomes., Methods: This is a retrospective observational review. We collected patient data in St. James' Hospital using the Hospital In-Patient Enquiry database and Electronic Patient Records for in-hospital hip fractures between 10/02/2017 and 22/04/2020. Comorbidity, survival, and discharge destination data were gathered., Results: We identified 40 fractures, representing 11.5% of all hip fractures treated at our center during the study period. The patients were 60-95 years old. Median age was 77 years for males and 86 years for females. Most (72.5%) were identified as fall risks, and 52% were unwitnessed falls. Many had a history of falls (67.5%), dementia (52.5%), or both (42.5%). Delirium was common (42.5%), and 75% had at least one vascular/coagulation disorder. Mortality was 10.25% at 30 days, 23.1% at 90 days, and 51.4% at 12 months. Although 70% were admitted from home, only 10% were discharged back home. 30% were admitted to a nursing home, and 55% were discharged from a nursing home., Conclusion: In-hospital hip fractures accounted for 11.5% of all hip fractures treated at our center, confirming the need for a well-defined hospital protocol. Patients often present with previous falls, dementia, and cardiovascular disease. Outcomes are poor, with 51.4% mortality at 12 months and significant morbidity reflected by a loss of independent living., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Condon et al.)

Background: Total hip arthroplasty aims to provide patients with a pain-free and stable hip joint through optimization of biomechanics such as femoral anteversion. There are studies evaluating the limits of cementless stem version, however, none assessing the range of version achieved by a cemented collarless stem. A computed tomography (CT)-based study was performed, utilizing a contemporary robotic planning platform to assess the amount of rotation afforded by a cemented collarless stem, whilst maintaining native biomechanics., Methods: The study utilized 36 cadaveric hips. All had CT scans of the pelvis and hip joints. The CT scans were then loaded into a contemporary robotic planning platform. A stem that restored the patients native femoral offset was selected and positioned in the virtual femur. The stem was rotated while checking for cortical contact at the level of the neck cut. Cortical contact was regarded as the rotation limit, assessed in both anteversion and retroversion. Target range for stem anteversion was 10°-20°. Failure to achieve target version triggered a sequence of adjustments to simulate surgical decisions., Results: Native femoral offset and target version range was obtained in 29 of 36 (80.5%) cases. Following an adjustment sequence, 4 further stems achieved target anteversion with a compromise in offset of 2.3 mm. Overall 33 of 36 (91.7%) stems achieved the target anteversion range of 10°-20°., Conclusions: Target femoral stem anteversion can be achieved using a cemented, collarless stem in a CT-based 3-dimensional model in 80.5% of hips. With a small compromise in offset (mean 2.3 mm), this can be increased to 91.7%., (© 2022 The Authors.)

The daily and seasonal activity patterns of snow leopards (Panthera uncia) are poorly understood, limiting our ecological understanding and hampering our ability to mitigate threats such as climate change and retaliatory killing in response to livestock predation. We fitted GPS-collars with activity loggers to snow leopards, Siberian ibex (Capra sibirica: their main prey), and domestic goats (Capra hircus: common livestock prey) in Mongolia between 2009 and 2020. Snow leopards were facultatively nocturnal with season-specific crepuscular activity peaks: seasonal activity shifted towards night-sunrise during summer, and day-sunset in winter. Snow leopard activity was in contrast to their prey, which were consistently diurnal. We interpret these results in relation to: (1) darkness as concealment for snow leopards when stalking in an open landscape (nocturnal activity), (2) low-intermediate light preferred for predatory ambush in steep rocky terrain (dawn and dusk activity), and (3) seasonal activity adjustments to facilitate thermoregulation in an extreme environment. These patterns suggest that to minimise human-wildlife conflict, livestock should be corralled at night and dawn in summer, and dusk in winter. It is likely that climate change will intensify seasonal effects on the snow leopard's daily temporal niche for thermoregulation in the future., (© 2022. The Author(s).)

