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1.  Is Ghana’s pro-poor health insurance scheme really for the poor? Evidence from Northern Ghana 
Background
Protecting the poor and vulnerable against the cost of unforeseen ill health has become a global concern culminating in the 2005 World Health Assembly resolution urging member states to ensure financial protection to all citizens, especially children and women of reproductive age. Ghana provides financial protection to its citizens through the National Health Insurance Scheme (NHIS). Launched in 2004, its proponents claim that the NHIS is a pro-poor financial commitment that implements the World Health Assembly resolution.
Methods
Using 2011 survey data collected in seven districts in northern Ghana from 5469 women aged 15 to 49 the paper explores the extent to which poor child-bearing age mothers are covered by the NHIS in Ghana’s poorest and most remote region. Factors associated with enrolment into the NHIS are estimated with logistic regression models employing covariates for household relative socio-economic status (SES), location of residence and maternal educational attainment, marital status, age, religion and financial autonomy.
Results
Results from the analysis showed that 33.9 percent of women in the lowest SES quintile compared to 58.3 percent for those in the highest quintile were insured. About 60 percent of respondents were registered. However, only 40 percent had valid insurance cards indicating that over 20 percent of the registered respondents did not have insurance cards. Thus, a fifth of the respondents were women who were registered but unprotected from the burden of health care payments. Results show that the relatively well educated, prosperous, married and Christian respondents were more likely to be insured than other women. Conversely, women living in remote households that were relatively poor or where traditional religion was practised had lower odds of insurance coverage.
Conclusion
The results suggest that the NHIS is yet to achieve its goal of addressing the need of the poor for insurance against health related financial risks. To ultimately attain adequate equitable financial protection for its citizens, achieve universal health coverage in health care financing, and fully implement the World Health Assembly resolution, Ghana must reform enrolment policies in ways that guarantee pre-payment for the most poor and vulnerable households.
doi:10.1186/s12913-014-0637-7
PMCID: PMC4268792  PMID: 25494816
National health insurance scheme; Universal health coverage; Pro-poor; Poor; Ghana
2.  Evaluation of the integrated disease surveillance and response system for infectious diseases control in northern Ghana 
BMC Public Health  2015;15:75.
Background
Well-functioning surveillance systems are crucial for effective disease control programs. The Integrated Disease Surveillance and Response (IDSR) strategy was developed and adopted in 1998 for Africa as a comprehensive public health approach and subsequently, Ghana adopted the IDSR technical guidelines in 2002. Since 2012, the IDSR data is reported through the new District Health Information Management System II (DHIMS2) network. The objective was to evaluate the Integrated Disease Surveillance and Response (IDSR) system in northern Ghana.
Methods
This was an observational study using mixed methods. Weekly and monthly IDSR data on selected infectious diseases were downloaded and analyzed for 2011, 2012 and 2013 (the years before, of and after DHIMS2 implementation) from the DHIMS2 databank for the Upper East Region (UER) and for two districts of UER. In addition, key informant interviews were conducted among local and regional health officers on the functioning of the IDSR.
Results
Clinically diagnosed malaria was the most prevalent disease in UER, with an annual incidence rate close to 1. Around 500 suspected HIV/AIDS cases were reported each year. The highest incidence of cholera and meningitis was reported in 2012 (257 and 392 cases respectively). Three suspected cases of polio and one suspected case of guinea worm were reported in 2013. None of the polio and guinea worm cases and only a fraction of the reported cases of the other diseases were confirmed. A major observation was the large and inconclusive difference in reported cases when comparing weekly and monthly reports. This can be explained by the different reporting practice for the sub-systems. Other challenges were low priority for surveillance, ill-equipped laboratories, rare supervision and missing feedback.
Conclusions
The DHIMS2 has improved the availability of IDSR reports, but the quality of data reported is not sufficient. Particularly the inconsistencies between weekly and monthly data need to be addressed. Moreover, support for and communication within the IDSR system is inadequate and calls for attention.
doi:10.1186/s12889-015-1397-y
PMCID: PMC4331174  PMID: 25648630
Integrated; Disease surveillance; Response; Infectious diseases; Data quality; Health information system; Ghana
3.  Impact of an electronic clinical decision support system on workflow in antenatal care: the QUALMAT eCDSS in rural health care facilities in Ghana and Tanzania 
Global Health Action  2015;8:10.3402/gha.v8.25756.
