Estimating minimum dietary diversity for children aged 6-23 months: a comparison of agreement and cost of two recall methods in Cambodia and Zambia.

OBJECTIVE: To compare the agreement and cost of two recall methods for estimating children's minimum dietary diversity (MDD). DESIGN: We assessed child's dietary intake on two consecutive days: an observation on day one, followed by two recall methods (list-based recall and multiple-pass recall) administered in random order by different enumerators at two different times on day two. We compared the estimated MDD prevalence using survey-weighted linear probability models following a two one-sided test equivalence testing approach. We also estimated the cost-effectiveness of the two methods. SETTING: Cambodia (Kampong Thom, Siem Reap, Battambang, and Pursat provinces) and Zambia (Chipata, Katete, Lundazi, Nyimba, and Petauke districts). PARTICIPANTS: Children aged 6-23 months: 636 in Cambodia and 608 in Zambia. RESULTS: MDD estimations from both recall methods were equivalent to the observation in Cambodia but not in Zambia. Both methods were equivalent to the observation in capturing most food groups. Both methods were highly sensitive although the multiple-pass method accurately classified a higher proportion of children meeting MDD than the list-based method in both countries. Both methods were highly specific in Cambodia but moderately so in Zambia. Cost-effectiveness was better for the list-based recall method in both countries. CONCLUSION: The two recall methods estimated MDD and most other infant and young child feeding indicators equivalently in Cambodia but not in Zambia, compared to the observation. The list-based method produced slightly more accurate estimates of MDD at the population level, took less time to administer and was less costly to implement.

Assessing the performance of national sentinel food lists at subnational levels in six countries.

OBJECTIVE: To assess how well national sentinel lists of the most frequently consumed foods in each food group capture data at subnational levels to measure minimum diet diversity (MDD). DESIGN: We analysed data from seven surveys with 24-h open dietary recalls to evaluate: (1) the percentage of reported foods that were included in each sentinel food list; (2) whether these lists captured consumption of some food groups better than others and (3) differences between estimates of dietary diversity calculated from all food items mentioned in the open 24-h recall v. only food items included in the sentinel lists. SETTING: Seven subnational areas: Bangladesh (2), Benin, Colombia, Kenya, Malawi and Nepal. PARTICIPANTS: 8094 women 15-49 years; 4588 children 6-23 months. RESULTS: National sentinel food lists captured most foods reportedly consumed by women (84 %) and children (86 %). Food groups with the highest variability were 'other fruits' and 'other vegetables.' MDD calculated from the sentinel list was, on average, 6·5 (women) and 4·1 (children) percentage points lower than when calculated from open 24-h recalls, with a statistically significant difference in most subnational areas. CONCLUSION: National sentinel food lists can provide reliable data at subnational levels for most food groups, with some variability by country and sub-region. Assessing the accuracy of national sentinel food lists, especially for fruits and vegetables, before using them at the subnational level could avoid potentially underestimating dietary diversity and provide more accurate local information for programmes, policy and research.

Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins.

WHAT IS KNOWN AND OBJECTIVES: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin). METHODS: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay. RESULTS: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/- 79.59 ng/ml vs. control 104.09 +/- 44.56 ng/ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/- 157.53 ng/ml vs control 207.6 +/- 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/- 95.93 ng/ml vs control 112.32 +/- 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co-administered apixaban and diltiazem were statistically significant compared with the aggregated non-CYP3A4 control groups (no statin and rosuvastatin). WHAT IS NEW AND CONCLUSION: Herein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P-gp and CYP3A4 inhibitors (amiodarone or diltiazem) co-administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events in high-risk patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non-3A4 statin.

Exclusive breastfeeding: Measurement to match the global recommendation.

