Facilitators and barriers to adolescent participation in a TB clinical trial.

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Total hip arthroplasty in Cambodia - Our experience of two hundred and fifty six consecutive total hip arthroplasties in a low-income country & the challenge of service delivery in this setting.

The Children's Surgical Centre has performed 256 THAs since 2007, We aim to assess the outcome of arthroplasty in a LMIC. Primary outcome: all cause of re-operation, Secondary outcome: any other complication. A retrospective review of all consecutive THA since 2007 was conducted. Electronic and physical case notes were reviewed. Statistical analysis was performed using MedCalc. 256 THA. Mean age: 43, gender M2:1F. Common pathologies include (1) AVN (44%), (2) OA (11%) and (3) DDH (11%). Revision rate 13%. Time to revision was 2.8 years (0-9). Common revision reasons: (1) stem fracture (5.8%), (2) aseptic loosening (4.8%) and (3) infection (2.7%). Complications were identified in 85 patients (33.2%). Common complications included (1) aseptic loosening (10.5%) (2) stem fracture (5.8%) and (3) dislocation (5.8%). Patients at CSC benefit from THA, the complication rates at CSC are declining suggesting the apex of the 'learning curve' has passed. Cheap poorly manufactured implants continue to cause catastrophic failure.

Management of acute paediatric fractures treated surgically in the UK: a cross-sectional study.

INTRODUCTION: The epidemiology of acute paediatric orthopaedic trauma managed surgically across the NHS is poorly described. Compliance against national standards for the management of supracondylar humeral fractures is also unknown at a national level. METHODS: Collaborators in 129 NHS hospitals prospectively collected data on surgically managed acute paediatric orthopaedic trauma cases. Data were collected over a seven-day period and included demographics, injury characteristics, operative details and timing of surgery. A national audit was also undertaken to evaluate compliance with the British Orthopaedic Association Standards for Trauma Guideline 11: Supracondylar Fractures of the Humerus in Children. RESULTS: Data were captured on 770 surgically treated cases. The three most common injuries were forearm fractures of both bones (n = 235), distal radius fractures (n = 194) and supracondylar elbow fractures (n = 89). The mode day of injury was Friday (n = 136) and the mode day of surgery was Saturday (n = 138). 88% of supracondylar fractures received surgery on the day of presentation or the following day. Only 14% of supracondylar fractures were treated surgically after 8pm; 33/89 used 2.0mm Kirschner wires, 38/89 used 1.6mm wires and 2/89 used 1.2mm wires. CONCLUSION: Forearm fractures of both bones, distal radius fractures and supracondylar humeral fractures were the three most common injuries treated surgically. There is wide variation in compliance against national standards in the management of supracondylar humeral fractures with 88% undertaking surgery on the day of or the day following presentation but only 37% using the recommended 2.0mm Kirschner wires.

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Novel Tools in Determining the Physiological Demands and Nutritional Practices of Ontario FireRangers during Fire Deployments.

INTRODUCTION: The seasonal profession of wildland fire fighting in Canada requires individuals to work in harsh environmental conditions that are physically demanding. The purpose of this study was to use novel technologies to evaluate the physiological demands and nutritional practices of Canadian FireRangers during fire deployments. METHODS: Participants (n = 21) from a northern Ontario Fire Base volunteered for this study and data collection occurred during the 2014 fire season and included Initial Attack (IA), Project Fire (P), and Fire Base (B) deployments. Deployment-specific energy demands and physiological responses were measured using heart-rate variability (HRV) monitoring devices (Zephyr BioHarness3 units). Food consumption behaviour and nutrient quantity and quality were captured using audio-video food logs on iPod Touches and analyzed by NutriBase Pro 11 software. RESULTS: Insufficient kilocalories were consumed relative to expenditure for all deployment types. Average daily kilocalories consumed: IA: 3758 (80% consumption rate); P: 2945±888.8; B: 2433±570.8. Average daily kilocalorie expenditure: IA: 4538±106.3; P: 4012±1164.8; B: 2842±649.9. The Average Macronutrient Distribution Range (AMDR) for protein was acceptable: 22-25% (across deployment types). Whereas the AMDR for fat and carbohydrates were high: 40-50%; and low: 27-37% respectively, across deployment types. CONCLUSIONS: This study is the first to use the described methodology to simultaneously evaluate energy expenditures and nutritional practices in an occupational setting. The results support the use of HRV monitoring and video-food capture, in occupational field settings, to assess job demands. FireRangers expended the most energy during IA, and the least during B deployments. These results indicate the need to develop strategies centered on maintaining physical fitness and improving food practices.

Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis.

