Protective effects of diversified diets for dietary folate adequacy and serum homocysteine in breastfeeding mothers amid historic drought.

OBJECTIVES: The United Nations recommends that women consume ≥5 food groups, also known as the minimum dietary diversity score for women (MDD-W), for nutritional health. This is increasingly unattainable for populations in climate hot zones coping with food insecurity by prioritizing calories over dietary breadth. Breastfeeding mothers may be particularly vulnerable to adverse health impacts of low dietary diversity due to elevated nutritional requirements for lactation. We investigated how the protective effects of MDD-W for folate adequacy varies by MDD-W score and mother-infant life history characteristics. METHODS: We conducted a secondary analysis of cross-sectional data from breastfeeding mothers (n = 228) in northern Kenya, surveyed during the 2006 Horn-of-Africa drought. Logistic regression models for adequate dietary folate (and vitamins B12 and B6) and normal homocysteine (folate-replete status) evaluated the effect of MDD-W alone and in interaction with infant/maternal characteristics. RESULTS: MDD-W (as ordinal or dichotomous variable) was positively associated with adequate folate (and vitamin B12). Having male infant was inversely associated with adequate dietary folate. MDD-W was generally unassociated with homocysteine. However, there was an interaction between MDD-W and sex of the infant. Namely, MDD-W ≥ 3 predicted increased probability of normal homocysteine among mothers with female infants but not male infants. CONCLUSIONS: Diets consisting of three or more food groups may protect adequate folate intake for many breastfeeding mothers. More research is needed to establish what level of dietary diversity would protect against hyperhomocysteinemia during breastfeeding and what factors promote or hinder the benefit of diversified diets on maternal folate nutrition.

In-kitchen aerosol exposure in twelve cities across the globe.

Poor ventilation and polluting cooking fuels in low-income homes cause high exposure, yet relevant global studies are limited. We assessed exposure to in-kitchen particulate matter (PM2.5 and PM10) employing similar instrumentation in 60 low-income homes across 12 cities: Dhaka (Bangladesh); Chennai (India); Nanjing (China); Medellín (Colombia); São Paulo (Brazil); Cairo (Egypt); Sulaymaniyah (Iraq); Addis Ababa (Ethiopia); Akure (Nigeria); Blantyre (Malawi); Dar-es-Salaam (Tanzania) and Nairobi (Kenya). Exposure profiles of kitchen occupants showed that fuel, kitchen volume, cooking type and ventilation were the most prominent factors affecting in-kitchen exposure. Different cuisines resulted in varying cooking durations and disproportional exposures. Occupants in Dhaka, Nanjing, Dar-es-Salaam and Nairobi spent > 40% of their cooking time frying (the highest particle emitting cooking activity) compared with âˆ¼ 68% of time spent boiling/stewing in Cairo, Sulaymaniyah and Akure. The highest average PM2.5 (PM10) concentrations were in Dhaka 185 ± 48 (220 ± 58) µg m-3 owing to small kitchen volume, extensive frying and prolonged cooking compared with the lowest in Medellín 10 ± 3 (14 ± 2) µg m-3. Dual ventilation (mechanical and natural) in Chennai, Cairo and Sulaymaniyah reduced average in-kitchen PM2.5 and PM10 by 2.3- and 1.8-times compared with natural ventilation (open doors) in Addis Ababa, Dar-es-Salam and Nairobi. Using charcoal during cooking (Addis Ababa, Blantyre and Nairobi) increased PM2.5 levels by 1.3- and 3.1-times compared with using natural gas (Nanjing, Medellin and Cairo) and LPG (Chennai, Sao Paulo and Sulaymaniyah), respectively. Smaller-volume kitchens (<15 m3; Dhaka and Nanjing) increased cooking exposure compared with their larger-volume counterparts (Medellin, Cairo and Sulaymaniyah). Potential exposure doses were highest for Asian, followed by African, Middle-eastern and South American homes. We recommend increased cooking exhaust extraction, cleaner fuels, awareness on improved cooking practices and minimising passive occupancy in kitchens to mitigate harmful cooking emissions.

