Optimal balance of benefit versus risk for tafenoquine in the treatment of Plasmodium vivax malaria.

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile.

Limited versus full sternotomy for aortic valve replacement.

BACKGROUND: Aortic valve disease is a common condition easily treatable with cardiac surgery. This is conventionally performed by opening the sternum ('median sternotomy') and replacing the valve under cardiopulmonary bypass. Median sternotomy is well tolerated, but as less invasive options become available, the efficacy of limited incisions has been called into question. In particular, the effects of reducing the visibility and surgical access have raised safety concerns with regard to the placement of cannulae, venting of the heart, epicardial wire placement, and de-airing of the heart at the end of the procedure. These difficulties may increase operating times, affecting outcome. The benefits of smaller incisions are thought to include decreased pain; improved respiratory mechanics; reductions in wound infections, bleeding, and need for transfusion; shorter intensive care stay; better cosmesis; and a quicker return to normal activity. This is an update of a Cochrane review first published in 2017, with seven new studies. OBJECTIVES: To assess the effects of minimally invasive aortic valve replacement via a limited sternotomy versus conventional aortic valve replacement via median sternotomy in people with aortic valve disease requiring surgical replacement. SEARCH METHODS: We performed searches of CENTRAL, MEDLINE and Embase from inception to August 2021, with no language limitations. We also searched two clinical trials registries and manufacturers' websites. We reviewed references of primary studies to identify any further studies of relevance. SELECTION CRITERIA: We included randomised controlled trials comparing aortic valve replacement via a median sternotomy versus aortic valve replacement via a limited sternotomy. We excluded trials that performed other minimally invasive incisions such as mini-thoracotomies, port access, transapical, transfemoral or robotic procedures. Although some well-conducted prospective and retrospective case-control and cohort studies exist, these were not included in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial papers to extract data, assess quality, and identify risk of bias. A third review author provided arbitration where required. We determined the certainty of evidence using the GRADE methodology and summarised results of patient-relevant outcomes in a summary of findings table. MAIN RESULTS: The review included 14 trials with 1395 participants. Most studies had at least two domains at high risk of bias. We analysed 14 outcomes investigating the effects of minimally invasive limited upper hemi-sternotomy on aortic valve replacement as compared to surgery performed via full median sternotomy. Upper hemi-sternotomy may have little to no effect on mortality versus full median sternotomy (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.45 to 1.94; 10 studies, 985 participants; low-certainty evidence). Upper hemi-sternotomy for aortic valve replacement may increase cardiopulmonary bypass time slightly, although the evidence is very uncertain (mean difference (MD) 10.63 minutes, 95% CI 3.39 to 17.88; 10 studies, 1043 participants; very low-certainty evidence) and may increase aortic cross-clamp time slightly (MD 6.07 minutes, 95% CI 0.79 to 11.35; 12 studies, 1235 participants; very low-certainty evidence), although the evidence is very uncertain. Most studies had at least two domains at high risk of bias. Postoperative blood loss was probably lower in the upper hemi-sternotomy group (MD -153 mL, 95% CI -246 to -60; 8 studies, 767 participants; moderate-certainty evidence). Low-certainty evidence suggested that there may be no change in pain scores by upper hemi-sternotomy (standardised mean difference (SMD) -0.19, 95% CI -0.43 to 0.04; 5 studies, 649 participants). Upper hemi-sternotomy may result in little to no difference in quality of life (MD 0.03 higher, 95% CI 0 to 0.06 higher; 4 studies, 624 participants; low-certainty evidence). Two studies reporting index admission costs concluded that limited sternotomy may be more costly at index admission in the UK National Health Service (MD 1190 GBP more, 95% CI 420 GBP to 1970 GBP, 2 studies, 492 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence was of very low to moderate certainty. Sample sizes were small and underpowered to demonstrate differences in some outcomes. Clinical heterogeneity was also noted. Considering these limitations, there may be little to no effect on mortality. Differences in extracorporeal support times are uncertain, comparing upper hemi-sternotomy to full sternotomy for aortic valve replacement. Before widespread adoption of the minimally invasive approach can be recommended, there is a need for a well-designed and adequately powered prospective randomised controlled trial. Such a study would benefit from also performing a robust cost analysis. Growing patient preference for minimally invasive techniques merits thorough quality of life analyses to be included as end points, as well as quantitative measures of physiological reserve.