BACKGROUND: Rifapentine (RPT) has potent activity against Mycobacterium tuberculosis; however, the optimal dose for anti-tuberculosis treatment is unknown. OBJECTIVE: To determine the antimicrobial activity, safety and tolerability of RPT 450 mg or 600 mg administered daily during the first 8 weeks of treatment for pulmonary tuberculosis (TB). DESIGN: In a two-stage, randomised open-label study, adults with sputum smear-positive TB were randomised to receive RPT 450 mg, RPT 600 mg or rifampicin (RMP) 600 mg daily for 8 weeks with isoniazid, pyrazinamide and ethambutol. The primary endpoint was sputum culture status on Löwenstein-Jensen (LJ) medium at completion of 8 weeks of treatment. RESULTS: A total of 153 participants were enrolled. Both RPT regimens met pre-specified criteria to advance to stage 2. At completion of 8 weeks of treatment, LJ culture conversion occurred in 85% (35/41), 96% (43/45) and 94% (34/36) of participants in the RPT 450 mg, RPT 600 mg and RMP groups, respectively. The proportions of participants discontinuing treatment were similar (respectively 1/54 [2.0%], 1/51 [2.0%] and 4/48 [8.3%] in the RPT 450 mg, RPT 600 mg and RMP groups), as were ⩾grade 3 adverse events (0/54 [0%], 1/51 [2.0%] and 4/48 [8.3%]). CONCLUSIONS: There was a trend towards greater efficacy with RPT 600 mg than with RPT 450 mg. Daily RPT was safe and well-tolerated.

Advances in the diagnosis of tuberculosis: current status and future prospects.

Lack of diagnosis and diagnostic capacity remain barriers to tuberculosis (TB) control. This review describes recent advances in TB diagnostics, the current TB diagnostic landscape, and some of the key challenges in the quest for accurate, simple diagnostic tests that have meaningful impact on the health of individual patients and on TB epidemiology.

Establishing a children's orthopaedic hospital for Malawi: A review after 10 years.

BACKGROUND: BEIT CURE International Hospital (BCIH) opened in 2002 providing orthopaedic surgical services to children in Malawi. This study reviews the hospital's progress 10 years after establishment of operational services. In addition we assess the impact of the hospital's Malawi national clubfoot programme (MNCP) and influence on orthopaedic training. METHODS: All operative paediatric procedures performed by BCIH services in the 10th operative year were included. Data on clubfoot clinic locations and number of patients treated were obtained from the MNCP. BCIH records were reviewed to identify the number of healthcare professionals who have received training at the BCIH. RESULTS: 609 new patients were operated on in the 10th year of hospital service. Patients were treated from all regions; however 60% came from Southern regions compared with the 48% in the 5th year. Clubfoot, burn contracture and angular lower limb deformities were the three most common pathologies treated surgically. In total BCIH managed 9,842 patients surgically over a 10-year period. BCIH helped to establish and co-ordinate the MNCP since 2007. At present the program has a total of 29 clinics, which have treated 5748 patients. Furthermore, BCIH has overseen the full or partial training of 5 orthopaedic surgeons and 82 orthopaedic clinical officers in Malawi. CONCLUSION: The BCIH has improved the care of paediatric patients in a country that prior to its establishment had no dedicated paediatric orthopaedic service, treating almost 10,000 patients surgically and 6,000 patients in the MNCP. This service has remained consistent over a 10-year period despite times of global austerity. Whilst the type of training placement offered at BCIH has changed in the last 10 years, the priority placed on training has remained paramount. The strategic impact of long-term training commitments are now being realised, in particular by the addition of Orthopaedic surgeons serving the nation.

Cost-effectiveness of routine diagnostic evaluation of pulmonary tuberculosis in a primary care unit in Brazil.

SETTING: Primary health care unit in Rio de Janeiro City, Brazil. OBJECTIVE: To estimate and compare the cost-effectiveness of strategies used for passive case finding of pulmonary tuberculosis (PTB) cases using tests available at the primary care level. DESIGN: Data on PTB suspects were reviewed, and a decision model was developed using sputum smear microscopy and chest radiography (CXR) according to three different strategies for PTB detection. A cost-effectiveness analysis was performed to estimate the cost per correct PTB diagnosis. Mycobacterial culture was used to calculate the effectiveness of the strategies. Unit costs of health resource utilisation were obtained from the payer's perspective (the Brazilian Public Health System). RESULTS: For the evaluation of 254 PTB suspects, the total costs of strategies ranged from US$5369 to US$5944; the probability of a correct PTB diagnosis ranged from 0.66 to 0.86; the number of visits required to complete the diagnostic process ranged from two to three, and cost per PTB case identified ranged from US$47.93 to US$53.07. The cost-effectiveness of the three strategies studied varied between US$56.69 and US$72.55 per correct PTB case detected. CONCLUSION: A strategy in which sputum smears and CXR were requested for all PTB suspects at the initial evaluation was cost-effective, had a high probability of correct PTB diagnosis and could be accomplished in two visits.

