Efficacy and safety of praziquantel 40 mg/kg in preschool-aged and school-aged children: a meta-analysis

BACKGROUND: Children carry most of the schistosomiasis burden. While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited information on efficacy and safety exists for preschool-aged children. METHODS: Here, we conducted a meta-analysis of clinical trials of praziquantel for treating children with any form of schistosomiasis. Efficacy was reported as cure rate (CR) and egg reduction rates (ERR); statistical corrections were applied based on methodological disparities across trials to derive the predicted geometrical mean ERR (pERRgm). Safety was reported as frequencies of adverse events. RESULTS: Forty-seven comparative and non-comparative studies were identified, enrolling 15,549 children of whom 14,340 (92%) were assessed between 3 and 8 weeks post-treatment with praziquantel 40 mg/kg (the WHO-recommended treatment, n = 8,380, 56%) or comparators (n = 5,960, 44%). The median age was 10 years (range 1-19), 11% (n = 1,694) were preschool-aged. The CR and pERRgm with praziquantel 40 mg/kg were respectively: S. haematobium, 73.6% (95% CI: 63.5-81.40, 25 study arms) and 94.7% (95% CI: 92.7-96.4); S. mansoni, 76.4% (95% CI: 71.5-81.0, 34 arms) and 95.3% (95% CI: 94.2-96.2); S. mansoni/S. haematobium, 67.6% (95% CI: 54.1-80.7, 5 arms) and 93.4% (95% CI: 89.9-96.2); S. japonicum, 94.7% (95% CI: 92.2-98.0) and 98.7% (95% CI: 98.3-99.2). Mixed-effect multivariate analysis found no significant difference between preschool- and school-aged children for CR or pERRgm in S. haematobium (P = 0.309 and P = 0.490, respectively) or S. mansoni (P = 0.982 and P = 0.895) after controlling for time of assessment, formulation, intensity of infection and detection method. Praziquantel was reportedly safe at all ages, with only mild reported adverse events which cleared rapidly after treatment. CONCLUSIONS: Praziquantel 40 mg/kg was effective at reducing infection intensity in all Schistosoma species without differences between preschool- and school-aged children. However, conclusions should be tempered because of the limited number of preschool-aged children enrolled, disparities in study procedures and limited information made available in publications, as well as the current imperfect test-of-cure. Also, although reportedly well-tolerated, safety was inconsistently assessed. Studies in target groups, individual-data meta-analysis and standardised methodologies are needed for more robust evidence-base

Epidemiological Study of Landmines/ ERW Accidents and Victims in Kachin, Kayah, and Shan States, Burma

In Burma, there is no systematic and organized victim information system (VIS) of landmine and explosive remnants of war (ERW) victims, and few studies have been conducted on the topic, in particular in Kachin, Kayah, and Northern Shan States (NSS), where most of the accidents have recently occurred. Between 2015 and 2016, casualty reports compiled by the Mine Risk Working Group (MRWG) chaired by the Department of Social Welfare (DSW) showed that the number of mine/ERW victims increased by 58% in the country, particularly in Kachin and Shan States, while the number of victims decreased in Kayin State. Documenting victims’ profiles and risk behaviors are needed to help design victim assistance and mine risk education (MRE) programs. To collect this information, Danish Refugee Council/Danish Demining Group (DRC/DDG) conducted an epidemiological study in Kachin, Kayah, and NSS to analyze data collected about mine/ERW victims and accidents

Total quality management in the supply chain of a petrochemical organisation

Abstract: The objective was to investigate the extent of the use of total quality management (TQM) practices in a supply chain of a petrochemical organisation. TQM is a method by which management and employees can become involved in the continuous improvement of the production of goods and services. It is a combination of quality and management tools aimed at increasing business and reducing losses due to wasteful practices. The study was carried out in the petrochemical industry, which is of economic significance to the country. An existing TQM questionnaire was used and a total of 200 employees were targeted. The questionnaire had a seven-factor structure with acceptable Cronbach Alpha co-efficients. Overall, there was a significant number of employees who agree that total quality management is not practiced within their work areas and leading to a high number of quality related customer complaints. Management and employees are encouraged to be visibly involved in the development of a TQM transformation. TQM requires support from management, long-term strategic decision-making and motivated personnel

Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in Oral Squamous Cell Carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlation

One main etiology for oral squamous cell carcinoma (OSCC) is inflammation. Inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) are the important molecules showing close relation to not only inflammation but also carcinogenesis and angiogenesis. Angiogenesis is defined as the formation of new blood vessels from existing vasculature. It is necessary for tumor growth and progression and also involved in metastasis. The objective of this research was to study the expression and relationship among iNOS, VEGF, COX-2, angiogenesis and their clinico-pathological correlation in OSCC. In this study, standard indirect immunohistochemical technique using polyclonal antibodies specific to human iNOS, VEGF, COX-2 and CD31 was performed in formalin-fixed paraffin-embedded tissue sections of 66 OSCC samples. The staining patterns and intensity are measured and analyzed statistically. The results showed that epithelial components of squamous cell carcinomas demonstrated moderate to intense staining for iNOS, VEGF and COX-2. iNOS shows correlation with cervical lymph node metastasis and tumor staging (TNM) of the patients and angiogenesis.VEGF shows correlation with tumor grading, tumor staging and angiogenesis. COX-2 shows correlation with cervical lymph node metastasis. In conclusion, the expression of iNOS, VEGF and COX-2 exists in OSCC. The data provided show the expression of these chemical mediators associated with carcinogenesis and angiogenesis in OSCC. It can be the primary database before using angiogenesis drug against these mediators for OSCC treatment

Clinical tolerability of artesunate-amodiaquine versus comparator treatments for uncomplicated falciparum malaria: an individual-patient analysis of eight randomized controlled trials in sub-Saharan Africa

BACKGROUND: The widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability. METHODS: An individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28. RESULTS: Of the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments. CONCLUSION: ASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity

Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa.

