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Objectives:The objectives of the study were to describe outcomes of children with uncomplicated severe acute malnutrition (SAM) attending community-based management of acute malnutrition (CMAM) treatment centres in Accra Metropolitan Area (AMA) and explore factors associated with non-adherence to clinic visits and defaulting from the treatment programme.Design:A retrospective cohort study analysing routinely collected data on children with uncomplicated SAM enrolled into CMAM in 2017 was conducted.Setting:Study was conducted at seven sites comprising Princess Marie Louise Children’s Hospital, three sub-metropolitan health facilities and three community centres, located in five sub-metropolitan areas in AMA.Participants:Children with uncomplicated SAM aged 6–59 months, enrolled from community-level facilities (pure uncomplicated SAM, PUSAM) or transferred after completing inpatient care (post-stabilisation uncomplicated SAM, PSSAM), participated in the study.Results:Out of 174 cases studied (105 PUSAM, sixty-nine PSSAM), 56·3 % defaulted, 34·5 % recovered and 8·6 % were not cured by 16 weeks. No deaths were recorded. Mid-upper arm circumference (MUAC) increased by 2·2 (95 % CI 1·8, 2·5) mm/week with full compliance and 0·9 (95 % CI 0·6, 1·2) mm/week with more than two missed visits. In breast-feeding children, MUAC increased at a slower rate than in other children by 1·3 (95 % CI 1·0, 1·5) mm/week. Independent predictors of subsequent missed visits were diarrhoea and fever, while children with MUAC < 110 mm on enrolment were at increased risk of defaulting.Conclusion:A high default rate and a long time to recovery are challenges for CMAM in AMA. Efforts must be made to improve adherence to treatment to improve outcomes.

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.

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Background In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections. Methods We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789. Findings Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57). Interpretation ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections. Funding Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.

Summary Background Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. Methods We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18–58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov , number NCT01864148 . Findings Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Interpretation Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Funding Biogen.

Microscopy of stained blood films is essential for the diagnosis of malaria, differentiation of parasite species, and estimation of parasite density performed for assessments of antimalarial drug efficacy. The accuracy and comparability of these measures over time and space are vital to discern the emergence or spread of antimalarial drug resistance. Although evidence-based guidelines for malaria microscopy methods exist, the age-old microscopy techniques for parasitological assessments are subject to considerable methodological variations. The purpose of this review was to explore critically how microscopy methods were reported in published malarial studies between 2013 and 2017 with the focus on outlining the methodological differences and improving reporting standards in practice.

Study question Is conservative laparoscopic treatment with RFA (radiofrequency thermal ablation) related to a good outcome on a long-term follow-up? Summary answer RFA for diffuse adenomyosis was related to a good outcome on a long-term follow-up in terms of pain and ultrasonographic reduction. What is known already Uterine adenomyosis may cause symptoms refractory to medical treatment. New, uterine-sparing treatments have been introduced for patients who desire avoiding hysterectomy. Among surgical techniques used for this purpose, radiofrequency thermal ablation (RFA) has been introduced, first for the treatment of uterine fibroids and then for focal adenomyosis. Diffuse adenomyosis is characterized by an extensive involvement of uterus, as on ultrasound less than 25% of the lesion is surrounded by healthy myometrium. It often leads to enhanced uterine volume, which presents soft consistence and globular aspect. Conservative treatment of diffuse adenomyosis is a real challenge. Study design, size, duration All consecutive patients who underwent RFA for diffuse adenomyosis in our institution between July 2011 and August 2017. Patients with focal adenomyosis were not included in the study. The treatment was reserved to selected patients who wanted to conserve the uterus and presented symptoms such as pain or abnormal uterine bleeding refractory to medical treatment. In all cases the treatment was performed by laparoscopy, which allowed for complete removal of extrauterine endometriosis, if associated. Participants/materials, setting, methods Nineteen patients (aged 33–49, mean 40) underwent radiofrequency thermal ablation for diffuse adenomyosis, and all of them completed the follow-up. Setting: referral center for endometriosis (Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally-Invasive Pelvic Surgery, International School of Surgical Anatomy, Negrar). Follow-up consisted on ambulatory clinical evaluation with pelvic ultrasound and assessment of pain using the visual analog scale (VAS) ranging from 0 to 10 points for all pain components. Main results and the role of chance: Endometriosis was associated in12 cases, (63%) and in all cases was removed completely during surgery. The mean follow-up was 64 months (range 29–105). Abnormal uterine bleeding was present in 11 (60%) patients before the treatment and only in four of them (21%) during the follow-up. Preoperative and postoperative mean VAS score for dysmenorrea, dyspareunia, dyschezia and chronic pelvic pain was 6.95 vs 3.7, 4.1 vs 1.4, 3.7 vs 0.9 and 3.9 vs 1.5 respectively (p Limitations, reasons for caution The present study reports outcome in a limited population as the treatment was reserved to selected cases. The results, particularly regarding fertility and pregnancy outcome should be taken with caution because of small numbers. In our opinion for the moment the treatment should be performed in selected cases. Wider implications of the findings: The present treatment could be performed to avoid hysterectomy, as it was necessary only in two cases in our study. No cases of hysterectomy were reported within the first two years from surgery, so we can consider that RFA allows at least a temporary benefit on symptoms. Trial registration number Not applicable

Background Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. Methodology/Principal findings A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. Conclusions/Significance Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance., Author summary Oral ivermectin is a safe and efficacious drug for the treatment of neglected tropical diseases. To date, ivermectin is not indicated in children weighing less than 15 kg because there have been insufficient safety data to support a change of recommendation. A PRISMA-level systematic review was conducted, and 97 potential sources were identified. All lead investigators were contacted to share individual patient data if they could provide the minimum criteria. These were the known weights of the children less than 15 kg in whom there were possible adverse events. A total of 17 investigators replied, sharing individual-level patient data (IPD) from 15 studies, which represent a database of 1,088 children weighing less than 15 kg treated with oral ivermectin. Overall 18 adverse events were reported in 1.4% (15/1,088) of children, all of which were mild and self-limiting. No serious adverse events were recorded. These data suggest that ivermectin is safe for use in children weighing less than 15 kilograms. Further data from well-designed clinical trials are needed to assess the safety of oral ivermectin at escalating doses in children weighing less than 15 kg.

