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1.  An increase in the burden of neonatal admissions to a rural district hospital in Kenya over 19 years 
BMC Public Health  2010;10:591.
Background
Most of the global neonatal deaths occur in developing nations, mostly in rural homes. Many of the newborns who receive formal medical care are treated in rural district hospitals and other peripheral health centres. However there are no published studies demonstrating trends in neonatal admissions and outcome in rural health care facilities in resource poor regions. Such information is critical in planning public health interventions. In this study we therefore aimed at describing the pattern of neonatal admissions to a Kenyan rural district hospital and their outcome over a 19 year period, examining clinical indicators of inpatient neonatal mortality and also trends in utilization of a rural hospital for deliveries.
Methods
Prospectively collected data on neonates is compared to non-neonatal paediatric (≤ 5 years old) admissions and deliveries' in the maternity unit at Kilifi District Hospital from January 1st 1990 up to December 31st 2008, to document the pattern of neonatal admissions, deliveries and changes in inpatient deaths. Trends were examined using time series models with likelihood ratios utilised to identify indicators of inpatient neonatal death.
Results
The proportion of neonatal admissions of the total paediatric ≤ 5 years admissions significantly increased from 11% in 1990 to 20% by 2008 (trend 0.83 (95% confidence interval 0.45 -1.21). Most of the increase in burden was from neonates born in hospital and very young neonates aged < 7days. Hospital deliveries also increased significantly. Clinical diagnoses of neonatal sepsis, prematurity, neonatal jaundice, neonatal encephalopathy, tetanus and neonatal meningitis accounted for over 75% of the inpatient neonatal admissions. Inpatient case fatality for all ≤ 5 years declined significantly over the 19 years. However, neonatal deaths comprised 33% of all inpatient death among children aged ≤ 5 years in 1990, this increased to 55% by 2008. Tetanus 256/390 (67%), prematurity 554/1,280(43%) and neonatal encephalopathy 253/778(33%) had the highest case fatality. A combination of six indicators: irregular respiration, oxygen saturation of <90%, pallor, neck stiffness, weight < 1.5 kg, and abnormally elevated blood glucose > 7 mmol/l predicted inpatient neonatal death with a sensitivity of 81% and a specificity of 68%.
Conclusions
There is clear evidence of increasing burden in neonatal admissions at a rural district hospital in contrast to reducing numbers of non-neonatal paediatrics' admissions aged ≤ 5years. Though the inpatient case fatality for all admissions aged ≤ 5 years declined significantly, neonates now comprise close to 60% of all inpatient deaths. Simple indicators may identify neonates at risk of death.
doi:10.1186/1471-2458-10-591
PMCID: PMC2965720  PMID: 20925939
2.  Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Kassebaum, Nicholas J | Bertozzi-Villa, Amelia | Coggeshall, Megan S | Shackelford, Katya A | Steiner, Caitlyn | Heuton, Kyle R | Gonzalez-Medina, Diego | Barber, Ryan | Huynh, Chantal | Dicker, Daniel | Templin, Tara | Wolock, Timothy M | Ozgoren, Ayse Abbasoglu | Abd-Allah, Foad | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie E | Akena, Dickens | Alasfoor, Deena | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Al Kahbouri, Mazin J | Alla, François | Allen, Peter J | AlMazroa, Mohammad A | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzmán, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Antonio, Carl A T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asad, Majed Masoud | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Basu, Arindam | Basu, Sanjay | Beardsley, Justin | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku J | Bhutta, Zulfiqar | Abdulhak, Aref Bin | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Breitborde, Nicholas | Cárdenas, Rosario | Castañeda-Orjuela, Carlos A | Castro, Ruben Estanislao | Catalá-López, Ferrán | Cavlin, Alanur | Chang, Jung-Chen | Che, Xuan | Christophi, Costas A | Chugh, Sumeet S | Cirillo, Massimo | Colquhoun, Samantha M | Cooper, Leslie Trumbull | Cooper, Cyrus | da Costa Leite, Iuri | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Degenhardt, Louisa | De Leo, Diego | del Pozo-Cruz, Borja | Deribe, Kebede | Dessalegn, Muluken | deVeber, Gabrielle A | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Dorrington, Rob E | Driscoll, Tim R | Ermakov, Sergei Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Felicio, Manuela Mendonca | Fereshtehnejad, Seyed-Mohammad | de Lima, Graça Maria Ferreira | Forouzanfar, Mohammad H | França, Elisabeth B | Gaffikin, Lynne | Gambashidze, Ketevan | Gankpé, Fortuné Gbètoho | Garcia, Ana C | Geleijnse, Johanna M | Gibney, Katherine B | Giroud, Maurice | Glaser, Elizabeth L | Goginashvili, Ketevan | Gona, Philimon | González-Castell, Dinorah | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rahul | Gupta, Rajeev | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Havmoeller, Rasmus | Hay, Simon I | Heredia Pi, Ileana B | Hoek, Hans W | Hosgood, H Dean | Hoy, Damian G | Husseini, Abdullatif | Idrisov, Bulat T | Innos, Kaire | Inoue, Manami | Jacobsen, Kathryn H | Jahangir, Eiman | Jee, Sun Ha | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kan, Haidong | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazanjan, Konstantin | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kulkarni, Chanda | Kulkarni, Veena S | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Kwan, Gene | Lai, Taavi | Lalloo, Ratilal | Lam, Hilton | Lansingh, Van C | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Xiaohong | Li, Yichong | Li, Yongmei | Liang, Juan | Liang, Xiaofeng | Lim, Stephen S | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | London, Stephanie J | Lotufo, Paulo A | Ma, Jixiang | Ma, Stefan | Machado, Vasco Manuel Pedro | Mainoo, Nana Kwaku | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Mason-Jones, Amanda J | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | de la Cruz Monis, Jonathan | Hernandez, Julio Cesar Montañez | Moore, Ami R | Moradi-Lakeh, Maziar | Mori, Rintaro | Mueller, Ulrich O | Mukaigawara, Mitsuru | Naheed, Aliya | Naidoo, Kovin S | Nand, Devina | Nangia, Vinay | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nieuwenhuijsen, Mark J | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Park, Jae-Hyun | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pesudovs, Konrad | Petzold, Max | Poenaru, Dan | Polanczyk, Guilherme V | Polinder, Suzanne | Pope, Dan | Pourmalek, Farshad | Qato, Dima | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad ur | Raju, Murugesan | Rana, Saleem M | Refaat, Amany | Ronfani, Luca | Roy, Nobhojit | Sánchez Pimienta, Tania Georgina | Sahraian, Mohammad Ali | Salomon, Joshua A | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Sayinzoga, Felix | Schneider, Ione J C | Schumacher, Austin | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Shakh-Nazarova, Marina | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Sreeramareddy, Chandrashekhar T | Stroumpoulis, Konstantinos | Sturua, Lela | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tan, Feng | Teixeira, Carolina Maria | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thorne-Lyman, Andrew L | Tirschwell, David L | Towbin, Jeffrey A | Tran, Bach X | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Undurraga, Eduardo A | Uzun, Selen Begüm | Vallely, Andrew J | van Gool, Coen H | Vasankari, Tommi J | Vavilala, Monica S | Venketasubramanian, N | Villalpando, Salvador | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vos, Theo | Waller, Stephen | Wang, Haidong | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Woldeyohannes, Solomon Meseret | Wong, John Q | Wordofa, Muluemebet Abera | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa Z | Yu, Chuanhua | Jin, Kim Yun | El SayedZaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Naghavi, Mohsen | Murray, Christopher J L | Lozano, Rafael
Lancet  2014;384(9947):980-1004.
Summary
Background
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
Methods
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
Findings
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Interpretation
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60696-6
PMCID: PMC4255481  PMID: 24797575
3.  The INTERGROWTH-21st Project Neurodevelopment Package: A Novel Method for the Multi-Dimensional Assessment of Neurodevelopment in Pre-School Age Children 
PLoS ONE  2014;9(11):e113360.
Background
The International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Project is a population-based, longitudinal study describing early growth and development in an optimally healthy cohort of 4607 mothers and newborns. At 24 months, children are assessed for neurodevelopmental outcomes with the INTERGROWTH-21st Neurodevelopment Package. This paper describes neurodevelopment tools for preschoolers and the systematic approach leading to the development of the Package.
Methods
An advisory panel shortlisted project-specific criteria (such as multi-dimensional assessments and suitability for international populations) to be fulfilled by a neurodevelopment instrument. A literature review of well-established tools for preschoolers revealed 47 candidates, none of which fulfilled all the project's criteria. A multi-dimensional assessment was, therefore, compiled using a package-based approach by: (i) categorizing desired outcomes into domains, (ii) devising domain-specific criteria for tool selection, and (iii) selecting the most appropriate measure for each domain.
Results
The Package measures vision (Cardiff tests); cortical auditory processing (auditory evoked potentials to a novelty oddball paradigm); and cognition, language skills, behavior, motor skills and attention (the INTERGROWTH-21st Neurodevelopment Assessment) in 35–45 minutes. Sleep-wake patterns (actigraphy) are also assessed. Tablet-based applications with integrated quality checks and automated, wireless electroencephalography make the Package easy to administer in the field by non-specialist staff. The Package is in use in Brazil, India, Italy, Kenya and the United Kingdom.
Conclusions
The INTERGROWTH-21st Neurodevelopment Package is a multi-dimensional instrument measuring early child development (ECD). Its developmental approach may be useful to those involved in large-scale ECD research and surveillance efforts.
doi:10.1371/journal.pone.0113360
PMCID: PMC4244160  PMID: 25423589
4.  Burden of epilepsy in rural Kenya measured in disability-adjusted life years 
Epilepsia  2014;55(10):1626-1633.
Objectives
The burden of epilepsy, in terms of both morbidity and mortality, is likely to vary depending on the etiology (primary [genetic/unknown] vs. secondary [structural/metabolic]) and with the use of antiepileptic drugs (AEDs). We estimated the disability-adjusted life years (DALYs) and modeled the remission rates of active convulsive epilepsy (ACE) using epidemiologic data collected over the last decade in rural Kilifi, Kenya.
Methods
We used measures of prevalence, incidence, and mortality to model the remission of epilepsy using disease-modeling software (DisMod II). DALYs were calculated as the sum of Years Lost to Disability (YLD) and Years of Life Lost (YLL) due to premature death using the prevalence approach, with disability weights (DWs) from the 2010 Global Burden of Disease (GBD) study. DALYs were calculated with R statistical software with the associated uncertainty intervals (UIs) computed by bootstrapping.
Results
A total of 1,005 (95% UI 797–1,213) DALYs were lost to ACE, which is 433 (95% UI 393–469) DALYs lost per 100,000 people. Twenty-six percent (113/100,000/year, 95% UI 106–117) of the DALYs were due to YLD and 74% (320/100,000/year, 95% UI 248–416) to YLL. Primary epilepsy accounted for fewer DALYs than secondary epilepsy (98 vs. 334 DALYs per 100,000 people). Those taking AEDs contributed fewer DALYs than those not taking AEDs (167 vs. 266 DALYs per 100,000 people). The proportion of people with ACE in remission per year was estimated at 11.0% in males and 12.0% in females, with highest rates in the 0–5 year age group.
