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1.  A potassium leak channel silences hyperactive neurons and ameliorates status epilepticus 
Epilepsia  2013;55(2):203-213.
To develop a constitutively active K+ leak channel using TREK-1 (TWIK-related potassium channel 1; TREK-M) that is resistant to compensatory down-regulation by second messenger cascades, and to validate the ability of TREK-M to silence hyperactive neurons using cultured hippocampal neurons. To test if adenoassociated viral (AAV) delivery of TREK-M could reduce the duration of status epilepticus and reduce neuronal death induced by lithium-pilocarpine administration.
Molecular cloning techniques were used to engineer novel vectors to deliver TREK–M via plasmids, lentivirus, and AAV using a cytomegalovirus (CMV)-enhanced GABRA4 promoter. Electrophysiology was used to characterize the activity and regulation of TREK–M in human embryonic kidney (HEK-293) cells, and the ability to reduce spontaneous activity in cultured hippocampal neurons. Adult male rats were injected bilaterally with self-complementary AAV particles composed of serotype 5 capsid into the hippocampus and entorhinal cortex. Lithium-pilocarpine was used to induce status epilepticus. Seizures were monitored using continuous video–electroencephalography (EEG) monitoring. Neuronal death was measured using Fluoro-Jade C staining of para-formaldehyde-fixed brain slices.
TREK-M inhibited neuronal firing by hyperpolarizing the resting membrane potential and decreasing input resistance. AAV delivery of TREK-M decreased the duration of status epilepticus by 50%. Concomitantly it reduced neuronal death in areas targeted by the AAV injection.
These findings demonstrate that TREK-M can silence hyperexcitable neurons in the brain of epileptic rats and treat acute seizures. This study paves the way for an alternative gene therapy treatment of status epilepticus, and provides the rationale for studies of AAV-TREK-M’s effect on spontaneous seizures in chronic models of temporal lobe epilepsy.
PMCID: PMC4161023  PMID: 24299204
Potassium currents; Gene therapy; Hippocampus; Status epilepticus; T-type calcium channel; Temporal lobe epilepsy
2.  Maladaptive autonomic regulation in PTSD accelerates physiological aging 
Frontiers in Psychology  2015;5:1571.
A core manifestation of post-traumatic stress disorder (PTSD) is a disconnection between physiological state and psychological or behavioral processes necessary to adequately respond to environmental demands. Patients with PTSD experience abnormal oscillations in autonomic states supporting either fight and flight behaviors or withdrawal, immobilization, and dissociation without an intervening “calm” state that would provide opportunities for positive social interactions. This defensive autonomic disposition is adaptive in dangerous and life threatening situations, but in the context of every-day life may lead to significant psychosocial distress and deteriorating social relationships. The perpetuation of these maladaptive autonomic responses may contribute to the development of comorbid mental health issues such as depression, loneliness, and hostility that further modify the nature of cardiovascular behavior in the context of internal and external stressors. Over time, changes in autonomic, endocrine, and immune function contribute to deteriorating health, which is potently expressed in brain dysfunction and cardiovascular disease. In this theoretical review paper, we present an overview of the literature on the chronic health effects of PTSD. We discuss the brain networks underlying PTSD in the context of autonomic efferent and afferent contributions and how disruption of these networks leads to poor health outcomes. Finally, we discuss treatment approaches based on our theoretical model of PTSD.
PMCID: PMC4300857  PMID: 25653631
PTSD; aging; polyvagal theory; chronic stress; autonomic nervous system
3.  A Longitudinal Analysis of the Effect of Mass Drug Administration on Acute Inflammatory Episodes and Disease Progression in Lymphedema Patients in Léogane, Haiti 
We conducted a longitudinal analysis of 117 lymphedema patients in a filariasis-endemic area of Haiti during 1995–2008. No difference in lymphedema progression between those who received or did not receive mass drug administration (MDA) was found on measures of foot (P = 0.24), ankle (P = 0.87), or leg (P = 0.46) circumference; leg volume displacement (P = 0.09), lymphedema stage (P = 0.93), or frequency of adenolymphangitis (ADL) episodes (P = 0.57). Rates of ADL per year were greater after initiation of MDA among both groups (P < 0.01). Nevertheless, patients who received MDA reported improvement in four areas of lymphedema-related quality of life (P ≤ 0.01). Decreases in foot and ankle circumference and ADL episodes were observed during the 1995-1998 lymphedema management study (P ≤ 0.01). This study represents the first longitudinal, quantitative, leg-specific analysis examining the clinical effect of diethylcarbamazine on lymphedema progression and ADL episodes.