BACKGROUND: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. METHODS: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. RESULTS: Eight thousand eight hundred ninety-seven patients (77.0% <5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5's had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 μl) than older subjects (2784 μl). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5's the estimated nadir was ~35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach +13.8% compared to baseline. Severe anaemia (<5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. CONCLUSION: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment

Considerations on the use of nucleic acid-based amplification for malaria parasite detection

<p>Abstract</p> <p>Background</p> <p>Nucleic acid amplification provides the most sensitive and accurate method to detect and identify pathogens. This is primarily useful for epidemiological investigations of malaria because the infections, often with two or more <it>Plasmodium </it>species present simultaneously, are frequently associated with microscopically sub-patent parasite levels and cryptic mixed infections. Numerous distinct equally adequate amplification-based protocols have been described, but it is unclear which to select for epidemiological surveys. Few comparative studies are available, and none that addresses the issue of inter-laboratory variability.</p> <p>Methods</p> <p>Blood samples were collected from patients attending malaria clinics on the Thai-Myanmar border. Frozen aliquots from 413 samples were tested independently in two laboratories by nested PCR assay. Dried blood spots on filter papers from the same patients were also tested by the nested PCR assay in one laboratory and by a multiplex PCR assay in another. The aim was to determine which protocol best detected parasites below the sensitivity level of microscopic examination.</p> <p>Results</p> <p>As expected PCR-based assays detected a substantial number of infected samples, or mixed infections, missed by microscopy (27 and 42 for the most sensitive assay, respectively). The protocol that was most effective at detecting these, in particular mixed infections, was a nested PCR assay with individual secondary reactions for each of the species initiated with a template directly purified from the blood sample. However, a lesser sensitivity in detection was observed when the same protocol was conducted in another laboratory, and this significantly altered the data obtained on the parasite species distribution.</p> <p>Conclusions</p> <p>The sensitivity of a given PCR assay varies between laboratories. Although, the variations are relatively minor, they primarily diminish the ability to detect low-level and mixed infections and are sufficient to obviate the main rationale to use PCR assays rather than microscopy or rapid diagnostic tests. The optimal approach to standardise methodologies is to provide PCR template standards. These will help researchers in different settings to ensure that the nucleic acid amplification protocols they wish to use provide the requisite level of sensitivity, and will permit comparison between sites.</p

Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology <it>vs </it>other anti-malarials is needed in view of potential safety liabilities.</p> <p>Methods</p> <p>Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.</p> <p>Results</p> <p>4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, <it>p </it>= 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.</p> <p>Conclusion</p> <p>The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.</p

Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis

BACKGROUND: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. METHODS AND FINDINGS: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). CONCLUSIONS: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3

Evaluation of commercially available diagnostic tests for the detection of dengue virus NS1 antigen and anti-dengue virus IgM antibody.

Commercially available diagnostic test kits for detection of dengue virus (DENV) non-structural protein 1 (NS1) and anti-DENV IgM were evaluated for their sensitivity and specificity and other performance characteristics by a diagnostic laboratory network developed by World Health Organization (WHO), the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the Pediatric Dengue Vaccine Initiative (PDVI). Each network laboratory contributed characterized serum specimens for the panels used in the evaluation. Microplate enzyme-linked immunosorbent assay (ELISA) and rapid diagnostic test (RDT formats) were represented by the kits. Each ELISA was evaluated by 2 laboratories and RDTs were evaluated by at least 3 laboratories. The reference tests for IgM anti-DENV were laboratory developed assays produced by the Armed Forces Research Institute for Medical Science (AFRIMS) and the Centers for Disease Control and Prevention (CDC), and the NS1 reference test was reverse transcriptase polymerase chain reaction (RT-PCR). Results were analyzed to determine sensitivity, specificity, inter-laboratory and inter-reader agreement, lot-to-lot variation and ease-of-use. NS1 ELISA sensitivity was 60-75% and specificity 71-80%; NS1 RDT sensitivity was 38-71% and specificity 76-80%; the IgM anti-DENV RDTs sensitivity was 30-96%, with a specificity of 86-92%, and IgM anti-DENV ELISA sensitivity was 96-98% and specificity 78-91%. NS1 tests were generally more sensitive in specimens from the acute phase of dengue and in primary DENV infection, whereas IgM anti-DENV tests were less sensitive in secondary DENV infections. The reproducibility of the NS1 RDTs ranged from 92-99% and the IgM anti-DENV RDTs from 88-94%