The difficulty with responding to policy changes for HIV and infant feeding in Malawi

<p>Abstract</p> <p>Background</p> <p>When and how to wean breastfed infants exposed to HIV infection has provoked extensive debate, particularly in low-income countries where safe alternatives to breastfeeding are rarely available. Although there is global consensus on optimal infant-feeding practices in the form of guidelines, practices are sub-optimal in much of sub-Saharan Africa. Policy-makers and health workers face many challenges in adapting and implementing these guidelines.</p> <p>Methods</p> <p>This paper is based on in-depth interviews with five policy-makers and 11 providers of interventions to prevent mother-to-child transmission (PMTCT) of HIV, participant observations during clinic sessions and site visits.</p> <p>Results</p> <p>The difficulties with adapting the global infant-feeding guidelines in Malawi have affected the provision of services. There was a lack of consensus on HIV and infant-feeding at all levels and general confusion about the 2006 guidelines, particularly those recommending continued breastfeeding after six months if replacement feeding is not acceptable, feasible, affordable, sustainable and safe. Health workers found it particularly difficult to advise women to continue breastfeeding after six months. They worried that they would lose the trust of the PMTCT clients and the population at large, and they feared that continued breastfeeding was unsafe. Optimal support for HIV-infected women was noted in programmes where health workers were multi-skilled; coordinated their efforts and had functional, multidisciplinary task forces and engaged communities. The recent 2009 recommendations are the first to support antiretroviral (ARV) use by mothers or children during breastfeeding. Besides promoting maternal health and providing protection against HIV infection in children, the new Rapid Advice has the potential to resolve the difficulties and confusion experienced by health workers in Malawi.</p> <p>Conclusions</p> <p>The process of integrating new evidence into institutionalised actions takes time. The challenge of keeping programmes, and especially health workers, up-to-standard is a dynamic process. Effective programmes require more than basic resources. Along with up-to-date information, health workers need contextualized, easy-to-follow guidelines in order to effectively provide services. They also require supportive supervision during the processes of change. Policy-makers should ensure that consensus is carefully considered and that comprehensive perspectives are incorporated when adapting the global guidelines.</p

Caesarean Section among Referred and Self-Referred Birthing Women: A Cohort Study from a Tertiary Hospital, Northeastern Tanzania.

The inequity in emergency obstetric care access in Tanzania is unsatisfactory. Despite an existing national obstetric referral system, many birthing women bypass referring facilities and go directly to higher-level care centres. We wanted to compare Caesarean section (CS) rates among women formally referred to a tertiary care centre versus self-referred women, and to assess the effect of referral status on adverse outcomes after CS. We used data from 21,011 deliveries, drawn from the birth registry of a tertiary hospital in northeastern Tanzania, during 2000-07. Referral status was categorized as self-referred if the woman had bypassed or not accessed referral, or formally-referred if referred by a health worker. Because CS indications were insufficiently registered, we applied the Ten-Group Classification System to determine the CS rate by obstetric group and referral status. Associations between referral status and adverse outcomes after CS delivery were analysed using multiple regression models. Outcome measures were CS, maternal death, obstetric haemorrhage ≥ 750 mL, postpartum stay > 9 days, neonatal death, Apgar score < 7 at 5 min and neonatal ward transfer. Referral status contributed substantially to the CS rate, which was 55.0% in formally-referred and 26.9% in self-referred birthing women. In both groups, term nulliparous singleton cephalic pregnancies and women with previous scar(s) constituted two thirds of CS deliveries. Low Apgar score (adjusted OR 1.42, 95% CI 1.09-1.86) and neonatal ward transfer (adjusted OR 1.18, 95% CI 1.04-1.35) were significantly associated with formal referral. Early neonatal death rates after CS were 1.6% in babies of formally-referred versus 1.2% in babies of self-referred birthing women, a non-significant difference after adjusting for confounding factors (adjusted OR 1.37, 95% CI 0.87-2.16). Absolute neonatal death rates were > 2% after CS in breech, multiple gestation and preterm deliveries in both referral groups. Women referred for delivery had higher CS rates and poorer neonatal outcomes, suggesting that the formal referral system successfully identifies high-risk birth, although low volume suggests underutilization. High absolute rates of post-CS adverse outcomes among breech, multiple gestation and preterm deliveries suggest the need to target self-referred birthing women for earlier professional intrapartum care