Background
The implementation of new technology can interrupt established workflows in health care settings. The Quality of Maternal Care (QUALMAT) project has introduced an electronic clinical decision support system (eCDSS) for antenatal care (ANC) and delivery in rural primary health care facilities in Africa.
Objective
This study was carried out to investigate the influence of the QUALMAT eCDSS on the workflow of health care workers in rural primary health care facilities in Ghana and Tanzania.
Design
A direct observation, time-and-motion study on ANC processes was conducted using a structured data sheet with predefined major task categories. The duration and sequence of tasks performed during ANC visits were observed, and changes after the implementation of the eCDSS were analyzed.
Results
In 24 QUALMAT study sites, 214 observations of ANC visits (144 in Ghana, 70 in Tanzania) were carried out at baseline and 148 observations (104 in Ghana, 44 in Tanzania) after the software was implemented in 12 of those sites. The median time spent combined for all centers in both countries to provide ANC at baseline was 6.5 min [interquartile range (IQR) =4.0–10.6]. Although the time spent on ANC increased in Tanzania and Ghana after the eCDSS implementation as compared to baseline, overall there was no significant increase in time used for ANC activities (0.51 min, p=0.06 in Ghana; and 0.54 min, p=0.26 in Tanzania) as compared to the control sites without the eCDSS. The percentage of medical history taking in women who had subsequent examinations increased after eCDSS implementation from 58.2% (39/67) to 95.3% (61/64) p<0.001 in Ghana but not in Tanzania [from 65.4% (17/26) to 71.4% (15/21) p=0.70].
Conclusions
The QUALMAT eCDSS does not increase the time needed for ANC but partly streamlined workflow at sites in Ghana, showing the potential of such a system to influence quality of care positively.
doi:10.3402/gha.v8.25756
PMCID: PMC4309829  PMID: 25630707
electronic clinical decision support system; workflow; antenatal care; health care providers; sequence of events; rural setting; developing countries; sub-Saharan Africa
4.  Cost to households in treating maternal complications in northern Ghana: a cross sectional study 
Background
The cost of treating maternal complications has serious economic consequences to households and can hinder the utilization of maternal health care services at the health facilities. This study estimated the cost of maternal complications to women and their households in the Kassena-Nankana district of northern Ghana.
Methods
We carried out a cross-sectional study between February and April 2014 in the Kassena-Nankana district. Out of a total of 296 women who were referred to the hospital for maternal complications from the health centre level, sixty of them were involved in the study. Socio-demographic data of respondents as well as direct and indirect costs involved in the management of the complications at the hospital were collected from the patient’s perspective. Analysis was performed using STATA 11.
Results
Out of the 60 respondents, 60% (36) of them suffered complications due to prolonged labour, 17% (10) due to severe abdominal pain, 10% (6) due to anaemia/malaria and 7% (4) due to pre-eclampsia. Most of the women who had complications were primiparous and were between 21–25 years old. Transportation cost accounted for the largest cost, representing 32% of total cost of treatment. The median direct medical cost was US$8.68 per treatment, representing 44% of the total cost of treatment. Indirect costs accounted for the largest proportion of total cost (79%). Overall, the median expenditure by households on both direct and indirect costs per complication was US$32.03. Disaggregating costs by type of complication, costs ranged from a median of US$58.33 for pre-eclampsia to US$6.84 for haemorrrhage. The median number of days spent in the hospital was 2 days - five days for pre-eclampsia. About 33% (6) of households spent more than 5% of annual household expenditure and therefore faced catastrophic payments.
Conclusion
Although maternal health services are free in Ghana, women still incur substantial costs when complications occur and face the risk of incurring catastrophic health expenditure.
doi:10.1186/s12913-014-0659-1
PMCID: PMC4310136  PMID: 25608609
Maternal complication; Pregnancy; Economic burden; Household cost; Kassena-Nankana district; Ghana
5.  Intimate partner violence: associations with low infant birthweight in a South African birth cohort 
Metabolic brain disease  2014;29(2):281-299.
Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r2=0.14 (adjusted r2=0.11, F(8, 212) = 4.16, p=0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t=−2.04, p=0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.
doi:10.1007/s11011-014-9525-4
PMCID: PMC4300125  PMID: 24729207
Intimate partner violence; Trauma; Pregnancy; Low birth weight; South Africa
6.  Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting 
Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk predictors, including a young age, female sex, lack of smoking, and a history of motion sickness. Genetic studies are beginning to shed light on the variability in patient experiences of PONV by assessing polymorphisms of gene targets known to play roles in emesis (serotonin type 3, 5-HT3; opioid; muscarinic; and dopamine type 2, D2, receptors) and the metabolism of antiemetic drugs (e.g., ondansetron). Significant numbers of clinical trials have produced valuable information on pharmacological targets important for controlling PONV (e.g., 5-HT3 and D2), leading to the current multi-modal approach to inhibit multiple sites in this complex neural system. Despite these significant advances, there is still a lack of fundamental knowledge of the mechanisms that drive the hindbrain central pattern generator (emesis) and forebrain pathways (nausea) that produce PONV, particularly the responses to inhalational anesthesia. This gap in knowledge has limited the development of novel effective therapies of PONV. The current review presents the state of knowledge on the biological mechanisms responsible for PONV, summarizing both preclinical and clinical evidence. Finally, potential ways to advance the research of PONV and more recent developments on the study of postdischarge nausea and vomiting (PDNV) are discussed.
doi:10.1016/j.ejphar.2013.10.037
PMCID: PMC3915298  PMID: 24495419
Nausea; Vomiting; Emesis; Anesthesia; Surgery; Opioid
7.  Small Molecule Inhibitors of Anthrax Lethal Factor Toxin 
Bioorganic & medicinal chemistry  2013;22(1):419-434.
This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds.
doi:10.1016/j.bmc.2013.11.009
PMCID: PMC3925373  PMID: 24290062
Bacillus anthracis; anthrax; lethal factor; botulinum neurotoxin A; light chain; zinc metalloprotease; matrix metalloprotease; quinoline; hybrid compound; desymmetrized
8.  Depression among Black Bisexual Men with Early and Later Life Adversities 
This study examined the role of adulthood adversities in the relationship between childhood adversities and depression in 117 HIV-positive Black men who have sex with men and women (MSMW) and who have histories of childhood sexual abuse (CSA). Men were participants in the Enhanced Sexual Health Intervention for Men, a six-session health intervention, and at baseline reported their experiences of CSA, childhood adversities, perceived discrimination, chronic stress, social support, and depressive symptoms. The relationship between childhood adversities, including CSA, and depression was mediated by experiences with racial and HIV discrimination (R2 = .25, F3, 112 = 12.67, p < .001) and chronic stress (R2 = .17, F3, 112 = 7.41, p < .001). Social support moderated the mediated effects of both racial and HIV discrimination (b = −.154, t(111) = −2.82, p < .01) and chronic stress (b = −.019, t(111) = −3.759, p < .01). Men’s early adverse experiences were predictive of depression in adulthood; however, this relationship was largely affected by adulthood experiences, specifically discrimination, high chronic stress, and low social support. These findings illustrate pathways by which Black MSMW’s early vulnerability for depression is either exacerbated or attenuated by their experiences as adults.
doi:10.1037/a0034128
PMCID: PMC4058315  PMID: 24099486
Black MSMW; chronic stress; CSA; depression; discrimination
9.  Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: synthesis and SAR of novel analogs of MBX 1066 and MBX 1090 
Bioorganic & medicinal chemistry  2013;21(24):7790-7806.
The prevalence of drug-resistant bacteria in the clinic has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We have previously described a set of bisamidine antibiotics that contains a core composed of two indoles and a central linker. The first compounds of the series, MBX 1066 and MBX 1090, have potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. We have conducted a systematic exploration of the amidine functionalities, the central linker, and substituents at the indole 3-position to determine the factors involved in potent antibacterial activity. Some of the newly synthesized compounds have even more potent and broad-spectrum activity than MBX 1066 and MBX 1090.
doi:10.1016/j.bmc.2013.10.014
PMCID: PMC3906850  PMID: 24239389
antibiotic; antibacterial; broad-spectrum; indole; Cadogan-Sundberg reaction; Reissert indole synthesis; McMurry reductive homocoupling reaction; amidine; imidazoline; tetrahydropyrimidine
10.  A Dose- rather than Delivery Profile–Dependent Mechanism Regulates the “Muscle-Full” Effect in Response to Oral Essential Amino Acid Intake in Young Men12 
The Journal of Nutrition  2014;145(2):207-214.
