ABSTRACT
Subject(s)
Community Health Workers , Pharmacies , Tuberculosis , Humans , Male , Female , Cross-Sectional Studies , Community Health Workers/organization & administration , Adult , Uganda , Middle Aged , Tuberculosis/drug therapy , Tuberculosis/diagnosis , Health Services Accessibility , Private Sector , Young Adult , Patient Acceptance of Health Care/statistics & numerical dataSubject(s)
Diabetes Mellitus , Tuberculosis , Adult , Humans , Comorbidity , Diabetes Mellitus/epidemiology , Uganda/epidemiology , Tuberculosis/epidemiologyABSTRACT
Clinical trials during public health emergencies of novel medical products such as therapeutics and vaccines in resource-limited settings are daunting due to the limited capacity for regulatory assessment. Regulating clinical trials during the Ebola outbreak in Sierra Leone required expedited evaluation to identify medical products that could be promptly introduced to combat the epidemic in the absence of approved treatment or prevention. This article explored the decisions taken by the Pharmacy Board of Sierra Leone through its Expert Committee on Medicine Safety and Clinical Trials regarding clinical trials oversight during the Ebola epidemic and the lessons learned. This independent expert committee assessed and provided scientific opinions to the Pharmacy Board of Sierra Leone to inform approval of all clinical trials within 10-15 working days. We also requested for assisted review from the African Vaccine Regulatory Forum and support from the US Food and Drug Administration through a unilateral recognition and reliance memorandum of understanding. In addition, the Agency-ensured structures and systems were in place for reporting and reviewing adverse events and serious adverse events, management of biological samples, submission and review of progress reports, and good clinical practice inspections. Unfortunately, the Ebola epidemic revealed many weaknesses in the country's clinical trials regulatory structure and processes. Government and partners should further offer more resources to build the clinical trial structures and systems so that the Agency will be better poised to handle future public health emergencies.
Subject(s)
Epidemics , Hemorrhagic Fever, Ebola , Emergencies , Epidemics/prevention & control , Hemorrhagic Fever, Ebola/diagnosis , Hemorrhagic Fever, Ebola/epidemiology , Hemorrhagic Fever, Ebola/therapy , Humans , Public Health , Sierra Leone/epidemiologyABSTRACT
Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD.
Subject(s)
Stress Disorders, Post-Traumatic , Adolescent , Child , Extinction, Psychological/physiology , Fear/physiology , Humans , Phobic Disorders , Reflex, Startle/physiology , UncertaintyABSTRACT
OBJECTIVE: 1) To determine the prevalence of diabetes mellitus and impaired fasting glucose (IFG) in patients with TB and HIV co-infection, and 2) to investigate the effect of fasting plasma glucose (FPG) on rifampicin (RIF) and isoniazid (INH) serum concentrations.DESIGN: Retrospective data analysis of a cohort of HIV-infected adults with newly diagnosed pulmonary TB. Plasma glucose and TB drug levels were obtained at Week 0, 2, 8 and 24 of TB treatment.RESULTS: A total of 107 patients were included in this analysis. Random plasma glucose ≥200 mg/dL was found in 1/53 (2%) participant at Week 0. The prevalence of FPG ≥ 126 mg/dL decreased from 8/41 (20%) at Week 2 to 3/89 (3%) at Week 24. IFG (100-125 mg/dL) was observed in 23/41 (56%) participants at Week 2, and 39/89 (44%) at Week 24. FPG was inversely correlated with lower area under the curve (AUC0-24h) for RIF (c = -0.52; 95%CI -0.84 to -0.21; P = 0.001). FPG was not associated with lower INH AUC0-24h.CONCLUSION: We found a high prevalence of FPG ≥ 126 mg/dL, which decreased significantly during treatment, and a high proportion of IFG at the end of TB treatment. Higher FPG was associated with lower AUC for RIF.
Subject(s)
HIV Infections , Hyperglycemia , Isoniazid , Rifampin , Tuberculosis , Adult , Humans , Blood Glucose , Coinfection/epidemiology , Fasting , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Hyperglycemia/epidemiology , Isoniazid/pharmacokinetics , Retrospective Studies , Rifampin/pharmacokinetics , Uganda/epidemiology , Tuberculosis/drug therapyABSTRACT
Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.
Subject(s)
Developing Countries , Drug Costs , Drug Approval , Drug DevelopmentABSTRACT
Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10-2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91-2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66-2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41-3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.