Significance
The DALYs for ACE are high in rural Kenya, but less than the estimates of 2010 GBD study. Three-fourths of DALYs resulted from secondary epilepsy. Use of AEDs was associated with 40% reduction of DALYs. Improving adherence to AEDs may reduce the burden of epilepsy in this area.
doi:10.1111/epi.12741
PMCID: PMC4238788  PMID: 25131901
Burden; Disability-adjusted life years; Epilepsy; Remission; Treatment gap
5.  Evaluation of Kilifi Epilepsy Education Programme: A randomized controlled trial 
Epilepsia  2014;55(2):344-352.
Objectives
The epilepsy treatment gap is largest in resource-poor countries. We evaluated the efficacy of a 1-day health education program in a rural area of Kenya. The primary outcome was adherence to antiepileptic drugs (AEDs) as measured by drug levels in the blood, and the secondary outcomes were seizure frequency and Kilifi Epilepsy Beliefs and Attitudes Scores (KEBAS).
Methods
Seven hundred thirty-eight people with epilepsy (PWE) and their designated supporter were randomized to either the intervention (education) or nonintervention group. Data were collected at baseline and 1 year after the education intervention was administered to the intervention group. There were 581 PWE assessed at both time points. At the end of the study, 105 PWE from the intervention group and 86 from the nonintervention group gave blood samples, which were assayed for the most commonly used AEDs (phenobarbital, phenytoin, and carbamazepine). The proportions of PWE with detectable AED levels were determined using a standard blood assay method. The laboratory technicians conducting the assays were blinded to the randomization. Secondary outcomes were evaluated using questionnaires administered by trained field staff. Modified Poisson regression was used to investigate the factors associated with improved adherence (transition from nonoptimal AED level in blood at baseline to optimal levels at follow-up), reduced seizures, and improved KEBAS, which was done as a post hoc analysis. This trial is registered in ISRCTN register under ISRCTN35680481.
Results
There was no significant difference in adherence to AEDs based on detectable drug levels (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 0.74–2.90, p = 0.28) or by self-reports (OR 1.00, 95% CI 0.71–1.40, p = 1.00) between the intervention and nonintervention group. The intervention group had significantly fewer beliefs about traditional causes of epilepsy, cultural treatment, and negative stereotypes than the nonintervention group. There was no difference in seizure frequency. A comparison of the baseline and follow-up data showed a significant increase in adherence—intervention group (36–81% [p < 0.001]) and nonintervention group (38–74% [p < 0.001])—using detectable blood levels. The number of patients with less frequent seizures (≤3 seizures in the last 3 months) increased in the intervention group (62–80% [p = 0.002]) and in the nonintervention group (67–75% [p = 0.04]). Improved therapeutic adherence (observed in both groups combined) was positively associated with positive change in beliefs about risks of epilepsy (relative risk [RR] 2.00, 95% CI 1.03–3.95) and having nontraditional religious beliefs (RR 2.01, 95% CI 1.01–3.99). Reduced seizure frequency was associated with improved adherence (RR 1.72, 95% CI 1.19–2.47). Positive changes in KEBAS were associated with having tertiary education as compared to none (RR 1.09, 95% CI 1.05–1.14).
Significance
Health education improves knowledge about epilepsy, but once only contact does not improve adherence. However, sustained education may improve adherence in future studies.