Exploring perspectives on antimicrobial stewardship: a qualitative study of health managers in Kenya.

BACKGROUND: Antimicrobial resistance is a significant public health concern with the establishment of antimicrobial stewardship in hospitals being increasingly obligatory. Perspectives and insights of health managers on antimicrobial stewardship (AMS), complementary health services and building blocks are imperative towards implementation of robust AMS programs. This study aimed to understand perspectives of hospital managers on AMS and identify areas of management engagement while addressing potential blockades to change. METHODS: A cross-sectional, qualitative, multicenter study was conducted in three hospitals in Kenya. Key-informant interviews on perspectives on AMS were administered to hospital managers. Qualitative data was captured using audio tapes and field notes, transcribed and managed using NVivo 12 software. An iterative process was used to develop the thematic framework and updated in two rounds of iteration analysis. Analysis charts for each emergent theme were developed and categorized across all participants. RESULTS: Perspectives on AMS are described in five thematic categories; Importance of antimicrobial stewardship and the role of medicines and therapeutics committee, availability of antimicrobial formulary and usage surveillance systems, laboratory competency and recommendations for infection prevention and management, educational resources and communications channels available, building blocks and low-lying fruits for Antimicrobial Stewardship Committees. The role of stewardship collaboration in diagnosis and antimicrobial prescription was alluded to with managers indicating a growing rise in occurrence of antimicrobial resistance. There lacked contextualized, hospital specific antimicrobial formulary and adequate laboratory competency. Staff training and communication channels were available in varying capacity across the three hospitals. Building blocks identified include medicines and therapeutics committee, education, and training platforms (Continuous Medical Education and Continuous Professional Development activities) and hospital leadership commitment. CONCLUSIONS: The practice of antimicrobial stewardship is not implemented and well developed as demonstrated by lack of core AMS complementary health services. However, the health managers are aware of the fundamental importance of antimicrobial stewardship programs and the vast benefits of implementation and institutionalization of AMS to hospitals and their clients. The findings underpin the importance of understanding and incorporating perspectives of health managers on existing contextual mechanisms that can be leveraged on to establish robust AMS programs in the fight against antimicrobial resistance.

Detection of Brucella spp. in raw milk from various livestock species raised under pastoral production systems in Isiolo and Marsabit Counties, northern Kenya.

INTRODUCTION: Brucellosis is an important zoonotic disease in Kenya, and identifying the bacteria in milk is important in assessing the risk of exposure in people. METHODS: A cross-sectional study that involved 175 households was implemented in the pastoral counties of Marsabit and Isiolo in Kenya. Pooled milk samples (n = 164) were collected at the household level, and another 372 were collected from domesticated lactating animals (312 goats, 7 sheep, 50 cattle and 3 camels). Real-time polymerase chain reaction (qPCR) testing of the milk samples was performed to identify Brucella species. Brucella anti-LPS IgG antibodies were also detected in bovine milk samples using an indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: Based on the qPCR, the prevalence of the pathogen at the animal level (considering samples from individual animals) was 2.4% (95% confidence interval (CI) 1.1-4.5) and 3.0% (CI: 1.0-7.0) in pooled samples. All 14 samples found positive by qPCR were from goats, with 10 contaminated with B. abortus and 4 with B. melitensis. The Brucella spp. antibody prevalence in bovine milk using the milk ELISA was 26.0% (95% CI: 14.6-40.3) in individual animal samples and 46.3% (95% CI: 30.7-62.6) in pooled samples. CONCLUSION: The study is the first in Kenya to test for Brucella spp. directly from milk using qPCR without culturing for the bacteria. It also detected B. abortus in goats, suggesting transmission of brucellosis between cattle and goats. The high prevalence of Brucella spp. is a significant public health risk, and there is a need for intervention strategies necessary in the study area.

Preoperative Fasting among Adult Patients for Elective Surgery in a Kenyan Referral Hospital.