PMCID: PMC3886433  PMID: 24218408
4.  Clinical and molecular implications of mosaicism in FMR1 full mutations 
Frontiers in Genetics  2014;5:318.
Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome.
PMCID: PMC4166380  PMID: 25278957
mosaicism; fragile X; FMR1; FMRP; methylation; premutation
6.  Optimizing Empiric Antibiotic Therapy in Patients with Severe β-Lactam Allergy 
Antimicrobial Agents and Chemotherapy  2013;57(12):5918-5923.
Antibiotic selection is challenging in patients with severe β-lactam allergy due to declining reliability of alternate antibiotics. Organisms isolated from these patients may exhibit unique resistance phenotypes. The objective of this study was to determine which alternate antibiotics or combinations provide adequate empirical therapy for patients with β-lactam allergy who develop Gram-negative infections at our institution. We further sought to determine the effects of risk factors for drug resistance on empirical adequacy. A retrospective analysis was conducted for adult patients hospitalized from September 2009 to May 2010 who had a severe β-lactam allergy and a urine, blood, or respiratory culture positive for a Gram-negative organism and who met predefined criteria for infection. Patient characteristics, culture and susceptibility data, and predefined risk factors for antibiotic resistance were collected. Adequacies of β-lactam and alternate antibiotics were compared for all infections and selected subsets. The primary outcome was adequacy of each alternate antibiotic or combination for all infections. One hundred sixteen infections (40 pneumonias, 67 urinary tract infections, and 9 bacteremias) were identified. Single alternate agents were adequate less frequently than β-lactams and combination regimens. Only in cases without risk factors for resistance did single-agent regimens demonstrate acceptable adequacy rates; each factor conferred a doubling of risk for resistance. Resistance risk factors should be considered in selecting empirical antibiotics for Gram-negative pathogens in patients unable to take β-lactams due to severe allergy.
PMCID: PMC3837866  PMID: 24041892
7.  Village-Randomized Clinical Trial of Home Distribution of Zinc for Treatment of Childhood Diarrhea in Rural Western Kenya 
PLoS ONE  2014;9(5):e94436.
Zinc treatment shortens diarrhea episodes and can prevent future episodes. In rural Africa, most children with diarrhea are not brought to health facilities. In a village-randomized trial in rural Kenya, we assessed if zinc treatment might have a community-level preventive effect on diarrhea incidence if available at home versus only at health facilities.
We randomized 16 Kenyan villages (1,903 eligible children) to receive a 10-day course of zinc and two oral rehydration solution (ORS) sachets every two months at home and 17 villages (2,241 eligible children) to receive ORS at home, but zinc at the health–facility only. Children’s caretakers were educated in zinc/ORS use by village workers, both unblinded to intervention arm. We evaluated whether incidence of diarrhea and acute lower respiratory illness (ALRI) reported at biweekly home visits and presenting to clinic were lower in zinc villages, using poisson regression adjusting for baseline disease rates, distance to clinic, and children’s age.
There were no differences between village groups in diarrhea incidence either reported at the home or presenting to clinic. In zinc villages (1,440 children analyzed), 61.2% of diarrheal episodes were treated with zinc, compared to 5.4% in comparison villages (1,584 children analyzed, p<0.0001). There were no differences in ORS use between zinc (59.6%) and comparison villages (58.8%). Among children with fever or cough without diarrhea, zinc use was low (<0.5%). There was a lower incidence of reported ALRI in zinc villages (adjusted RR 0.68, 95% CI 0.46–0.99), but not presenting at clinic.