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure." METHODS: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. METHODS: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Oxford consensus on primary cam morphology and femoroacetabular impingement syndrome: part 1-definitions, terminology, taxonomy and imaging outcomes.

INTRODUCTION: Primary cam morphology is a mostly benign bony prominence that develops at the femoral head-neck junction of the hip, but it is highly prevalent in many athlete populations. In the small proportion of athletes for whom it is not benign, the resulting hip osteoarthritis can be debilitating. Clinicians, athletes, patients and researchers do not yet agree on important primary cam morphology elements. We aimed to ascertain and improve the level of agreement on primary cam morphology definitions, terminology, taxonomy and imaging outcome measures. METHODS: To collect and aggregate informed opinions, an expert panel-the Young Athlete's Hip Research Collaborative-rated primary cam morphology definition, terminology, taxonomy and imaging outcome statements through an online Delphi exercise followed by an online meeting to explore areas of tension and dissent. Reporting followed Conducting and REporting DElphi Studies. RESULTS: A diverse and inclusive Delphi panel (n=65 for rounds 1 and 2, representing 18 countries; 6 stakeholder groups; 40% women) agreed on 35 of 47 statements in 4 domains, while surfacing areas of tension and dissent. This Delphi panel agreed on four key issues essential to moving research and clinical care forward around primary cam morphology. They agreed on: (1) definition, confirming its conceptual attributes (tissue type, size, location, shape and ownership); (2) terminology-use 'morphology' and not terms with a negative connotation like 'lesion', 'abnormality' or 'deformity'; (3) taxonomy, distinguishing between primary and secondary cam morphology, and (4) imaging outcomes, a continuous bone/cartilage alpha angle on radial femoral head-neck MRI for primary cam morphology aetiology research. CONCLUSION: This consensus provides athletes, patients, clinicians and researchers with a strong foundation to guide more precise communication, better clinical decision-making and higher value research about primary cam morphology and its natural history.

Oxford consensus on primary cam morphology and femoroacetabular impingement syndrome: part 2-research priorities on conditions affecting the young person's hip.

INTRODUCTION: Primary cam morphology is highly prevalent in many athlete populations, causing debilitating hip osteoarthritis in some. Existing research is mired in confusion partly because stakeholders have not agreed on key primary cam morphology elements or a prioritised research agenda. We aimed to inform a more rigorous, inclusive and evidence-based approach to research on primary cam morphology and its natural history by working towards agreement on a set of research priorities for conditions affecting the young person's hip. METHODS: An international expert panel-the Young Athlete's Hip Research (YAHiR) Collaborative-rated research priority statements through an online two-round Delphi exercise and met online to explore areas of tension and dissent. Panellists ranked the prioritised research statements according to the Essential National Health Research (ENHR) ranking strategy. Reporting of results followed REPRISE (REporting guideline for PRIority SEtting of health). RESULTS: A diverse Delphi panel (n=65, Delphi rounds 1 and 2; three ENHR strategy surveys: n=49; n=44; n=42) from 18 countries representing six stakeholder groups, prioritised and ranked 18 of 38 research priority statements. The prioritised statements outlined seven research domains: (1) best practice physiotherapy, (2) rehabilitation progression and return to sport, (3) exercise intervention and load management, (4) primary cam morphology prognosis and aetiology, (5) femoroacetabular impingement syndrome prognosis and aetiology, (6) diagnostic criteria, and (7) screening. The panel recommended areas of tension and dissent for the research community to focus on immediately. CONCLUSION: While informing more rigorous, inclusive and evidence-based research, this consensus is a roadmap for researchers, policy-makers and funders to implement research dedicated to reducing the cost and burden of hip disease related to primary cam morphology.

