Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.

Partial arytenoidectomy with transoral vocal fold lateralisation in treating airway obstruction secondary to bilateral vocal fold immobility.

OBJECTIVE: To report the outcome of 18 patients with a tracheostomy secondary to bilateral vocal fold immobility, who were managed using reconstructive transoral laser microsurgical techniques. METHODS: A retrospective review was conducted of the surgical outcome of 18 patients with bilateral vocal fold immobility and a tracheostomy resulting from different aetiologies. Follow-up duration ranged from one to five years. RESULTS: A total of 18 patients had a tracheostomy at presentation because of bilateral true vocal fold immobility and stridor. All cases were treated using reconstructive transoral laser microsurgery with arytenoidectomy and vocal fold lateralisation. All patients were successfully decannulated by eight weeks after surgery. CONCLUSION: Reconstructive transoral laser microsurgery using partial arytenoidectomy with vocal fold lateralisation is minimally invasive, feasible, safe and effective for airway reconstruction in patients who present with stridor due to bilateral true vocal fold immobility.

Molecular Study of Acinetobacter baumannii that Lacking Some Essentials Genes Responsible of Toxin-Antitoxin System.

Acinetobacter genus has various species that are widespread in different environments and can exist in non-living environment samples as well. Acinetobacter baumannii (A. baumannii) is known to be one of the main causes of nosocomial infection. Few studies have examined the possibility of the presence of this opportunistic pathogen in non-living environment samples. In this study, A. baumannii strain cl-2 was isolated from dishwasher basket samples and it was identified by 16S ribosomal RNA sequencing analysis. The present study also investigated the presence of some important genes responsible for toxin-antitoxin (TA) systems necessary for the resistance of this bacterium in improper environmental conditions. Additionally, attempts were made to study some essential virulence factors, such as hemolysin, lipase, protease, and lecithinase production, as well as biofilm formation and surface motility. The findings revealed that the isolate belongs to the A. baumannii strain cl-2. The isolate was deposed in the National Center for Biotechnology Information, (NCBI) and the data can be accessed via the NCBI accession number (MW642251). The results of screening the TA system by higBA, mazEF, and relBE genes showed the isolate did not contain these genes. The hemolysin toxin activity (phenotypic test) was performed by using the streaking and spot methods on blood agar. It was found that the A. baumannii strain cl-2 had the ability to hemolyze red blood cells and produce lecithinase and protease enzymes. Finally, it was revealed that the A. baumannii strain cl-2 had surface motility based on the concentric diffusion ring of growth observed on Luria Broth agar (0.3%). In conclusion, the isolates under study showed association patterns between their ability to produce hemolysin, lipase, lecithinase, as well as protease, and other virulence factors, including surface motility and biofilm formation.

Reduced Birth Weight Caused by Sextuple Drug-Resistant Plasmodium falciparum Infection in Early Second Trimester.

Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps, particularly the sextuple mutant haplotype threatens the antimalarial effectiveness of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment during pregnancy (IPTp). To explore the impact of sextuple mutant haplotype infections on outcome measures after provision of IPTp with SP, we monitored birth outcomes in women followed up from before conception or from the first trimester until delivery. Women infected with sextuple haplotypes, in the early second trimester specifically, delivered newborns with a lower birth weight compared with women who did not have malaria during pregnancy (difference, -267 g; 95% confidence interval, -454 to -59; P = .01) and women infected with less SP-resistant haplotypes (-461 g; -877 to -44; P = .03). Thus, sextuple haplotype infections seem to affect the effectiveness of SP for IPTp and directly affect birth outcome by lowering birth weight. Close monitoring and targeted malaria control during early pregnancy is therefore crucial to improving birth outcomes.

Identifying a stochastic clock network with light entrainment for single cells of Neurospora crassa.

Stochastic networks for the clock were identified by ensemble methods using genetic algorithms that captured the amplitude and period variation in single cell oscillators of Neurospora crassa. The genetic algorithms were at least an order of magnitude faster than ensemble methods using parallel tempering and appeared to provide a globally optimum solution from a random start in the initial guess of model parameters (i.e., rate constants and initial counts of molecules in a cell). The resulting goodness of fit [Formula: see text] was roughly halved versus solutions produced by ensemble methods using parallel tempering, and the resulting [Formula: see text] per data point was only [Formula: see text] = 2,708.05/953 = 2.84. The fitted model ensemble was robust to variation in proxies for "cell size". The fitted neutral models without cellular communication between single cells isolated by microfluidics provided evidence for only one Stochastic Resonance at one common level of stochastic intracellular noise across days from 6 to 36 h of light/dark (L/D) or in a D/D experiment. When the light-driven phase synchronization was strong as measured by the Kuramoto (K), there was degradation in the single cell oscillations away from the stochastic resonance. The rate constants for the stochastic clock network are consistent with those determined on a macroscopic scale of 107 cells.

An unusual cause of a common presentation: a case of metastatic basal cell carcinoma.

Metastasis of basal cell carcinoma is exceedingly rare and usually not considered in the differential diagnosis of neck lumps. We present a case highlighting the importance of a thorough history and consideration of metastatic basal cell carcinoma in patients with a basaloid metastasis and an unknown primary.

Epidemiology and Antimicrobial Susceptibility of Salmonella enterica Bloodstream Isolates Among Febrile Children in a Rural District in Northeastern Tanzania: A Cross-sectional Study.

BACKGROUND: Salmonella enterica including Salmonella Typhi and nontyphoidal Salmonella (NTS) are the predominant cause of community-acquired bloodstream infections in sub-Saharan Africa (sSA). Multiple-drug resistance and emerging fluoroquinolone resistance are of concern. Data on the age distribution of typhoid fever in sSA are scarce but essential for typhoid conjugate vaccine policy. We sought to describe Salmonella bloodstream infections, antimicrobial resistance, and age distribution at a rural district hospital in northeastern Tanzania. METHODS: From 2008 to 2016, febrile children or children with a history of fever aged 1 month to 5 years admitted to Korogwe District Hospital were enrolled. Demographic, clinical data and blood cultures were collected. Organisms were identified by conventional microbiological methods, and antimicrobial susceptibility test was done by disc diffusion. RESULTS: Of 4176 participants receiving blood cultures, 383 (9.2 %) yielded pathogens. Of pathogens, 171 (44.6%) were Salmonella enterica of which 129 (75.4%) were Salmonella Typhi, and 42 (24.6%) were NTS. The median (interquartile range age of participants was 13.1 (6.3-28.0) months for those with Salmonella Typhi and 11.5 (8.5-23.4) months for NTS. Of 129 Salmonella Typhi, 89 (89.9%) were resistant to amoxicillin, 85 (81.0%) to chloramphenicol, and 93 (92.1%) to trimethoprim-sulfamethoxazole compared with 22 (62.9%), 15 (39.4%), and 27 (79.4%), respectively, for NTS. Multidrug resistance was present in 68 (81.0%) of Salmonella Typhi and 12 (41.4%) of NTS. CONCLUSION: Salmonella Typhi was the leading cause of bloodstream infection among infants and young children <2 years of age admitted to Korogwe District Hospital. Multidrug resistance was common, highlighting a role for typhoid conjugate vaccine into routine infant vaccine schedules.

Malaria in Early Pregnancy and the Development of the Placental Vasculature.

BACKGROUND: Pregnancy malaria has a negative impact on fetal outcome. It is uncertain whether infections in early pregnancy have a clinical impact by impeding the development of the placental vasculature. METHODS: Tanzanian women (n = 138) were closely monitored during pregnancy. Placentas collected at birth were investigated using stereology to establish the characteristics of placental villi and vessels. Placental vasculature measures were compared between women infected with malaria and controls. RESULTS: Compared with controls, placentas from women infected with malaria before a gestational age (GA) of 15 weeks had a decreased volume of transport villi (mean decrease [standard deviation], 12.45 [5.39] cm3; P = .02), an increased diffusion distance in diffusion vessels (mean increase, 3.33 [1.27] µm; P = .01), and a compensatory increase in diffusion vessel surface area (mean increase, 1.81 [0.74 m2]; P = .02). In women who had malaria before a GA of 15 weeks diffusion vessel surface area and transport vessel length distance were positive predictors for birth weight (multilinear regression: P = .007 and P = .055 for diffusion surface area and transport length, respectively) and GA at delivery (P = .005 and P = .04). CONCLUSIONS: Malaria infection in early pregnancy impedes placental vascular development. The resulting phenotypic changes, which can be detected at delivery, are associated with birth weight and gestational length. CLINICAL TRIALS REGISTRATION: NCT02191683.

Prevalence and risk factors of preconception anemia: A community based cross sectional study of rural women of reproductive age in northeastern Tanzania.