Background Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). Methods For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. Results We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041–0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001–2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368–1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021–0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244–1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020–0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. Conclusion Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research., Author summary Visceral leishmaniasis, also known as Kala-Azar, is a neglected infectious disease of poverty affecting countries in the Indian Subcontinent and Eastern Africa. Existing treatments have concerning safety profiles and are far from ideal, with documented reports of serious adverse events (SAEs) following therapy. We did a systematic review of all published clinical trials in VL (1980–2019) to document SAEs following treatment administration reported in clinical literature and carried out a meta-analysis to quantify the incidence rate of mortality within 30 days of treatment initiation. We found that safety outcomes are poorly reported in published literature with substantial missing information regarding timing and frequency of the events. We also observed that mortality following treatment with antileishmanial drugs, as reported in the literature, is a rare event. There was substantial variability in mortality rates across geographical regions and patient sub-groups. Results from this review can provide benchmark estimates for comparing data from prospective trials and pharmacovigilance studies and support the need to assemble individual patient data (IPD) to conduct a robust IPD meta-analyses to overcome some of the underlying limitations.

Background Health workers’ compliance with outpatient malaria case-management guidelines has been improving in Africa. This study examined the factors associated with the improvements. Methods Data from 11 national, cross-sectional health facility surveys undertaken from 2010–2016 were analysed. Association between 31 determinants and improvement trends in five outpatient compliance outcomes were examined using interactions between each determinant and time in multilevel logistic regression models and reported as an adjusted odds ratio of annual trends (T-aOR). Results Among 9,173 febrile patients seen at 1,208 health facilities and by 1,538 health workers, a higher annual improvement trend in composite “test and treat” performance was associated with malaria endemicity-lake endemic (T-aOR = 1.67 annually; p25 febrile patients (T-aOR = 1.46; p = 0.003); and with under-five children compared to older patients (T-aOR = 1.07; p = 0.013). Other factors associated with the improvement trends in the “test and treat” policy components and artemether-lumefantrine administration at the facility included the absence of previous RDT stock-outs, community health workers dispensing drugs, access to malaria case-management and Integrated Management of Childhood Illness (IMCI) guidelines, health workers’ gender, correct health workers’ knowledge about the targeted malaria treatment policy, and patients’ main complaint of fever. The odds of compliance at the baseline were variable for some of the factors. Conclusions Targeting of low malaria risk areas, low caseload facilities, male and government health workers, continuous availability of RDTs, improving health workers’ knowledge about the policy considering age and fever, and dissemination of guidelines might improve compliance with malaria guidelines. For prompt treatment and administration of the first artemether-lumefantrine dose at the facility, task-shifting duties to community health workers can be considered.

Background Health workers' compliance with outpatient malaria case-management guidelines has been improving, specifically regarding the universal testing of suspected cases and the use of artemisinin-based combination therapy (ACT) only for positive results (i.e., ‘test and treat’). Whether the improvements in compliance with ‘test and treat’ guidelines are consistent across different malaria endemicity areas has not been examined. Methods Data from 11 national, cross-sectional, outpatient malaria case-management surveys undertaken in Kenya from 2010 to 2016 were analysed. Four primary indicators (i.e., ‘test and treat’) and eight secondary indicators of artemether-lumefantrine (AL) dosing, dispensing, and counselling were measured. Mixed logistic regression models were used to analyse the annual trends in compliance with the indicators across the different malaria endemicity areas (i.e., from highest to lowest risk being lake endemic, coast endemic, highland epidemic, semi-arid seasonal transmission, and low risk). Results Compliance with all four ‘test and treat’ indicators significantly increased in the area with the highest malaria risk (i.e., lake endemic) as follows: testing of febrile patients (OR = 1.71 annually; 95% CI = 1.51–1.93), AL treatment for test-positive patients (OR = 1.56; 95% CI = 1.26–1.92), no anti-malarial for test-negative patients (OR = 2.04; 95% CI = 1.65–2.54), and composite ‘test and treat’ compliance (OR = 1.80; 95% CI = 1.61–2.01). In the low risk areas, only compliance with test-negative results significantly increased (OR = 2.27; 95% CI = 1.61–3.19) while testing of febrile patients showed declining trends (OR = 0.89; 95% CI = 0.79–1.01). Administration of the first AL dose at the facility significantly increased in the areas of lake endemic (OR = 2.33; 95% CI = 1.76–3.10), coast endemic (OR = 5.02; 95% CI = 2.77–9.09) and semi-arid seasonal transmission (OR = 1.44; 95% CI = 1.02–2.04). In areas of the lowest risk of transmission and highland epidemic zone, none of the AL dosing, dispensing, and counselling tasks significantly changed over time. Conclusions There is variability in health workers' compliance with outpatient malaria case-management guidelines across different malaria-risk areas in Kenya. Major improvements in areas of the highest risk have not been seen in low-risk areas. Interventions to improve practices should be targeted geographically.

Background In the absence of definitive diagnosis, healthcare providers are likely to prescribe empirical antibacterials to those who test negative for malaria. This problem is of critical importance in Southern Asia (SA) and South-eastern Asia (SEA) where high levels of antimicrobial consumption and high prevalence of antimicrobial resistance have been reported. To improve management and guide further diagnostic test development, better understanding is needed of the true causative agents of fever and their geographical variability. Methods We conducted a systematic review of published literature (1980–2015) to characterise the spectrum of pathogens causing non-malarial febrile illness in SA and SEA. We searched six databases in English and French languages: MEDLINE, EMBASE, Global Health (CABI) database, WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. Results A total of 29,558 records from 19 countries in SA and SEA were screened, of which 2410 (8.1%) met the selection criteria. Bacterial aetiologies were reported in 1235 (51.2%) articles, viral in 846 (35.1%), parasitic in 132 (5.5%), and fungal in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group. In descending order of frequency, Salmonella Typhi, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and coagulase negative Staphylococcus were the commonly reported bacteria, while dengue virus, chikungunya virus, Japanese encephalitis virus, hepatitis B virus, and hepatitis C virus were common viral pathogens reported. Reports of rarely reported or emerging pathogens included a case report of Borrelia burgdorferi (Lyme disease) in India in 2010 and reports of Nipah virus in Singapore and India. Conclusions This review summarises the reported non-malaria pathogens that may cause febrile illness in SA and SEA. The findings emphasise the need of standardising the reporting of aetiological studies to develop effective, evidence-based fever management and improved surveillance. Research and development of diagnostic tools would benefit from up-to-date epidemiological reporting of the regional diversities of non-malaria fever aetiologies. Trial registration PROSPERO registration, CRD42016049281