The World Health Organization (WHO) and United Nations Children's Fund (UNICEF) recommend exclusive breastfeeding (EBF) for the first 6 months of life. To estimate the proportion of infants that are exclusively breastfed, many agencies use the point prevalence of EBF among infants currently 0-5.9 months of age, as recommended by WHO and UNICEF. This measure tends to overestimate the percentage of infants that are exclusively breastfed for the entire recommended period. We compared five methods of measuring EBF, using data from three large-scale cross-sectional surveys. The five methods were: the WHO/UNICEF recommended method (EBF-24H); an estimate of EBF for 6 months, using the 24-h recall among infants 4-5.9 and 6-7.9 months (EBF-24H-Pul); a since birth recall (EBF-SB); an estimate of EBF for 6 months, using the since-birth recall among infants 4-5.9 and 6-7.9 months (EBF-SB-Pul); a retrospective measure of EBF collected from infants 6-11.9 months, based on the age of introduction of liquids and foods (EBF-AI). EBF-24H-Pul and EBF-SB-Pul produced lower estimates of EBF than other measures, while also aligning better with the WHO recommendation, but may be difficult to estimate from multipurpose surveys due to sample size limitations. The EBF-AI method produced estimates between these, aligns well with the WHO recommendation and can be easily collected in large-scale household surveys. Additional validation of the EBF-24-Pul, EBF-SB-Pul, and EBF-AI methods is recommended to understand how accurately they measure EBF for the recommended 6-month period.

Global mid-upper arm circumference cut-offs for adults: a call to action.

Since 2009, mid-upper arm circumference (MUAC) has become an accepted measure for screening children for acute malnutrition and determining eligibility for services to manage acute malnutrition. Use of MUAC has increased the reach and enhanced the quality of community-based management of acute malnutrition services. Increasingly, MUAC is also used to assess nutritional status and eligibility for nutrition support among adolescents and adults, including pregnant and lactating women and HIV and TB clients. However, globally recognised cut-offs have not been established to classify malnutrition among adults using MUAC. Therefore, different countries and programmes use different MUAC cut-offs to determine eligibility for programme services. Patient monitoring guidelines provided by WHO for country adaptation to support the integrated management of adult illness do not include MUAC, in part because guidance does not exist about what MUAC cut-off should trigger further action.

Human health alters the sustainability of fishing practices in East Africa.

Understanding feedbacks between human and environmental health is critical for the millions who cope with recurrent illness and rely directly on natural resources for sustenance. Although studies have examined how environmental degradation exacerbates infectious disease, the effects of human health on our use of the environment remains unexplored. Human illness is often tacitly assumed to reduce human impacts on the environment. By this logic, ill people reduce the time and effort that they put into extractive livelihoods and, thereby, their impact on natural resources. We followed 303 households living on Lake Victoria, Kenya over four time points to examine how illness influenced fishing. Using fixed effect conditional logit models to control for individual-level and time-invariant factors, we analyzed the effect of illness on fishing effort and methods. Illness among individuals who listed fishing as their primary occupation affected their participation in fishing. However, among active fishers, we found limited evidence that illness reduced fishing effort. Instead, ill fishers shifted their fishing methods. When ill, fishers were more likely to use methods that were illegal, destructive, and concentrated in inshore areas but required less travel and energy. Ill fishers were also less likely to fish using legal methods that are physically demanding, require travel to deep waters, and are considered more sustainable. By altering the physical capacity and outlook of fishers, human illness shifted their effort, their engagement with natural resources, and the sustainability of their actions. These findings show a previously unexplored pathway through which poor human health may negatively impact the environment.

Updating the modified Thompson test by using whole-body bioluminescence imaging to replace traditional efficacy testing in experimental models of murine malaria.