Subject(s)
Pharmaceutical Preparations , Tuberculosis , Adult , Antitubercular Agents/therapeutic use , Case-Control Studies , Humans , Isoniazid , Observational Studies as Topic , Pyrazinamide , Retrospective Studies , Treatment Outcome , Tuberculosis/drug therapyABSTRACT
Few low and middle-income countries (LMIC) have fully operational pharmacovigilance structures, systems and legal framework to collect and collate safety data and evaluate the risks and benefits by active and passive approaches. However, in a LMIC such as Sierra Leone, the capacity to manage the risks by taking appropriate preventative actions to help inform therapeutic decisions, promote rational use of medicines, guide risk management and communications is gradually growing but yet to be fully optimized. This study sought to assess the current status of pharmacovigilance in Sierra Leone since it became the 87th member of the World Health Organisation International Drug Monitoring Programme. This study evaluated the pharmacovigilance system in Sierra Leone through a comprehensive and system-based approach that covered the national medicines regulatory authority, health facilities and public health programmes. A descriptive cross-sectional study design was employed. Using a convenience sampling method, 14 respondents from the national medicines regulatory authority, six health facilities and six public health programmes were interviewed. Data were collected using a validated metric instrument: Indicator-Based Pharmacovigilance Assessment Tool. A scoring system was used for the quantification of assessment results with a score greater than 60% indicating that an organization has structural and policy frameworks to collect and collate safety data in a national database and evaluate the risks and benefits by both active and passive approaches. The study findings showed that the national medicines regulatory authority scored 79% and thus met the standard requirements of pharmacovigilance. On the other hand, the health facilities and public health programmes scored less than 60% indicating the need to fully operationalise pharmacovigilance frameworks at these levels. The study further demonstrated that the national medicine regulatory authority which hosts the national pharmacovigilance centre had functional pharmacovigilance structures and processes with potential to providing leadership in the implementation of pharmacovigilance in Sierra Leone.
ABSTRACT
Subject(s)
Anti-HIV Agents/administration & dosage , Antitubercular Agents/administration & dosage , HIV Infections/drug therapy , Tuberculosis/drug therapy , Adult , CD4 Lymphocyte Count , Coinfection , Delivery of Health Care, Integrated/organization & administration , Female , HIV Infections/epidemiology , HIV Infections/mortality , Humans , Lost to Follow-Up , Male , Retrospective Studies , Treatment Outcome , Tuberculosis/epidemiology , Tuberculosis/mortality , UgandaABSTRACT
OBJECTIVES: The aim of the study was to clarify how HIV infection affects tuberculosis liquid and solid culture results in a resource-limited setting. METHODS: We used baseline data from the Study on Outcomes Related to Tuberculosis and HIV Drug Concentrations in Uganda (SOUTH), which included 268 HIV/tuberculosis (TB)-coinfected individuals. Culture results from Löwenstein-Jensen (LJ) solid culture and mycobacteria growth indicator tube (MGIT) liquid culture systems and culture-based correlates for bacillary density from the sputum of HIV/TB-coinfected individuals at baseline were analysed. RESULTS: Of 268 participants, 243 had a CD4 cell count available and were included in this analysis; 72.2% of cultures showed growth on solid culture and 82.2% in liquid culture systems (P < 0.015). A higher CD4 cell count was predictive of LJ positivity [adjusted odds ratio (OR) 1.14; 95% confidence interval (CI) 1.03-1.25 per 50 cells/µL increase; P = 0.008]. The same, but insignificant trend was observed for MGIT positivity (adjusted OR 1.09; 95% CI 0.99-1.211 per 50 cells/µL increase; P = 0.094). A higher CD4 cell count was associated with a higher LJ colony-forming unit grade (adjusted OR 1.14; 95% CI 1.05-1.25 per 50 cells/µL increase; P = 0.011) and a shorter time to MGIT positivity [adjusted hazard ratio (HR) 1.08; 95% CI 1.04-1.12 per 50 cells/µL increase; P < 0.001]. CONCLUSIONS: In a resource-limited setting, the MGIT liquid culture system outperformed LJ solid culture in terms of culture yield and dependence on CD4 cell counts in HIV/TB-coinfected individuals. We therefore suggest considering an adaptation of diagnostic algorithms: when resources allow only one culture method to be performed, we recommend that MGIT liquid culture should be used exclusively in HIV-positive individuals as a first-line culture method, to reduce costs and make TB culture results accessible to more patients in resource-limited settings.