Primary cam morphology; bump, burden or bog-standard? A concept analysis.

BACKGROUND: Cam morphology, a distinct bony morphology of the hip, is prevalent in many athletes, and a risk factor for hip-related pain and osteoarthritis. Secondary cam morphology, due to existing or previous hip disease (eg, Legg-Calve-Perthes disease), is well-described. Cam morphology not clearly associated with a disease is a challenging concept for clinicians, scientists and patients. We propose this morphology, which likely develops during skeletal maturation as a physiological response to load, should be referred to as primary cam morphology. The aim of this study was to introduce and clarify the concept of primary cam morphology. DESIGN: We conducted a concept analysis of primary cam morphology using articles that reported risk factors associated with primary cam morphology; we excluded articles on secondary cam morphology. The concept analysis method is a rigorous eight-step process designed to clarify complex 'concepts'; the end product is a precise definition that supports the theoretical basis of the chosen concept. RESULTS: We propose five defining attributes of primary cam morphology-tissue type, size, site, shape and ownership-in a new conceptual and operational definition. Primary cam morphology is a cartilage or bony prominence (bump) of varying size at the femoral head-neck junction, which changes the shape of the femoral head from spherical to aspherical. It often occurs in asymptomatic male athletes in both hips. The cartilage or bone alpha angle (calculated from radiographs, CT or MRI) is the most common method to measure cam morphology. We found inconsistent reporting of primary cam morphology taxonomy, terminology, and how the morphology is operationalised. CONCLUSION: We introduce and clarify primary cam morphology, and propose a new conceptual and operational definition. Several elements of the concept of primary cam morphology remain unclear and contested. Experts need to agree on the new taxonomy, terminology and definition that better reflect the primary cam morphology landscape-a bog-standard bump in most athletic hips, and a possible hip disease burden in a selected few.

Consensus recommendations on the classification, definition and diagnostic criteria of hip-related pain in young and middle-aged active adults from the International Hip-related Pain Research Network, Zurich 2018.

There is no agreement on how to classify, define or diagnose hip-related pain-a common cause of hip and groin pain in young and middle-aged active adults. This complicates the work of clinicians and researchers. The International Hip-related Pain Research Network consensus group met in November 2018 in Zurich aiming to make recommendations on how to classify, define and diagnose hip disease in young and middle-aged active adults with hip-related pain as the main symptom. Prior to the meeting we performed a scoping review of electronic databases in June 2018 to determine the definition, epidemiology and diagnosis of hip conditions in young and middle-aged active adults presenting with hip-related pain. We developed and presented evidence-based statements for these to a panel of 37 experts for discussion and consensus agreement. Both non-musculoskeletal and serious hip pathological conditions (eg, tumours, infections, stress fractures, slipped capital femoral epiphysis), as well as competing musculoskeletal conditions (eg, lumbar spine) should be excluded when diagnosing hip-related pain in young and middle-aged active adults. The most common hip conditions in young and middle-aged active adults presenting with hip-related pain are: (1) femoroacetabular impingement (FAI) syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without a distinct osseous morphology (labral, chondral and/or ligamentum teres conditions), and that these terms are used in research and clinical practice. Clinical examination and diagnostic imaging have limited diagnostic utility; a comprehensive approach is therefore essential. A negative flexion-adduction-internal rotation test helps rule out hip-related pain although its clinical utility is limited. Anteroposterior pelvis and lateral femoral head-neck radiographs are the initial diagnostic imaging of choice-advanced imaging should be performed only when requiring additional detail of bony or soft-tissue morphology (eg, for definitive diagnosis, research setting or when planning surgery). We recommend clear, detailed and consistent methodology of bony morphology outcome measures (definition, measurement and statistical reporting) in research. Future research on conditions with hip-related pain as the main symptom should include high-quality prospective studies on aetiology and prognosis. The most common hip conditions in active adults presenting with hip-related pain are: (1) FAI syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without distinct osseous morphology including labral, chondral and/or ligamentum teres conditions. The last category should not be confused with the incidental imaging findings of labral, chondral and/or ligamentum teres pathology in asymptomatic people. Future research should refine our current recommendations by determining the clinical utility of clinical examination and diagnostic imaging in prospective studies.