Background Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. Methods A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and Results Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p Conclusions The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Objective To study possible associations between endometriosis and pelvic inflammatory disease (PID). Design Retrospective cohort analysis over 14 consecutive years, based on medical records and insurance coding in a tertiary care endometriosis reference center. Setting Tertiary care reference center for endometriosis. Patients Retrospective analysis on all women submitted to laparoscopy in our Unit Main Outcome Measures Intra-operative data about complications and fertility-impairing procedures, intra-, peri- and post-operative complications. Interventions Retrospective disease codes–triggered chart analysis. Results The study population was divided into two groups: Group 1 included women with PID and no endometriosis (n = 115); Group 2 included women with PID and endometriosis (n = 96). Endometriosis had a prevalence of 63 % in patients submitted to surgery for PID, significantly higher than the one reported in general population and than the one reported in a Tertiary Care Endometriosis Unit. A significantly higher number of salpingectiomes was needed in group 2 patients (208 versus 80, p Conclusions This study seems to confirm an higher prevalence of pelvic inflammatory disease in endometriosis patients. Intra-operative findings of PID with associated endometriosis show more aggressive patterns

Objective WHO recommends optimisation of available interventions to reduce deaths of under‐five children with diarrhoea and dehydration (DD). Clinical networks may help improve practice across many hospitals but experience with such networks is scarce. We describe magnitude and patterns of changes in processes of care for children with DD over the first 3 years of a clinical network. Methods Observational study involving children aged 2–59 months with DD admitted to 13 hospitals participating in the clinical network. Processes of individual patient care including agreement of assessment, diagnosis and treatment according to WHO guidelines were combined using the composite Paediatric Admission Quality of Care (PAQC) score (range 0–6). Results Data from 7657 children were analysed and improvements in PAQC scores were observed. Predicted mean PAQC score for all the hospitals at enrolment was 59.8% (95% CI: 54.7, 64.9) but showed a wide variation (variance 10.7%, 95% CI: 5.8, 19.6). Overall mean PAQC score increased by 13.8% (95% CI: 8.7–18.9, SD between hospitals: ±8.2) in the first 12 months, with an average 0.9% (95% CI: 0.3–1.5, SD ± 1.0) increase per month and plateaued thereafter, and changes were similar in two groups of hospitals joining the network at different times. Conclusion Adherence to guidelines for children admitted with DD can be improved through participation in a clinical network but improvement is limited, not uniform for all aspects of care and contexts and occurs early. Future research should address these issues.

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.

Aim: Even though systematic reviews have examined how aspects of propensity score methods are used, none has reviewed how the challenge of missing data is addressed with these methods. This review therefore describes how missing data are addressed with propensity score methods in observational comparative effectiveness studies. Methods: Published articles on observational comparative effectiveness studies were extracted from MEDLINE and EMBASE databases. Results: Our search yielded 167 eligible articles. Majority of these studies (114; 68%) conducted complete case analysis with only 53 of them stating this in the methods. Only 16 articles reported use of multiple imputation. Conclusion: Few researchers use correct methods for handling missing data or reported missing data methodology which may lead to reporting biased findings.

Introduction Transvaginal ultrasound is fundamental for the mapping of endometriosis, and the imaging criteria have been clearly described for different organs study. However, no specific ultrasonographic signs of tubal endometriosis have been reported, with the exception of hydrosalpinx, which is the expression of an extreme tubal damage and obstruction. The detection of tubal pathology in infertile patients is fundamental, therefore the aim of the study was to evaluate incidence of tubal endometriosis in infertile patients, and to analyze ultrasonographic signs useful for detection of this condition. Material and methods It is a single-center, retrospective cohort study. All 500 consecutive infertile women who underwent laparoscopic surgery for endometriosis were included. The preoperative workup included transvaginal ultrasound and was compared to intraoperative findings and histologic study. Results The incidence of tubal endometriosis in our study was 8%. Using hydrosalpinx as the ultrasonographic marker for tubal involvement the overall pooled, sensitivity and specificity of TVU were 12% (95%CI, 5–23%) and 99% (95%CI, 98–100%), respectively. If at least one ultrasonographic parameter like hydrosalpinx, periadnexal adhesions or ovarian cyst was considered as a sign of tubal endometriosis, a sensitivity, VPN and specificity were 94% (95% IC, 85–98%), 97% (95%IC, 93–99%) and 31% (95%CI, 27–36%), respectively. Discussion Hydrosalpinx as ultrasonographic sign alone is characterized by a high specificity but low sensitivity for detection of tubal endometriosis; its sensitivity can be improved by the addition of other markers such as endometrioma and/or periadnexal adhesions.

Diffusion MRI fiber tractography has been increasingly used to map the structural connectivity of the human brain. However, this technique is not without limitations, for example, there is a growing concern over anatomically-correlated bias in tractography findings. In this study, we demonstrate that there is a bias for fiber tracking algorithms to terminate preferentially on gyral crowns, rather than the banks of sulci. We investigate this issue by comparing diffusion MRI (dMRI) tractography with equivalent measures made on myelin-stained histological sections. We begin by investigating the orientation and trajectories of axons near the white matter/gray matter boundary, as well as the density of axons entering the cortex at different locations along gyral blades. These results are compared with dMRI orientations and tract densities at the same locations, where we find a significant gyral bias in many gyral blades across the brain. This effect is shown for a range of tracking algorithms, both deterministic and probabilistic, and multiple diffusion models, including the diffusion tensor and a high angular resolution diffusion imaging technique. Additionally, the gyral bias occurs for a range of diffusion weightings, and even for very high-resolution datasets. The bias could significantly affect connectivity results using the current generation of tracking algorithms.

We describe the development of the first digital atlas of the normal squirrel monkey brain and present the resulting product, VALiDATe29. The VALiDATe29 atlas is based on multiple types of magnetic resonance imaging (MRI) contrast acquired on 29 squirrel monkeys, and is created using unbiased, nonlinear registration techniques, resulting in a population-averaged stereotaxic coordinate system. The atlas consists of multiple anatomical templates (proton density, T1, and T2* weighted), diffusion MRI templates (fractional anisotropy and mean diffusivity), and ex vivo templates (fractional anisotropy and a structural MRI). In addition, the templates are combined with histologically defined cortical labels, and diffusion tractography defined white matter labels. The combination of intensity templates and image segmentations make this atlas suitable for the fundamental atlas applications of spatial normalization and label propagation. Together, this atlas facilitates 3D anatomical localization and region of interest delineation, and enables comparisons of experimental data across different subjects or across different experimental conditions. This article describes the atlas creation and its contents, and demonstrates the use of the VALiDATe29 atlas in typical applications. The atlas is freely available to the scientific community.

