Group versus individual antenatal and first year postpartum care: Study protocol for a multi-country cluster randomized controlled trial in Kenya and Nigeria [version 1; referees: 2 approved]

Background: Antenatal care (ANC) in many low- and middle-income countries is under-utilized and of sub-optimal quality. Group ANC (G-ANC) is an intervention designed to improve the experience and provision of ANC for groups of women (cohorts) at similar stages of pregnancy. Methods: A two-arm, two-phase, cluster randomized controlled trial (cRCT) (non-blinded) is being conducted in Kenya and Nigeria. Public health facilities were matched and randomized to either standard individual ANC (control) or G-ANC (intervention) prior to enrollment. Participants include pregnant women attending first ANC at gestational age <24 weeks, health care providers, and sub-national health managers. Enrollment ended in June 2017 for both countries. In the intervention arm, pregnant women are assigned to cohorts at first ANC visit and receive subsequent care together during five meetings facilitated by a health care provider (Phase 1). After birth, the same cohorts meet four times over 12 months with their babies (Phase 2). Data collection was performed through surveys, clinical data extraction, focus group discussions, and in-depth interviews. Phase 1 data collection ended in January 2018 and Phase 2 concludes in November 2018. Intention-to-treat analysis will be used to evaluate primary outcomes for Phases 1 and 2: health facility delivery and use of a modern method of family planning at 12 months postpartum, respectively. Data analysis and reporting of results will be consistent with norms for cRCTs. General estimating equation models that account for clustering will be employed for primary outcome analyzes. Results: Overall 1,075 and 1,013 pregnant women were enrolled in Nigeria and Kenya, respectively. Final study results will be available in February 2019. Conclusions: This is the first cRCT on G-ANC in Africa. It is among the first to examine the effects of continuing group care through the first year postpartum. Registration: Pan African Clinical Trials Registry PACTR201706002254227 May 02, 201

Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age

<p>Abstract</p> <p>Background</p> <p>In <it>Plasmodium falciparum</it>-infected children, the relationships between blood cell histopathology, blood plasma components, development of immunocompetence and disease severity remain poorly understood. Blood from Nigerian children with uncomplicated malaria was analysed to gain insight into these relationships. This investigation presents evidence for circulating neutrophil extracellular traps (NETs) and antinuclear IgG antibodies (ANA). The presence of NETs and ANA to double-stranded DNA along with the cytokine profiles found suggests autoimmune mechanisms that could produce pathogenesis in children, but immunoprotection in adults.</p> <p>Methods</p> <p>Peripheral blood smear slides and blood samples obtained from 21 Nigerian children under six years of age, presenting with uncomplicated malaria before and seven days after initiation of sulphadoxine-pyrimethamine (SP) treatment were analysed. The slides were stained with Giemsa and with DAPI. Levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF, CRP, and IL-6, select anti-inflammatory cytokines TGF-β and IL-10, and ANA were determined by immunoassay.</p> <p>Results</p> <p>The children exhibited circulating NETs with adherent parasites and erythrocytes, elevated ANA levels, a Th2 dominated cytokine profile, and left-shifted leukocyte differential counts. Nonspecific ANA levels were significant in 86% of the children pretreatment and in 100% of the children seven days after SP treatment, but in only 33% of age-matched control samples collected during the season of low parasite transmission. Levels of ANA specific for dsDNA were significant in 81% of the children both pre-treatment and post treatment.</p> <p>Conclusion</p> <p>The results of this investigation suggest that NET formation and ANA to dsDNA may induce pathology in falciparum-infected children, but activate a protective mechanism against falciparum malaria in adults. The significance of in vivo circulating chromatin in NETs and dsDNA ANA as a causative factor in the hyporesponsiveness of CpG oligonucleotide-based malaria vaccines is discussed.</p

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Investigation of Mechanisms of Response in Multiple Myeloma Via Bayesian Causal Inference: An Early Analysis of the Commpass Study Data

Abstract CoMMpass [NCT0145429], a study by the Multiple Myeloma Research Foundation (MMRF), collects longitudinal data of newly diagnosed patients' responses to treatment in the context of their genetic and genomic profiles. The rapidly shifting treatment landscape highlights the importance of a deeper understanding of drug response pathways in order to enable better drug targeting and guide drug development. CoMMpass Interim Analysis 7 (IA7) dataset provides extensive genetic and genomic data on a population of almost 800 enrolled patients. Taking advantage of the rich dataset, we apply REFS™ state-of-the-art Bayesian causal inference engine to reverse-engineer the molecular pathways that most likely affect treatment outcomes in the CoMMpass population and to assess their significance in treatment response. The CoMMpass IA7 dataset, after reducing to patients with reasonably complete clinical and molecular data, comprises 452 patients. We aggregated genetic variables into gene region burden scores, drop mRNA and miRNA variables with excessive zero-inflation, and collate a final model data frame of 28200 variables by 452 patients. We then performed causal modeling constrained only by a minimal set of biological considerations but otherwise entirely de novo. The objective of the modeling is to explain the variability in the dataset and, in particular, in the outcomes, by a set of models that are all consistent with the observed disease biology. Such model ensemble captures uncertainty in inference and highlights similarities among the models, allowing us to distinguish confident predictions from incidental ones. For this study, we constructed an ensemble of 256 models (Figure 1). We investigated our model ensemble by the means of systematic perturbations to model variables, observing effects from such perturbations upon treatment outcomes, an approach that we have successfully applied elsewhere. Thus we are able to assess a prospective effect upon an outcome arising from an in vitro intervention, an adjuvant drug treatment, or an imposition of an enrollment criterion upon a clinical study. Assessing the effects of these in silico perturbations upon clinical outcomes, we conclude that key drivers of clinical outcomes, as defined by outcomes' sensitivity to perturbation, fall into broad categories of known response drivers, drivers in known pathways, and potential novel biology, or false positives. All three groups are broadly represented among top results (Table 1). The broad range of known disease modifiers, biomarkers, and drivers, such as stem cell transplant, Ig light chain, or RN7SK, identified as such by the REFS™ model de novo, leads us to have a higher confidence in the importance of the other predicted drivers of clinical outcomes, whether partially known (e.g., DNAH5, FAT1) or novel (e.g., mir3648-1, C19orf68). Furthermore, it will be possible to use future CoMMpass Interim Analyses to validate the significance of the predicted novel drivers and to help improve the quality of the causal model, promoting the discovery of further drivers of clinical outcomes. Figure 1. (a) A REFS model consists of an ensemble of causal networks (b) Consensus (average) causal network topology for the CoMMpass IA7 model, with key outcome variables highlighted Figure 1. (a) A REFS model consists of an ensemble of causal networks (b) Consensus (average) causal network topology for the CoMMpass IA7 model, with key outcome variables highlighted Figure 2. Predicted drivers of clinical outcomes Figure 2. Predicted drivers of clinical outcomes Disclosures Gruber: GNS Healthcare: Employment. Hayete:GNS Healthcare: Employment. Keats:Translational Genomic Research Institute: Employment. Karl:GNS Healthcare: Employment. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Khalil:GNS Healthcare: Employment. </jats:sec

Bayesian Network Models of Multiple Myeloma: Drivers of High Risk and Durable Response

Abstract Introduction Multiple Myeloma (MM)is characterizedby heterogeneous clinical outcomes to existing therapies, which reflects the diverse genetic and molecular properties of tumor clones among patients. This intra-clonal heterogeneity may affect distinct molecular pathways within individual patients, contributing to reduced treatment efficacy over time and eventual relapse. In this work we investigate this problem by applying Bayesian network inference to develop high-dimensional network models of MM based on the Interim Analysis 9 (IA9) CoMMpass trial dataset (NCT0145429), an effort by the Multiple Myeloma Research Foundation (MMRF) to collect longitudinal data of newly-diagnosed patients from the United States, Canada and Europe. We demonstrate that our approach finds a number of known drug targets and identifies potentially novel ones. These targets, in our simulations, affect a number of treatment efficacy outcomes. Methods The IA9 dataset encompasses 645 patients with complete clinical and molecular data. We created an integrated table of clinical and genomic data including RNAseqmeasurements, somatic copy numbers, single nucleotide variants, and structural variants, for a combined input table of 30426 variables by 645 patients. We performed causal modeling using REFS™ Bayesian causal inference engine, constrained only by a minimal set of biological considerations but otherwise entirely de novo. The objective of modeling is to discover the causal mechanisms among variables and, in particular, with respect to the outcomes, by means of a set of Bayesian network models that are consistent with the observed disease biology. Such a model ensemble captures uncertainty in inference and highlights similarities among the models, allowing us to distinguish confident predictions from incidental ones. We investigated our model ensemble by means of systematic perturbations to model variables while observing effects upon treatment outcomes within specific patient backgrounds. Results Drivers of High Risk High riskwas definedas having disease progression before 18 months. The model uncovered a pathway involved in cell cycle regulation that leads to high risk when overexpressed. Specifically, the model identified CDK1, PKMY1, MELK, and NEK2 as the top drivers of the probability of high risk. These genes are "actionable", having drugsbeing investigatedclinically in the context of MM or in other cancers. Drivers of Durable Response Durable responsewas definedas a treatment response that lasts over a year before disease progression. The model was able to identify several novel pathways that appear to drive the probability of a durable response: a pathway of ribosomal genes (RPL6, RPL23, RPL12), a pathway of translation elongation factor EEF1A1 and associated pseudogenes, and a pathway of regulatory noncoding genes MIR1302-9, RP11-946L20.4, RP11-346D14.1, and RP11-506N2.1. Not much is known regarding the connection of these genes to MM. However, the ubiquitin-proteasome pathway, which is central to ribosomal biogenesis, is a major drug target in MM. Conclusions In this work we have developed a causal model of MM. In-silico perturbations of the model uncovered known and novel causal mechanisms for relevant endpoints, including a pathway involved in cell cycle that leads to high risk when dysregulated; a pathway involving ribosomal proteins and translation elongation factors that drives durable response; and several novel noncoding regulatory genes that are relevant to various measures of response. Beyond generating novel targets of immediate biological interest, our work demonstrates the promise of large-scale de novo network inference to this and similar problems in the future. Disclosures Gruber: GNS Healthcare: Employment. McBride:Instat: Employment. Runge:GNS Healthcare: Employment. Wuest:GNS Healthcare: Employment. Hadzi:GNS Healthcare: Employment. Lonial:BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Onyx: Consultancy. Khalil:GNS Healthcare: Employment. Hayete:GNS Healthcare: Employment. </jats:sec

Technico-Economical Diagnosis of Traditional Goats Farms Based on Zootechnical Performances in the Locality of Wakwa (Adamawa Region-Cameroon)

A survey was carried out in the locality of Wakwa, region of Adamawa-Cameroon during the month of April 2021. The purpose of this study was to determine the elements of calculation of the gross product, intermediate consumption, and the method of calculation of the added value of traditional farms in the area with the zootechnical parameters of the goat as elements of economic production through the administration of a previously established questionnaire. The questions asked concerned: the socio-economic profile of the breeders, the farming or breeding system practiced the zootechnical parameters and the price and cost elements of inputs. It was noticed from this survey that the gender profile of the farmers is made up mostly of men (80%), most of who were above twenty years (92%), with agriculture (56%) as principal activity, trade (20%), handicrafts, pottery, sewing and other side activities (24%). They were mostly persons having received no formal education (68%). Regarding zootechnical parameters, the size of the herd did not exceed 10 animals for the majority of farms (76%). The selling price of the animals varied between 15,000 FCFA and 60,000 FCFA. The Litter of birth goat obeyed the principle of twinning with less than two litters per year or five cubs for a goat. The mortality of neonates and kids was less than 30%, which brings the number of adult goats to between 3 and 4 per year. Grosso modo, the goat breeding activity provides breeders with an estimated annual income of around 64,251.709 CFA, with a total cost of intermediate consumption over the mother's career of 7,904.9922 FCFA for a Gross Added Value of a mother over the duration of her career estimated at 143,300.698 FCFA

Group versus individual antenatal and first year postpartum care: Study protocol for a multi-country cluster randomized controlled trial in Kenya and Nigeria

Background: Antenatal care (ANC) in many low- and middle-income countries is under-utilized and of sub-optimal quality. Group ANC (G-ANC) is an intervention designed to improve the experience and provision of ANC for groups of women (cohorts) at similar stages of pregnancy. Methods: A two-arm, two-phase, cluster randomized controlled trial (cRCT) (non-blinded) is being conducted in Kenya and Nigeria. Public health facilities were matched and randomized to either standard individual ANC (control) or G-ANC (intervention) prior to enrollment. Participants include pregnant women attending first ANC at gestational age &lt;24 weeks, health care providers, and sub-national health managers. Enrollment ended in June 2017 for both countries. In the intervention arm, pregnant women are assigned to cohorts at first ANC visit and receive subsequent care together during five meetings facilitated by a health care provider (Phase 1). After birth, the same cohorts meet four times over 12 months with their babies (Phase 2). Data collection was performed through surveys, clinical data extraction, focus group discussions, and in-depth interviews. Phase 1 data collection ended in January 2018 and Phase 2 concludes in November 2018. Intention-to-treat analysis will be used to evaluate primary outcomes for Phases 1 and 2: health facility delivery and use of a modern method of family planning at 12 months postpartum, respectively. Data analysis and reporting of results will be consistent with norms for cRCTs. General estimating equation models that account for clustering will be employed for primary outcome analyzes. Results: Overall 1,075 and 1,013 pregnant women were enrolled in Nigeria and Kenya, respectively. Final study results will be available in February 2019. Conclusions: This is the first cRCT on G-ANC in Africa. It is among the first to examine the effects of continuing group care through the first year postpartum. Registration: Pan African Clinical Trials Registry PACTR201706002254227 May 02, 2017</ns4:p

Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in infected children under six years of age-2

E Pre-Rx samples in (A) and (B) were collected before SP treatment. The Post-Rx samples in (A) and (B) were collected seven days after SP treatment. Samples from children exhibiting no evidence of falciparum infection were collected during a season of low transmission (A, LT). ANA Index values were calculated according to assay kit instructions and interpreted as negative, ≤0.90; equivocal, 0.91-1.09; and positive, ≥1.10. Anti-dsDNA levels were calculated according to assay kit instructions and interpreted as negative 200 IU/ml.<p><b>Copyright information:</b></p><p>Taken from "Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in infected children under six years of age"</p><p>http://www.malariajournal.com/content/7/1/41</p><p>Malaria Journal 2008;7():41-41.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2275287.</p><p></p