Background: The anabolic response of skeletal muscle to essential amino acids (EAAs) is dose dependent, maximal at modest doses, and short lived, even with continued EAA availability, a phenomenon termed “muscle-full.” However, the effect of EAA ingestion profile on muscle metabolism remains undefined.
Objective: We determined the effect of Bolus vs. Spread EAA feeding in young men and hypothesized that muscle-full is regulated by a dose-, not delivery profile–, dependent mechanism.
Methods: We provided 16 young healthy men with 15 g mixed-EAA, either as a single dose (“Bolus”; n = 8) or in 4 fractions at 45-min intervals (“Spread”; n = 8). Plasma insulin and EAA concentrations were assayed by ELISA and ion-exchange chromatography, respectively. Limb blood flow by was determined by Doppler ultrasound, muscle microvascular flow by Sonovue (Bracco) contrast-enhanced ultrasound, and phosphorylation of mammalian target of rapamycin complex 1 substrates by immunoblotting. Intermittent muscle biopsies were taken to quantify myofibrillar-bound 13C6-phenylalanine to determine muscle protein synthesis (MPS).
Results: Bolus feeding achieved rapid insulinemia (13.6 μIU · mL−1, 25 min after commencement of feeding), aminoacidemia (∼2500 μM at 45 min), and capillary recruitment (+45% at 45 min), whereas Spread feeding achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (peak: ∼1500 μM at 135 min), and no detectable capillary recruitment (all P < 0.01 vs. Bolus). Despite these differences, identical anabolic responses were observed; fasting fractional synthetic rates of 0.054% · h−1 (Bolus) and 0.066% · h−1 (Spread) increased to 0.095% and 0.104% · h−1 (no difference in increment or final values between regimens). With both Spread and Bolus feeding strategies, a latency of at least 90 min was observed before an upswing in MPS was evident. Similarly with both feeding strategies, MPS returned to fasting rates by 180 min despite elevated circulating EAAs.
Conclusion: These data do not support EAA delivery profile as an important determinant of anabolism in young men at rest, nor rapid aminoacidemia/leucinemia as being a key factor in maximizing MPS. This trial was registered at clinicaltrials.gov as NCT01735539.
doi:10.3945/jn.114.199604
PMCID: PMC4304023  PMID: 25644339
muscle protein synthesis; nutrition; essential amino acids; skeletal muscle; blood flow; anabolic signaling; muscle-full
11.  Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model 
Journal of Virology  2014;88(11):6368-6379.
ABSTRACT
Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. G. Cox, S. B. Livesay, M. Johnson, M. D. Ohi, and J. V. Williams, J. Virol. 86:12148–12160, 2012), which we hypothesized would elicit F-specific antibody and T cell responses. In this study, we tested whether VLP immunization could induce protective immunity to HMPV by using a mouse model. C57BL/6 mice were injected twice intraperitoneally with VLPs alone or with adjuvant and subsequently challenged with HMPV. Mice were euthanized 5 days postinfection, and virus titers, levels of neutralizing antibodies, and numbers of CD3+ T cells were quantified. Mice immunized with VLPs mounted an F-specific antibody response and generated CD8+ T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant, though adjuvant reduced cellular immune responses. Two doses of VLPs conferred complete protection from HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.
IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach. We generated HMPV VLPs by expressing the viral matrix (M) and fusion (F) proteins in mammalian cells. We found that mice immunized with VLPs mounted an F-specific antibody response and generated CD8+ T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant. Two doses of VLPs conferred complete protection against HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.
doi:10.1128/JVI.00332-14
PMCID: PMC4093842  PMID: 24672031
13.  Assessing patient reported outcome measures: A practical guide for gastroenterologists 
Gastrointestinal illnesses cause physical, emotional and social impact on patients. Patient reported outcome measures (PROMs) are increasingly used in clinical decision-making, clinical research and approval of new therapies. In the last decade, there has been a rapid increase in the number of PROMs in gastroenterology and, therefore, the choice between which of these PROMs to use can be difficult. Not all PROM instruments currently used in research and clinical practice in gastroenterology have gone through a rigorous development methodology. New drugs and therapies will not have access to the market if the PROMs used in their clinical trials are not validated according to the guidelines of the international agencies. Therefore, it is important to know the required properties of PROMs when choosing or evaluating a drug or a clinical intervention. This paper reviews the current literature on how to assess the validity and reliability of PROMs. It summarises the required properties into a practical guide for gastroenterologists to use in assessing an instrument for use in clinical practice or research.
doi:10.1177/2050640614558345
PMCID: PMC4245310  PMID: 25452841
Patient reported outcome measures; quality of life
14.  An evaluation of POSSUM and P-POSSUM scoring in predicting post-operative mortality in a level 1 critical care setting 
BMC Anesthesiology  2014;14(1):104.