Background Over 28 000 individuals were infected with Ebola virus during the West Africa (2013–2016) epidemic, yet there has been criticism of the lack of robust clinical descriptions of Ebola virus disease (EVD) illness from that outbreak. Objectives To perform a meta-analysis of published data from the epidemic to describe the clinical presentation, evolution of disease, and predictors of mortality in individuals with EVD. To assess the quality and utility of published data for clinical and public health decision-making. Data sources Primary articles available in PubMed and published between January 2014 and May 2017. Eligibility Studies that sequentially enrolled individuals hospitalized for EVD and that reported acute clinical outcomes. Methods We performed meta-analyses using random-effect models and assessed heterogeneity using the I2 method. We assessed data representativeness by comparing meta-analysis estimates with WHO aggregate data. We examined data utility by examining the availability and compatibility of data sets. Results In all, 3653 articles were screened and 34 articles were included, representing 16 independent cohorts of patients (18 overlapping cohorts) and at least 6168 individuals. The pooled estimate for case fatality rate was 51% (95% CI 46%–56%). However, pooling of estimates for clinical presentation, progression, and predictors of mortality in individuals with EVD were hampered by significant heterogeneity, and inadequate data on clinical progression. Our assessment of data quality found that heterogeneity was largely unexplained, and data availability and compatibility were poor. Conclusions We have quantified a missed opportunity to generate reliable estimates of the clinical manifestations of EVD during the West Africa epidemic. Clinical data standards and data capture platforms are urgently needed.

Background The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7–15.7) for AL and 15.2 days (95% CI 12.8–18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7–18.6 days for AL and 10.2–18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated ( 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. Conclusion Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Production of large-size, bulk, and bubble-free melt-quenched Zeolitic Imidazolate Framework (ZIF) glasses is a challenge due to the difficulty in up-scaling of the synthesis of the initial ZIF crystals, to the extremely high viscosity at melting point and to their relatively high brittleness. In this work, we optimize the melt-quenching process to increase the size of ZIF-62 glass products and to increase their homogeneity and transparency. By finding the optimum melting time (i.e., 10 mm large glass samples with a certain degree of transparency and low bubble content, which can be used for mechanical characterizations. We have found the condition (e.g., melting time >30 min) for obtaining ZIF-62 glass foams, which result from partial decomposition during melting. This work provides some information for up-scaling the ZIF glass production.

Study Objective To compare the tolerability and diagnostic accuracy of virtual ultrasonographic hysteroscopy (VUH) with that of conventional diagnostic outpatient hysteroscopy in the workup of patients who are infertile. Design A single-center, retrospective cohort study. Setting Department of Obstetrics and Gynecology, Gynecologic Oncology, and Minimally Invasive Pelvic Surgery Unit of Sacred Heart Hospital Don Calabria in Negrar, Italy. Patients A total of 120 consecutive women who underwent hysterosalpingosonography and subsequent VUH and conventional hysteroscopy for infertility evaluation were included. The inclusion criterion was infertility for at least 1 year, with evaluation in the early or intermediate follicular phase of the menstrual cycle. Interventions After the placement of an intracervical catheter, a Ringer Lactate solution was injected into the uterine cavity and fallopian tubes, and a 3D volume was obtained. The ultrasound volume acquired was successively elaborated offline, and a VUH was performed. Subsequently, a variable amount of air was introduced into the uterine cavity, and the patency of the salpinges was evaluated. Measurements and Main Results The VUH findings were compared with those of conventional hysteroscopy performed in the subsequent month. For the detection of endometrial pathology in the overall pool, the sensitivity and specificity of VUH in comparison with conventional hysteroscopy were 100% (95% confidence interval [CI], 84.6%–100%) and 100% (95% CI, 96.3%–100%), respectively. For the detection of uterine cavity pathology and uterine malformations in the overall pool, the sensitivities of VUH were 80% (95% CI, 28.4%–99.5%) and 100% (95% CI, 75.3%–100%), respectively, with specificities of 100% (95% CI, 96.8%–100%) and 100% (95% CI, 96.6%–100%), respectively, when compared with conventional hysteroscopy. The positive predictive values for endometrial pathology, uterine cavity alterations, and uterine malformations were 100% (95% CI, 84.6%–100%), 100% (95% CI, 39.8%–100%), and 100% (95% CI, 75.3%–100%), respectively, with a receiver operating characteristic area of 100%, 90% (95% CI, 70%–100%), and 100%, respectively. There were no cases of severe vasovagal reactions or other complications. Most patients (67%, 81 of 120 women) described the examination as “less painful than expected,” 25% (30 of 120 women) “just as expected,” and only 7% (9 of 120 women) as “more painful than expected.” Conclusion VUH was well tolerated and showed a high accuracy (100%) in the study of the uterine cavity when compared with conventional hysteroscopy.

Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Mohammad S. Hossain and colleagues explore P. vivax infection following P. falciparum treatment in this analysis of 42 published studies., Author summary Why was this study done? Plasmodium vivax is the most geographically widespread human malaria species; outside of sub-Saharan Africa, it almost invariably coexists with P. falciparum. A recent systematic review of 153 studies across 21 countries revealed that within 63 days of being treated for P. falciparum monoinfection, more than 15% of patients treated with an artemisinin-based combination therapy (ACT) had an episode of P. vivax malaria, far greater than expected for patients in similar locations who do not have acute malaria. We hypothesised that patients presenting with P. falciparum in coendemic locations are at high risk of carrying P. vivax dormant liver stages (hypnozoites) and would therefore potentially benefit from presumptive radical cure. What did the researchers do and find? We undertook an individual patient data meta-analysis to define the risk of vivax parasitaemia (blood stream infection) after treatment of P. falciparum malaria in different coendemic environments and to explore the factors underlying these risks. In total, 42 studies enrolling 15,341 patients were included in the analysis. By day 63, the risk of P. vivax ranged from 12.8% following dihydroartemisinin-piperaquine (DP) to 42.4% following artesunate-amodiaquine (AA). The highest rate of P. vivax malaria was in patients residing in areas with high risk of relapses and those who were slow to clear their initial parasitaemia. What do these findings mean? There is a high risk of vivax malaria after treatment of falciparum infection after all ACTs, although the risk varies substantially between locations. The correlation between the risk of P. vivax and the initial clearance of P. falciparum raises the possibility that the host response to acute malaria may be triggering the reactivation of P. vivax dormant liver stages. Universal radical cure with treatment to kill the liver stages may be warranted for reducing P. vivax, but the benefits will vary considerably between geographical locations, and further prospective clinical efficacy studies will be needed to determine the risks and benefits of such a strategy.