BACKGROUND: Rodent malaria models are extensively used to predict treatment outcomes in human infections. There is a constant need to improve and refine these models by innovating ways to apply new scientific findings and cutting edge technologies. In addition, and in accordance with the three R's of animal use in research, in vivo studies should be constantly refined to avoid unnecessary pain and distress to the experimental animals by using preemptive euthanasia as soon as the main scientific study objective has been accomplished. METHODS: The new methodology described in this manuscript uses the whole-body bioluminescence signal emitted by transgenic, luciferase-expressing Plasmodium berghei parasites to assess the parasite load predicted parasitaemia (PLPP) in drug and control treated female ICR-CD1 mice infected with 1 × 105 luciferase-expressing P. berghei (ANKA strain) infected erythrocytes. This methodology can replace other time-consuming and expensive methods that are routinely used to measure parasitaemia in infected animals, such as Giemsa-stained thin blood smears and flow cytometry. RESULTS: There is a good correlation between whole-body bioluminescence signal and parasitaemia measured using Giemsa-stained thin blood smears and flow cytometry respectively in donor and study mice in the modified Thompson test. The algebraic formulas which represent these correlations can be successfully used to assess PLPP in donor and study mice. In addition, the new methodology can pinpoint sick animals 2-8 days before they would have been otherwise diagnosed based on behavioural or any other signs of malaria disease. CONCLUSIONS: The new method for predicting parasitaemia in the modified Thompson test is simple, precise, objective, and minimizes false positive results that can lead to the premature removal of animals from study. Furthermore, from the animal welfare perspective of replace, reduce, and refine, this new method facilitates early removal of sick animals from study as soon as the study objective has been achieved, in many cases well before the clinical signs of disease are present.

Evaluation of a social network intervention on child feeding practices and caregiver knowledge.

Food insecurity and poor infant and young child feeding (IYCF) practices contribute to undernutrition. The Kanyakla Nutrition Program was developed in rural Kenya to provide knowledge alongside social support for recommended IYCF practices. Utilizing a social network approach, the Kanyakla Nutrition Program trained community health workers (CHWs) to engage mothers, fathers, and grandparents in nutrition education and discussions about strategies to provide instrumental, emotional, and information support within their community. The 12-week programme included six sessions and was implemented on Mfangano Island, Kenya, in 2014-2015. We analysed intervention effects on (a) nutrition knowledge among community members or CHWs and (2) IYCF practices among children 1-3 years. Nutrition knowledge was assessed using a postintervention comparison among intervention (community, n = 43; CHW, n = 22) and comparison groups (community, n = 149; CHW, n = 64). We used a quasi-experimental design and difference-in-difference to assess IYCF indicators using dietary recall data from an ongoing cohort study among intervention participants (n = 48) with individuals living on Mfangano Island where the intervention was not implemented (n = 178) before the intervention, within 1 month postintervention, and 6 months postintervention. Findings showed no effect of the intervention on IYCF indicators (e.g., dietary diversity and meal frequency), and less than 15% of children met minimum acceptable diet criteria at any time point. However, knowledge and confidence among community members and CHWs were significantly higher 2 years postintervention. Thus, a social network approach had an enduring effect on nutrition knowledge, but no effects on improved IYCF practices.

Quantity and species of fish consumed shape breast-milk fatty acid concentrations around Lake Victoria, Kenya.

OBJECTIVE: Long-chain PUFA (LCPUFA) found in breast milk are derived from dietary sources and critical for optimal infant development. We examined associations between fish consumption and concentrations of LCPUFA and essential n-3 and n-6 fatty acids in breast milk among mothers living around Lake Victoria. DESIGN: We used cross-sectional analyses of associations between recent fish consumption and breast-milk fatty acid concentrations. SETTING: The study was conducted around Lake Victoria on Mfangano Island, Kenya, where multiple fish species are key dietary components and also are widely exported. SUBJECTS: Breast-feeding mothers (n 60) provided breast-milk samples, anthropometric measurements and questionnaire responses. RESULTS: In the previous 3 d, 97 % of women consumed a mean of 178 (sd 111) g fish (~2 servings/3 d). Mean breast-milk concentrations included DHA (0·75 % of total fatty acids), EPA (0·16 %), α-linolenic acid (ALA; 0·54 %), arachidonic acid (AA; 0·44 %) and linoleic acid (LA; 12·7 %). Breast-milk DHA concentrations exceeded the global average of 0·32 % in fifty-nine of sixty samples. We found native cichlids (Cichlidae) and dagaa (Rastrineobola argentea) contributed high levels of DHA, EPA and AA to local diets. We also found evidence for associations between fish species consumed and breast-milk LCPUFA concentrations when controlling for intake of other fish species, maternal body mass, maternal age, child age and exclusive breast-feeding. CONCLUSIONS: The fatty acid composition of breast milk was influenced by the fish species consumed. Ensuring access to diverse fish and particularly inexpensive, locally available species, may be important for diet quality as well as infant growth and development.