Background: Femoroacetabular impingement (FAI) is a common pathology in athletes that often requires operative management in the form of hip arthroscopy., Purpose: To systematically review the rates and level of return to play (RTP) and the criteria used for RTP after hip arthroscopy for FAI in athletes., Study Design: Systematic review; Level of evidence, 4., Methods: A systematic review of the literature, based on the PRISMA guidelines, was performed using PubMed, Embase, and Scopus databases. Studies reporting outcomes after the use of hip arthroscopy for FAI were included. Outcomes analyzed were RTP rate, RTP level, and criteria used for RTP. Statistical analysis was performed using SPSS software., Results: Our review found 130 studies, which included 14,069 patients (14,517 hips) and had a mean methodological quality of evidence (MQOE) of 40.4 (range, 5-67). The majority of patients were female (53.7%), the mean patient age was 30.4 years (range, 15-47 years), and the mean follow-up was 29.7 months (range, 6-75 months). A total of 81 studies reported RTP rates, with an overall RTP rate of 85.4% over a mean period of 6.6 months. Additionally, 49 studies reported the rate of RTP at preinjury level as 72.6%. Specific RTP criteria were reported in 97 studies (77.2%), with time being the most commonly reported item, which was reported in 80 studies (69.2%). A total of 45 studies (57.9%) advised RTP at 3 to 6 months after hip arthroscopy., Conclusion: The overall rate of reported RTP was high after hip arthroscopy for FAI. However, more than one-fourth of athletes who returned to sports did not return at their preinjury level. Development of validated rehabilitation criteria for safe return to sports after hip arthroscopy for FAI could potentially improve clinical outcomes while also increasing rates of RTP at preinjury levels.

Introduction: Fragility hip fractures are common and costly. Secondary fracture prevention is a treatment goal following hip fracture; however, the number of those that proceed to fracture their contralateral hip in Ireland is unknown. There are plans to introduce a Fracture Liaison Service Database in Ireland which will aim to prevent secondary fractures. To establish a baseline figure for secondary hip fractures, the injury radiographs of 1284 patients from 6 teaching hospitals over a 1-year period were reviewed., Methods: Irish Hip Fracture Datasheets and corresponding injury radiographs were reviewed locally for all hip fractures within each respective teaching hospital for a 1-year period (2019)., Results: A total of 8.7% of all fragility hip fractures across the 6 hospitals were secondary hip fractures (range 4.9-11.5%). 46% occurred within years 1 to 3 following index hip fracture. Forty-eight per cent of patients were started on bone protection medications following their second hip fracture., Discussion/conclusion: Approximately 1 in 11 hip fractures treated across the 6 teaching hospitals assessed in 2019 was a patient's second hip fracture. We advocate for the widespread availability of Fracture Liaison Services to patients throughout Ireland to assist secondary fracture prevention., (© 2021. Royal Academy of Medicine in Ireland.)

Hip fractures are a significant cause of morbidity and mortality in the elderly population. The number of hip fractures is set to increase significantly by 2050 as the global population ages. The costs associated with hip fracture patients are significant due to prolonged hospitalisation and rehabilitation. Hip protectors have been advocated as a strategy to reduce the risk of hip fractures in a high-risk population. Evidence suggests that hip protectors are a cost-effective method for reducing the risk of hip fractures. There have, however, been issues with adherence with wearing hip protectors amongst patients and healthcare staff. Despite prevention strategies, many patients continue to present with hip fractures. Many of these patients have cognitive impairment or experience peri-operative delirium. This can cause issues with patients' interference with the operative wound and presents a significant burden to the healthcare team with the need for increased wound monitoring and care in the post-operative period. Applying a well-fitted hip protector provides a substantial additional barrier to protect the surgical wound. Hip fracture surgical wounds can be difficult to manage in these patients and our standard post-operative protocol is to apply compression dressings in this group of patients. We have found that a well-fitted hip protector can provide adequate compression to the surgical site. We describe a brief technical report on a novel use of hip protectors in providing wound security in the agitated patient post-operatively as well as a method of providing compression to the surgical wound site., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Nolan et al.)