In this study, home zinc use to treat diarrhea did not decrease disease rates in the community. However, with proper training, availability of zinc at home could lead to more episodes of pediatric diarrhea being treated with zinc in parts of rural Africa where healthcare utilization is low.
Trial Registration NCT00530829
PMCID: PMC4023937  PMID: 24835009
8.  The Blindside: Impact of monocular occlusion on spatial attention 
Monocular occlusion has been posited to reduce activation of the contralateral hemisphere (“Sprague effect”), thus inducing a contralateral spatial bias (toward the viewing eye). Healthy right-handed participants bisected horizontal lines during monocular eye viewing. Although subjects tended to deviate away from the viewing eye, only left eye viewing deviated significantly right of midline. These results suggest that eye patching may induce an attentional compensation similar to hemianopic patients. Alternatively, increased activation of higher cortical regions mediating spatial attention in contralateral hemispace may be an adaptive response to decreased activation of its ipsilateral superior colliculus induced by contralateral eye patching.
PMCID: PMC3602898  PMID: 23419120
monocular occlusion; eye patching; constrained monocular viewing; Sprague effect; attention; intention; line bisection; spatial neglect; hemianopia; rehabilitation
9.  Incidence of Malaria among Mosquito Collectors Conducting Human Landing Catches in Western Kenya 
The human landing catch (HLC) has long been the gold standard for estimating malaria transmission by mosquitoes, but has come under scrutiny because of ethical concerns of exposing collectors to infectious bites. We estimated the incidence of Plasmodium falciparum malaria infection in a cohort of 152 persons conducting HLCs and compared it with that of 147 non-collectors in western Kenya. Participants were presumptively cleared of malaria with Coartem™ (artemether-lumefantrine) and tested for malaria every 2 weeks for 12 weeks. The HLC collections were conducted four nights per week for six weeks. Collectors were provided chemoprophylaxis with Malarone™ (atovaquone-proguanil) during the six weeks of HLC activities and one week after HLC activities were completed. The incidence of malaria was 96.6% lower in collectors than in non-collectors (hazard ratio = 0.034, P < 0.0001). Therefore, with proper prophylaxis, concern about increased risk of malaria among collectors should not be an impediment to conducting HLC studies.
PMCID: PMC3583321  PMID: 23249685
10.  Evaluation of Quantification of HIV-1 RNA Viral Load in Plasma and Dried Blood Spots by Use of the Semiautomated Cobas Amplicor Assay and the Fully Automated Cobas Ampliprep/TaqMan Assay, Version 2.0, in Kisumu, Kenya 
Journal of Clinical Microbiology  2013;51(4):1208-1218.
In Kenya, HIV-1 viral load monitoring is commonly performed with the Cobas Amplicor using plasma specimens. Interest is growing in transitioning to real-time PCR (RT-PCR), such as the Cobas Ampliprep/Cobas TaqMan (CAP/CTM), using dried blood spots (DBS). Before implementation, direct evaluation of the two assays using DBS field specimens is required. This study compares the sensitivity, specificity, negative and positive predictive values (NPV and PPV, respectively), concordance, and agreement between HIV-1 viral load measurements using plasma and DBS specimens obtained from 512 HIV-1-infected pregnant females enrolled in the Kisumu Breastfeeding Study and tested with the Cobas Amplicor and CAP/CTM assays. The sensitivity and NPV of viral load detection in DBS specimens were higher with CAP/CTM (sensitivity, 100%; 95% confidence interval [CI], 99.1 to 100.0%; NPV, 100%; 95% CI, 59.0 to 100.0%) than the Cobas Amplicor (sensitivity, 96.6%; 95% CI, 94.3 to 98.1%; NPV, 58.8%; 95% CI, 40.7 to 75.4%). The PPVs were comparable between both assays when using DBS. The specificity of viral load detection in DBS specimens was lower with CAP/CTM (77.8%; 95% CI, 40.0 to 97.2%) than that of the Cobas Amplicor (95.2%; 95% CI, 76.2 to 99.9%). Good concordance and agreement were observed when paired plasma and DBS specimens were tested with both assays. Lower specificity with the CAP/CTM is likely due to proviral HIV-1 DNA amplification and lower detection limits with RT-PCR. However, the CAP/CTM has better sensitivity and higher throughput than the Cobas Amplicor. These findings suggest that DBS may be a suitable alternative to plasma when using RT-PCR, which could increase access to viral load monitoring in resource-limited settings.
PMCID: PMC3666812  PMID: 23390278
11.  The Effect on Peritoneal Dialysis Pathogens of Changing Topical Antibiotic Prophylaxis 
♦ Background: Prophylactic gentamicin 0.1% cream has demonstrated efficacy in preventing both exit-site infection (ESI) and peritonitis attributable to gram-positive and gram-negative organisms; however, the effect of this practice on the gentamicin susceptibility patterns of bacterial pathogens isolated from such infections is unknown. We therefore examined the effect of a change in our prophylactic topical antibiotic exit-site protocol (from mupirocin 2% cream to gentamicin 0.1% cream) on infection rates and susceptibility patterns.
♦ Methods: This retrospective observational cohort study examined two periods of time: before and after the change in exit-site protocol. Each period was 30 months in duration, with a 2-month implementation period between, during which patient data were excluded. Demographic, clinical, and microbiology data were collected for each patient and episode of infection.
♦ Results: Overall, 377 patients were evaluated. In the mupirocin period (MUP), 145 infections occurred in 79 patients, and in the gentamicin period, 145 infections occurred in 93 patients. No significant effect was found either in overall episodes of infection (0.53 per year) or in episodes of peritonitis (0.429 vs 0.375 per year), but episodes of ESI increased significantly (0.098 vs 0.153 per year; p = 0.024; odds ratio: 1.55; 95% confidence interval: 1.05 to 2.28). Episodes of Staphylococcus aureus peritonitis increased by 38% (0.018 vs 0.025 per year), and episodes of S. aureus ESI increased significantly by 150% (0.022 vs 0.055 per year; p = 0.03; hazard ratio: 3.00; 95% confidence interval: 1.09 to 8.26). Episodes of pseudomonal peritonitis declined by 68% (0.022 vs 0.007 per year), and episodes of pseudomonal ESI increased by 150% (0.007 vs 0.018 per year). The gentamicin susceptibility for gram-positive isolates demonstrated no significant change; however, the gentamicin susceptibility for Enterobacteriaceae decreased by 12% and for Pseudomonas, by 14%.
♦ Conclusions: The significant increase in episodes of ESI and the decrease in susceptibility for both Enterobacteriaceae and Pseudomonas isolates represent a concerning trend. Centers should examine trends in infection rates and in bacterial susceptibilities to determine the most appropriate agent for ESI prophylaxis.
PMCID: PMC3524877  PMID: 22302770
Antibiotic cream; pathogen susceptibilities; peritonitis; exit-site infection
12.  A randomized trial of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated malaria among children in western Kenya 
Malaria Journal  2013;12:254.
Artemether-lumefantrine (AL) was adopted as first-line treatment for uncomplicated malaria in Kenya in 2006. Monitoring drug efficacy at regular intervals is essential to prevent unnecessary morbidity and mortality. The efficacy of AL and dihydroartemisinin-piperaquine (DP) were evaluated for the treatment of uncomplicated malaria in children aged six to 59 months in western Kenya.
From October 2010 to August 2011, children with fever or history of fever with uncomplicated Plasmodium falciparum mono-infection were enrolled in an in vivo efficacy trial in accordance with World Health Organization (WHO) guidelines. The children were randomized to treatment with a three-day course of AL or DP and efficacy outcomes were measured at 28 and 42 days after treatment initiation.
A total of 137 children were enrolled in each treatment arm. There were no early treatment failures and all children except one had cleared parasites by day 3. Polymerase chain reaction (PCR)-uncorrected adequate clinical and parasitological response rate (ACPR) was 61% in the AL arm and 83% in the DP arm at day 28 (p = 0.001). PCR-corrected ACPR at day 28 was 97% in the AL group and 99% in the DP group, and it was 96% in both arms at day 42.
