Immune responses to typhoid conjugate vaccine in a two dose schedule among Nepalese children <2 years of age.

BACKGROUND: Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. METHODS: Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FINDINGS: Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). INTERPRETATION: Vi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses.

Development and testing of a checklist to assess compliance with the faculty of pain medicine's core standards for pain management services: experience in a new national tertiary pain service.

INTRODUCTION: The Faculty of Pain Medicine recently published the first UK-focused Core Standards for Pain Management Services (CSPMS). We present an audit checklist tool developed to map compliance to the CSPMS, which offers a practical method of auditing any pain management service against the standards. METHODS: The checklist tool was developed and its utility was field-tested in the Scottish National Residential Pain Management Programme (SNRPMP), a newly established service offering residential service to people in Scotland. RESULTS: The checklist tool developed provides an easy and practical approach to evaluating any pain service against the national standards. Its application to evaluate the SNRPMP indicates that the service meets the majority of CSPMS standards and highlights aspects of the service requiring improvement. CONCLUSION: The layout of the developed checklist tool offers an alternative format for the structuring of the national standards in possible future revisions. The audit checklist tool enables evaluation of services with a numerical score, enabling monitoring of their compliance with national standards as well as comparisons between pain services.

Xpert MTB/RIF Ultra for Tuberculosis Testing in Children: A Mini-Review and Commentary.

Tuberculosis (TB) remains a significant, yet under-recognized cause of death in the pediatric population, with a WHO estimate of 1 million new cases of childhood TB in 2016 resulting in 250,000 deaths. Diagnosis is notoriously difficult; manifestations are protean due to the high proportion of cases of extra-pulmonary TB in children, and logistical problems exist in obtaining suitable specimens. These issues are compounded by the paucibacillary nature of disease with the result that an estimated 96% of pediatric TB-associated mortality occurs prior to commencing anti-tuberculous treatment. Further development of sensitive, rapid diagnostic tests and their incorporation into diagnostic algorithms is vital in this population, and central to the WHO End-TB strategy. Initial gains were made with the expansion of nucleic acid amplification technology, particularly the introduction of the GeneXpert fully-automated PCR Xpert MTB/Rif assay in 2010, and more recently, the Xpert MTB/Rif Ultra (Ultra) assay in 2017. Ultra provides increased analytical sensitivity when compared with the initial Xpert assay in vitro; a finding now also supported by six clinical studies to date, two of which included pediatric samples. Here, we review the published evidence for the performance of Ultra in TB diagnosis in children, as well as studies in adults with paucibacillary disease providing results relevant to the pediatric population. Following on from this, we speculate upon future directions for Ultra, with focus on its potential use with alternative diagnostic specimens, which may be of particular utility in children.

Intensified antibiotic treatment of tuberculosis meningitis.

INTRODUCTION: Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 50% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcomes. Areas covered: In this review, we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance, and children; and optimal research strategies. Expert commentary: There is good evidence from preclinical, clinical, and modeling studies to support the use of high-dose rifampicin in TBM, likely to be at least 30 mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate the use of molecular pharmacological approaches, physiologically based pharmacokinetic modeling and pharmacokinetic-pharmacodynamic studies to define optimal regimens to be tested in clinical trials. Exciting data from recent studies hold promise for improved regimens and better clinical outcomes in future.

Ophthalmic signs in Ugandan adults with HIV-associated cryptococcal meningitis: A nested analysis of the ASTRO-CM cohort.

Cryptococcal meningitis is a leading cause of morbidity and mortality among HIV-infected persons, accounting for 15% of AIDS-related deaths. Visual disturbance is commonly reported, and a wide range of ophthalmic signs may be present on examination. There is limited published literature to date describing the range and incidence of ophthalmic signs in HIV-associated cryptococcal meningitis. Nested within the Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM) trial (ClinicalTrials.gov number: NCT01802385), we conducted an observational study of 696 Ugandan adults with HIV-associated cryptococcal meningitis. Patients were screened for visual disturbance and external ophthalmic signs at initial presentation and at follow-up appointments over 18 weeks. Assessment comprised simple clinical history and basic examination and required no specialist equipment. More than a quarter of our cohort demonstrated ocular signs or symptoms, which were observed throughout the study period.  A broad range of ocular signs were demonstrated: these included neurological signs (10.9%), localized ocular pathology (4.5%), and evidence of concurrent systemic disease (12.9%). The range of signs observed demonstrates the complexities of case management in patients with advanced HIV and cryptococcosis and also the importance of basic ocular examination in low resource settings. There remains an urgent need for studies conducting comprehensive ocular examination in patients with HIV-associated cryptococcal meningitis; these studies should include formal assessment of visual acuity, slit lamp examination and dilated indirect ophthalmoscopy. Prospective studies should investigate whether there is a correlation between reported visual disturbance and objective signs, in order to further clarify the underlying mechanisms and to guide effective diagnosis, follow-up and management.