Purpose: Patients with haemophilia suffer from recurrent joint haemarthrosis. This can progress to symptomatic arthropathy commonly affecting the knee. While modern coagulation strategies have reduced those proceeding to end-stage arthropathy, total knee arthroplasty (TKA) remains the optimal treatment for some patients. Despite innovation in perioperative haematological management, concerns about the potential for excessive haemorrhage still exist. The aim of this study is to quantify immediate postoperative blood loss and haematological complications in haemophiliacs following TKA., Methods: A retrospective study of patients with haemophilia types A or B who underwent a TKA over a 12-year period at a single institution was conducted. These patients were compared to both a non-haemophiliac control group and to published standards in non-haemophiliacs undergoing TKA., Results: Twenty-one TKA procedures in 18 patients (72% haemophilia A, 28% haemophilia B) were suitable for inclusion with a mean age of 44 years. The mean haemoglobin drops at 24 and 48 h postoperatively were 2.7 g/dl and 3.8 g/dl respectively. There was no significant difference in haemoglobin drop at 48 h postoperatively when compared to the non-haemophiliac control group ( P = 0.2644). There were no immediate perioperative complications and two patients (9.6%) required postoperative transfusion., Conclusion: Haemophiliacs undergoing a unilateral primary TKA in a specialised tertiary referral centre appear to have comparable rates of perioperative blood loss when compared to both a non-haemophiliac control group as and published haemostatic standards in non-haemophiliac patients following TKA. Perioperative management with expert orthopaedic and haematological input is recommended to optimise outcomes in this complex patient group.

Purpose: The purpose of this study was to systematically review the evidence in the literature to ascertain whether acetabular labral repair (ALR) or debridement (ALD) resulted in superior patient outcomes., Methods: The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Peer-reviewed studies comparing ALR and ALD published in English with full text available were included. Patients undergoing both open and arthroscopic surgery in randomized controlled trials, prospective cohort studies, retrospective cohort studies, and case-control studies were included. Studies were quantified for methodological quality using the MINORS criteria. Clinical outcomes were compared, with qualitative analysis, and quantitative analyses were performed using GraphPad Prism version 7. A P value <.05 was considered to be statistically significant., Results: There were 8 studies included (level of evidence [LOE] I = 1; LOE II = 2; LOE III = 5). The 7 studies compared 364 patients (369 hips) with ALR to 318 patients (329 hips) with ALD, with a mean follow-up time ranging between 32-120 months. Five studies found significantly improved patient reported outcomes with ALR (Harris Hip Score, Merle d'Aubigné, Pain, SF-12). Several studies compared the outcomes after ALR and ALD and found statistical significance in all investigated metrics in favor of ALR. One study found a significant improvement in abduction but no other study found any difference in range of motion. No study found any difference in complication rate, revision rate or conversion to total hip arthroplasty. Although, 2 studies found ALR reduced the rate of osteoarthritic progression., Conclusion: Current literature suggests that acetabular labral repair may result in superior patient reported outcomes. However, there appears to be no significant difference in the rate of progression to total hip arthroplasty at up to 10-year follow-up., Level of Evidence: Level III, systematic review of Level I, II, and III studies., (© 2021 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Introduction Hip fractures are a significant cause of morbidity and mortality in the elderly and are also associated with increased healthcare costs. A second contralateral hip fracture can lead to even more complications and healthcare costs. A significant proportion of the Irish hip fracture population does not receive a bone health assessment or falls specialist assessment to reduce the risk of future falls and fractures. This study aimed to analyze the incidence of a non-simultaneous contralateral hip fracture in an Irish population. Methods We retrospectively analyzed 1,344 patients presenting to our institution with a hip fracture from January 2007 to June 2019. Patients aged ≥ 60 years old presenting with a neck of femur or pertrochanteric fracture were included in our study. We excluded patients who had sub-trochanteric and femoral shaft fractures, high energy fractures, and pathological fractures. We also excluded patients less than 60 years old, as fractures in these younger patients may not be purely related to osteoporosis. Results A total of 1,099 hip fractures meeting the inclusion criteria were treated at our unit during the designated time period. A total of 102 (9.3%) patients experienced a second hip fracture. The mean age at first presentation in our institution was 78.5 years old, with a mean time between first and second hip fractures of 37.2 months. Conclusions Patients presenting with a second hip fracture may represent 9.3% of the Irish hip fracture population. We hope that this study will help inform on the rate of second hip fractures in an Irish population and help advocate for improved resources and implementation of secondary prevention strategies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Nolan et al.)