AL and DP remain efficacious for the treatment of uncomplicated malaria among children in western Kenya. The longer half-life of piperaquine relative to lumefantrine may provide a prophylactic effect, accounting for the lower rate of re-infection in the first 28 days after treatment in the DP arm.
PMCID: PMC3722085  PMID: 23870627
13.  Health Care-Seeking Behavior During Childhood Diarrheal Illness: Results of Health Care Utilization and Attitudes Surveys of Caretakers in Western Kenya, 2007–2010 
We interviewed caretakers of 1,043 children < 5 years old in a baseline cross-sectional survey (April to May 2007) and > 20,000 children on five separate subsequent occasions (May of 2009 to December 31, 2010) to assess healthcare seeking patterns for diarrhea. Diarrhea prevalence during the preceding 2 weeks ranged from 26% at baseline to 4–11% during 2009–2010. Caretakers were less likely to seek healthcare outside the home for infants (versus older children) with diarrhea (adjusted odds ratio [aOR] = 0.33, confidence interval [CI] = 0.12–0.87). Caretakers of children with reduced food intake (aOR = 3.42, CI = 1.37–8.53) and sunken eyes during their diarrheal episode were more likely to seek care outside home (aOR = 4.76, CI = 1.13–8.89). Caretakers with formal education were more likely to provide oral rehydration solution (aOR = 3.01, CI = 1.41–6.42) and visit a healthcare facility (aOR = 3.32, CI = 1.56–7.07). Studies calculating diarrheal incidence and healthcare seeking should account for seasonal trends. Improving caretakers' knowledge of home management could prevent severe diarrhea.
PMCID: PMC3748498  PMID: 23629929
14.  Use of Population-based Surveillance to Define the High Incidence of Shigellosis in an Urban Slum in Nairobi, Kenya 
PLoS ONE  2013;8(3):e58437.
Worldwide, Shigella causes an estimated 160 million infections and >1 million deaths annually. However, limited incidence data are available from African urban slums. We investigated the epidemiology of shigellosis and drug susceptibility patterns within a densely populated urban settlement in Nairobi, Kenya through population-based surveillance.
Surveillance participants were interviewed in their homes every 2 weeks by community interviewers. Participants also had free access to a designated study clinic in the surveillance area where stool specimens were collected from patients with diarrhea (≥3 loose stools within 24 hours) or dysentery (≥1 stool with visible blood during previous 24 hours). We adjusted crude incidence rates for participants meeting stool collection criteria at household visits who reported visiting another clinic.
Shigella species were isolated from 224 (23%) of 976 stool specimens. The overall adjusted incidence rate was 408/100,000 person years of observation (PYO) with highest rates among adults 34–49 years old (1,575/100,000 PYO). Isolates were: Shigella flexneri (64%), S. dysenteriae (11%), S. sonnei (9%), and S. boydii (5%). Over 90% of all Shigella isolates were resistant to trimethoprim-sulfamethoxazole and sulfisoxazole. Additional resistance included nalidixic acid (3%), ciprofloxacin (1%) and ceftriaxone (1%).
More than 1 of every 200 persons experience shigellosis each year in this Kenyan urban slum, yielding rates similar to those in some Asian countries. Provision of safe drinking water, improved sanitation, and hygiene in urban slums are needed to reduce disease burden, in addition to development of effective Shigella vaccines.
PMCID: PMC3591331  PMID: 23505506
15.  Association between Immunoglobulin GM and KM Genotypes and Placental Malaria in HIV-1 Negative and Positive Women in Western Kenya 
PLoS ONE  2013;8(1):e53948.
Immunoglobulin (Ig) GM and KM allotypes, genetic markers of γ and κ chains, are associated with humoral immune responsiveness. Previous studies have shown the relationships between GM6-carrying haplotypes and susceptibility to malaria infection in children and adults; however, the role of the genetic markers in placental malaria (PM) infection and PM with HIV co-infection during pregnancy has not been investigated. We examined the relationship between the gene polymorphisms of Ig GM6 and KM allotypes and the risk of PM infection in pregnant women with known HIV status. DNA samples from 728 pregnant women were genotyped for GM6 and KM alleles using polymerase chain reaction-restriction fragment length polymorphism method. Individual GM6 and KM genotypes and the combined GM6 and KM genotypes were assessed in relation to PM in HIV-1 negative and positive women, respectively. There was no significant effect of individual GM6 and KM genotypes on the risk of PM infection in HIV-1 negative and positive women. However, the combination of homozygosity for GM6(+) and KM3 was associated with decreased risk of PM (adjusted OR, 0.25; 95% CI, 0.08–0.8; P = 0.019) in HIV-1 negative women while in HIV-1 positive women the combination of GM6(+/−) with either KM1-3 or KM1 was associated with increased risk of PM infection (adjusted OR, 2.10; 95% CI, 1.18–3.73; P = 0.011). Hardy-Weinberg Equilibrium (HWE) tests further showed an overall significant positive F(is) (indication of deficit in heterozygotes) for GM6 while there was no deviation for KM genotype frequency from HWE in the same population. These findings suggest that the combination of homozygous GM6(+) and KM3 may protect against PM in HIV-1 negative women while the HIV-1 positive women with heterozygous GM6(+/−) combined with KM1-3 or KM1 may be more susceptible to PM infection. The deficit in heterozygotes for GM6 further suggests that GM6 could be under selection likely by malaria infection.
PMCID: PMC3543394  PMID: 23326546
16.  Vanishing bile duct syndrome in human immunodeficiency virus infected adults: A report of two cases 
Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.
PMCID: PMC3542762  PMID: 23326172
Human immunodeficiency virus; Antiretroviral therapy; Vanishing bile duct syndrome; Ductopenia; Liver biopsy
17.  A possible mechanism for PTSD symptoms in patients with traumatic brain injury: central autonomic network disruption 
Patients with traumatic brain injuries (TBI) often develop post traumatic stress disorder (PTSD). This syndrome, defined and diagnosed by psychological and behavioral features, is associated with symptoms such as anxiety and anger with an increase of arousal and vigilance, as well as flashbacks and nightmares. Many of these features and symptoms observed in PTSD may be in part the result of altered autonomic nervous system (ANS) activity in response to psychological and physical challenges. Brain imaging has documented that TBI often induces white matter damage to pathways associated with the anterior limb of the internal capsule and uncinate fasciculus. Since these white matter structures link neocortical networks with subcortical and limbic structures that regulate autonomic control centers, injury to these pathways may induce a loss of inhibitory control of the ANS. In this review, the autonomic features associated with PTSD are discussed in the context of traumatic brain injury. We posit that TBI induced damage to networks that regulate the ANS increase vulnerability to PTSD. The means by which the vulnerability can be measured and tested are also discussed.
PMCID: PMC3867662  PMID: 24391583
emotion; autonomic nervous system; traumatic brain injury; post traumatic stress disorder; white matter; TBI; PTSD
18.  The Combination of Indoor Residual Spraying and Insecticide-Treated Nets Provides Added Protection against Malaria Compared with Insecticide-Treated Nets Alone 
Both insecticide-treated bed nets (ITNs) and indoor residual spraying (IRS) reduce malaria in high malaria transmission areas.1–3 The combined effect of these interventions is unknown. We conducted a non-randomized prospective cohort study to determine protective efficacy of IRS with ITNs (ITN + IRS) compared with ITNs alone (ITN only) in preventing Plasmodium falciparum parasitemia. At baseline, participants provided blood samples for malaria smears, were presumptively treated for malaria, and received ITNs. Blood smears were made monthly and at sick visits. In total, 1,804 participants were enrolled. Incidence of P. falciparum parasitemia in the ITN + IRS and ITN only groups was 18 and 44 infections per 100 persons-years at risk, respectively (unadjusted rate ratio = 0.41; 95% confidence interval [CI] = 0.31–0.56). Adjusted protective efficacy of ITN + IRS compared with ITN only was 62% (95% CI = 0.50–0.72). The combination of IRS and ITN might be a feasible strategy to further reduce malaria transmission in areas of persistent perennial malaria transmission.