Background
POSSUM and P-POSSUM are used in the assessment of outcomes in surgical patients. Neither scoring systems’ accuracy has been established where a level 1 critical care facility (level 1 care ward) is available for perioperative care. We compared POSSUM and P-POSSUM predicted with observed mortality on a level 1 care ward.
Methods
A prospective, observational study was performed between May 2000 and June 2008. POSSUM and P-POSSUM scores were calculated for all postoperative patients who were admitted to the level 1 care ward. Data for post-operative mortality were obtained from hospital records for 2552 episodes of patient care. Observed vs expected mortality was compared using receiver operating characteristic (ROC) curves and the goodness of fit assessed using the Hosmer-Lemeshow equation.
Results
ROC curves show good discriminative ability between survivors and non-survivors for POSSUM and P-POSSUM. Physiological score had far higher discrimination than operative score. Both models showed poor calibration and poor goodness of fit (Hosmer-Lemeshow). Observed to expected (O:E) mortality ratio for POSSUM and P-POSSUM indicated significantly fewer than expected deaths in all deciles of risk.
Conclusions
Our data suggest a 30-60% reduction in O:E mortality. We suggest that the use of POSSUM models to predict mortality in patients admitted to level 1 care ward is inappropriate or that a recalibration of POSSUM is required to make it useful in a level 1 care ward setting.
doi:10.1186/1471-2253-14-104
PMCID: PMC4247634  PMID: 25469106
15.  Three-Dimensional Structure of CAP-Gly Domain of Mammalian Dynactin Determined by Magic Angle Spinning NMR Spectroscopy: Conformational Plasticity and Interactions with End Binding Protein EB1 
Journal of molecular biology  2013;425(22):10.1016/j.jmb.2013.04.027.
Microtubules (MTs) and their associated proteins (MAPs) play important roles in vesicle and organelle transport, cell motility and cell division. Perturbation of these processes by mutation typically gives rise to severe pathological conditions. In our efforts to obtain atomic information on MAP/MT interactions with the goal to understand mechanisms that might potentially assist in the development of treatments for these diseases, we have determined the 3D structure of CAP-Gly domain of mammalian dynactin by MAS NMR spectroscopy. We observe two conformations in the β2 strand encompassing residues T43-V44-A45, residues that are adjacent to the disease associated mutation, G59S. Upon binding of CAP-Gly to microtubule plus-end tracking protein EB1, the CAP-Gly shifts to a single conformer. We find extensive chemical shift perturbations in several stretches of residues of CAP-Gly upon binding to EB1, from which we define accurately the CAP-Gly/EB1 binding interface. We also observe that the loop regions may exhibit unique flexibility, especially in the GKNDG motif, which participates in the microtubule binding. This study in conjunction with our previous reports suggests that conformational plasticity is an intrinsic property of CAP-Gly likely due to its unusually high loop content and may be required for its biological functions.
doi:10.1016/j.jmb.2013.04.027
PMCID: PMC3812427  PMID: 23648839
solid-state NMR; magic angle spinning; MAS; structure determination; dynactin; CAP-Gly; p150Glued domain; end-binding protein EB1; distal spinal bulbar muscular atrophy; dSBMA
16.  4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist 
Journal of medicinal chemistry  2013;56(21):8826-8833.
In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b–e), or 7α-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties.
doi:10.1021/jm401250s
PMCID: PMC3893112  PMID: 24144404
17.  Acute Viral Respiratory Illnesses in Andean Children: a Household-Based Cohort Study 
Background
Few community studies have measured the incidence, severity, and etiology of acute respiratory illness (ARI) among children living at high-altitude in remote rural settings.
Methods
We conducted active, household-based ARI surveillance among children aged <3 years in rural highland communities of San Marcos, Cajamarca, Peru from May 2009 through September 2011 (RESPIRA-PERU study). ARI (defined by fever or cough) were considered lower respiratory tract infections (LRTI) if tachypnea, wheezing, grunting, stridor, or retractions were present. Nasal swabs collected during ARI episodes were tested for respiratory viruses by real-time reverse-transcriptase polymerase chain reaction. ARI incidence was calculated using Poisson regression.