Subject(s)
Bacteriological Techniques/methods , HIV Infections/microbiology , Mycobacterium tuberculosis/growth & development , Tuberculosis/diagnosis , Adult , CD4 Lymphocyte Count , Developing Countries , Diagnostic Tests, Routine , Female , HIV Infections/immunology , Humans , Male , Mycobacterium tuberculosis/isolation & purification , Socioeconomic Factors , UgandaABSTRACT
OBJECTIVE: To evaluate the feasibility of Deep Learning-based detection and classification of pathological patterns in a set of digital photographs of chest X-ray (CXR) images of tuberculosis (TB) patients. MATERIALS AND METHODS: In this prospective, observational study, patients with previously diagnosed TB were enrolled. Photographs of their CXRs were taken using a consumer-grade digital still camera. The images were stratified by pathological patterns into classes: cavity, consolidation, effusion, interstitial changes, miliary pattern or normal examination. Image analysis was performed with commercially available Deep Learning software in two steps. Pathological areas were first localised; detected areas were then classified. Detection was assessed using receiver operating characteristics (ROC) analysis, and classification using a confusion matrix. RESULTS: The study cohort was 138 patients with human immunodeficiency virus (HIV) and TB co-infection (median age 34 years, IQR 28-40); 54 patients were female. Localisation of pathological areas was excellent (area under the ROC curve 0.82). The software could perfectly distinguish pleural effusions from intraparenchymal changes. The most frequent misclassifications were consolidations as cavitations, and miliary patterns as interstitial patterns (and vice versa). CONCLUSION: Deep Learning analysis of CXR photographs is a promising tool. Further efforts are needed to build larger, high-quality data sets to achieve better diagnostic performance.
Subject(s)
Coinfection/diagnostic imaging , Deep Learning , HIV Infections/diagnostic imaging , Radiography, Thoracic/methods , Tuberculosis, Pulmonary/diagnostic imaging , Adult , Feasibility Studies , Female , Humans , Male , Predictive Value of Tests , Prospective Studies , ROC Curve , Radiography, Thoracic/instrumentation , Software , Teleradiology , UgandaABSTRACT
Background: Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients. Objectives: To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients. Methods: TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations. Results: Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) µg/mL, 7.39 (IQR 5.10-10.20) µg/mL, 7.00 (IQR 6.05-10.95) µg/mL and 3.86 (IQR 2.81-14.24) µg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P = 0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) µg/mL and those who did not 2.21 (1.45-3.11) µg/mL ( P = 0.49). Conclusions: There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.
Subject(s)
Antitubercular Agents/adverse effects , Antitubercular Agents/blood , Coinfection/microbiology , Coinfection/virology , Tuberculosis/drug therapy , Adult , Antitubercular Agents/therapeutic use , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Coinfection/drug therapy , Coinfection/epidemiology , Female , HIV Infections/complications , HIV Infections/epidemiology , Humans , Isoniazid/administration & dosage , Isoniazid/adverse effects , Isoniazid/therapeutic use , Male , Middle Aged , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/etiology , Prospective Studies , Regression Analysis , Rifampin/adverse effects , Rifampin/blood , Rifampin/therapeutic use , Tuberculosis/complications , Tuberculosis/epidemiology , Tuberculosis/microbiology , Tuberculosis, Pulmonary/drug therapy , Young AdultABSTRACT
Environment-friendly farming techniques seek to increase invertebrate biodiversity in part with the intention of encouraging greater numbers of predators that will help to control crop pests. However, in theory, this effect may be negated if the availability of a greater abundance and diversity of alternative prey diverts predators away from feeding on pests. The hypothesis that access to alternative prey can lead to reduced pest suppression under semi-field conditions was tested. Alternative prey type and diversity were manipulated in 70 mesocosms over 7+ weeks in the presence of the carabid Pterostichus melanarius (Illiger), a known predator of slugs, and reproducing populations of the slug Deroceras reticulatum (Müller). Significantly fewer slugs survived where no alternative prey were provided. Maximum slug numbers and biomass were found in treatments containing either carabids plus a high diversity of alternative prey (many species of earthworm and three of Diptera larvae) or a single additional prey (blowfly larvae, Calliphora vomitoria Linnaeus). In these treatments slug numbers and biomass were as high as in plots lacking predators. The effects of alternative prey were taxon-specific. Alternative prey strongly affected carabid fitness in terms of biomass and egg load. The fittest predators (those with access to high alternative prey diversity or C. vomitoria larvae) reduced slug numbers the least. The mean individual slug weights were greater in treatments with alternative prey than where no alternative prey were provided to the carabids. These results suggest that pests may survive and reproduce more rapidly in patches where predators have access to alternative prey.