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study).

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration.  With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018).

Detection of Mycobacterium tuberculosis in urine by Xpert MTB/RIF Ultra: A useful adjunctive diagnostic tool in HIV-associated tuberculosis.

In January 2017, the World Health Organisation recommended the Xpert® MTB/RIF Ultra assay (Ultra) for tuberculosis (TB) diagnosis. Ultra offers improved analytical sensitivity when compared with the initial Xpert® MTB/RIF (Xpert) assay for the detection of Mycobacterium tuberculosis. Ultra is therefore likely to be of particular benefit for detecting paucibacillary TB. We present a case from Uganda demonstrating Ultra positivity in urine from an HIV-infected patient presenting with altered mental status and urinary incontinence, and no other signs of active pulmonary or extrapulmonary TB. This represents the first published instance of a diagnosis of extrapulmonary TB made on the basis of a positive urine Ultra assay. The use of Ultra on urine may be a useful addition to the diagnostic armamentarium for disseminated TB in persons with HIV co-infection. The diagnostic accuracy of urine Ultra should be characterised further via prospective studies.

Exposure of patients to ionising radiation during lung cancer diagnostic work-up.

We examined the dose of radiation received during diagnosis of lung cancer as this may add to the risk of a second primary cancer. Patients undergoing surgery (n=40) or (chemo)radiotherapy (n=40) received comparable doses (28.6 and 25.8 mSv, respectively), significantly higher than that for supportive care (n=40; 15.1 mSv). The effective dose of radiation received was higher for early stage disease than for those with metastatic disease. The mean lifetime attributable risk of malignancy for those receiving treatment with curative intent in our cohort was 0.059%, and lung-specific risk 0.019%.

Suboptimal identification of patient-specific risk factors for poor wound healing can be improved by simple interventions.

Poor wound healing is an important surgical complication. At-risk wounds must be identified early and monitored appropriately. Wound surveillance is frequently inadequate, leading to increased rates of surgical site infections (SSIs). Although the literature demonstrates that risk factor identification reduces SSI rates, no studies have focused on wound management at a junior level. Our study assesses documentation rates of patient-specific risk factors for poor wound healing at a large district general hospital in the UK. It critically evaluates the efficacy of interventions designed to promote surveillance of high-risk wounds. We conducted a full-cycle clinical audit examining medical records of patients undergoing elective surgery over 5 days. Interventions included education of the multidisciplinary team and addition of a Wound Healing Risk Assessment (WHRA) checklist to surgical admissions booklets. This checklist provided a simple stratification tool for at-risk wounds and recommendations for escalation. Prior to interventions, the documentation of patient-specific risk factors ranged from 0·0% to 91·7% (mean 42·6%). Following interventions, this increased to 86·4-95·5% (mean 92·5%), a statistically significant increase of 117·1% (P < 0·01). This study demonstrates that documentation of patient-specific risk factors for poor wound healing is inadequate. We have shown the benefit of introducing interventions to increase risk factor awareness.

Does mindfulness improve outcomes in patients with chronic pain? Systematic review and meta-analysis.

BACKGROUND: Chronic pain and its associated distress and disability are common reasons for seeking medical help. Patients with chronic pain use primary healthcare services five times more than the rest of the population. Mindfulness has become an increasingly popular self-management technique. AIM: To assess the effectiveness of mindfulness-based interventions for patients with chronic pain. DESIGN AND SETTING: Systematic review and meta-analysis including randomised controlled trials of mindfulness-based interventions for chronic pain. There was no restriction to study site or setting. METHOD: The databases MEDLINE(®), Embase, AMED, CINAHL, PsycINFO, and Index to Theses were searched. Titles, abstracts, and full texts were screened iteratively against inclusion criteria of: randomised controlled trials of mindfulness-based intervention; patients with non-malignant chronic pain; and economic, clinical, or humanistic outcome reported. Included studies were assessed with the Yates Quality Rating Scale. Meta-analysis was conducted. RESULTS: Eleven studies were included. Chronic pain conditions included: fibromyalgia, rheumatoid arthritis, chronic musculoskeletal pain, failed back surgery syndrome, and mixed aetiology. Papers were of mixed methodological quality. Main outcomes reported were pain intensity, depression, physical functioning, quality of life, pain acceptance, and mindfulness. Economic outcomes were rarely reported. Meta-analysis effect sizes for clinical outcomes ranged from 0.12 (95% confidence interval [CI] = -0.05 to 0.30) (depression) to 1.32 (95% CI = -1.19 to 3.82) (sleep quality), and for humanistic outcomes 0.03 (95% CI = -0.66 to 0.72) (mindfulness) to 1.58 (95% CI = -0.57 to 3.74) (pain acceptance). Studies with active, compared with inactive, control groups showed smaller effects. CONCLUSION: There is limited evidence for effectiveness of mindfulness-based interventions for patients with chronic pain. Better-quality studies are required.