Hip replacement.

Total hip replacement is a frequently done and highly successful surgical intervention. The procedure is undertaken to relieve pain and improve function in individuals with advanced arthritis of the hip joint. Symptomatic osteoarthritis is the most common indication for surgery. In paper 1 of this Series, we focus on how patient factors should inform the surgical decision-making process. Substantial demands are placed upon modern implants, because patients expect to remain active for longer. We discuss the advances made in implant performance and the developments in perioperative practice that have reduced complications. Assessment of surgery outcomes should include patient-reported outcome measures and implant survival rates that are based on data from joint replacement registries. The high-profile failure of some widely used metal-on-metal prostheses has shown the shortcomings of the existing regulatory framework. We consider how proposed changes to the regulatory framework could influence safety.

Validation of hip osteoarthritis diagnosis recording in the UK Clinical Practice Research Datalink.

PURPOSE: The diagnosis of hip osteoarthritis is subject to several uncertainties, especially in primary care. The aims of this study were to determine (i) the diagnostic accuracy of coding of hip osteoarthritis by primary care physicians in the UK Clinical Practice Research Datalink (CPRD), (ii) the relative influence of radiographic and clinical parameters on diagnostic accuracy, and (iii) the accuracy of the diagnosis date. METHODS: An extract of all patients aged over 65 years, with a Read code for hip osteoarthritis listed between January 1995 and December 2014, was obtained from CPRD. A random sample was selected of 170 participants. A questionnaire concerning data in medical records on relevant clinical and radiographic criteria used to establish the diagnosis of hip osteoarthritis was distributed to primary care physicians of participants. Using diagnostic criteria, we formulated thresholds for diagnosis based on clinical, radiographic, and combined grounds. RESULTS: One hundred nineteen completed questionnaires were returned (70% response rate). The positive predictive value (PPV) of hip osteoarthritis codes, based on radiological criteria, was 79.8%. The PPV, based on clinical criteria, was 79.0%, with substantial but not complete overlap. Overall 12% of diagnoses were not confirmed. In 42% of cases, there was disparity between date of diagnosis in CPRD and the medical record. Median difference in date was ±425 days (interquartile range, 18-1448 days). CONCLUSIONS: Despite the difficulties in reaching a diagnosis of hip osteoarthritis in primary care, CPRD Read codes have a sufficiently high PPV for most research uses. However, the accuracy of diagnosis date may not be as reliable.

ASA class is associated with early revision and reoperation after total hip arthroplasty: an analysis of the Geneva and Swedish Hip Arthroplasty Registries.

Background and purpose - Data from several joint replacement registries suggest that the rate of early revision surgery after primary total hip arthroplasty (THA) is increasing. The ASA class, now widely recorded in arthroplasty registries, may predict early revision. We investigated the influence of ASA class on the risk of revision and other reoperation within 3 months and within 5 years of primary THA. Patients and methods - We used data from the Geneva and Swedish Hip Arthroplasty Registries, on primary elective THAs performed in 1996-2016 and 2008-2016, respectively. 5,319 and 122,241 THAs were included, respectively. Outcomes were all-cause revision and other reoperations evaluated using Kaplan-Meier survival and Cox regression analyses. Results - Within 3 months after surgery, higher ASA class was associated with greater risk of revision and other reoperation. 3-month cumulative incidences of revision by ASA class I, II, and III-IV respectively, were 0.6%, 0.7%, and 2.3% in Geneva and 0.5%, 0.8%, and 1.6% in Sweden. 3-month cumulative incidences of other reoperation were 0.4%, 0.7%, and 0.9% in Geneva and 0.2%, 0.4%, and 0.7% in Sweden. Adjusted hazard ratios (ASA III-IV vs. I) for revision within 3 months were 2.7 (95% CI 1.2-5.9) in Geneva and 3.3 (CI 2.6-4.0) in Sweden. Interpretation - Assessment of ASA class of patients prior to THA will facilitate risk stratification. Targeted risk-reduction strategies may be appropriate during the very early postoperative period for patients identified as at higher risk. Systematically recording ASA class in arthroplasty registries will permit risk adjustment and facilitate comparison of revision rates internationally.