Background. Preoperative fasting (POF) is physiologically and precautionary important during anesthesia and surgery. POF from midnight has been practiced despite the recommended shorter practice. Objective. Assessing preoperative fasting among adult patients scheduled for elective surgery at Kenyatta National Hospital (KNH). Methods. A descriptive cross-sectional study involving 65 surgical patients. A questionnaire of mixed questions on demographics, reasons, source of instructions, opinion on instructions, time, premedication practices, outcome, and complains on NPO was used. Analysis was quantitatively done with SPSS v. 22. Ethical approval was obtained from KNH-UoN ERC. Results. Of the respondents 93.8% lacked knowledge on the correct reasons for POF and felt that the instructions were unclear and less important <50%. POF instructions were administered by nurses 80%, anesthetists 15%, and surgeons 5%. Most of respondents (73.8%) fasted > 15 hours. The POF outcomes were rated moderately challenging as follows: prolonged wait for surgery 44.6%, thirst 43.1%, hunger 36.9%, and anxiety 29.2%. Conclusion. Nurses are critical in providing POF instructions and care, and patient knowledge level is a mirror reflection of the quality of interventions. This underscores the need to build capacity for nurses and strengthen the health system to offer individualized preoperative interventions as well as monitoring and clinical auditing of fasting practices.

Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 µM, replicon EC(50)>100 µM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 µM, replicon EC(50)=1.4 µM) and 7r (NS5B IC(50)=0.017 µM, replicon EC(50)=0.3 µM) with improved enzyme and replicon activity.

Screening and rank ordering of reversible mechanism-based inhibitors of hepatitis C virus NS3 protease using electrospray ionization mass spectrometry.

An affinity-selection study using size exclusion chromatography (SEC) combined with off-line electrospray ionization mass spectrometry (ESI-MS) was performed on libraries of peptidic α-ketoamide inhibitors directed against the hepatitis C virus (HCV) NS3 protease. A limiting amount of HCV NS3 protease (25 µM) was incubated with equimolar amounts (100 µM) of 49 reversible mechanism-based ketoamide inhibitors, previously grouped into seven sets to ensure clearly distinguishable mass differences of the enzyme-inhibitor complexes (>10 Da). The unbound compounds were separated rapidly from the protease and the protease-inhibitor complexes by SEC spin columns. The eluate of the SEC was immediately analyzed by direct-infusion ESI-MS. An enzyme-inhibitor complex, with a molecular mass corresponding to the NS3 protease binding to the preferred inhibitor, SCH212986, was the only molecular species detected. By increasing the molar ratio of HCV NS3 protease to inhibitors to 1:2 while keeping the inhibitors' concentration constant, the complex of the second most tightly bound inhibitor, SCH215426, was also identified. Although the potencies of these inhibitors were virtually un-measurable by kinetic assays, a rank order of CVS4441 > SCH212986 > SCH215426 was deduced for their inhibition potencies by direct competition experiment with CVS4441 (K(i)*>80 µM). As discussed in the article, through judicious application of this strategy, even large libraries of fairly weak, reversible and slow-binding inhibitors could be rapidly screened and rank ordered to provide critical initial structure-activity insights.

Current drug discovery strategies for treatment of hepatitis C virus infection.

OBJECTIVES: Hepatitis C virus (HCV) infection represents a major worldwide-health problem. The current standard of care is combination therapy with pegylated interferon and ribavirin, which achieves a successful response in only approximately 40% of genotype I patients. KEY FINDINGS: The biology of HCV infection has been under intensive research and important progress has been made in understanding the replication cycle of the virus. Several therapeutic targets have been under investigation, such as NS3 protease, NS4A replicase and NS5B polymerase. New potential targets, such as NS2 protease, as well as CD-81 and claudin-1 entry co-receptors, have also been identified. SUMMARY: Clinical evaluations of drug candidates targeting NS3 protease, NS4A cofactor, and NS5B polymerase have demonstrated the potential of developing small molecules that interfere with the replication of the virus. Additional issues, including genotype coverage, resistant mutations, and combination therapy represent major challenges for future drug discovery efforts.

Discovery of C-imidazole azaheptapyridine FPT inhibitors.

The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.