Use of voltammetric solid-state (micro)electrodes for studying biogeochemical processes: Laboratory measurements to real time measurements with an in situ electrochemical analyzer (ISEA)

Solid-state voltammetric (micro)electrodes have been used in a variety of environments to study biogeochemical processes. Here we show the wealth of information that has been obtained in the study of sediments, microbial mats, cultures and the water column including hydrothermal vents. Voltammetric analyzers have been developed to function with operator guidance and in unattended mode for temporal studies with an in situ electrochemical analyzer (ISEA). The electrodes can detect the presence (or absence) of a host of redox species and trace metals simultaneously. The multi-species capacity of the voltammetric electrode can be used to examine complex heterogeneous environments such as the root zone of salt marsh sediments. The data obtained with these systems clearly show that O2 and Mn2+ profiles in marine sedimentary porewaters and in microbial biofilms on metal surfaces rarely overlap indicating that O2 is not a direct oxidant for Mn2+. This lack of overlap was suggested originally by Joris Gieskes\u27 group. In waters emanating from hydrothermal vents, Fe2+, H2S and soluble molecular FeS clusters (FeSaq) are detected indicating that the reactants for the pyrite formation reaction are H2S and soluble molecular FeS clusters. Using the ISEA with electrodes at fixed positions, data collected continuously over three days near a Riftia pachyptila tubeworm field generally show that O2 and H2S anti-correlate and that H2S and temperature generally correlate. Unlike sedimentary environments, the data clearly show that Riftia live in areas where both O2 and H2S co-exist so that its endosymbiont bacteria can perform chemosynthesis. However, physical mixing of diffuse flow vent waters with oceanic bottom waters above or to the side of the tubeworm field can dampen these correlations or even reverse them. Voltammetry is a powerful technique because it provides chemical speciation data (e.g.; oxidation state and different elemental compounds/ions) as well as quantitative data. Because (micro)organisms occupy environmental niches due to the system\u27s chemistry, it is necessary to know chemical speciation. Voltammetric methods allow us to study how chemistry drives biology and how biology can affect chemistry for its own benefit

Pregnancy outcome among HIV-infected women on different antiretroviral therapies in Ethiopia:a cohort study

Objective: The objective of the study was to compare pregnancy outcomes according to maternal antiretroviral treatment (ART) regimens. Design: A retrospective cohort study. Participants and settings: Clinical data was extracted from ART exposed pregnancies of HIV-infected Ethiopian women attending antenatal care follow-up in public health facilities in Addis Ababa between February 2010 and October 2016. Outcomes: The primary outcomes evaluated were preterm birth, low birth weight and small-for-gestational-age. Results: A total 1663 of pregnancies exposed to ART were included in the analyses. Of these pregnancies, 17% resulted in a preterm birth, 19% in low birth weight and 32% in a small-for-gestational-age baby. Compared with highly active antiretroviral therapy (HAART) initiated during pregnancy, zidovudine monotherapy was less likely to result in preterm birth (adjusted OR 0.35, 95% CI 0.19 to 0.64) and low birth weight (adjusted OR 0.48, 95% CI 0.24 to 0.94). We observed no differential risk of preterm birth, low birth weight and small-for-gestational-age, when comparing women who initiated HAART during pregnancy to women who initiated HAART before conception. The risk for preterm birth was higher in pregnancies exposed to nevirapine-based HAART (adjusted OR 1.44, 95% CI 1.06 to 1.96) compared with pregnancies exposed to efavirenz-based HAART. Comparing nevirapine-based HAART with efavirenz-based HAART indicated no strong evidence of increased risk of low birth weight or small-for-gestational-age. Conclusions: We observed a higher risk of preterm birth among women who initiated HAART during pregnancy compared with zidovudine monotherapy. Pregnancies exposed to nevirapine-based HAART also had a greater risk of preterm births compared with efavirenz-based HAART

MEK inhibition synergizes with TYK2 inhibitors in NF1-associated malignant peripheral nerve sheath tumors

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. RESULTS: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. CONCLUSIONS: These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST

Influence of larval transport and temperature on recruitment dynamics of North Sea cod (Gadus morhua) across spatial scales of observation

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Romagnoni, G., Kvile, K. o., Dagestad, K., Eikeset, A. M., Kristiansen, T., Stenseth, N. C., & Langangen, O. Influence of larval transport and temperature on recruitment dynamics of North Sea cod (Gadus morhua) across spatial scales of observation. Fisheries Oceanography, (2020): 1-16, doi:10.1111/fog.12474.The survival of fish eggs and larvae, and therefore recruitment success, can be critically affected by transport in ocean currents. Combining a model of early‐life stage dispersal with statistical stock–recruitment models, we investigated the role of larval transport for recruitment variability across spatial scales for the population complex of North Sea cod (Gadus morhua ). By using a coupled physical–biological model, we estimated the egg and larval transport over a 44‐year period. The oceanographic component of the model, capable of capturing the interannual variability of temperature and ocean current patterns, was coupled to the biological component, an individual‐based model (IBM) that simulated the cod eggs and larvae development and mortality. This study proposes a novel method to account for larval transport and success in stock–recruitment models: weighting the spawning stock biomass by retention rate and, in the case of multiple populations, their connectivity. Our method provides an estimate of the stock biomass contributing to recruitment and the effect of larval transport on recruitment variability. Our results indicate an effect, albeit small, in some populations at the local level. Including transport anomaly as an environmental covariate in traditional stock–recruitment models in turn captures recruitment variability at larger scales. Our study aims to quantify the role of larval transport for recruitment across spatial scales, and disentangle the roles of temperature and larval transport on effective connectivity between populations, thus informing about the potential impacts of climate change on the cod population structure in the North Sea.G.R. was supported by the Norden Top‐level Research Initiative sub‐programme “Effect Studies and Adaptation to Climate Change” through the Nordic Centre for Research on Marine Ecosystems and Resources under Climate Change (NorMER). K.Ø.K. was supported by the WHOI John H. Steele Post‐doctoral Scholar award and VISTA – a basic research program in collaboration between The Norwegian Academy of Science and Letters, and Equinor. We thank an anonymous referee for valuable comments that substantially improved the article

Adult body growth and reproductive investment vary markedly within and across Atlantic and Pacific herring: a meta-analysis and review of 26 stocks

Life-history traits of Pacific (Clupea pallasii) and Atlantic (Clupea harengus) herring, comprising both local and oceanic stocks subdivided into summer-autumn and spring spawners, were extensively reviewed. The main parameters investigated were body growth, condition, and reproductive investment. Body size of Pacific herring increased with increasing latitude. This pattern was inconsistent for Atlantic herring. Pacific and local Norwegian herring showed comparable body conditions, whereas oceanic Atlantic herring generally appeared stouter. Among Atlantic herring, summer and autumn spawners produced many small eggs compared to spring spawners, which had fewer but larger eggs—findings agreeing with statements given several decades ago. The 26 herring stocks we analysed, when combined across distant waters, showed clear evidence of a trade-off between fecundity and egg size. The size-specific individual variation, often ignored, was substantial. Additional information on biometrics clarified that oceanic stocks were generally larger and had longer life spans than local herring stocks, probably related to their longer feeding migrations. Body condition was only weakly, positively related to assumingly in situ annual temperatures (0–30 m depth). Contrarily, body growth (cm × y−1), taken as an integrator of ambient environmental conditions, closely reflected the extent of investment in reproduction. Overall, Pacific and local Norwegian herring tended to cluster based on morphometric and reproductive features, whereas oceanic Atlantic herring clustered separately. Our work underlines that herring stocks are uniquely adapted to their habitats in terms of trade-offs between fecundity and egg size whereas reproductive investment mimics the productivity of the water in question.publishedVersio

Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study

BACKGROUND: The leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors. METHODS AND FINDINGS: This multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier that differentiates MPNST from PN with 86% pretreatment accuracy (91% specificity, 75% sensitivity) and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (participants = 16, plasma samples = 16), PN (participants = 23, plasma samples = 23), and MPNST (participants = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001) as well as cfDNA fragment length (P \u3c 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. No other covariates were significant on multivariate logistic regression. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from 2 major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort. CONCLUSIONS: Tumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations