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Blood transfusion remains an important aspect of patient management in visceral leishmaniasis (VL). However, transfusion triggers considered are poorly understood. This review summarises the transfusion practices adopted in VL efficacy studies using the Infectious Diseases Data Observatory VL clinical trials library. Of the 160 studies (1980–2021) indexed in the IDDO VL library, description of blood transfusion was presented in 16 (10.0%) (n=3459 patients) studies. Transfusion was initiated solely based on haemoglobin (Hb) measurement in nine studies, combining Hb measurement with an additional condition (epistaxis/poor health/clinical instability) in three studies and the criteria was not mentioned in four studies. The Hb threshold range for triggering transfusion was 3–8 g/dL. The number of patients receiving transfusion was explicitly reported in 10 studies (2421 patients enrolled, 217 underwent transfusion). The median proportion of patients who received transfusion in a study was 8.0% (Interquartile range: 4.7% to 47.2%; range: 0–100%; n=10 studies). Of the 217 patients requiring transfusion, 58 occurred before VL treatment initiation, 46 during the treatment/follow-up phase and the time was not mentioned in 113. This review describes the variation in clinical practice and is an important initial step in policy/guideline development, where both the patient's Hb concentration and clinical status must be considered. [ABSTRACT FROM AUTHOR]

Background: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy.Methods: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected.Results: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.Conclusions: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP. [ABSTRACT FROM AUTHOR]

Background: Artemisinin resistance in falciparum malaria is associated with kelch13 propeller mutations, reduced ring stage parasite killing, and, consequently, slow parasite clearance. We assessed how parasite age affects parasite clearance in artemisinin resistance.Methods: Developmental stages of Plasmodium falciparum parasites on blood films performed at hospital admission and their kelch13 genotypes were assessed for 816 patients enrolled in a multinational clinical trial of artemisinin combination therapy.Results: Early changes in parasitemia level (ie, 0-6 hours after admission) were determined mainly by modal stage of asexual parasite development, whereas the subsequent log-linear decline was determined mainly by kelch13 propeller mutations. Older circulating parasites on admission were associated with more-rapid parasite clearance, particularly in kelch13 mutant infections. The geometric mean parasite clearance half-life decreased by 11.6% (95% CI 3.4%-19.1%) in kelch13 wild-type infections and by 30% (95% CI 17.8%-40.4%) in kelch13 mutant infections as the mean age of circulating parasites rose from 3 to 21 hours.Conclusion: Following the start of antimalarial treatment, ongoing parasite sequestration and schizogony both affect initial changes in parasitemia. The greater dependency of parasite clearance half-life on parasite age in artemisinin resistant infections is consistent with ring stage resistance and consequent parasite clearance by sequestration. The stage of parasite development should be incorporated in individual assessments of artemisinin resistance. [ABSTRACT FROM AUTHOR]