Timing, intensity, and duration of household food insecurity are associated with early childhood development in Kenya.

This study examines the association between 3 dimensions of food insecurity (timing, intensity, and duration) and 3 domains of child development (gross motor, communication, and personal social). Longitudinal data from 303 households (n = 309 children) visited 9 times over 2 years were collected. Children in households experiencing severe food insecurity 3 months prior (timing) had significantly lower gross motor (ß -0.14; 95% CI [0.27, -0.0033]; p = .045), communication (ß -0.16; 95% CI [-0.30, -0.023]; p = .023), and personal social (ß -0.20; 95% CI [-0.33, -0.073]; p = .002) Z-scores, using lagged longitudinal linear models controlling for current food insecurity; these results were attenuated in full models, which included maternal education, household asset index, and child anthropometry. Children in households that experienced greater aggregate food insecurity over the past 2 years (intensity) had significantly lower gross motor (ß -0.047; 95% CI [-0.077, -0.018]; p = .002), communication (ß -0.042; 95% CI [-0.076, -0.0073]; p = .018), and personal social (ß -0.042; 95% CI [-0.074, -0.010]; p = .010) Z-scores; these results were also attenuated in full models. Children with more time exposed to food insecurity (duration) had significantly lower gross motor (ß -0.050; 95% CI [-0.087, -0.012]; p = .010), communication (ß -0.042; 95% CI [-0.086, 0.0013]; p = .057), and personal social (ß -0.037; 95% CI [-0.077, 0.0039]; p = .076) Z-scores; these results were no longer significant in full models. Our findings suggest that acute and chronic food insecurity and child development are related, but that many associations are attenuated with the inclusion of relevant covariates.

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).

Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei.

BACKGROUND: Due to the ability of the 8-aminoquinolines (8AQs) to kill different stages of the malaria parasite, primaquine (PQ) and tafenoquine (TQ) are vital for causal prophylaxis and the eradication of erythrocytic Plasmodium sp. parasites. Recognizing the potential role of cytochrome (CYP) 450 2D6 in the metabolism and subsequent hepatic efficacy of 8-aminoquinolines, studies were designed to explore whether CYP2D-mediated metabolism was related to the ability of single-dose PQ and TQ to eliminate the asexual and sexual erythrocytic stages of Plasmodium berghei. METHODS: An IV P. berghei sporozoite murine challenge model was utilized to directly compare causal prophylactic and erythrocytic activity (asexual and sexual parasite stages) dose-response relationships in C57BL/6 wild-type (WT) mice and subsequently compare the erythrocytic activity of PQ and TQ in WT and CYP2D knock-out (KO) mice. RESULTS: Single-dose administration of either 25 mg/kg TQ or 40 mg/kg PQ eradicated the erythrocytic stages (asexual and sexual) of P. berghei in C57BL WT and CYP2D KO mice. In WT animals, the apparent elimination of hepatic infections occurs at lower doses of PQ than are required to eliminate erythrocytic infections. In contrast, the minimally effective dose of TQ needed to achieve causal prophylaxis and to eradicate erythrocytic parasites was analogous. CONCLUSION: The genetic deletion of the CYP2D cluster does not affect the ability of PQ or TQ to eradicate the blood stages (asexual and sexual) of P. berghei after single-dose administration.

Around the Table: Food Insecurity, Socioeconomic Status, and Instrumental Social Support among Women Living in a Rural Kenyan Island Community.

The objective of this study was to investigate the relationship among socioeconomic status, social support, and food insecurity in a rural Kenyan island community. A cross-sectional random sample of 111 female heads of households representing 583 household members were surveyed in Mfangano Island, Kenya from August to October 2010 using adaptations of the Household Food Insecurity Access Scale and the Medical Outcomes Study Social Support Survey. In multiple linear regression models, less instrumental social support, defined as concrete direct ways people help others (B = -0.81; 95% confidence interval [CI] -1.45 to -0.17), and decreased ownership scale based on owning material assets (B = -2.93; 95% CI -4.99 to -0.86) were significantly associated with increased food insecurity, controlling for age, education, marital status, and household size. Social support interventions geared at group capacity and resilience may be crucial adjuncts to improve and maintain the long term food security and health of persons living in low-resource regions.