Background Antimalarial clinical efficacy studies for uncomplicated Plasmodium falciparum malaria frequently encounter situations in which molecular genotyping is unable to discriminate between parasitic recurrence, either new infection or recrudescence. The current WHO guideline recommends excluding these individuals with indeterminate outcomes in a complete case (CC) analysis. Data from the four artemisinin-based combination (4ABC) trial was used to compare the performance of multiple imputation (MI) and inverse probability weighting (IPW) against the standard CC analysis for dealing with indeterminate recurrences. Methods 3369 study participants from the multicentre study (4ABC trial) with molecularly defined parasitic recurrence treated with three artemisinin-based combination therapies were used to represent a complete dataset. A set proportion of recurrent infections (10, 30 and 45%) were reclassified as missing using two mechanisms: a completely random selection (mechanism 1); missingness weakly dependent (mechanism 2a) and strongly dependent (mechanism 2b) on treatment and transmission intensity. The performance of MI, IPW and CC approaches in estimating the Kaplan-Meier (K-M) probability of parasitic recrudescence at day 28 was then compared. In addition, the maximum likelihood estimate of the cured proportion was presented for further comparison (analytical solution). Performance measures (bias, relative bias, standard error and coverage) were reported as an average from 1000 simulation runs. Results The CC analyses resulted in absolute underestimation of K-M probability of day 28 recrudescence by up to 1.7% and were associated with reduced precision and poor coverage across all the scenarios studied. Both MI and IPW method performed better (greater consistency and greater efficiency) compared to CC analysis. In the absence of censoring, the analytical solution provided the most consistent and accurate estimate of cured proportion compared to the CC analyses. Conclusions The widely used CC approach underestimates antimalarial failure; IPW and MI procedures provided efficient and consistent estimates and should be considered when reporting the results of antimalarial clinical trials, especially in areas of high transmission, where the proportion of indeterminate outcomes could be large. The analytical solution estimating the cured proportion could provide an alternative approach, in scenarios with minimal censoring due to loss to follow-up or new infections.

Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis., In this systematic review and individual patient data meta-analysis, Robert Commons and colleagues compare the clinical efficacy of different artemisinin-based combination therapies for treating Plasmodium vivax malaria., Author summary Why was this study done? The susceptibility of Plasmodium vivax to chloroquine is decreasing in many malaria-endemic locations. Artemisinin-based combination therapies (ACTs) are recommended in areas of emerging chloroquine resistance; however, the optimal ACT is not clear. Knowledge of the comparative advantages and disadvantages of different ACTs will help guide national policy makers. What did the researchers do and find? Following a systematic review, individual data from 2,017 patients were pooled from 19 studies undertaken between January 1, 2000, and January 31, 2018. Cox regression analysis showed that the risk of recurrence at day 42 was 12-fold greater following treatment with artemether-lumefantrine (AL) alone compared with dihydroartemisinin-piperaquine (DP), although by day 63 the risk of recurrence following DP was also high. For every 5-mg/kg increase in the dose of piperaquine, the risk of recurrence at day 42 fell by 37%. A delay in the time to symptomatic recurrence was associated with an increase in haemoglobin. Coadministration with primaquine reduced the risk of recurrence at day 42 after AL by 80% and at day 63 after DP by 92%. What do these findings mean? There is a high risk of recurrence following AL or DP unless they are combined with primaquine. Compared with AL, patients treated with DP have a reduced risk of early P. vivax recurrence. Delaying the time to recurrence was associated with greater haematological recovery, and this has potential to prevent morbidity related to multiple rapid recurrences by preventing a cumulative risk of anaemia.

IntroductionPregnant women are more vulnerable to malaria leading to adverse impact on both mothers and fetuses. However, knowledge on the efficacy and safety of antimalarials in pregnancy is limited by the paucity of randomised control trials and the lack of standardised protocols in this special subpopulation. Pooling individual patient data (IPD) for meta-analysis could address in part these limitations to summarise accurately the currently available evidence on treatment efficacy and risk factors for treatment failure.Methods and analysisTo assess the treatment efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy, seven databases (Medline, Embase, Global Health, Cochrane Library, Scopus, Web of Science and Literatura Latino Americana em Ciências da Saúde) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrial.gov) were searched. Both interventional and observational cohort studies following up for at least 28 days will be included. IPD of the identified eligible published or unpublished studies will be sought by inviting principal investigators. Raw IPD will be shared through the web-based secure platform developed by the WorldWide Antimalarial Resistance Network using the established methodology. The primary objective is to compare the risk of PCR-corrected treatment failure among different treatments and to find the risk factors. One-stage IPD meta-analysis by Cox model with shared frailty will be conducted. A risk of bias assessment will be conducted to address the impact of unshared potential data and of the quality of individual studies. Potential limitations include difficulty in acquiring the IPD and heterogeneity of the study designs due to the lack of standard.Ethics and disseminationThis IPD meta-analysis consists of secondary analyses of existing anonymous data and meets the criteria for waiver of ethics review by the Oxford Tropical Research Ethics Committee. The results of this IPD meta-analysis will be disseminated through open-access publications at peer-reviewed journals. The study results will lead to a better understanding of malaria treatment in pregnancy, which can be used for clinical decision-making and conducting further studies.PROSPERO registration numberCRD42018104013.

Background The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability. Methods A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980–2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented. Results A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles. Conclusions This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship. Trial registration PROSPERO, CRD42016049281

Artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ) are the most commonly-used treatments against Plasmodium falciparum malaria in Africa. The lumefantrine and amodiaquine partner drugs may provide differing durations of post-treatment prophylaxis, an important additional benefit to patients. Analyzing 4214 individuals from clinical trials in 12 sites, we estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ after allowing for transmission intensity. However, the duration varied substantially between sites: where wild type pfmdr1 86 and pfcrt 76 parasite genotypes predominated, AS-AQ provided ∼2-fold longer protection than AL. Conversely, AL provided up to 1.5-fold longer protection than AS-AQ where mutants were common. We estimate that choosing AL or AS-AQ as first-line treatment according to local drug sensitivity could alter population-level clinical incidence of malaria by up to 14% in under-five year olds where malaria transmission is high.

IntroductionAntimalarial posology based on weight bands leaves patients at the margins vulnerable to receiving either lower or higher weight-adjusted (mg/kg) dosages. This article aims to describe the protocol for systematic review and individual patient meta-analysis (MA) for a study of the distribution of artesunate and mefloquine dosage administered in patients with uncomplicatedPlasmodium falciparummalaria treated with an artesunate-mefloquine (AS-MQ) regimen. Relationship between mg/kg dose and therapeutic outcomes will be assessed through a one-stage individual participant data (IPD) MA.Methods and analysisTherapeutic efficacy studies with the AS-MQ regimen will be identified by searching the following databases: PUBMED, EMBASE and Web of Science. The corresponding authors of the relevant studies will be requested to share the IPD for the purpose of this MA to a secured repository. All available studies will be standardised using a common data management protocol and pooled into a single database. The relationship between mg/kg dosage and treatment failures will be assessed using a Cox regression model with study sites considered as a shared frailty term. Safety parameters will be explored where available.Ethics and disseminationThis IPD MA met the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee as the research consisted of secondary analysis of existing anonymous data. The results of this analysis will be disseminated at conferences, WorldWide Antimalarial Resistance Network website and any peer-reviewed publication arising will be made open source.PROSPERO registration numberCRD42018103776.