Motivation Fingerprints (FPs) are the most common small molecule representation in cheminformatics. There are a wide variety of FPs, and the Extended Connectivity Fingerprint (ECFP) is one of the best-suited for general applications. Despite the overall FP abundance, only a few FPs represent the 3D structure of the molecule, and hardly any encode protein–ligand interactions. Results Here, we present a Protein–Ligand Extended Connectivity (PLEC) FP that implicitly encodes protein–ligand interactions by pairing the ECFP environments from the ligand and the protein. PLEC FPs were used to construct different machine learning models tailored for predicting protein–ligand affinities (pKi∕ d ). Even the simplest linear model built on the PLEC FP achieved Rp  = 0.817 on the Protein Databank (PDB) bind v2016 'core set', demonstrating its descriptive power. Availability and implementation The PLEC FP has been implemented in the Open Drug Discovery Toolkit (https://github.com/oddt/oddt). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Structure based ligand discovery is one of the most successful approaches for augmenting the drug discovery process. Currently, there is a notable shift towards machine learning (ML) methodologies to aid such procedures. Deep learning has recently gained considerable attention as it allows the model to 'learn' to extract features that are relevant for the task at hand. Results We have developed a novel deep neural network estimating the binding affinity of ligand–receptor complexes. The complex is represented with a 3D grid, and the model utilizes a 3D convolution to produce a feature map of this representation, treating the atoms of both proteins and ligands in the same manner. Our network was tested on the CASF-2013 'scoring power' benchmark and Astex Diverse Set and outperformed classical scoring functions. Availability and implementation The model, together with usage instructions and examples, is available as a git repository at http://gitlab.com/cheminfIBB/pafnucy. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) shape genomes via recombination and transposition, lead to chromosomal rearrangements, create new gene neighborhoods, and alter gene expression. They play key roles in adaptation either to symbiosis in Amanita genus or to pathogenicity in Pyrenophora tritici-repentis. Despite growing evidence of their importance, the abundance and distribution of mobile elements replicating in a "cut-and-paste" fashion is barely described so far. In order to improve our knowledge on this old and ubiquitous class of transposable elements, 1,730 fungal genomes were scanned using both de novo and homology-based approaches. DNA TEs have been identified across the whole data set and display uneven distribution from both DNA TE classification and fungal taxonomy perspectives. DNA TE content correlates with genome size, which confirms that many transposon families proliferate simultaneously. In contrast, it is independent from intron density, average gene distance and GC content. TE count is associated with species' lifestyle and tends to be elevated in plant symbionts and decreased in animal parasites. Lastly, we found that fungi with both RIP and RNAi systems have more total DNA TE sequences but less elements retaining a functional transposase, what reflects stringent control over transposition. [ABSTRACT FROM AUTHOR]

Study Question: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)?Summary Answer: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE.What Is Known Already: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE.Study Design, Size, Duration: International expert consensus based on a systematic review of literature.Participants/materials, Setting, Methods: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings.Main Results and the Role Of Chance: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE.Limitations, Reasons For Caution: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here.Wider Implications Of the Findings: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population.Study Funding/competing Interests: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Asymptomatic parasitemia is common even in areas of low seasonal malaria transmission, but the true proportion of the population infected has not been estimated previously because of the limited sensitivity of available detection methods.Methods: Cross-sectional malaria surveys were conducted in areas of low seasonal transmission along the border between eastern Myanmar and northwestern Thailand and in western Cambodia. DNA was quantitated by an ultrasensitive polymerase chain reaction (uPCR) assay (limit of accurate detection, 22 parasites/mL) to characterize parasite density distributions for Plasmodium falciparum and Plasmodium vivax, and the proportions of undetected infections were imputed.Results: The prevalence of asymptomatic malaria as determined by uPCR was 27.5% (1303 of 4740 people tested). Both P. vivax and P. falciparum density distributions were unimodal and log normal, with modal values well within the quantifiable range. The estimated proportions of all parasitemic individuals identified by uPCR were >70% among individuals infected with P. falciparum and >85% among those infected with P. vivax. Overall, 83% of infections were predicted to be P. vivax infections, 13% were predicted to be P. falciparum infections, and 4% were predicted to be mixed infections. Geometric mean parasite densities were similar; 5601 P. vivax parasites/mL and 5158 P. falciparum parasites/mL.Conclusions: This uPCR method identified most infected individuals in malaria-endemic areas. Malaria parasitemia persists in humans at levels that optimize the probability of generating transmissible gametocyte densities without causing illness. [ABSTRACT FROM AUTHOR]

We present a principled technique for estimating the effect of covariates on malaria parasite clearance rates in the presence of 'lag' and 'tail' phases through the use of a Bayesian hierarchical linear model. The hierarchical approach enables us to appropriately incorporate the uncertainty in both estimating clearance rates in patients and assessing the potential impact of covariates on these rates into the posterior intervals generated for the parameters associated with each covariate. Furthermore, it permits us to incorporate information about individuals for whom there exists only one observation time before censoring, which alleviates a systematic bias affecting inference when these individuals are excluded. We use a changepoint model to account for both lag and tail phases, and hence base our estimation of the parasite clearance rate only on observations within the decay phase. The Bayesian approach allows us to treat the delineation between lag, decay, and tail phases within an individual's clearance profile as themselves being random variables, thus taking into account the additional uncertainty of boundaries between phases. We compare our method to existing methodology used in the antimalarial research community through a simulation study and show that it possesses desirable frequentist properties for conducting inference. We use our methodology to measure the impact of several covariates on Plasmodium falciparum clearance rate data collected in 2009 and 2010. Though our method was developed with this application in mind, it can be easily applied to any biological system exhibiting these hindrances to estimation. [ABSTRACT FROM AUTHOR]