BACKGROUND: Anemia is a major public health problem that adversely affects pregnancy outcomes. The prevalence of anemia among pregnant women before conception is not well known in Tanzania. The aim of this study was to determine the prevalence, types, and risk factors of preconception anemia in women of reproductive age from a rural Tanzanian setting. METHODS: Trained field workers visited households to identify all female residents aged 18-40 years and invited them to the nearby health facility for screening and enrolment into this study. Baseline samples were collected to measure hemoglobin levels, serum ferritin, vitamin B12, folate, C-reactive protein, alanine amino-transferase, the presence of malaria, HIV, and soil transmitted helminth infections. Anthropometric and socio-economic data were recorded alongside with clinical information of participants. Logistic regression analysis was used to determine the adjusted odds ratios (AOR) for the factors associated with preconception anemia. FINDINGS: Of 1248 women enrolled before conception, 36.7% (95% confidence interval (CI) 34.1-39.4) had anemia (hemoglobin <12 g/dL) and 37.6% (95% CI 34.9-40.4) had iron deficiency. For more than half of the anemic cases, iron deficiency was also diagnosed (58.8%, 95% CI 54.2-63.3). Anemia was independently associated with increased age (AOR 1.05, 95% CI 1.03-1.07), malaria infection at enrolment (AOR 2.21, 95% CI 1.37-3.58), inflammation (AOR 1.77, 95% CI 1.21-2.60) and iron deficiency (AOR 4.68, 95% CI 3.55-6.17). The odds of anemia were reduced among women with increased mid-upper arm circumference (AOR 0.90, 95% CI 0.84-0.96). CONCLUSION: Anemia among women of reproductive age before conception was prevalent in this rural setting. Increased age, iron deficiency, malaria infection and inflammation were significant risk factors associated with preconception anemia, whereas increased mid-upper arm circumference was protective against anemia. Interventions to ensure adequate iron levels as well as malaria control before conception are needed to prevent anemia before and during pregnancy and improve birth outcomes in this setting. TRIAL REGISTRATION: NCT02191683.

Risk factors of pre-hypertension and hypertension among non-pregnant women of reproductive age in northeastern Tanzania: a community based cross-sectional study.

OBJECTIVES: To determine risk factors of pre-hypertension and hypertension in a cohort of 1247 rural Tanzanian women before conception. METHODS: Demographic and socioeconomic data, anthropometric measurements, past medical and obstetric history and other risk factors for pre-hypertension and hypertension were collected using a structured questionnaire. Multiple logistic regression analysis was used to evaluate the associations between anthropometric indices and other risk factors of pre-hypertension and hypertension. The predictive power of different anthropometric indicators for identification of pre-hypertension and hypertension patients was determined by Receiver Operating Characteristic curves (ROC). RESULTS: The median (range) age was 28.0 (18-40) years. The age-standardised prevalences of pre-hypertension and hypertension were 37.2 (95% CI 34.0-40.6) and 8.5% (95%CI 6.7-10.8), respectively. Of hypertensive patients (n = 98), only 20 (20.4%) were aware of their condition. In multivariate analysis, increasing age, obesity and haemoglobin levels were significantly associated with pre-hypertension and hypertension. CONCLUSION: Despite a low prevalence of hypertension, over one third of the women had pre-hypertension. This poses a great challenge ahead as pre-hypertensive women may progress into hypertension as they grow older without appropriate interventions. Obesity was the single most important modifiable risk factor for pre-hypertension and hypertension.

Ensemble methods for stochastic networks with special reference to the biological clock of Neurospora crassa.

A major challenge in systems biology is to infer the parameters of regulatory networks that operate in a noisy environment, such as in a single cell. In a stochastic regime it is hard to distinguish noise from the real signal and to infer the noise contribution to the dynamical behavior. When the genetic network displays oscillatory dynamics, it is even harder to infer the parameters that produce the oscillations. To address this issue we introduce a new estimation method built on a combination of stochastic simulations, mass action kinetics and ensemble network simulations in which we match the average periodogram and phase of the model to that of the data. The method is relatively fast (compared to Metropolis-Hastings Monte Carlo Methods), easy to parallelize, applicable to large oscillatory networks and large (~2000 cells) single cell expression data sets, and it quantifies the noise impact on the observed dynamics. Standard errors of estimated rate coefficients are typically two orders of magnitude smaller than the mean from single cell experiments with on the order of ~1000 cells. We also provide a method to assess the goodness of fit of the stochastic network using the Hilbert phase of single cells. An analysis of phase departures from the null model with no communication between cells is consistent with a hypothesis of Stochastic Resonance describing single cell oscillators. Stochastic Resonance provides a physical mechanism whereby intracellular noise plays a positive role in establishing oscillatory behavior, but may require model parameters, such as rate coefficients, that differ substantially from those extracted at the macroscopic level from measurements on populations of millions of communicating, synchronized cells.