Cozen's phenomenon: a reminder.

A four-year-old child attended Accident and Emergency following a fall from a slide with a displaced and angulated proximal tibial metaphyseal fracture. Treatment included closed manipulation under anaesthesia and an above knee cast for seven weeks. Serial radiographs over the following few months were satisfactory demonstrating good alignment and evidence of healing. However, at four-months review new-onset genu valgum with mechanical axis deviation was noted. No evidence of spontaneous resolution was noted over the following 12 months and hence a corrective hemi-epiphysiodesis was performed. At 12-months post-operatively, there was marked clinical and radiographical improvement in alignment. Classically Cozen's phenomenon is described as the late-onset post-traumatic valgus deformity associated with proximal tibial metaphyseal fractures in children. We want to reemphasise the early recognition of children at risk of this unique complication. In addition, we wish to highlight the progression of the late-onset valgus and its subsequent management.

Cost utility of lateral-flow urine lipoarabinomannan for tuberculosis diagnosis in HIV-infected African adults.

SETTING: In-patient hospitals in South Africa and Uganda. OBJECTIVE: To evaluate the cost-effectiveness of a lateral-flow urine lipoarabinomannan (LAM) test when added to existing strategies for tuberculosis (TB) diagnosis in human immunodeficiency virus infected adults (CD4(+) T-cell counts < 100 cells/l) with symptoms of active TB. DESIGN: Decision-analytic cost-utility model, with the primary outcome being the incremental cost-effectiveness ratio, expressed in 2010 US dollars per disability-adjusted life year (DALY) averted from the perspective of a public sector TB control program. RESULTS AND CONCLUSION: For every 1000 patients tested, adding lateral-flow urine LAM generated 80 incremental appropriate anti-tuberculosis treatments and averted 224 DALYs. Estimated cost utility was US$353 per DALY averted (95% uncertainty range $192$1161) in South Africa and $86 per DALY averted (95% uncertainty range $49$239) in Uganda, reflecting the lower treatment costs in Uganda. Cost utility was most sensitive to assay specificity, cost of anti-tuberculosis treatment, life expectancy after TB cure and cohort TB prevalence, but did not rise above $1500 per DALY averted in South Africa under any one-way sensitivity analysis. The probability of acceptability was >99.8% at a per-DALY willingness-to-pay threshold equal to the per capita gross domestic product in South Africa ($7275) and Uganda ($509).

Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration­time curve (AU C0­24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0­12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

A national infection control evaluation of drug-resistant tuberculosis hospitals in South Africa.

BACKGROUND: The importance of infection control (IC) in health care settings with tuberculosis (TB) patients has been highlighted by recent health care-associated outbreaks in South Africa. OBJECTIVE: To conduct operational evaluations of IC in drug-resistant TB settings at a national level. METHODS: A cross-sectional descriptive study was conducted from June to September 2009 in all multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB) facilities in South Africa. Structured interviews with key informants were completed, along with observation of IC practices. Health care workers (HCWs) were asked to complete an anonymous knowledge, attitudes and practices (KAP) questionnaire. Multilevel modeling was used to take into consideration the relationship between center and HCW level variables. RESULTS: Twenty-four M(X)DR-TB facilities (100%) were enrolled. Facility infrastructure and staff adherence to IC recommendations were highly varied between facilities. Key informant interviews were incongruent with direct observation of practices in all settings. A total of 499 HCWs were enrolled in the KAP evaluation. Higher level of clinical training was associated with greater IC knowledge (P < 0.001), more appropriate attitudes (P < 0.001) and less time spent with coughing patients (P < 0.001). IC practices were poor across all disciplines. CONCLUSION: These findings demonstrate a clear need to improve and standardize IC infrastructure in drug-resistant TB settings in South Africa.

QuantiFERON-TB Gold In-Tube for the detection of Mycobacterium tuberculosis infection in children with household tuberculosis contact.