The effect of patient age at intervention on risk of implant revision after total replacement of the hip or knee: a population-based cohort study.

BACKGROUND: Total joint replacements for end-stage osteoarthritis of the hip and knee are cost-effective and demonstrate significant clinical improvement. However, robust population based lifetime-risk data for implant revision are not available to aid patient decision making, which is a particular problem in young patient groups deciding on best-timing for surgery. METHODS: We did implant survival analysis on all patients within the Clinical Practice Research Datalink who had undergone total hip replacement or total knee replacement. These data were adjusted for all-cause mortality with data from the Office for National Statistics and used to generate lifetime risks of revision surgery based on increasing age at the time of primary surgery. FINDINGS: We identified 63 158 patients who had undergone total hip replacement and 54 276 who had total knee replacement between Jan 1, 1991, and Aug 10, 2011, and followed up these patients to a maximum of 20 years. For total hip replacement, 10-year implant survival rate was 95·6% (95% CI 95·3-95·9) and 20-year rate was 85·0% (83·2-86·6). For total knee replacement, 10-year implant survival rate was 96·1% (95·8-96·4), and 20-year implant survival rate was 89·7% (87·5-91·5). The lifetime risk of requiring revision surgery in patients who had total hip replacement or total knee replacement over the age of 70 years was about 5% with no difference between sexes. For those who had surgery younger than 70 years, however, the lifetime risk of revision increased for younger patients, up to 35% (95% CI 30·9-39·1) for men in their early 50s, with large differences seen between male and female patients (15% lower for women in same age group). The median time to revision for patients who had surgery younger than age 60 was 4·4 years. INTERPRETATION: Our study used novel methodology to investigate and offer new insight into the importance of young age and risk of revision after total hip or knee replacement. Our evidence challenges the increasing trend for more total hip replacements and total knee replacements to be done in the younger patient group, and these data should be offered to patients as part of the shared decision making process. FUNDING: Oxford Musculoskeletal Biomedical Research Unit, National Institute for Health Research.

Physical activity during adolescence and the development of cam morphology: a cross-sectional cohort study of 210 individuals.

INTRODUCTION: Cam morphology is a strong risk factor for the development of hip pain and osteoarthritis. It is increasingly thought to develop in association with intense physical activity during youth; however, the aetiology remains uncertain. The study aim was to characterise the effect of physical activity on morphological hip development during adolescence. METHODS: Cross-sectional study of individuals aged 9-18 years recruited from Southampton Football Club Academy (103 male) with an age-matched control population (52 males and 55 females). Assessments included questionnaires and 3 Tesla MRI of both hips. Alpha angle, epiphyseal extension and epiphyseal tilt were measured on radial images. RESULTS: Alpha angle and epiphyseal extension increased most rapidly between ages 12 and 14 years. Soft-tissue hypertrophy at the femoral head-neck junction preceded osseous cam morphology and was first evident at age 10 years. The greatest increase and highest absolute values of alpha angle and epiphyseal extension were colocalised at 1 o'clock. Maximum alpha angles were 6.7 degrees greater in males than females (p=0.005). Compared with individuals who play no regular sport, alpha angles were 4.0 degrees higher in individuals who play sport for a school or club (p=0.041) and 7.7 degrees higher in individuals competing at a national or international level (p=0.035). There was no association with leg dominance . CONCLUSIONS: Sporting activity during adolescence is strongly associated with the development of cam morphology secondary to epiphyseal hypertrophy and extension with a dose-response relationship. Males participating in competitive sport are at particularly elevated risk of developing cam morphology and secondary hip pathology.