Coeliac disease in children with type 1 diabetes: are current guidelines proving difficult to implement in practice?

Updated European guidelines for the diagnosis of coeliac disease (CD) in the paediatric population (the European Society for Gastroenterology, Hepatology, and Nutrition, January 2012) outlined distinct diagnostic algorithms for patients with type 1 diabetes mellitus (T1DM). In this short report we demonstrate a period prevalence of CD in the T1DM population of 5.8% at a large tertiary centre. In addition to this, using a questionnaire circulated to paediatricians, we assessed present practice in the diagnosis of CD in T1DM 16 months following the European Society for Gastroenterology, Hepatology, and Nutrition guideline publication. Our results indicate that present practice and adherence to guidelines varies substantially. Further dissemination and perhaps simplification of guidelines may be required.

Use of fat mass and fat free mass standard deviation scores obtained using simple measurement methods in healthy children and patients: comparison with the reference 4-component model.

BACKGROUND: Clinical application of body composition (BC) measurements for individual children has been limited by lack of appropriate reference data. OBJECTIVES: (1) To compare fat mass (FM) and fat free mass (FFM) standard deviation scores (SDS) generated using new body composition reference data and obtained using simple measurement methods in healthy children and patients with those obtained using the reference 4-component (4-C) model; (2) To determine the extent to which scores from simple methods agree with those from the 4-C model in identification of abnormal body composition. DESIGN: FM SDS were calculated for 4-C model, dual-energy X-ray absorptiometry (DXA; GE Lunar Prodigy), BMI and skinfold thicknesses (SFT); and FFM SDS for 4CM, DXA and bioelectrical impedance analysis (BIA; height(2)/Z)) in 927 subjects aged 3.8-22.0 y (211 healthy, 716 patients). RESULTS: DXA was the most accurate method for both FM and FFM SDS in healthy subjects and patients (mean bias (limits of agreement) FM SDS 0.03 (± 0.62); FFM SDS -0.04 (± 0.72)), and provided best agreement with the 4-C model in identifying abnormal BC (SDS ≤-2 or ≥ 2). BMI and SFTs were reasonable predictors of abnormal FM SDS, but poor in providing an absolute value. BIA was comparable to DXA for FFM SDS and in identifying abnormal subjects. CONCLUSIONS: DXA may be used both for research and clinically to determine FM and FFM SDS. BIA may be used to assess FFM SDS in place of DXA. BMI and SFTs can be used to measure adiposity for groups but not individuals. The performance of simpler techniques in monitoring longitudinal BC changes requires investigation. Ultimately, the most appropriate method should be determined by its predictive value for clinical outcome.

Mindfulness, functioning and catastrophizing after multidisciplinary pain management for chronic low back pain.

We examined mindfulness in people with chronic low back pain who were attending a multidisciplinary pain management programme. Participants completed questionnaires at baseline (n=116) and after a 3-month cognitive-behaviourally informed multidisciplinary intervention (n=87). Self-reported mindfulness was measured before and after the intervention, and relationships were explored between mindfulness, disability, affect and pain catastrophizing. Mindfulness increased following participation in the intervention, and greater mindfulness was predictive of lower levels of disability, anxiety, depression and catastrophizing, even when pain severity was controlled. Mediator analyses suggested that the relationship between mindfulness and disability was mediated by catastrophizing. It is possible that cognitive-behavioural interventions and processes can affect both catastrophizing and mindfulness.

Psychological adjustment to lower limb amputation amongst prosthesis users.

PURPOSE: Clinical reports indicate that many lower limb amputees experience problems with psychological adjustment. Although depressive responses to amputation have been well investigated, there has been insufficient attention to other aspects of adjustment. This study aimed to determine the prevalence of psychological morbidity in an amputee population and identify variables associated with increased distress. Particular attention was given to cognitive models of emotion which postulate a key role for self-consciousness and appearance-related beliefs. METHOD: A cross-sectional survey of 67 adult lower limb prosthesis users who had experienced amputation within the last five years. Outcome measures were the Psychosocial Adjustment Scale of the Trinity Amputation and Prosthesis Experience Scales, the Hospital Anxiety and Depression Scale, the Self Consciousness Scale and the Appearance Schemas Inventory. RESULTS: Using conservative cut-off scores the prevalence of anxiety and depression was 29.9 and 13.4%, respectively. Appearance-related beliefs were associated with both distress and psychosocial adjustment difficulties. Public but not private self-consciousness was associated with distress and psychosocial adjustment difficulties. CONCLUSIONS: Clinicians need to monitor amputees for distress over a longer time period than the initial post-operative phase. It is particularly important to assess for anxiety. Interventions that target appearance-related beliefs may be of benefit to this population.