doi:10.1111/epi.12498
PMCID: PMC4233970  PMID: 24447063
Epilepsy; Education intervention; Adherence; Beliefs about epilepsy; Seizure frequency
6.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Murray, Christopher J L | Ortblad, Katrina F | Guinovart, Caterina | Lim, Stephen S | Wolock, Timothy M | Roberts, D Allen | Dansereau, Emily A | Graetz, Nicholas | Barber, Ryan M | Brown, Jonathan C | Wang, Haidong | Duber, Herbert C | Naghavi, Mohsen | Dicker, Daniel | Dandona, Lalit | Salomon, Joshua A | Heuton, Kyle R | Foreman, Kyle | Phillips, David E | Fleming, Thomas D | Flaxman, Abraham D | Phillips, Bryan K | Johnson, Elizabeth K | Coggeshall, Megan S | Abd-Allah, Foad | Ferede, Semaw | Abraham, Jerry P | Abubakar, Ibrahim | Abu-Raddad, Laith J | Abu-Rmeileh, Niveen Me | Achoki, Tom | Adeyemo, Austine Olufemi | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie Elisabet | Akena, Dickens | Al Kahbouri, Mazin J | Alasfoor, Deena | Albittar, Mohammed I | Alcalá-Cerra, Gabriel | Alegretti, Miguel Angel | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Alla, Francois | Allen, Peter J | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzman, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Anderson, Benjamin O | Antonio, Carl Abelardo T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Banerjee, Amitava | Basu, Sanjay | Beardsley, Justin | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku Jibat | Bhala, Neeraj | Bhalla, Ashish | Bhutta, Zulfiqar A | Abdulhak, Aref Bin | Binagwaho, Agnes | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Brainin, Michael | Breitborde, Nicholas | Castañeda-Orjuela, Carlos A | Catalá-López, Ferrán | Chadha, Vineet K | Chang, Jung-Chen | Chiang, Peggy Pei-Chia | Chuang, Ting-Wu | Colomar, Mercedes | Cooper, Leslie Trumbull | Cooper, Cyrus | Courville, Karen J | Cowie, Benjamin C | Criqui, Michael H | Dandona, Rakhi | Dayama, Anand | De Leo, Diego | Degenhardt, Louisa | Del Pozo-Cruz, Borja | Deribe, Kebede | Jarlais, Don C Des | Dessalegn, Muluken | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Driscoll, Tim R | Durrani, Adnan M | Ellenbogen, Richard G | Ermakov, Sergey Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Forouzanfar, Mohammad H | Paleo, Urbano Fra. | Gaffikin, Lynne | Gamkrelidze, Amiran | Gankpé, Fortuné Gbètoho | Geleijnse, Johanna M | Gessner, Bradford D | Gibney, Katherine B | Ginawi, Ibrahim Abdelmageem Mohamed | Glaser, Elizabeth L | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rajeev | Gupta, Rahul | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Haro, Josep Maria | Havmoeller, Rasmus | Hay, Simon I | Hedayati, Mohammad T | Pi, Ileana B Heredia | Hoek, Hans W | Hornberger, John C | Hosgood, H Dean | Hotez, Peter J | Hoy, Damian G | Huang, John J | Iburg, Kim M | Idrisov, Bulat T | Innos, Kaire | Jacobsen, Kathryn H | Jeemon, Panniyammakal | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kan, Haidong | Kankindi, Ida | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Keren, Andre | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Khonelidze, Irma | Kinfu, Yohannes | Kinge, Jonas M | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, S | Defo, Barthelemy Kuate | Kulkarni, Veena S | Kulkarni, Chanda | Kumar, Kaushalendra | Kumar, Ravi B | Kumar, G Anil | Kwan, Gene F | Lai, Taavi | Balaji, Arjun Lakshmana | Lam, Hilton | Lan, Qing | Lansingh, Van C | Larson, Heidi J | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Yichong | Li, Yongmei | De Lima, Graça Maria Ferreira | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | Lotufo, Paulo A | Machado, Vasco Manuel Pedro | Maclachlan, Jennifer H | Magis-Rodriguez, Carlos | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Masci, Joseph R | Mashal, Mohammad Taufiq | Mason-Jones, Amanda J | Mayosi, Bongani M | Mazorodze, Tasara T | Mckay, Abigail Cecilia | Meaney, Peter A | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Melaku, Yohannes Adama | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Mori, Rintaro | Moturi, Wilkister Nyaora | Mukaigawara, Mitsuru | Murthy, Kinnari S | Naheed, Aliya | Naidoo, Kovin S | Naldi, Luigi | Nangia, Vinay | Narayan, K M Venkat | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nowaseb, Vincent | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pervaiz, Aslam | Pesudovs, Konrad | Petzold, Max | Pourmalek, Farshad | Qato, Dima | Quezada, Amado D | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad Ur | Raju, Murugesan | Rana, Saleem M | Razavi, Homie | Reilly, Robert Quentin | Remuzzi, Giuseppe | Richardus, Jan Hendrik | Ronfani, Luca | Roy, Nobhojit | Sabin, Nsanzimana | Saeedi, Mohammad Yahya | Sahraian, Mohammad Ali | Samonte, Genesis May J | Sawhney, Monika | Schneider, Ione J C | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Shivakoti, Rupak | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Simard, Edgar P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soneji, Samir | Soshnikov, Sergey S | Sreeramareddy, Chandrashekhar T | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Swaminathan, Soumya | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thomson, Alan J | Thorne-Lyman, Andrew L | Towbin, Jeffrey A | Traebert, Jefferson | Tran, Bach X | Dimbuene, Zacharie Tsala | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Uzun, Selen Begüm | Vallely, Andrew J | Vasankari, Tommi J | Venketasubramanian, N | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Waller, Stephen | Wallin, Mitchell T | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | White, Richard A | Wilkinson, James D | Williams, Thomas Neil | Woldeyohannes, Solomon Meseret | Wong, John Q | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | El Sayed Zaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Vos, Theo
Lancet  2014;384(9947):1005-1070.
Summary
Background
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
Methods
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Findings
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Interpretation
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60844-8
PMCID: PMC4202387  PMID: 25059949
7.  Accuracy of clinical stroke scores for distinguishing stroke subtypes in resource poor settings: A systematic review of diagnostic test accuracy 
Background:
Stroke is the second leading cause of death globally. Computerized tomography is used to distinguish between ischemic and hemorrhagic subtypes, but it is expensive and unavailable in low and middle income countries. Clinical stroke scores are proposed to differentiate between stroke subtypes but their reliability is unknown.
Materials and Methods:
We searched online databases for studies written in English and identified articles using predefined criteria. We considered studies in which the Siriraj, Guy's Hospital, Besson and Greek stroke scores were compared to computerized tomography as the reference standard. We calculated the pooled sensitivity and specificity of the clinical stroke scores using a bivariate mixed effects binomial regression model.
Results:
In meta-analysis, sensitivity and specificity for the Siriraj stroke score, were 0.69 (95% CI 0.62-0.75) and 0.83 (95% CI 0.75-0.88) for ischemic stroke and 0.65 (95% CI 0.56-0.73) and 0.88 (95% CI 0.83-0.91) for hemorrhagic stroke. For the Guy's hospital stroke score overall sensitivity and specificity were 0.70 (95% CI 0.53-0.83) and 0.79 (95% CI 0.68-0.87) for ischemic stroke and 0.54 (95% CI 0.42-0.66) and 0.89 (95% CI 0.83-0.94) for hemorrhagic stroke.
Conclusions:
Clinical stroke scores are not accurate enough for use in clinical or epidemiological settings. Computerized tomography is recommended for differentiating stroke subtypes. Larger studies using different patient populations are required for validation of clinical stroke scores.
doi:10.4103/0976-3147.139966
PMCID: PMC4173228  PMID: 25288833
Besson score; Guy's hospital stroke score; Greek stroke score; Siriraj stroke score; stroke
8.  Retinopathy, histidine-rich protein-2 and perfusion pressure in cerebral malaria 
Brain  2014;137(9):e298.
doi:10.1093/brain/awu144
PMCID: PMC4132642  PMID: 24919968
9.  Child Neurology Services in Africa 
Journal of child neurology  2011;26(12):1555-1563.