Background Antimalarial efficacy studies in patients with uncomplicated Plasmodium falciparum are confounded by a new infection (a competing risk event) since this event can potentially preclude a recrudescent event (primary endpoint of interest). The current WHO guidelines recommend censoring competing risk events when deriving antimalarial efficacy. We investigated the impact of considering a new infection as a competing risk event on the estimation of antimalarial efficacy in single-armed and comparative drug trials using two simulation studies. Methods The first simulation study explored differences in the estimates of treatment failure for areas of varying transmission intensities using the complement of the Kaplan-Meier (K-M) estimate and the Cumulative Incidence Function (CIF). The second simulation study extended this to a comparative drug efficacy trial for comparing the K-M curves using the log-rank test, and Gray’s k-sample test for comparing the equality of CIFs. Results The complement of the K-M approach produced larger estimates of cumulative treatment failure compared to the CIF method; the magnitude of which was correlated with the observed proportion of new infection and recrudescence. When the drug efficacy was 90%, the absolute overestimation in failure was 0.3% in areas of low transmission rising to 3.1% in the high transmission settings. In a scenario which is most likely to be observed in a comparative trial of antimalarials, where a new drug regimen is associated with an increased (or decreased) rate of recrudescences and new infections compared to an existing drug, the log-rank test was found to be more powerful to detect treatment differences compared to the Gray’s k-sample test. Conclusions The CIF approach should be considered for deriving estimates of antimalarial efficacy, in high transmission areas or for failing drugs. For comparative studies of antimalarial treatments, researchers need to select the statistical test that is best suited to whether the rate or cumulative risk of recrudescence is the outcome of interest, and consider the potential differing prophylactic periods of the antimalarials being compared. Electronic supplementary material The online version of this article (10.1186/s12874-019-0748-2) contains supplementary material, which is available to authorized users.

In recent years machine learning (ML) took bio- and cheminformatics fields by storm, providing new solutions for a vast repertoire of problems related to protein sequence, structure, and interactions analysis. ML techniques, deep neural networks especially, were proven more effective than classical models for tasks like predicting binding affinity for molecular complex. In this work we investigated the earlier stage of drug discovery process – finding druggable pockets on protein surface, that can be later used to design active molecules. For this purpose we developed a 3D fully convolutional neural network capable of binding site segmentation. Our solution has high prediction accuracy and provides intuitive representations of the results, which makes it easy to incorporate into drug discovery projects. The model’s source code, together with scripts for most common use-cases is freely available at http://gitlab.com/cheminfIBB/kalasanty.

Purpose Diffusion-weighted magnetic resonance imaging (DW-MRI) is of critical importance for characterizing in-vivo white matter. Models relating microarchitecture to observed DW-MRI signals as a function of diffusion sensitization are the lens through which DW-MRI data are interpreted. Numerous modern approaches offer opportunities to assess more complex intra-voxel structures. Nevertheless, there remains a substantial gap between intra-voxel estimated structures and ground truth captured by 3-D histology. Methods Herein, we propose a novel data-driven approach to model the non-linear mapping between observed DW-MRI signals and ground truth structures using a sequential deep neural network regression using residual block deep neural network (ResDNN). Training was performed on two 3-D histology datasets of squirrel monkey brains and validated on a third. A second validation was performed using scan-rescan datasets of 12 subjects from Human Connectome Project. The ResDNN was compared with multiple micro-structure reconstruction methods and super resolved-constrained spherical deconvolution (sCSD) in particular as baseline for both the validations. Results Angular correlation coefficient (ACC) is a correlation/similarity measure and can be interpreted as accuracy when compared with a ground truth. The median ACC of ResDNN is 0.82 and median ACC's of different variants of CSD are 0.75, 0.77, 0.79. The mean, median and std. of ResDNN & sCSD ACC across 12 subjects from HCP are 0.74, 0.88, 0.31 and 0.61, 0.71, 0.31 respectively. Conclusion This work highlights the ability of deep learning to capture linkages between ex-vivo ground truth data with feasible MRI sequences. The data-driven approach is applicable to human in-vivo data and results in intriguingly high reproducibility of orientation structure.

Diffusion weighted magnetic resonance imaging (DW-MRI) is interpreted as a quantitative method that is sensitive to tissue microarchitecture at a millimeter scale. However, the sensitization is dependent on acquisition sequences (e.g., diffusion time, gradient strength, etc.) and susceptible to imaging artifacts. Hence, comparison of quantitative DW-MRI biomarkers across field strengths (including different scanners, hardware performance, and sequence design considerations) is a challenging area of research. We propose a novel method to estimate microstructure using DW-MRI that is robust to scanner difference between 1.5T and 3T imaging. We propose to use a null space deep network (NSDN) architecture to model DW-MRI signal as fiber orientation distributions (FOD) to represent tissue microstructure. The NSDN approach is consistent with histologically observed microstructure (on previously acquired ex vivo squirrel monkey dataset) and scan-rescan data. The contribution of this work is that we incorporate identical dual networks (IDN) to minimize the influence of scanner effects via scan-rescan data. Briefly, our estimator is trained on two datasets. First, a histology dataset was acquired on three squirrel monkeys with corresponding DW-MRI and confocal histology (512 independent voxels). Second, 37 control subjects from the Baltimore Longitudinal Study of Aging (67-95 y/o) were identified who had been scanned at 1.5T and 3T scanners (b-value of 700 s/mm(2), voxel resolution at 2.2mm, 30-32 gradient volumes) with an average interval of 4 years (standard deviation 1.3 years). After image registration, we used paired white matter (WM) voxels for 17 subjects and 440 histology voxels for training and 20 subjects and 72 histology voxels for testing. We compare the proposed estimator with super-resolved constrained spherical deconvolution (CSD) and a previously presented regression deep neural network (DNN). NSDN outperformed CSD and DNN in angular correlation coefficient (ACC) 0.81 versus 0.28 and 0.46, mean squared error (MSE) 0.001 versus 0.003 and 0.03, and general fractional anisotropy (GFA) 0.05 versus 0.05 and 0.09. Further validation and evaluation with contemporaneous imaging are necessary, but the NSDN is promising avenue for building understanding of microarchitecture in a consistent and device-independent manner.