Results
During 755.1 child-years of observation among 892 children in 58 communities, 4,475 ARI were observed, yielding an adjusted incidence of 6.2 ARI/child-year (95% CI 5.9 – 6.5). Families sought medical care for 24% of ARI, 4% were classified as LRTI, and 1% led to hospitalization. Two of five deaths among cohort children were attributed to ARI. One or more respiratory virus was detected in 67% of 3957 samples collected. Virus-specific incidence rates per 100 child-years were: rhinovirus, 236; adenovirus, 73; parainfluenza virus, 46; influenza, 37; respiratory syncytial virus, 30; and human metapneumovirus, 17. Respiratory syncytial virus, metapneumovirus, and parainfluenza virus 1-3 comprised a disproportionate share of LRTI compared to other etiologies.
Conclusions
In this high-altitude rural setting with low population density, ARI in young children were common, frequently severe, and associated with a number of different respiratory viruses. Effective strategies for prevention and control of these infections are needed.
doi:10.1097/INF.0000000000000135
PMCID: PMC4223552  PMID: 24378948
influenza; respiratory syncytial virus; human metapneumovirus; acute respiratory infection; Peru
18.  Trauma Exposures and Posttraumatic Stress among Zimbabwean refugees in South Africa 
Life science journal  2013;10(3):349.
Zimbabwean refugees can be considered a vulnerable group in terms of how they are displaced with many of them having lived through hardships on their way to South Africa and other African countries. Zimbabwe is known to be Africa’s most extraordinary producer of migrants and the biggest producer of refugees in Southern Africa. It is estimated that 3.4 million Zimbabweans, a quarter of the country’s population, have fled the country. Economic collapse, hunger and political repression have been blamed for the mass exodus. The present study examines the impact of trauma exposures (pre- and post-migration stressors and poor mental health) on posttraumatic stress disorder (PTSD) among homeless Zimbabwean refugees living in South Africa. Through a guided convenient sampling, in-depth interviews using questionnaires were collected from 125 homeless Zimbabwean refugees in Polokwane, Limpopo Province, South Africa. The study was anchored on the hypothesis that predictor variables (pre- and post- migration stressors, poor mental health) would significantly affect outcomes (PTSD). Participants were assessed on demographic variables, pre- and post-migration difficulties checklists, mental health using the General Health Questionnaire (GHQ-28) and the PTSD Checklist (Civilian Version (PCL). Participants ranged from 18 to 48 years with a mean age of 28.3 years (SD = 6.27). The majority of the sample had at least a secondary education (76.8%) and were employed as unskilled labourers (61.6%) in South Africa. Being married was reported by 54.4% in Zimbabwe but changed to only 19.2% in South Africa. Hierarchical multiple regression analyses showed that the overall model significantly predicted PTSD among homeless Zimbabweans (R2 = 0.17, adjusted R2 = 0.11, F (6, 124) = 2.960, p < .01). Thus, the entire set of pre- and post-migration variables (Post total stress, PreThreat to life, Presexabuse, PrePoverty, Postsexabuse, Postpoverty and two mental health symptoms (Anxiety and Insomnia, and Social dysfunction) explained 41.2 % of the total variance on PTSD. However, main significant predictors were Post total stress (t (125) = 2.571, P < .001); Postsexabuse (t (125) = 2.175, P < .003); Postpoverty (t (125) = 3.450, P < .001); Anxiety and Insomnia (t (125) = 2.000, P < .04) and Social dysfunction (t (125) = 2.113, P < .003). Of these variables in order of strong impact predictor is Post total stress (β = 0.737) followed by Postpoverty (β = 0.701), Postsexabuse (β = 0.377) and Social dysfunction (β = 0.196). The Dubin-Watson results (2.252) also showed that the assumption of independent errors was tenable and almost certainly met for this model. Variables excluded in the model were Pre total Stress, Post threat to life, Somatic complaints (GHQ A), Severe depression (GHQ D) and Total GHQ. Zimbabwean refugees constitute a particularly vulnerable group to poor mental health and PTSD. These findings have significant implications for refugees in South Africa and other places where integrating refugee treament in the main stream health system is undermined. As a migratory group, there is need to develop ways of using probability sampling methods in further research and increasing sample size. In addition, there is need to develop culturally relevant interventions to address the sequalaes of pre- and post-migration traumas and poor mental health.