Introduction Hip fractures are increasingly prevalent and can result in substantial morbidity, mortality, and cost. Despite the existence of enhanced management strategies, prolonged hip fracture admissions persist. This study's objective was to ascertain characteristics associated with a prolonged length of stay (LOS) and quantify return to baseline once discharged. Methods A retrospective audit of hip fractures over a four-year period was conducted, identifying patients with a LOS over 100 days. Demographics, comorbidities, pre- and post-admission function, and status were assessed. Patients sustaining inpatient hip fractures were excluded to negate the effect of initial admission on LOS. Results Seven hundred and eleven hip fractures were treated, of which 48 (6.8%) were suitable for inclusion. The patients' median age and LOS was 83.5 years and 153 days, respectively. Preoperative American Society of Anesthesiologists - Physical Status (ASA-PS) Grades II and III predominated at 41.7% and 39.6%, respectively. Eighteen of patients had a diagnosis of dementia before admission, increasing to 29 on discharge (P = 0.0026). One patient was in long-term care prior to admission, rising to 30 on discharge (P < 0.0001), with only 25.6% returning to pre-admission residential status (P < 0.0001). Nineteen patients were mobilising unaided prior to admission, decreasing to only two following discharge, with a mere 37.1% returning to their pre-admission mobility baseline (P < 0.0001). Discussion Hip fracture patients with multiple comorbidities or a diagnosis of dementia were most likely to have a prolonged LOS which, in turn, impacted upon return to baseline mobility, cognitive status, and independence. Early identification and management of this cohort may help reduce the potential disease burden and economic effects that a prolonged LOS creates., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Mohan et al.)

Concomitant ipsilateral femoral neck and shaft fractures are uncommon, occurring in 1-9% of femoral shaft fractures. While this injury typically occurs in young patients following high-energy trauma, little consensus has been established regarding the optimal fixation approach. A multitude of treatment strategies exist, with limited evidence as to which is more favorable. The aim of this study was to appraise current evidence, comparing management with either one single or separate devices for both fractures. A systematic review was undertaken in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies published between 1992 and 2018 comparing the rate of postoperative nonunion, malunion, delayed union, avascular necrosis, infection or reoperation between at least one method of single device fixation and one method of separate device fixation were included. Six non-randomized cohort studies assessing 173 patients were suitable for inclusion, each comparing single device cephalomedullary nail fixation of both fractures with a combination of devices. All patients presented following high-energy trauma, at a median age of 32 years. While low complication rate and favorable outcomes were found across both groups, no significant difference could be inferred between either treatment strategy. This injury continues to occur in the traditionally described patient group, and results in acceptable postoperative outcomes. A paucity of randomized studies limits the ability to recommend a single or separate device treatment approach, and as such prospective, randomized trials with adequately powered sample sizes are required to definitively compare surgical management strategies in this rare but complex injury., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

