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..

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.

The immunogenetic basis of severe infections caused by bacille Calmette-Guérin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

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.

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.

Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon.

Neutrophil-specific granule deficiency (SGD) is a rare disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins. CCAAT/enhancer binding protein (C/EBP)epsilon, a member of the leucine zipper family of transcription factors, is expressed primarily in myeloid cells, and its knockout mouse model possesses distinctive defects, including a lack of neutrophil secondary granule proteins. Sequence analysis of the genomic DNA of a patient with SGD revealed a five-basepair deletion in the second exon of the C/EBPepsilon locus. The predicted frame shift results in a truncation of the 32-kD major C/EBPepsilon isoform, with loss of the dimerization domain, DNA binding region, and transcriptional activity. The multiple functional defects observed in these early neutrophil progenitor cells, a consequence of C/EBPepsilon deficiency, define SGD as a defect in myelopoiesis and establish the requirement for C/EBPepsilon for the promyelocyte-myelocyte transition in myeloid differentiation.

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.

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.

Acute aortic dissection mimicking an acute coronary syndrome through occlusion of the right coronary artery.

Occlusion of the right coronary artery (RCA) is an uncommon complication of type A aortic dissection. Aortic dissection and acute coronary syndrome (ACS) share a similar pathogenesis in atherosclerosis and hypertension. Consequently a patient with ischaemic risk factors presenting with chest pain and dynamic ECG change may well be incorrectly treated for ACS if careful attention is not paid to the presenting symptoms and signs. This case report describes a 59-year-old man who presented with chest pain, confusion and an ischaemic ECG and was initially treated for ACS. He subsequently deteriorated clinically and imaging confirmed type A aortic dissection complicated by RCA occlusion. Following emergent surgery with aortic root replacement and coronary artery bypass grafting he later made a good recovery.

Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection.

IFN-gamma is critical in the immune response to mycobacterial infections, and deficits in IFN-gamma production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN-gamma receptor ligand-binding chain (IFNgammaR1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-gamma receptor signal-transducing chain (IFNgammaR2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-gamma signaling due to a mutation in the extracellular domain of IFNgammaR2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-gamma production than in normal cells, while patient PHA-induced TNF-alpha production was normal. The normal augmentation of TNF-alpha production when IFN-gamma was added to endotoxin was absent from patient cells. Expression of IFNgammaR1 was normal, but there was no phosphorylation of Stat1 in response to IFN-gamma stimulation. DNA sequence analysis of the gene for IFNgammaR2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN-gamma plays in host defense against mycobacteria.

Interferon-gamma and interleukin-12 pathway defects and human disease.

A genetic component to human mycobacterial disease susceptibility has long been postulated. Over the past five years, mutations in the interferon-gamma (IFNgamma) receptor, IL-12 receptor beta1 (IL-12Rbeta1), and IL-12 p40 genes have been recognized. These mutations are associated with heightened susceptibility to disease caused by intracellular pathogens including nontuberculous mycobacteria, vaccine-associated bacille Calmette Guerin (BCG), Salmonella species, and some viruses. We describe the genotype-phenotype correlations in IFNgamma receptor, IL-12Rbeta1, and IL-12 p40 deficiency, and discuss how study of these diseases has enhanced knowledge of human host defense against mycobacteria and other intracellular pathogens.

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.

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.

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.

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.