PMCID: PMC4222742  PMID: 25382966
Trauma exposure; Zimbabwean Refugees; PTSD; Mental health; Post-migration/Pre-migration difficulties
19.  Malaria mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites 
Global Health Action  2014;7:10.3402/gha.v7.25369.
Background
Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies.
Objective
To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions.
Design
From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992–2012, but two-thirds of the observations related to 2006–2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality.
Results
Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level.
Conclusions
The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology.
doi:10.3402/gha.v7.25369
PMCID: PMC4220130  PMID: 25377329
malaria; Africa; Asia; mortality; INDEPTH Network; verbal autopsy; InterVA
20.  Pregnancy-related mortality in Africa and Asia: evidence from INDEPTH Health and Demographic Surveillance System sites 
Global Health Action  2014;7:10.3402/gha.v7.25368.
Background
Women continue to die in unacceptably large numbers around the world as a result of pregnancy, particularly in sub-Saharan Africa and Asia. Part of the problem is a lack of accurate, population-based information characterising the issues and informing solutions. Population surveillance sites, such as those operated within the INDEPTH Network, have the potential to contribute to bridging the information gaps.
Objective
To describe patterns of pregnancy-related mortality at INDEPTH Network Health and Demographic Surveillance System sites in sub-Saharan Africa and southeast Asia in terms of maternal mortality ratio (MMR) and cause-specific mortality rates.
Design
Data on individual deaths among women of reproductive age (WRA) (15–49) resident in INDEPTH sites were collated into a standardised database using the INDEPTH 2013 population standard, the WHO 2012 verbal autopsy (VA) standard, and the InterVA model for assigning cause of death.
Results
These analyses are based on reports from 14 INDEPTH sites, covering 14,198 deaths among WRA over 2,595,605 person-years observed. MMRs varied between 128 and 461 per 100,000 live births, while maternal mortality rates ranged from 0.11 to 0.74 per 1,000 person-years. Detailed rates per cause are tabulated, including analyses of direct maternal, indirect maternal, and incidental pregnancy-related deaths across the 14 sites.
Conclusions
As expected, these findings confirmed unacceptably high continuing levels of maternal mortality. However, they also demonstrate the effectiveness of INDEPTH sites and of the VA methods applied to arrive at measurements of maternal mortality that are essential for planning effective solutions and monitoring programmatic impacts.
doi:10.3402/gha.v7.25368
PMCID: PMC4220143  PMID: 25377328
maternal mortality; cause of death; Africa; Asia; verbal autopsy; INDEPTH Network
21.  Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System 
The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structure-activity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF, encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF, together with its chaperone and cochaperone genes pscE and pscG, to a ΔpscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF.
doi:10.1128/AAC.02795-13
PMCID: PMC4023729  PMID: 24468789
22.  B cell intrinsic and extrinsic regulation of antibody responses by PARP14, an intracellular ADP-ribosyltransferase 
The capacity to achieve sufficient concentrations of Ag-specific Ab of the appropriate isotypes is a critical component of immunity that requires efficient differentiation and interactions of Ag-specific B and T helper (Th) cells along with dendritic cells. Numerous bacterial toxins catalyze mono-(ADP-ribosyl)ation of mammalian proteins to impact cell physiology and adaptive immunity. However, little is known about biological functions of intracellular mammalian mono-(ADP-ribosyl)transferases (mART), such as any ability to regulate Ab responses. Poly-(ADP-Ribose) Polymerase 14 (PARP14), an intracellular protein highly expressed in lymphoid cells, binds to STAT6 and encodes a catalytic domain with mART activity. Here we show that recall IgA as well as the STAT6-dependent IgE Ab responses are impaired in PARP14-deficient mice. Whereas PARP14 regulation of IgE involved a B cell intrinsic process, the predominant impact on IgA was B cell-extrinsic. Of note, PARP14 deficiency reduced the levels of Th17 cells and CD103+ DCs which are implicated in IgA regulation. PARP14 enhanced the expression of RORα, Runx1 and Smad3 after T cell activation, and, importantly, its catalytic activity of PARP14 promoted Th17 differentiation. Collectively, the findings show that PARP14 influences the class distribution, affinity repertoire, and recall capacity of antibody responses in mice, and provide direct evidence of requirement for protein mono-ADP-ribosylation in T helper differentiation.
doi:10.4049/jimmunol.1301106
PMCID: PMC3770464  PMID: 23956424
23.  Costs Associated with Implementation of Computer-Assisted Clinical Decision Support System for Antenatal and Delivery Care: Case Study of Kassena-Nankana District of Northern Ghana 
PLoS ONE  2014;9(9):e106416.