Introduction: Osteoporosis and related fractures constitute a significant burden on modern healthcare. The standard method of diagnosing osteoporosis with a dual-energy X-ray absorptiometry (DXA) scan is limited by accessibility and expense. The thickness of the cortex of the proximal femur on plain radiographs has been suggested to be a method for indicating osteoporosis and as a risk factor of hip fractures in the elderly., Methods: A retrospective study was undertaken to assess the usefulness of the canal-diaphysis ratio (CDR) as a risk factor for developing a hip fracture, excluding patients presenting under 50 years old, following high-energy trauma or pathological fractures. The CDR was measured in 84 neck of femur (NOF) fracture patients and 84 intertrochanteric hip fracture patients, and these were subsequently compared to the CDR of 84 patients without a hip fracture. Measurements were taken on two occasions by two members of the orthopaedic team, so as to assess the test's inter- and intraobserver reliability., Results: In comparison to those without a fracture, there was a significant difference in the CDR of patients with a NOF fracture (P < 0.0001) and intertrochanteric fracture (P < 0.0001). Furthermore, the odds of having a CDR above 60.67 and 64.41 were significantly higher in the NOF (OR = 2.214, P = 0.0129) and intertrochanteric fracture (OR = 32.27, P < 0.0001) groups respectively, when compared to the non-fractured group. The analysis of the test's inter- and intraobserver reliability showed strong levels of reproducibility., Discussion: We concluded that a raised CDR was associated with an increased incidence of NOF and intertrochanteric hip fracture. Measuring the CDR can thus be considered as a reproducible and inexpensive method of identifying elderly patients at risk of hip fractures., (© The Authors, published by EDP Sciences, 2017.)

Background: Quadriceps tendon (QT) ruptures are uncommon and mostly occur in those who are 50-60 years of age. Timely surgical repair can result in a good functional outcome, however, little is known about the outcome in the older patient., Methods: A retrospective review of all QT ruptures between 2009 and 2014 was conducted. Patients over the age of 80 were included. Those with penetrating trauma or partial ruptures were excluded. A chart review was undertaken to gather demographic and operative details. The patients were contacted by phone or by mail to have Lysholm and Rougraff scores completed., Results: Of the 32 QT ruptures identified, 6 (19%) patients were eligible for inclusion in our study. They were predominantly (83%) males with a mean age of 81.38 years. The mean follow up was 54 months. The mean Lysholm score at last follow up was 84.8/100, which falls within the range of a good outcome. The mean Rougraff score was 21.3/25, which is an excellent outcome. All patients felt they were close to their premorbid level of mobility., Conclusion: Good outcomes can be expected with QT repair in older patients, resulting in restoration of the pre-injury level of mobility. Level of evidence: Level V case series.

The use of alternative bearing surfaces for total hip arthroplasty has become popular to minimize wear and increase longevity, especially in young patients. Oxidized zirconium (Oxinium; Smith & Nephew, Memphis, Tennessee) femoral heads were introduced in the past decade for use in total hip arthroplasty. The advantages of oxidized zirconium include less risk of fracture compared with traditional ceramic heads. This case report describes a patient with a history of bilateral avascular necrosis of the femoral head after chemotherapy for acute lymphoblastic leukemia. Nonoperative management of avascular necrosis failed, and the patient was treated with bilateral total hip arthroplasty. The patient was followed at regular intervals and had slow eccentric polyethylene wear during a 10-year period. After 10 years, the patient had accelerated wear, with femoral and acetabular bone changes as a result of Oxinium and ultrahigh-molecular-weight polyethylene wear during a 6-month period. This article highlights the unusual accelerated bone changes that occurred as a result of Oxinium wear particles., (Copyright 2016, SLACK Incorporated.)

Background: quadriceps tendon (QT) ruptures are significant injuries that are relatively uncommon. The diagnosis of QT ruptures is frequently missed or delayed. An association between the presence of a patella spur and QT ruptures has been suggested in the literature., Patients and Methods: the Hospital Inpatient Enquiry system was used to gather data on all patients who sustained a QT rupture over a six year period from 2008 to 2014. A retrospective review of the medical notes as well as radiographs was undertaken. We reviewed 200 knee radiographs of patients without QT ruptures to establish the incidence of patella spurs in our normal population. Statistical analysis was performed using SPSS version 11.5 for Windows(®)., Results: the records of 20 consecutive patients with 21 QT ruptures were reviewed. The mean age was 60.9 yrs (range 44.9-82.1 yrs) and the majority were male (n=17; 85%). There was one bilateral QT ruptures. Patella spurs were noted in 13 cases (62%) which were significantly higher than in patients without QT rupture 19% (P≤0.05)., Conclusion: we noted a significantly higher incidence of patella spurs in patients with QT ruptures compared to those without. The presence of a QT rupture should be ruled out in patients with a knee injury and a patella spur on the knee radiographs.