The use of a prodrug approach to minimize potential CNS exposure of next generation quinoline methanols while maintaining efficacy in in vivo animal models.

The use of mefloquine (MQ) for antimalarial treatment and prophylaxis has diminished largely in response to concerns about its neurologic side effects. An analog campaign designed to maintain the efficacy of MQ while minimizing blood-brain barrier (BBB) penetration has resulted in the synthesis of a prodrug with comparable-to-superior in vivo efficacy versus mefloquine in a P. berghei mouse model while exhibiting a sixfold reduction in CNS drug levels. The prodrug, WR319670, performed poorly compared to MQ in in vitro efficacy assays, but had promising in vitro permeability in an MDCK-MDR1 cell line BBB permeability screen. Its metabolite, WR308245, exhibited high predicted BBB penetration with excellent in vitro efficacy. Both WR319670 and WR308245 cured 5/5 animals in separate in vivo efficacy studies. The in vivo efficacy of WR319670 was thought to be due to the formation of a more active metabolite, specifically WR308245. This was supported by pharmacokinetics studies in non-infected mice, which showed that both IV and oral administration of WR319670 produced essentially identical levels of WR319670 and WR308245 in both plasma and brain samples at all time points. In these studies, the levels of WR308245 in the brain were 1/4 and 1/6 that of MQ in similar IV and oral studies, respectively. These data show that the use of WR319670 as an antimalarial prodrug was able to maintain efficacy in in vivo efficacy screens, while significantly lowering overall penetration of drug and metabolites across the BBB.

Is child anemia associated with early childhood development? A cross-sectional analysis of nine Demographic and Health Surveys.

Anemia is a significant public health problem in many low- and middle-income countries (LMICs), with young children being especially vulnerable. Iron deficiency is a leading cause of anemia and prior studies have shown associations between low iron status/iron deficiency anemia and poor child development outcomes. In LMICs, 43% of children under the age of five years are at risk of not meeting their developmental potential. However, few studies have examined associations between anemia status and early childhood development (ECD) in large population-based surveys. We examined the associations between severe or moderate anemia and ECD domains (literacy-numeracy, physical, social-emotional, and learning) and an overall ECD index among children age 36-59 months. Nine Demographic and Health Surveys (DHS) from phase VII of The DHS Program (DHS-7) that included the ECD module and hemoglobin testing in children under age five years were used. Bivariate and multivariate logistic regressions were run for each of the five outcomes. Multivariate models controlled for early learning/interaction variables, child, maternal, and paternal characteristics, and socio-economic and household characteristics. Results showed almost no significant associations between anemia and ECD domains or the overall ECD index except for social-emotional development in Benin (AOR = 1.00 p < 0.05) and physical development in Maldives (AORs = 0.97 p < 0.05). Attendance at an early childhood education program was also significantly associated with the outcomes in many of the countries. Our findings reinforce the importance of the Nurturing Care Framework which describes a multi-sectoral approach to promote ECD in LMICs.

Reduced effectiveness of permethrin-treated military uniforms after prolonged wear measured by contact irritancy and toxicity bioassays with Ixodes scapularis (Acari: Ixodidae) nymphs.

Factory-treated permethrin uniforms are the primary method used by the US Army to prevent arthropod bites and transmission of arthropod-borne diseases. In this study previously worn uniforms were collected from cadets at the United States Military Academy in West Point, NY to determine the amount of permethrin remaining after prolonged wear and subsequent effects on ticks. Six trousers were collected from cadets in the sophomore, junior, and senior classes. A new, unwashed uniform served as a positive control and an untreated maternity uniform served as a negative control. Fabric samples were removed from each trouser and used in bioassays with laboratory-reared Ixodes scapularis Say nymphs. Contact irritancy bioassays measured the nymphs' ability to remain in contact with fabric for a period of 5 min. Toxicity bioassays measured tick survival at 1 and 24 h after contacting uniform samples. liquid chromatography-mass spectrometry was used to quantify the permethrin content (mg/cm2) in each uniform after the bioassays were complete. The results showed significant amounts of permethrin were lost after extended wear and it was related to the cadet year group. The contact irritancy assays found uniforms with less permethrin did not irritate ticks and cause them to dislodge. Mortality was also affected by permethrin levels, with less ticks dying at 24 h on older uniforms. The results from this study show older uniforms lose most of their permethrin and no longer provide the same levels of protection.