Limited versus full sternotomy for aortic valve replacement.

BACKGROUND: Aortic valve disease is a common condition that is easily treatable with cardiac surgery. This is conventionally performed by opening the sternum longitudinally down the centre ("median sternotomy") and replacing the valve under cardiopulmonary bypass. Median sternotomy is generally well tolerated, but as less invasive options have become available, the efficacy of limited incisions has been called into question. In particular, the effects of reducing the visibility and surgical access has raised safety concerns with regards to the placement of cannulae, venting of the heart, epicardial wire placement, and de-airing of the heart at the end of the procedure. These difficulties may increase operating times, affecting outcome. The benefits of smaller incisions are thought to include decreased pain; improved respiratory mechanics; reductions in wound infections, bleeding, and need for transfusion; shorter intensive care stay; better cosmesis; and a quicker return to normal activity. OBJECTIVES: To assess the effects of minimally invasive aortic valve replacement via a limited sternotomy versus conventional aortic valve replacement via median sternotomy in people with aortic valve disease requiring surgical replacement. SEARCH METHODS: We performed searches of CENTRAL, MEDLINE, Embase, clinical trials registries, and manufacturers' websites from inception to July 2016, with no language limitations. We reviewed references of identified papers to identify any further studies of relevance. SELECTION CRITERIA: Randomised controlled trials comparing aortic valve replacement via a median sternotomy versus aortic valve replacement via a limited sternotomy. We excluded trials that performed other minimally invasive incisions such as mini-thoracotomies, port access, trans-apical, trans-femoral or robotic procedures. Although some well-conducted prospective and retrospective case-control and cohort studies exist, these were not included in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial papers to extract data, assess quality, and identify risk of bias. A third review author provided arbitration where required. The quality of evidence was determined using the GRADE methodology and results of patient-relevant outcomes were summarised in a 'Summary of findings' table. MAIN RESULTS: The review included seven trials with 511 participants. These included adults from centres in Austria, Spain, Italy, Germany, France, and Egypt. We performed 12 comparisons investigating the effects of minimally invasive limited upper hemi-sternotomy on aortic valve replacement as compared to surgery performed via full median sternotomy.There was no evidence of any effect of upper hemi-sternotomy on mortality versus full median sternotomy (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.36 to 2.82; participants = 511; studies = 7; moderate quality). There was no evidence of an increase in cardiopulmonary bypass time with aortic valve replacement performed via an upper hemi-sternotomy (mean difference (MD) 3.02 minutes, 95% CI -4.10 to 10.14; participants = 311; studies = 5; low quality). There was no evidence of an increase in aortic cross-clamp time (MD 0.95 minutes, 95% CI -3.45 to 5.35; participants = 391; studies = 6; low quality). None of the included studies reported major adverse cardiac and cerebrovascular events as a composite end point.There was no evidence of an effect on length of hospital stay through limited hemi-sternotomy (MD -1.31 days, 95% CI -2.63 to 0.01; participants = 297; studies = 5; I2 = 89%; very low quality). Postoperative blood loss was lower in the upper hemi-sternotomy group (MD -158.00 mL, 95% CI -303.24 to -12.76; participants = 297; studies = 5; moderate quality). The evidence did not support a reduction in deep sternal wound infections (RR 0.71, 95% CI 0.22 to 2.30; participants = 511; studies = 7; moderate quality) or re-exploration (RR 1.01, 95% CI 0.48 to 2.13; participants = 511; studies = 7; moderate quality). There was no change in pain scores by upper hemi-sternotomy (standardised mean difference (SMD) -0.33, 95% CI -0.85 to 0.20; participants = 197; studies = 3; I2 = 70%; very low quality), but there was a small increase in postoperative pulmonary function tests with minimally invasive limited sternotomy (MD 1.98 % predicted FEV1, 95% CI 0.62 to 3.33; participants = 257; studies = 4; I2 = 28%; low quality). There was a small reduction in length of intensive care unit stays as a result of the minimally invasive upper hemi-sternotomy (MD -0.57 days, 95% CI -0.93 to -0.20; participants = 297; studies = 5; low quality). Postoperative atrial fibrillation was not reduced with minimally invasive aortic valve replacement through limited compared to full sternotomy (RR 0.60, 95% CI 0.07 to 4.89; participants = 240; studies = 3; moderate quality), neither were postoperative ventilation times (MD -1.12 hours, 95% CI -3.43 to 1.19; participants = 297; studies = 5; low quality). None of the included studies reported cost analyses. AUTHORS' CONCLUSIONS: The evidence in this review was assessed as generally low to moderate quality. The study sample sizes were small and underpowered to demonstrate differences in outcomes with low event rates. Clinical heterogeneity both between and within studies is a relatively fixed feature of surgical trials, and this also contributed to the need for caution in interpreting results.Considering these limitations, there was uncertainty of the effect on mortality or extracorporeal support times with upper hemi-sternotomy for aortic valve replacement compared to full median sternotomy. The evidence to support a reduction in total hospital length of stay or intensive care stay was low in quality. There was also uncertainty of any difference in the rates of other, secondary outcome measures or adverse events with minimally invasive limited sternotomy approaches to aortic valve replacement.There appears to be uncertainty between minimally invasive aortic valve replacement via upper hemi-sternotomy and conventional aortic valve replacement via a full median sternotomy. Before widespread adoption of the minimally invasive approach can be recommended, there is a need for a well-designed and adequately powered prospective randomised controlled trial. Such a study would benefit from performing a robust cost analysis. Growing patient preference for minimally invasive techniques merits thorough quality-of-life analyses to be included as end points, as well as quantitative measures of physiological reserve.