Background: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT2R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT2R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging., Results: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT2R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine., Conclusion: The major AT2R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways.

Population monitoring programmes and estimation of vital rates are key to understanding the mechanisms of population growth, decline or stability, and are important for effective conservation action. We report, for the first time, the population trends and vital rates of the endangered snow leopard based on camera trapping over four years in the Tost Mountains, South Gobi, Mongolia. We used robust design multi-season mark-recapture analysis to estimate the trends in abundance, sex ratio, survival probability and the probability of temporary emigration and immigration for adult and young snow leopards. The snow leopard population remained constant over most of the study period, with no apparent growth (λ = 1.08+-0.25). Comparison of model results with the "known population" of radio-collared snow leopards suggested high accuracy in our estimates. Although seemingly stable, vigorous underlying dynamics were evident in this population, with the adult sex ratio shifting from being male-biased to female-biased (1.67 to 0.38 males per female) during the study. Adult survival probability was 0.82 (SE+-0.08) and that of young was 0.83 (SE+-0.15) and 0.77 (SE +-0.2) respectively, before and after the age of 2 years. Young snow leopards showed a high probability of temporary emigration and immigration (0.6, SE +-0.19 and 0.68, SE +-0.32 before and after the age of 2 years) though not the adults (0.02 SE+-0.07). While the current female-bias in the population and the number of cubs born each year seemingly render the study population safe, the vigorous dynamics suggests that the situation can change quickly. The reduction in the proportion of male snow leopards may be indicative of continuing anthropogenic pressures. Our work reiterates the importance of monitoring both the abundance and population dynamics of species for effective conservation.

Background: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia., Methods: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987., Findings: 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo., Interpretation: EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients., Funding: Spinifex Pharmaceuticals., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In the decade after World War II, psychologists, eager to bring the benefits of counseling to larger numbers, convinced hundreds of American colleges and universities to establish counseling centers. Inspired by the educational-vocational counseling center founded by psychologists at the University of Minnesota in 1932, Carl R. Rogers's "client-centered" methods of personal adjustment counseling, and the 400-plus college counseling centers created by the Veterans Administration to provide the educational-vocational counseling benefit promised to returning World War II servicemen under the 1944 GI Bill, these counseling psychologists created a new place to practice where important currents in psychology, higher education, and federal policy converged and where they attempted to integrate educational-vocational counseling with personal adjustment counseling based on techniques from psychotherapy. By the mid-1960s, half of America's colleges and universities had established counseling centers, and more than 90% offered students educational, vocational, and psychological counseling services, a great achievement of the first generation of counseling psychologists.