Accurate measurement of malaria parasite clearance rates (CRs) following artemisinin (ART) treatment is critical for resistance surveillance and research, and various CR metrics are currently used. We measured 13 CR metrics in 1472 ART-treated hyperparasitemia infections for which 6-hour parasite counts and parasite genotypes (93 single nucleotide polymorphisms [SNPs]) were available. We used heritability to evaluate the performance of each metric. Heritability ranged from 0.06 ± 0.06 (SD) for 50% parasite clearance times to 0.67 ± 0.04 (SD) for clearance half-lives estimated from 6-hour parasite counts. These results identify the measures that should be avoided and show that reliable clearance measures can be obtained with abbreviated monitoring protocols. [ABSTRACT FROM AUTHOR]

Background. Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced.Methods. We treated P. falciparum malaria in 215 Malian children aged 0.5–15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite density every 6 hours until undetectable and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half-life. We quantified the proportion of parasitized RBCs recognized by autologous immunoglobulin G (IgG).Results. The geometric mean half-life was 1.9 hours (95% confidence interval, 1.8–2.0) and did not correlate with parasite ex vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half-life (r = −0.475; P = .0006).Conclusions. Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity and correlates of parasite-clearing immunity have not been identified.Clinical Trials Registration. NCT00669084. [ABSTRACT FROM AUTHOR]

Objectives Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks. Methods We conducted a parallel group, double blind, 2 (active drug) :1 (placebo) randomized trial of oral oseltamivir/placebo or inhaled zanamivir/placebo over 16 weeks in healthy, Thai hospital professionals at two Bangkok hospitals. The primary endpoint was study withdrawal due to drug-related (possibly, probably, definitely) serious or adverse events (AEs) graded ≥2. Results Recruited subjects numbered 129 oseltamivir/65 placebo and 131 zanamivir/65 placebo. A total of 102 grade ≥2 AEs were reported or detected in 69 subjects: 23/129 (17.8%) versus 15/65 (23.1%) (P = 0.26), and 23/131 (17.6%) versus 8/65 (12.3%) (P = 0.28). Intercurrent infections/fevers [26/102 (25.5%)], abnormal biochemistry [25/102 (24.5%)] and gastrointestinal symptoms [18/102 (17.6%)] were the most frequently reported AEs. There were no drug-related study withdrawals. Eight serious AEs were all due to intercurrent illnesses. Laboratory, lung function and ECG parameters were similar between drugs and placebos. Conclusions Oseltamivir and zanamivir were well tolerated in healthy hospital professionals. Both drugs can be recommended for primary influenza prophylaxis for up to 16 weeks. [ABSTRACT FROM PUBLISHER]

Background: Ureteral endometriosis is a rare entity that may lead to progressive hydroureteronephrosis and renal loss. When the localization of ureteral stenosis is close to the ureterovesical junction, ureterocystoneostomy may be required. The aim of the present study was to evaluate post-operative complication rates and clinical outcomes at 1- and 6-month follow-up after laparoscopic ureterocystoneostomy. Method: Twenty patients who underwent ureterocystoneostomy for pelvic endometriosis in our tertiary referral centre for endoscopic surgery during 1 year were studied. A cystography was performed on Day 7 after surgery to verify the integrity of anastomosis and a satisfactory bladder capacity. Follow-up consisted of gynaecological examination and transvaginal ultrasound at 1 and 6 months after surgery. At 6 months, urography and cystography were also performed. Measurements included results of a pre-operative clinical and instrumental assessment, intra- and post-operative complications, post-operative bladder capacity at cystography and improvement of pain, using a visual analogue scale for the main symptoms related to endometriosis and uro-specific pain. Results: Neither a case of ureteral fistula nor other complications requiring re-intervention were reported. Post-operative transient deficit of bladder voiding occurred in five cases (25%), urinary infection in one and post-operative pyrexia in four (20%) patients. The median time to resuming voiding function was 3 days (range 1-20 days). In six cases, a mild vesico-ureteral reflux at the operated side was observed at 7-day cystography. Post-operative symptomatology was improved significantly (P<0.05) for all symptoms. Urography and cystography performed at 6 months confirmed good post-operative reconstructions in all cases. Conclusions: The objective of surgical treatment of ureteral endometriosis is to remove the stenotic tract and to preserve renal function. In cases of intrinsic ureteral endometriosis, the procedure of laparoscopic ureterocystoneostomy is feasible and has good outcomes at short- and medium-term follow-up. [ABSTRACT FROM AUTHOR]