PMCID: PMC3225156  PMID: 22144448
19.  A Reversal in Reductions of Child Mortality in Western Kenya, 2003–2009 
We report and explore changes in child mortality in a rural area of Kenya during 2003–2009, when major public health interventions were scaled-up. Mortality ratios and rates were calculated by using the Kenya Medical Research Institute/Centers for Disease Control and Prevention Demographic Surveillance System. Inpatient and outpatient morbidity and mortality, and verbal autopsy data were analyzed. Mortality ratios for children less than five years of age decreased from 241 to 137 deaths/1,000 live-births in 2003 and 2007 respectively. In 2008, they increased to 212 deaths/1,000 live-births. Mortality remained elevated during the first 8 months of 2009 compared with 2006 and 2007. Malaria and/or anemia accounted for the greatest increases in child mortality. Stock-outs of essential antimalarial drugs during a time of increased malaria transmission and disruption of services during civil unrest may have contributed to increased mortality in 2008–2009. To maintain gains in child survival, implementation of good policies and effective interventions must be complemented by reliable supply and access to clinical services and essential drugs.
PMCID: PMC3183762  PMID: 21976557
20.  Bimanual-Vertical Hand Movements 
Patients often demonstrate attentional and action-intentional biases in both the transverse and coronal planes. In addition, when making forelimb movements in the transverse plane, normal participants also have spatial and magnitude asymmetries, but forelimb spatial asymmetries have not been studied in coronal space. Thus, to learn if when normal people make vertical movements they have right–left spatial and magnitude biases, seventeen healthy, blindfolded volunteers had their hands (holding pens) placed vertically in their midsagittal plane, 10 inches apart, on pieces of paper positioned above, below, and at eye-level. Participants were asked to move their hands together vertically and meet in the middle. Participants demonstrated less angular deviation in the below-eye condition than in the other spatial conditions, when moving down than up, and with their right than left hand. Movements toward eye level from upper or lower space were also more accurate than movements in the other directions. Independent of hand, lines were longer with downward than upward movements and the right hand moved more distance than the left. These attentional-intentional asymmetries may be related to gravitational force, hand-hemispheric dominance, and spatial “where” asymmetries; however, the mechanisms accounting for these asymmetries must be ascertained by future research.
PMCID: PMC3419484  PMID: 22882812
Intention; Attention; Hand asymmetry; Coronal plane; Hemispheric specialization; Motor control
22.  Lack of Knowledge of HIV Status a Major Barrier to HIV Prevention, Care and Treatment Efforts in Kenya: Results from a Nationally Representative Study 
PLoS ONE  2012;7(5):e36797.
We analyzed HIV testing rates, prevalence of undiagnosed HIV, and predictors of testing in the Kenya AIDS Indicator Survey (KAIS) 2007.
KAIS was a nationally representative sero-survey that included demographic and behavioral indicators and testing for HIV, HSV-2, syphilis, and CD4 cell counts in the population aged 15–64 years. We used gender-specific multivariable regression models to identify factors independently associated with HIV testing in sexually active persons.
Of 19,840 eligible persons, 80% consented to interviews and blood specimen collection. National HIV prevalence was 7.1% (95% CI 6.5–7.7). Among ever sexually active persons, 27.4% (95% CI 25.6–29.2) of men and 44.2% (95% CI 42.5–46.0) of women reported previous HIV testing. Among HIV-infected persons, 83.6% (95% CI 76.2–91.0) were unaware of their HIV infection. Among sexually active women aged 15–49 years, 48.7% (95% CI 46.8–50.6) had their last HIV test during antenatal care (ANC). In multivariable analyses, the adjusted odds ratio (AOR) for ever HIV testing in women ≥35 versus 15–19 years was 0.2 (95% CI: 0.1–0.3; p<0.0001). Other independent associations with ever HIV testing included urban residence (AOR 1.6, 95% CI: 1.2–2.0; p = 0.0005, women only), highest wealth index versus the four lower quintiles combined (AOR 1.8, 95% CI: 1.3–2.5; p = 0.0006, men only), and an increasing testing trend with higher levels of education. Missed opportunities for testing were identified during general or pregnancy-specific contacts with health facilities; 89% of adults said they would participate in home-based HIV testing.