Objective
This study analyzed cost of implementing computer-assisted Clinical Decision Support System (CDSS) in selected health care centres in Ghana.
Methods
A descriptive cross sectional study was conducted in the Kassena-Nankana district (KND). CDSS was deployed in selected health centres in KND as an intervention to manage patients attending antenatal clinics and the labour ward. The CDSS users were mainly nurses who were trained. Activities and associated costs involved in the implementation of CDSS (pre-intervention and intervention) were collected for the period between 2009–2013 from the provider perspective. The ingredients approach was used for the cost analysis. Costs were grouped into personnel, trainings, overheads (recurrent costs) and equipment costs (capital cost). We calculated cost without annualizing capital cost to represent financial cost and cost with annualizing capital costs to represent economic cost.
Results
Twenty-two trained CDSS users (at least 2 users per health centre) participated in the study. Between April 2012 and March 2013, users managed 5,595 antenatal clients and 872 labour clients using the CDSS. We observed a decrease in the proportion of complications during delivery (pre-intervention 10.74% versus post-intervention 9.64%) and a reduction in the number of maternal deaths (pre-intervention 4 deaths versus post-intervention 1 death). The overall financial cost of CDSS implementation was US$23,316, approximately US$1,060 per CDSS user trained. Of the total cost of implementation, 48% (US$11,272) was pre-intervention cost and intervention cost was 52% (US$12,044). Equipment costs accounted for the largest proportion of financial cost: 34% (US$7,917). When economic cost was considered, total cost of implementation was US$17,128–lower than the financial cost by 26.5%.
Conclusions
The study provides useful information in the implementation of CDSS at health facilities to enhance health workers' adherence to practice guidelines and taking accurate decisions to improve maternal health care.
doi:10.1371/journal.pone.0106416
PMCID: PMC4152286  PMID: 25180831
24.  Viral Etiologies of Infant Bronchiolitis, Croup, and Upper Respiratory Illness during Four Consecutive Years 
The Pediatric infectious disease journal  2013;32(9):10.1097/INF.0b013e31829b7e43.
Background
Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness in infants is limited.
Methods
This prospective cohort enrolled previously healthy term infants during inpatient or outpatient visits for acute upper respiratory illness (URI) or bronchiolitis during September - May 2004–2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time RT-PCR.
Results
Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup, and 27% URI. Among infants with bronchiolitis, 76% had RSV, 18% HRV, 10% influenza, 2% coronavirus, 3% HMPV, and 1% PIV. Among infants with croup, 39% had HRV, 28% PIV, 28% RSV, 11% influenza, 6% coronavirus, and none HMPV. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% PIV, and 4% HMPV. Individual viruses exhibited distinct seasonal, demographic, and clinical expression.
Conclusions
The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.
doi:10.1097/INF.0b013e31829b7e43
PMCID: PMC3880140  PMID: 23694832
bronchiolitis; croup; URI; rhinovirus; respiratory syncytial virus
25.  Cytomegalovirus Mutants Resistant to Ganciclovir and Cidofovir Differ in Susceptibilities to Synguanol and Its 6-Ether and 6-Thioether Derivatives 
The methylenecyclopropane nucleoside (MCPN) analogs synguanol and its 6-alkoxy (MBX2168) and 6-alkylthio (MBX1616) derivatives retained good in vitro activities against several common ganciclovir-resistant UL97 kinase variants of human cytomegalovirus. Foscarnet-MCPN cross-resistance was observed among UL54 polymerase variants. UL54 exonuclease domain ganciclovir-cidofovir dual-resistant variants were remarkably more hypersensitive to these MCPNs than to cyclopropavir, with some 50% effective concentration ratios that were <0.1× the wild type. Different categories of MCPNs may have therapeutically exploitable mechanistic differences in viral DNA polymerase inhibition.
doi:10.1128/AAC.02544-13
PMCID: PMC3957852  PMID: 24379208

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