We report a case of a primary vaginal adenosarcoma with sarcomatous overgrowth in a postmenopausal 58-year-old woman with recurrent endometriosis. In the past 5 years she underwent several biopsies of a polypoid lesion on the vaginal cuff, and the last histologic examination of the biopsy showed an adenosarcoma with "sarcomatous overgrowth" in a background of endometriosis. There was no evidence of distant metastatic disease on the diagnostic workup, and we performed a laparoscopy to remove the pelvic mass. We reviewed the literature on the electronic databases Medline, Embase, and Science Direct on articles published in English from 1990 to 2015. We identified 5 articles in which the surgical treatment was performed via a laparotomic approach. The present case is the first in the literature to report feasibility of laparoscopic treatment for this kind of pathology with a detailed description of the surgical technique.

This article was updated to correct the author listing, where given names and surnames were reversed.

Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive, an open access, cloud-based knowledge graph has been created using the results. Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25th, 75th percentile) sample size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at https://iddo.cognitive.city/. Conclusions: Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence. The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.

Background Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections. Methods Antimalarial studies typically report the risk of recrudescence derived using the Kaplan–Meier (K–M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K–M method (1 minus K–M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K–M curves was assessed using the log-rank test, and the equality of CIFs using Gray’s k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray’s sub-distributional hazard model. Results Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K–M approach was 0.04% (interquartile range (IQR): 0.00–0.27%, Range: 0.00–3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson’s correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30–0.46] or new infection [ρ: 0.43; 95% CI 0.35–0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K–M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold. Conclusions The 1 minus K–M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings. Electronic supplementary material The online version of this article (10.1186/s12936-019-2837-4) contains supplementary material, which is available to authorized users.

Diffusion-weighted magnetic resonance imaging (DW-MRI) allows for non-invasive imaging of the local fiber architecture of the human brain at a millimetric scale. Multiple classical approaches have been proposed to detect both single (e.g., tensors) and multiple (e.g., constrained spherical deconvolution, CSD) fiber population orientations per voxel. However, existing techniques generally exhibit low reproducibility across MRI scanners. Herein, we propose a data-driven tech-nique using a neural network design which exploits two categories of data. First, training data were acquired on three squirrel monkey brains using ex-vivo DW-MRI and histology of the brain. Second, repeated scans of human subjects were acquired on two different scanners to augment the learning of the network pro-posed. To use these data, we propose a new network architecture, the null space deep network (NSDN), to simultaneously learn on traditional observed/truth pairs (e.g., MRI-histology voxels) along with repeated observations without a known truth (e.g., scan-rescan MRI). The NSDN was tested on twenty percent of the histology voxels that were kept completely blind to the network. NSDN significantly improved absolute performance relative to histology by 3.87% over CSD and 1.42% over a recently proposed deep neural network approach. More-over, it improved reproducibility on the paired data by 21.19% over CSD and 10.09% over a recently proposed deep approach. Finally, NSDN improved gen-eralizability of the model to a third in vivo human scanner (which was not used in training) by 16.08% over CSD and 10.41% over a recently proposed deep learn-ing approach. This work suggests that data-driven approaches for local fiber re-construction are more reproducible, informative and precise and offers a novel, practical method for determining these models., Comment: 10 pages, 5 figures

Background Parenteral artesunate is the treatment of choice for severe malaria. Recently, haemolytic anaemia occurring 1 to 3 weeks after artesunate treatment of falciparum malaria has been reported in returning travellers in temperate countries. Methods To assess these potential safety concerns in African children, in whom most deaths from malaria occur, an open-labelled, randomized controlled trial was conducted in Kinshasa, Democratic Republic of Congo. 217 children aged between 6 months and 14 years with acute uncomplicated falciparum malaria and parasite densities over 100,000/μL were randomly allocated to intravenous artesunate or quinine, hospitalized for 3 days and then followed for 42 days. Results The immediate reduction in haemoglobin was less with artesunate than with quinine: median (IQR) fall at 72 h 1.4 g/dL (0.90–1.95) vs. 1.7 g/dL (1.10–2.40) (p = 0.009). This was explained by greater pitting then recirculation of once infected erythrocytes. Only 5% of patients (in both groups) had a ≥ 10% reduction in haemoglobin after day 7 (p = 0.1). One artesunate treated patient with suspected concomitant sepsis had a protracted clinical course and required a blood transfusion on day 14. Conclusions Clinically significant delayed haemolysis following parenteral artesunate is uncommon in African children hospitalised with acute falciparum malaria and high parasitaemias. Trial registration ClinicalTrials.gov; Identifier: NCT02092766 (18/03/2014) Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2678-0) contains supplementary material, which is available to authorized users.

Background Diarrhoea causes many deaths in children younger than 5 years and identification of risk factors for death is considered a global priority. The effectiveness of currently recommended fluid management for dehydration in routine settings has also not been examined. Methods For this observational, association study, we analysed prospective clinical data on admission, immediate treatment, and discharge of children age 1–59 months with diarrhoea and dehydration, which were routinely collected from 13 Kenyan hospitals. We analysed participants with full datasets using multivariable mixed-effects logistic regression to assess risk factors for in-hospital death and effect of correct rehydration on early mortality (within 2 days). Findings Between Oct 1, 2013, and Dec 1, 2016, 8562 children with diarrhoea and dehydration were admitted to hospital and eligible for inclusion in this analysis. Overall mortality was 9% (759 of 8562 participants) and case fatality was directly correlated with severity. Most children (7184 [84%] of 8562) with diarrhoea and dehydration had at least one additional diagnosis (comorbidity). Age of 12 months or younger (adjusted odds ratio [AOR] 1·71, 95% CI 1·42–2·06), female sex (1·41, 1·19–1·66), diarrhoea duration of more than 14 days (2·10, 1·42–3·12), abnormal respiratory signs (3·62, 2·95–4·44), abnormal circulatory signs (2·29, 1·89–2·77), pallor (2·15, 1·76–2·62), use of intravenous fluid (proxy for severity; 1·68, 1·41–2·00), and abnormal neurological signs (3·07, 2·54–3·70) were independently associated with inhospital mortality across hospitals. Signs of dehydration alone were not associated with in-hospital deaths (AOR 1·08, 0·87–1·35). Correct fluid prescription significantly reduced the risk of early mortality (within 2 days) in all subgroups: abnormal respiratory signs (AOR 1·23, 0·68–2·24), abnormal circulatory signs (0·95, 0·53–1·73), pallor (1·70, 0·95–3·02), dehydration signs only (1·50, 0·79–2·88), and abnormal neurological signs (0·86, 0·51–1·48). Interpretation Children at risk of in-hospital death are those with complex presentations rather than uncomplicated dehydration, and the prescription of recommended rehydration guidelines reduces risk of death. Strategies to optimise the delivery of recommended guidance should be accompanied by studies on the management of dehydration in children with comorbidities, the vulnerability of young girls, and the delivery of immediate care.