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/mL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24. [ABSTRACT FROM AUTHOR]

Background. Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint. Methods. We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses. Results. The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-γ levels. Conclusions. The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention. [ABSTRACT FROM AUTHOR]

Background. Recurrent melioidosis occurs in ~6% of patients in the first year following the initial presentation. A recent study revealed that 25% of patients with recurrence had reinfection rather than a relapse resulting from a failure to cure. The aim of this study was to reevaluate these 2 patient groups to define their individual risk factors. Methods. All adult patients who presented to Sappasithiprasong Hospital (Ubon Ratchathani, in northeast Thailand) with culture-confirmed melioidosis during the period 1986-2004 and who survived to receive oral antimicrobial therapy were observed until July 2005. Clinical factors and antimicrobial treatment of patients with recurrent disease due to relapse or reinfection, as confirmed by bacterial genotyping, were compared using a time-varying Cox proportional hazard model. Results. Of 889 patients who survived and underwent follow-up, 86 patients (9.7%) presented with relapse, and 30 patients (3.4%) became reinfected. There was no difference in acute outcome between the relapse and reinfection groups. No risk factors for reinfection were identified. Multivariate analyses identified choice and duration of oral antimicrobial therapy as the most important determinants of relapse, followed by positive blood culture result (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.18-2.92) and multifocal distribution (HR, 1.95; 95% CI, 1.03-3.67). Patients treated with an appropriate oral antibiotic regimen for 12-16 weeks had a 90% decreased risk of relapse (HR, 0.10; 95% CI, 0.02-0.44), compared with patients who were treated for ⩽8 weeks. Trimethoprim-sulfamethoxazole plus doxycycline was an effective oral therapy. Conclusions. This study highlights clinical factors associated with an increased likelihood of relapse and provides evidence for optimal oral antimicrobial therapy. [ABSTRACT FROM AUTHOR]

Background. Tuberculous meningitis occurs more commonly in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals, but whether HIV infection alters the presentation and outcome of tuberculous meningitis is unknown. Methods. We performed a prospective comparison of the presenting clinical features and response to treatment in 528 adults treated consecutively for tuberculous meningitis (96 were infected with HIV and 432 were uninfected with HIV) in 2 tertiary-care referral hospitals in Ho Chi Minh City, Vietnam. Logistic regression was used to model variables associated independently with HIV infection, 9-month survival, and the likelihood of having a relapse or an adverse drug event. Kaplan-Meier estimates were used to compare survival rates and times to fever clearance, coma clearance, relapse, and adverse events. Results. HIV infection did not alter the neurological presentation of tuberculous meningitis, although additional extrapulmonary tuberculosis was more likely to occur in HIV-infected patients. The 9-month survival rate was significantly decreased in HIV-infected patients (relative risk of death from any cause, 2.91 [95% confidence interval, 2.14-3.96]; P<.001), although the times to fever clearance and coma clearance and the number or timing of relapses or adverse drug events were not significantly different between the groups. Conclusions. HIV infection does not alter the neurological features of tuberculous meningitis but significantly reduces the survival rate. [ABSTRACT FROM AUTHOR]