The Internet has become a major source of health information for the public. However, there are concerns regarding the quality, accuracy, and currency of medical information available online. We assessed the quality of information about anterior cruciate ligament (ACL) reconstruction on the first 60 websites returned by the 4 most popular search engines. Each site was categorized by type and assessed for quality and validity using the DISCERN score, the Journal of the American Medical Association (JAMA) benchmark criteria, and a novel ACL reconstruction-specific content score. The presence of the Health On the Net Code (HONcode), a purported quality assurance marker, was noted. The quality of information on ACL reconstruction available online is variable, with many websites omitting basic information regarding treatment options, risks, and prognosis. Commercial websites predominate. Academic and allied health professional websites attained the highest DISCERN and JAMA benchmark scores, whereas physician sites achieved the highest content scores. Sites that bore the HONcode seal obtained higher DISCERN and ACL reconstruction content scores than those without this certification. The HONcode seal is a reliable indicator of website quality, and we can confidently advise our patients to search for this marker., (Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Conservation and research of the elusive snow leopard (Panthera uncia) have been hampered by inadequate knowledge about its basic life history. Global positioning system (GPS) collars can provide useful information, but there has been limited information available on safe capture methods, drug doses, and efficacy for effective immobilization of free-ranging snow leopards. We describe a drug protocol using a combination of medetomidine and tiletamine-zolazepam for the chemical immobilization of free-ranging snow leopards. We also describe physiologic responses to immobilization drugs, including rectal temperature, heart rate, respiratory rate, and relative hemoglobin oxygen saturation (SpO2) recorded every 10 min. Our study was carried out in the Tost Mountains adjacent to the Great Gobi Desert, in southern Mongolia, between August 2008 and April 2012. Eighteen snow leopards were captured or recaptured with foot-snares on 42 occasions and anesthetized for marking with GPS collars. The snow leopards received on average (±SD) 0.020±0.04 mg/kg body mass medetomidine and 2.17±0.45 mg/kg tiletamine-zolazepam. The duration of ensuing anesthesia was 69±13 min, including an induction period of 10 (±4) min. Anesthesia was reversed with 4 mg (0.10±0.04 mg/kg) atipamezole administered intramuscularly. The mean value for SpO2 for the 37 captures where we could record physiologic values was 91±4. The SpO2 increased significantly during anesthesia (+0.06±0.02%/min), whereas rectal temperature (average 38.1±0.7 C/min, change -0.04±0.003 C/min), heart rate (average 97±9 beats/min, change -0.20±0.03 beats/min), and respiratory rate (average 26±6 breaths/min, change -0.11±0.03 breaths/min) decreased significantly. A dose of 80 mg tiletamine-zolazepam (2 mg/kg body weight) and 0.72 mg medetomidine (0.02 mg/kg body weight) safely immobilized all adult and subadult snow leopards (weight 25-45 kg) in our study. All measured physiologic values remained within clinically acceptable limits.

Introduction: Osteomyelitis following anterior cruciate ligament (ACL) reconstruction is extremely rare., Presentation of Case: We present a thirty year old man who presented with pain in his proximal tibia six years after ACL reconstruction. Haematological investigations were normal. He was diagnosed with osteomyelitis of his proximal tibia. He was successfully treated with washout and debridement of his tibial tunnel., Discussion: This case highlights the need to exclude osteomyelitis as a late complication of ACL reconstruction in patients with proximal tibial pain. We also report on an unusual pathogen as casue of osteomyelitis., Conclusion: Osteomyelitis in a tibial tunnel can present as a late complication of ACL reconstruction, even in the presence of normal haematological investigations., (Copyright © 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published., Methods and Findings: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina., Conclusions: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

The interaction of immune complexes with the human Fc receptor, FcgammaRIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three-dimensional structure of an FcgammaRIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand-binding sites. These small chemical entities (SCEs) blocked immune complex-induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for FcgammaRIIa, as they inhibited only immune complex-induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in FcgammaRIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen-induced arthritis (CIA). The SCEs were more potent than methotrexate and anti-CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE FcgammaRIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.

The glmS ribozyme resides in the 5' untranslated region of glmS mRNA and functions as a catalytic riboswitch that regulates amino sugar metabolism in certain Gram-positive bacteria. The ribozyme catalyzes self-cleavage of the mRNA and ultimately inhibits gene expression in response to binding of glucosamine-6-phosphate (GlcN6P), the metabolic product of the GlmS protein. We have used nucleotide analog interference mapping (NAIM) and suppression (NAIS) to investigate backbone and nucleobase functional groups essential for ligand-dependent ribozyme function. NAIM using GlcN6P as ligand identified requisite structural features and potential sites of ligand and/or metal ion interaction, whereas NAIS using glucosamine as ligand analog revealed those sites that orchestrate recognition of ligand phosphate. These studies demonstrate that the ligand-binding site lies in close proximity to the cleavage site in an emerging model of ribozyme structure that supports a role for ligand within the catalytic core.