Subject(s)
Coleoptera/physiology , Ecosystem , Gastropoda , Pest Control, Biological/methods , Predatory Behavior , Animals , Body SizeABSTRACT
BACKGROUND: Plasma D-dimer measurement is a widely used diagnostic test for assessing individuals with suspected venous thromboembolism (VTE). Whilst a negative test is helpful in ruling out thrombosis, the significance and determinants of an elevated plasma D-dimer level in otherwise healthy subjects are poorly understood. OBJECTIVES: To determine the association between recognized risk factors for VTE and plasma D-dimer levels in an adult population. SUBJECTS AND METHODS: Blood samples for measurement of plasma D-dimer levels were obtained from 1000 adults aged <70 years who were participating in a study investigating the incidence of VTE in long distance air travellers. The relationship between D-dimer levels and selected risks factors for VTE including thrombophilia status was investigated. RESULTS: The median (Inter-quartile range) D-dimer level was 243 ng mL(-1) (175-345). Multivariate analysis showed that plasma D-dimer levels were positively associated with increasing age, larger body mass index, female gender, the use of hormone therapy, thrombophilia state, and the presence of co-morbid conditions. CONCLUSION: Plasma D-dimer levels vary markedly between individuals and are associated with known risk factors for VTE, including the presence of thrombophilia conditions. The potential role for the measurement of plasma D-dimer as a marker for thrombosis risk requires further investigation.
Subject(s)
Fibrin Fibrinogen Degradation Products/analysis , Thromboembolism/blood , Venous Thrombosis/blood , Age Factors , Body Mass Index , Female , Humans , Incidence , Male , New Zealand , Risk Factors , Sex Factors , Thromboembolism/diagnosis , Thromboembolism/epidemiology , Travel , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiologyABSTRACT
The JNK (c-Jun N-terminal kinase) pathway is activated by diverse stresses and can have an effect on a number of different cellular processes. Protein-protein interactions are critical for efficient signalling from JNK to multiple targets; through a screen for interacting proteins, we identified a novel JNK-interacting protein, Sab (SH3BP5). Sab has previously been found to interact with the Src homology 3 domain of Bruton's tyrosine kinase; however, the interaction with JNK occurs through a mitogen-activated protein KIM (kinase interaction motif) in a region distinct from the Bruton's tyrosine kinase-binding domain. As with c-Jun, the presence of this KIM is essential for Sab to act as a JNK substrate. Interestingly, Sab is associated with the mitochondria and co-localizes with a portion of active JNK after stress treatment. The present study and previously reported work may suggest a possible role for Sab in targeting JNK to this subcellular compartment and/or mediating crosstalk between different signal-transduction pathways.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Mitochondria/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Animals , Chick Embryo , Kinetics , MAP Kinase Kinase 4 , Oxidative Stress , Phosphoproteins/metabolism , Protein Binding , src Homology DomainsABSTRACT
Phyllodecta (= Phratora) vulgatissima and P. vitellinae (Coleoptera: Chrysomelidae) are important pests of willows and poplars. Their differences in host species preference may provide a non-chemical control strategy for pest control. However, little is known about population structure with respect to hosts, regions or seasons. Using five microsatellites, 850 P. vulgatissima and 1100 P. vitellinae individuals, comprising 17 and 22 UK samples, respectively, were genotyped. High diversity was observed at all loci. Migrant numbers exchanged per generation (Nm) were high (2.1-12.6 for P. vulgatissima and 0.9-12.2 for P. vitellinae), suggesting high genetic exchange between samples. Estimates of population differentiation (FST) and analyses of the data using Bayesian methods (Partition and Structure) showed little evidence of subdivision in relation to geography, sampling time or host.
Subject(s)
Coleoptera/genetics , Coleoptera/physiology , Genetic Variation , Genetics, Population , Salix , Animals , Bayes Theorem , Gene Frequency , Genotype , Geography , Microsatellite Repeats/genetics , Population Dynamics , United KingdomABSTRACT
OBJECTIVES: To summarize available knowledge about pharmacologic treatments that are used for first-onset (or early) psychosis in youths, with particular consideration of the prodromal stage and the effectiveness and safety of novel antipsychotic drugs and mood stabilizers. METHOD: A computerized search of medical databases (for example, Medline and Embase), a manual searching of articles and textbooks, and the use of vignettes to highlight treatment issues. RESULTS: There are limited data about the effectiveness and safety of psychotropic agents for youths with psychosis and scarce information about the drug treatment of the prodromal stage of early psychosis in all age groups. The available data are encouraging, although the newer agents are not without safety concerns. CONCLUSIONS: Despite the paucity of studies, there is a range of psychotropics that may be used in the early stages of psychotic illness in youths. Drug choice is influenced by several factors, including the clinical picture, side effect profile, and patient preference. In certain situations, the decision may be not to use medication.