Background. Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime mono-therapy. It is not known whether TMP-SMX provides an additional benefit. Methods. Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta- analysis. The primary end point was in-hospital mortality rate. Results. The in-hospital mortality rate among all enrolled patients (n = 449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P = .73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died ⩾48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P = .70) or for deaths that occurred ⩾48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P = .73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model. Conclusion. We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate. [ABSTRACT FROM AUTHOR]

Background. Tuberculous meningitis (TBM) caused by Myco bacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain. Methods. We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms. Results. Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21- 26.32]) and was independently associated with human immunodeficiency virus infection. Conclusions. Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death. [ABSTRACT FROM AUTHOR]

The relationship of the platelet-mediated autoagglutination of Plasmodium falciparum-infected red blood cells (IRBCs) to disease severity was investigated in 182 Thai patients with falciparum malaria; it was evident in 43% of uncomplicated malaria (n = 63), 41% of severe malaria (n = 104), and 100% of cerebral malaria (n = 15; P = .001) isolates. The median (range) number of IRBCs in agglutinates per 1000 IRBCs was significantly higher in cerebral malaria (6 [3-42]) than in severe (0 [0-52]) and uncomplicated (0 [0-24]) malaria (P = .01). In multivariate analyses, high parasitemia and cerebral malaria were associated independently with parasite agglutination. [ABSTRACT FROM AUTHOR]

Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit, > 30% (hazard ratio = 1.5, 95% CI 1.2–2, P = 0.001) and recent (⋜ 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P= 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy. [Copyright &y& Elsevier]

The pathophysiological basis of hemorrhage in dengue infections remains poorly understood, despite the increasing global importance of these infections. A large prospective study of 167 Vietnamese children with dengue shock syndrome documented only minor prolongations of prothrombin and partial thromboplastin times but moderate to severe depression of plasma fibrinogen concentrations. A detailed study of 48 children revealed low plasma concentrations of the anticoagulant proteins C, S, and antithrombin III, which decreased with increasing severity of shock, probably because of capillary leakage. Concurrent increases in the levels of thrombomodulin, tissue factor, and plasminogen activator inhibitor type 1 (PAI-1) indicated increased production of these proteins. Thrombomodulin levels suggestive of endothelial activation correlated with increasing shock severity, whereas PAI-1 levels correlated with bleeding severity. Dengue virus can directly activate plasminogen in vitro. Rather than causing true disseminated intravascular coagulation, dengue infection may activate fibrinolysis primarily, degrading fibrinogen directly and prompting secondary activation of procoagulant homeostatic mechanisms. [ABSTRACT FROM AUTHOR]

New treatment strategies are needed for artemisinin-resistant falciparum malaria. This randomized trial shows that neither increasing nor splitting the standard once-daily artesunate dose reverses the markedly reduced parasite clearance rate in patients with artemisinin-resistant falciparum malaria.Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.Methods. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009–2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.Results. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89–7.28) hours in Pailin versus 3.42 (2.20–4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum.Clinical Trials Registration. ISRCTN15351875. [ABSTRACT FROM PUBLISHER]

BACKGROUND The purpose of the study was to determine the influence of bowel endometriosis on fertility, and to study whether its removal improves fecundity in women with endometriosis-associated infertility. METHODS Three groups of infertile patients were included in the study. Group A (60 women) consisted of patients who underwent surgery for endometriosis with colorectal segmental resection. In group B, 40 patients with evidence of bowel endometriosis underwent endometriosis removal without bowel resection. Group C consisted of 55 women who underwent surgery for moderate or severe endometriosis with at least one endometrioma and deep infiltrating endometriosis but without bowel involvement. The women were clinically evaluated before laparoscopy and then at 1 month, at 6 months and at each year up to 4 years after surgery. Main outcome measures were surgical complications as well as post-operative pregnancy rate, time to conception and monthly fecundity rate. RESULTS The monthly fecundity rates (MFR) in groups A, B and C were 2.3, 0.84 and 3.95%, respectively. The difference in the MFR between groups was significant (P CONCLUSIONS The presence of bowel infiltration by endometriosis seems to negatively influence the reproductive outcome in women with endometriosis-associated infertility. The complete removal of endometriosis with bowel segmental resection seems to offer better results in terms of post-operative fertility. [ABSTRACT FROM AUTHOR]