Dendrimers are a novel class of polyanionic macromolecules with broad-spectrum antiviral activities and minimal toxicities. A new generation of amide dendrimer, SPL7013, was evaluated as a lead microbicide candidate against herpes simplex viruses (HSV). The plaque reduction assays showed that the 50% effective concentrations (EC(50)) determined by pre-treatment of cells were 2.0 microg/ml for HSV-1 and 0.5 microg/ml for HSV-2. Inhibitory effects were also observed on HSV-infected cells with EC(50)s of 6.1 microg/ml for HSV-1 and 3.8 microg/ml for HSV-2. These are the mean values from the test results of six batches of SPL7013. SPL7013 was also shown to be equally potent against HSV drug-resistant strains. SPL7013 completely inhibited viral adsorption to Vero cells at concentrations of higher than 3 microg/ml. Analyzed by a LightCycler assay after treatment of HSV-infected cells for 17 h, SPL7013 showed strong inhibition of HSV DNA synthesis with EC(50)s of approximately 6.2 and 2.0 microg/ml for HSV-1 and HSV-2, respectively. SPL7013 retained its anti-HSV activity even after treatment at acidic pHs 3.0 and 4.0 for 2 h. The presence of 10% human serum proteins did not affect the anti-HSV activity of SPL7013. SPL7013 was not toxic to Vero cells up to the highest concentration tested (10,000 microg/ml). Effects on cell proliferation were tested on two epithelial cell lines in both stationary and dividing phases. The 50% cytotoxic concentrations (CC(50)) in all cases were greater than 10,000 microg/ml. Our data indicate that SPL7013 is a promising candidate for development as a vaginal microbicide and a therapeutic agent.

Natural RNA catalysts (ribozymes) perform essential reactions in biological RNA processing and protein synthesis, whereby catalysis is intrinsic to RNA structure alone or in combination with metal ion cofactors. The recently discovered glmS ribozyme is unique in that it functions as a glucosamine-6-phosphate (GlcN6P)-dependent catalyst believed to enable "riboswitch" regulation of amino-sugar biosynthesis in certain prokaryotes. However, it is unclear whether GlcN6P functions as an effector or coenzyme to promote ribozyme self-cleavage. Herein, we demonstrate that ligand is absolutely requisite for glmS ribozyme self-cleavage activity. Furthermore, catalysis both requires and is dependent upon the acid dissociation constant (pKa) of the amine functionality of GlcN6P and related compounds. The data demonstrate that ligand is integral to catalysis, consistent with a coenzyme role for GlcN6P and illustrating an expanded capacity for biological RNA catalysis.

Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.

SPL7013 is a dendrimer with a polyanionic outer surface that allows multiple interactions with target sites. It potently binds and blocks HIV-1 and chimeric simian/HIV-1 viruses (SHIVs) replication in vitro. Gels containing different concentrations of SPL7013 were used as topical microbicides in female pigtailed macaques (Macaca nemestrina) to study their ability to prevent vaginal transmission of SHIV(89,6P). On virus challenge, all untreated macaques (8/8) and seven of eight macaques treated with placebo gel were infected within 2 weeks postinfection (PI) and showed high plasma viremia and dramatic CD4(+) cell decline within 4 weeks PI. In contrast, 6/6 macaques, 5/6 macaques, and 2/6 macaques treated with 5% w/w (50 mg/ml), 3% w/w (30 mg/ml), and 1% w/w (10 mg/ml) SPL7013 gels, respectively, resisted viral challenge. The results showed that animals treated with SPL7013 showed a dose-dependent resistance to virus challenge. Neither SPL7013 nor placebo gels produced any adverse effects following the single application in the study. These results showed that 3-5% w/w SPL7013 gels were effective in blocking vaginal transmission of SHIV in macaques after single gel application followed by single virus challenge. These results suggest that SPL7013 gel may be a promising anti-HIV microbicide formulation for further evaluation.

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.