Study Objective To create a classification of diaphragmatic endometriosis (DE) in order to better select the surgical treatment of endometriotic nodules, depending on their size and localization. Design All the patients treated for deep infiltrating endometriosis (DIE) with DE between January 2004 and December 2018 were retrospectively reviewed. All the patients underwent surgery by laparoscopic approach or video-assisted thoracoscopic surgery (VATS). Diaphragmatic lesions were classified in three groups according to size, shape and depth of muscular infiltration. Setting Department of Obstetrics & Gynecology, and Thoracic Surgery, IRCCS Sacro Cuore Don Calabria Hospital – Negrar (Verona), Italy. Patients or Participants 150 patients with DE were identified. Interventions 128 patients were treated by laparoscopy, 21 by VATS and 1 of them had VATS combined with laparoscopy. Measurements and Main Results Patients were divided into 3 groups, according to the proposed classification. The first group of 99 patients (66%) included those with superficial lesions ≤ 1 cm. These lesions were called ‘foci' and were treated by diathermocoagulation (DTC) or argon laser vaporization. The second group included 17 patients (11,3%) with lesions called ‘plaques', bigger than 1cm, bidimensional and caused thickening of the involved tissue, without deep infiltration of the muscular layer of the diaphragm. These lesions were usually removed by diaphragmatic stripping. In the last group, the lesions were called ‘nodules', they were larger than 10 mm, and with deep infiltration of the diaphragm These nodules were observed in 34 patients (22,6%) and were removed by laparoscopic excision with diaphragmatic resection or by VATS. Conclusion Diaphragmatic nodules can be easily classified in one of the proposed groups. Considering this classification, different methods of surgical treatments of DE can be chosen, in order to allow a total and safe removal of the lesions, with low complications rate and a significant improvement of patients' symptoms.

Ileocecal endometriosis is a very rare entity, and its diagnosis is usually made during surgery for other endometriosis sites or, rarely, because of direct complications of ileal involvement. This study was designed to analyze perioperative and long-term outcomes after bowel resection for ileocecal endometriosis.All patients who underwent surgery for ileocecal endometriosis between October 2004 and January 2008 were prospectively collected and analyzed.Thirty-one women (median age, 34 (range, 25-40) years) were identified. Ileocecal endometriosis was diagnosed during surgery in all patients, and it was associated with colorectal endometriosis in 29 patients (94\%). All patients underwent laparoscopic ileocecal resection with no laparotomic conversion. Rectosigmoid or rectal resections was associated in 28 patients (90\%) and nodulectomy for sigmoid endometriosis in 1 patient. Median duration of surgery was 301 (range, 90-480) min. Other associated surgical procedures included total hysterectomy (n = 3, 14\%), ureterolysis (n = 7, 23\%), excision of vesical (n = 4, 13\%), vaginal (n = 8, 26\%), and parametrial (n = 3, 14\%) nodules. There was no mortality. Four patients (13\%) required blood transfusions and one a reoperation for bleeding. In a patient who performed ureterolysis, a ureteral fistula occurred. The median hospital stay was 7 (range, 5-18) days. Long-term (>12 months) follow-up data were available for 18 patients. After a median follow-up of 27 months, in 12 of 18 patients (67\%) defecation after surgery was normal. Only one patient developed recurrence, which is under medical treatment.Laparoscopic ileocecal resection is safe and feasible and should be considered as part of surgery for endometriosis with radical intent.

It is now widely recognized that voxels with crossing fibers or complex geometrical configurations present a challenge for diffusion MRI (dMRI) reconstruction and fiber tracking, as well as microstructural modeling of brain tissues. This "crossing fiber" problem has been estimated to affect anywhere from 30% to as many as 90% of white matter voxels, and it is often assumed that increasing spatial resolution will decrease the prevalence of voxels containing multiple fiber populations. The aim of this study is to estimate the extent of the crossing fiber problem as we progressively increase the spatial resolution, with the goal of determining whether it is possible to mitigate this problem with higher resolution spatial sampling. This is accomplished using ex vivo MRI data of the macaque brain, followed by histological analysis of the same specimen to validate these measurements, as well as to extend this analysis to resolutions not yet achievable in practice with MRI. In both dMRI and histology, we find unexpected results: the prevalence of crossing fibers increases as we increase spatial resolution. The problem of crossing fibers appears to be a fundamental limitation of dMRI associated with the complexity of brain tissue, rather than a technical problem that can be overcome with advances such as higher fields and stronger gradients.

The accuracy of sonographic estimation of birthweight in suspected macrosomic fetuses is compromised by the imprecision of the biometrical measurements. This prospective study evaluated the performance of an equation based on linear measurement of the soft tissue above the external side of the fetal femur. The performance of this algorithm was compared with two classical algorithms. Sonographic measurements were taken within 48 h before of delivery. Sixty-two patients with fetuses with suspected macrosomia were enrolled. The studied formulas were compared between them and showed a significant correlation with birthweight (p0.0001) and satisfactory statistical performances (r0.9). The new formula showed a reduced standard deviation that means a lower internal error in the prediction. This study supports the potential of this new approach for the estimation of birthweight in large fetuses based on sonographic linear measurements only.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

Study Objective to prospectively assess the effectiveness and safety of RadioFrequency Thermal Ablation (RFA) for uterine nodular adenomyosis Design all patients with nodular adenomyosis who desired to preserve the uterus and who were selected for RFA were included. Setting third-level Referral Center for Endometriosis Patients or Participants One hundred twenty women with symptomatic nodular adenomyosis, aged 24-51 years, were collected. Interventions All the procedures were carried out by laparoscopic access in order to perform a concomitant surgery for endometriosis (75% of the cases), if preoperatively detected. In order to evaluate the impact of the treatment on the intensity symptoms related to the presence of uterine adenomyosis, the intensity of uterine bleeding and pain during the follow-up was compared to the properative symptomatology, and the ten-point visual analog scale (VAS) was used for pain assessment. Patients were asked about any hormonal or surgical treatments performed during the follow-up period and pregnancies occurred after the radiofrequency thermal ablation. Measurements and Main Results The median number of nodular lesions treated per patient was 1 (range, 1-2). The median reduction in volume was 66%. Follow-up period ranged from 6 to 94 months. A significant progressive improvement in the symptoms score was observed at the follow-up. Conclusion In this study, laparoscopic RFA reduced uterine adenomyosis-related symptoms and volume, with significant improvement on quality of life in the treated patients.