SETTING: Improved strategies are needed for detecting Mycobacterium tuberculosis infection in children in TB-endemic settings. OBJECTIVE: To determine the prevalence of M. tuberculosis infection by tuberculin skin testing (TST) and by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test in children with an adult household contact with pulmonary TB in South Africa. DESIGN: Cross-sectional study. RESULTS: A total of 167 adult pulmonary TB cases (153/167, 92% human immunodeficiency virus [HIV] infected) and 270 pediatric contacts (median age 6 years, 14/270, 5% HIV-infected) were enrolled. All children completed QFT-GIT testing and 254 (94.1%) completed TST testing. Prevalence of M. tuberculosis infection was 28% (71/254, 95%CI 23-34) using TST (5 mm cut-off) and 29% (79/270, 95%CI 24-35) using QFT-GIT (P = 0.49). Agreement between TST and QFT-GIT was 81% (kappa 0.58). Nineteen (7%) QFT-GIT results were indeterminate. Children aged <2 years were more likely than older children to have indeterminate QFT-GIT results (aOR 5.7, 95%CI 1.5-22, P = 0.01) and discordant QFT-GIT and TST results (aOR 3.5, 95%CI 1.7-7.6, P = 0.001). CONCLUSION: Prevalence of M. tuberculosis infection in pediatric contacts was high regardless of the diagnostic method used. TST should not be excluded for the detection of pediatric M. tuberculosis infection in this setting, but QFT-GIT may be a feasible alternative in children aged ≥ 2 years.

Atherothrombosis and the role of antiplatelet therapy.

Atherothrombosis remains a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across vascular beds, but when complicated by thrombosis can result in acute coronary syndrome, stroke, transient ischaemic attack and critical limb ischaemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous trials have examined the role of antiplatelet agents in primary and secondary prevention and several new antiplatelet drugs are under development. In secondary prevention, there is evidence of clear benefit of single and in some cases dual antiplatelet therapy in the prevention of recurrent cerebro-vascular complications. Dual antiplatelet therapy has emerged as the standard of care in acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent antiplatelet agents. Conversely, in chronic stable coronary disease, no benefit has yet been convincingly demonstrated from dual antiplatelet therapy. In cerebro-vascular disease, aspirin monotherapy remains the cornerstone of prevention of recurrent events, with clopidogrel or the combination of aspirin and dipyridamole being only modestly more efficacious. In primary prevention, the evidence for the routine use of aspirin or any other antiplatelet agent is mixed and suggests this should only be considered on an individual basis in high-risk groups where the thrombotic risk outweighs the risk of major bleeding complications.

Persistent idiopathic ventricular tachycardia in a 28-year-old woman.

The case history is presented of a normally fit and well 28-year-old woman with idiopathic right ventricular outflow tract ventricular tachycardia (RVOT VT). Presentation was with a broad complex tachycardia unresponsive to first-line anti-arrhythmic drugs and DC cardioversion (immediate recurrence) but highly sensitive to flecainide and eventually successfully treated with catheter ablation. Assessment and management of broad complex tachycardia is challenging but requires a structured approach to the underlying differential diagnosis. Ventricular tachycardia may occur in structurally normal hearts and not cause haemodynamic compromise despite persistence over 48 h, as in this case. The clinical history, ECG morphology and response to adenosine were all instrumental in making the diagnosis and hence tailoring appropriate anti-arrhythmic therapy when DC cardioversion failed.

What do patients with brain metastases from non-small cell lung cancer want from their treatment?

Brain metastases are a common complication of non-small cell lung cancer (NSCLC). Prognosis is poor and the effectiveness of whole brain radiotherapy (WBRT) is uncertain for patients with moderate performance status. Studies on WBRT effectiveness have thus far used outcome measures, such as survival, performance status and cognitive function. The aim of this study was to study what patients with recently diagnosed brain metastases from NSCLC want from their treatment. We carried out semistructured interviews with nine patients with brain metastases from NSCLC, for whom the benefit of WBRT is uncertain. Interpretative phenomenological analysis was used. Themes identified included quality versus quantity of life, factors contributing to quality of life (including family, mobility and normality), 'Go for it!' - the desire to try anything, the desire for a cure or 'magic wand', fear and other factors (including family in decision making, information or lack of information, relationship with professionals, experience of steroids and radiotherapy including adverse effects). Quality of life is important to patients, but many are keen to try any treatment which might prolong their life. Understanding patients' values regarding treatment and goals of treatment can help clinicians discuss these issues with patients and provide appropriate information and can aid selection of appropriate outcome measures.

Researching breathlessness in palliative care: consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup.

Breathlessness is common in advanced disease and can have a devastating impact on patients and carers. Research on the management of breathlessness is challenging. There are relatively few studies, and many studies are limited by inadequate power or design. This paper represents a consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup. The aims of this paper are to facilitate the design of adequately powered multi-centre interventional studies in breathlessness, to suggest a standardised, rational approach to breathlessness research and to aid future 'between study' comparisons. Discussion of the physiology of breathlessness is included.