The vast majority of HIV-infected persons in Kenya are unaware of their HIV status, posing a major barrier to HIV prevention, care and treatment efforts. New approaches to HIV testing provision and education, including home-based testing, may increase coverage. Targeted interventions should involve sexually active men, sexually active women without access to ANC, and rural and disadvantaged populations.
PMCID: PMC3344943  PMID: 22574226
23.  Population-Based Incidence of Typhoid Fever in an Urban Informal Settlement and a Rural Area in Kenya: Implications for Typhoid Vaccine Use in Africa 
PLoS ONE  2012;7(1):e29119.
High rates of typhoid fever in children in urban settings in Asia have led to focus on childhood immunization in Asian cities, but not in Africa, where data, mostly from rural areas, have shown low disease incidence. We set out to compare incidence of typhoid fever in a densely populated urban slum and a rural community in Kenya, hypothesizing higher rates in the urban area, given crowding and suboptimal access to safe water, sanitation and hygiene.
During 2007-9, we conducted population-based surveillance in Kibera, an urban informal settlement in Nairobi, and in Lwak, a rural area in western Kenya. Participants had free access to study clinics; field workers visited their homes biweekly to collect information about acute illnesses. In clinic, blood cultures were processed from patients with fever or pneumonia. Crude and adjusted incidence rates were calculated.
In the urban site, the overall crude incidence of Salmonella enterica serovar Typhi (S. Typhi) bacteremia was 247 cases per 100,000 person-years of observation (pyo) with highest rates in children 5–9 years old (596 per 100,000 pyo) and 2–4 years old (521 per 100,000 pyo). Crude overall incidence in Lwak was 29 cases per 100,000 pyo with low rates in children 2–4 and 5–9 years old (28 and 18 cases per 100,000 pyo, respectively). Adjusted incidence rates were highest in 2–4 year old urban children (2,243 per 100,000 pyo) which were >15-fold higher than rates in the rural site for the same age group. Nearly 75% of S. Typhi isolates were multi-drug resistant.
This systematic urban slum and rural comparison showed dramatically higher typhoid incidence among urban children <10 years old with rates similar to those from Asian urban slums. The findings have potential policy implications for use of typhoid vaccines in increasingly urban Africa.
PMCID: PMC3261857  PMID: 22276105
24.  Neuropsychological dysfunction in patients with end-stage pulmonary disease: lung transplant evaluation 
There has been a relative absence of studies that have examined the neuropsychological profiles of potential lung transplant candidates. Neuropsychological data are presented for 134 patients with end-stage pulmonary disease who were being evaluated as potential candidates for lung transplantation. Neuropsychological test results indicated that a significantly greater proportion of the patients exhibited impaired performances on a number of Selective Reminding Test (SRT) tasks as compared to the expected population frequency distributions for these measures. The highest frequencies of impairment were observed on the SRT’s Immediate Free Recall (46.43%), Long-term Retrieval (41.67%), and Consistent Long-term Retrieval (51.19%) variables. On the Minnesota Multiphasic Personality Inventory-2 (MMPI-2)/Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A), patients’ mean clinical profile revealed elevations on Scales 1 (Hypochondriasis) and 3 (Conversion Hysteria). This profile indicated that they were experiencing an array of symptomatology ranging from somatic complaints to lethargy and fatigue, and that they may have been functioning at a reduced level of efficiency. Findings are discussed in light of patients’ end-stage pulmonary disease and factors possibly contributing to their neuropsychological test performances. Implications for clinical practice and future research are also provided.
PMCID: PMC3219058  PMID: 14591451
Neuropsychology; Neurocognitive; Pulmonary disease; End-stage; Lung transplant
25.  Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS,S/AS01 malaria vaccine in African children 
Malaria Journal  2011;10:222.
There has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials.
The present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed.
The methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy.
Trial registration NCT00866619
PMCID: PMC3167766  PMID: 21816030

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