The Relationship Between Polyethylene Wear and Periprosthetic Osteolysis in Total Hip Arthroplasty at 12 Years in a Randomized Controlled Trial Cohort.

BACKGROUND: Polyethylene acetabular components are common in hip arthroplasty. Highly cross-linked polyethylene (HXLPE) has lower wear than ultra-high molecular weight polyethylene (UHMWPE). Evidence suggests that wear particles induce inflammation causing periprosthetic osteolysis contributing to implant loosening with wear rates of 0.05 mm/y were considered safe. We aimed to compare incidence and volume of periacetabular osteolysis between HXLPE and UHMWPE using computed tomography. METHODS: Initially, 54 hips in 53 patients were randomized to HXLPE or UHMWPE acetabular liner. At 10 years, 39 hips in 38 patients remained for the radiostereometric analysis' demonstrating significantly lower wear in the HXLPE group. At 12 years, 14 hips in 13 patients were lost to follow-up leaving 25 hips for computed tomography assessment. Images were reconstructed to detect osteolysis and where identified, areas were segmented and volumized. RESULTS: Osteolysis was observed in 8 patients, 7 from the UHMWPE group and only 1 from the HXLPE group (Fisher exact, P = .042). There was no correlation between the amount of polyethylene wear and osteolysis volume; however, the radiostereometric analysis-measured wear rate in patients with osteolysis from both groups was significantly higher than overall average wear rate. CONCLUSION: This data demonstrates lower incidence of periacetabular osteolysis in the HXLPE group of a small cohort. Although numbers are too low to estimate causation, in the context of lower wear in the HXLPE group, this finding supports the hypothesis that HXLPE may not elevate osteolysis risk, and hence does not suggest that HXLPE wear particles are more biologically active than those generated by earlier generations of polyethylene.

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects.

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-∞) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).