A Real-World Matched Cohort Study of the Effect of Concomitant Amiodarone or Diltiazem Administration on Apixaban Peak and Trough Concentrations.

BACKGROUND: Apixaban is a substrate for p-glycoprotein and is extensively metabolized by cytochrome P450 (CYP) 3A4. There are minimal published data regarding the effect of amiodarone and diltiazem on apixaban serum concentrations. OBJECTIVE: The aim of this study was to determine the degree of elevation of apixaban concentrations resulting from amiodarone or diltiazem. METHODS: This was a matched cohort study approved by the Institutional Review Board. Patients receiving apixaban 5 mg twice daily with concomitant diltiazem or amiodarone were enrolled. Control groups were enrolled via matching characteristics of sex, age, weight, creatinine clearance, and statin therapy. Exclusions were an inappropriate dosage of apixaban or concomitant dronedarone, verapamil, ranolazine, naproxen, or both amiodarone and diltiazem. Blood samples were collected 3-4 h after and 0.5-2 h before an apixaban dose, corresponding to peak and trough concentrations, respectively. Results were compared using a t test. RESULTS: Thirty patients were enrolled in each of the four groups. The mean peak apixaban concentration was 239 ± 82 ng/mL in the amiodarone group and 208 ± 66 ng/mL in the corresponding control group (p = 0.068). Trough concentrations were 142 ± 71 ng/mL and 117 ± 41 ng/mL, respectively (p = 0.055). The mean peak apixaban concentration was 243 ± 99 ng/mL in the diltiazem group and 213 ± 82 ng/mL in the control group (p = 0.11). Trough concentrations were 130 ± 65 ng/mL and 108 ± 54 ng/mL, respectively (p = 0.09). CONCLUSION: Coadministration of amiodarone and diltiazem resulted in a trend toward increased apixaban concentrations. The extent of elevation suggests that empiric dose changes are not necessary; however, individual patients may benefit from monitoring and dose adjustment.

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy.

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

The Underlying Effects of Celiac Disease and Subsequent Implications on Deployment in the United States Army.

INTRODUCTION: The purpose of this review is to provide an overview of the etiology, pathology, and treatments for celiac disease (CD), as well as to provide context as to how CD impacts the U.S. military. MATERIALS AND METHODS: To conduct this review, the authors surveyed recent epidemiology and immunology literature in order to provide a detailed summary of the current understanding of CD, its diagnosis, and the real-world impacts within the Department of Defense (DoD). RESULTS: We described the gluten proteins and both the immune response in CD. We further describe the underlying genetic risk factors and diagnosis and pathogenesis of the disease and conclude the review with a discussion of how current DoD regulations impact U.S. military readiness. CONCLUSION: Celiac disease (CD) is an autoimmune disorder that results in damage to the small intestine. Ingestion of gluten in a CD patient is usually followed by villous atrophy in the small intestine, often along with other gastrointestinal symptoms. Around 1% of patients diagnosed with CD can experience complications if gluten-free diet is not followed, including intestinal lymphoma and hyposplenism. Therefore, a patient showing possible symptoms should discuss the diagnostic process with their healthcare providers to ensure adequate understanding of serological and genetic tests along with the histological examination of intestinal biopsy. Patients should seek consults with registered dietitians to structure their diets appropriately. Considering the prevalence and incidence of CD and gluten intolerances are increasing, the military should consider providing gluten-free Meals Ready-to-Eat as an option for all service members. Given the retention of service members with CD, subsequent admission of personnel with mild CD that does not affect the duties will allow the DoD access to a growing population of fully capable service members with critical technical skills who are eager to serve the USA.