Application of the Rat Grimace Scale as a Marker of Supraspinal Pain Sensation after Cervical Spinal Cord Injury.

Experimental models of neuropathic pain (NP) typically rely on withdrawal responses to assess the presence of pain. Reflexive withdrawal responses to a stimulus are used to evaluate evoked pain and, as such, do not include the assessment of spontaneous NP nor evaluation of the affective and emotional consequences of pain in animal models. Additionally, withdrawal responses can be mediated by spinal cord reflexes and may not accurately indicate supraspinal pain sensation. This is especially true in models of traumatic spinal cord injury (SCI), wherein spastic syndrome, a motor disorder characterized by exaggeration of the stretch reflex that is secondary to hyperexcitability of the spinal reflex, can cause paroxysmal withdrawals not associated with NP sensation. Consequently, the aim of this study was to utilize an assessment of supraspinal pain sensation, the Rat Grimace Scale (RGS), to measure both spontaneous and evoked NP after a contusion SCI at cervical level 5 in adult male rats. Spontaneous and evoked pain were assessed using the RGS to score facial action units before and after the application of a stimulus, respectively. Rodents exhibited significantly higher RGS scores at week 5 post-injury as compared to baseline and laminectomy controls before the application of the stimulus, suggesting the presence of spontaneous NP. Additionally, there was a significant increase in RGS scores after the application of the acetone. These data suggest that the RGS can be used to assess spontaneous NP and determine the presence of evoked supraspinal pain sensation after experimental cervical SCI.

Uncoupling the solids retention times of flocs and granules in mainstream deammonification: A screen as effective out-selection tool for nitrite oxidizing bacteria.

This study focused on a physical separator in the form of a screen to out-select nitrite oxidizing bacteria (NOB) for mainstream sewage treatment. This separation relied on the principle that the NOB prefer to grow in flocs, while anammox bacteria (AnAOB) reside in granules. Two types of screens (vacuum and vibrating) were tested for separating these fractions. The vibrating screen was preferred due to more moderate normal forces and additional tangential forces, better balancing retention efficiency of AnAOB granules (41% of the AnAOB activity) and washout of NOB (92% activity washout). This operation resulted in increased NOB out-selection (AerAOB/NOB ratio of 2.3) and a total nitrogen removal efficiency of 70% at influent COD/N ratio of 1.4. An effluent total nitrogen concentration <10mgN/L was achieved using this novel approach combining biological selection with physical separation, opening up the path towards energy positive sewage treatment.

Impact of carbon to nitrogen ratio and aeration regime on mainstream deammonification.

While deammonification of high-strength wastewater in the sludge line of sewage treatment plants has become well established, the potential cost savings spur the development of this technology for mainstream applications. This study aimed at identifying the effect of aeration and organic carbon on the deammonification process. Two 10 L sequencing bath reactors with different aeration frequencies were operated at 25°C. Real wastewater effluents from chemically enhanced primary treatment and high-rate activated sludge process were fed into the reactors with biodegradable chemical oxygen demand/nitrogen (bCOD/N) of 2.0 and 0.6, respectively. It was found that shorter aerobic solids retention time (SRT) and higher aeration frequency gave more advantages for aerobic ammonium-oxidizing bacteria (AerAOB) than nitrite oxidizing bacteria (NOB) in the system. From the kinetics study, it is shown that the affinity for oxygen is higher for NOB than for AerAOB, and higher dissolved oxygen set-point could decrease the affinity of both AerAOB and NOB communities. After 514 days of operation, it was concluded that lower organic carbon levels enhanced the activity of anoxic ammonium-oxidizing bacteria (AnAOB) over denitrifiers. As a result, the contribution of AnAOB to nitrogen removal increased from 40 to 70%. Overall, a reasonably good total removal efficiency of 66% was reached under a low bCOD/N ratio of 2.0 after adaptation.