The first African Child Neurology Association meeting identified key challenges that the continent faces to improve the health of children with neurology disorders. The capacity to diagnose common neurologic conditions and rare disorders is lacking. The burden of neurologic disease on the continent is not known, and this lack of knowledge limits the ability to lobby for better health care provision. Inability to practice in resource-limited settings has led to the migration of skilled professionals away from Africa. Referral systems from primary to tertiary are often unpredictable and chaotic. There is a lack of access to reliable supplies of basic neurology treatments such as antiepileptic drugs. Few countries have nationally accepted guidelines either for the management of epilepsy or status epilepticus. There is a great need to develop better training capacity across Africa in the recognition and management of neurologic conditions in children, from primary health care to the subspecialist level.
doi:10.1177/0883073811420601
PMCID: PMC3672989  PMID: 22019842
Africa; child neurology; resources
10.  Exposure to Multiple Parasites Is Associated with the Prevalence of Active Convulsive Epilepsy in Sub-Saharan Africa 
Background
Epilepsy is common in developing countries, and it is often associated with parasitic infections. We investigated the relationship between exposure to parasitic infections, particularly multiple infections and active convulsive epilepsy (ACE), in five sites across sub-Saharan Africa.
Methods and Findings
A case-control design that matched on age and location was used. Blood samples were collected from 986 prevalent cases and 1,313 age-matched community controls and tested for presence of antibodies to Onchocerca volvulus, Toxocara canis, Toxoplasma gondii, Plasmodium falciparum, Taenia solium and HIV. Exposure (seropositivity) to Onchocerca volvulus (OR = 1.98; 95%CI: 1.52–2.58, p<0.001), Toxocara canis (OR = 1.52; 95%CI: 1.23–1.87, p<0.001), Toxoplasma gondii (OR = 1.28; 95%CI: 1.04–1.56, p = 0.018) and higher antibody levels (top tertile) to Toxocara canis (OR = 1.70; 95%CI: 1.30–2.24, p<0.001) were associated with an increased prevalence of ACE. Exposure to multiple infections was common (73.8% of cases and 65.5% of controls had been exposed to two or more infections), and for T. gondii and O. volvulus co-infection, their combined effect on the prevalence of ACE, as determined by the relative excess risk due to interaction (RERI), was more than additive (T. gondii and O. volvulus, RERI = 1.19). The prevalence of T. solium antibodies was low (2.8% of cases and 2.2% of controls) and was not associated with ACE in the study areas.
Conclusion
This study investigates how the degree of exposure to parasites and multiple parasitic infections are associated with ACE and may explain conflicting results obtained when only seropositivity is considered. The findings from this study should be further validated.
Author Summary
The prevalence of epilepsy is greater in developing countries compared to developed countries, and parasitic infestations are thought to contribute to this increased burden. We conducted a case-control study across five sites in sub-Saharan Africa to investigate the relationship between epilepsy and exposure to parasitic infections, and the association between epilepsy and multiple co-incidental infections. Exposure to Onchocerca volvulus, Toxocara canis and Toxoplasma gondii as well as high antibody levels (top tertile) to Toxocara canis was positively associated with the prevalence of active convulsive epilepsy (ACE). Multiple co-incidental parasitic infections were common, and the combined effect of T. gondii and O. volvulus co-infection on ACE was greater than the sum of the individual effects. The contribution of each of these parasitic infections on the burden of epilepsy in sub-Saharan Africa should be explored.
doi:10.1371/journal.pntd.0002908
PMCID: PMC4038481  PMID: 24875312
11.  Closing the mental health treatment gap in South Africa: a review of costs and cost-effectiveness 
Global Health Action  2014;7:10.3402/gha.v7.23431.
Background
Nearly one in three South Africans will suffer from a mental disorder in his or her lifetime, a higher prevalence than many low- and middle-income countries. Understanding the economic costs and consequences of prevention and packages of care is essential, particularly as South Africa considers scaling-up mental health services and works towards universal health coverage. Economic evaluations can inform how priorities are set in system or spending changes.
Objective
To identify and review research from South Africa and sub-Saharan Africa on the direct and indirect costs of mental, neurological, and substance use (MNS) disorders and the cost-effectiveness of treatment interventions.
Design
Narrative overview methodology.
Results and conclusions
Reviewed studies indicate that integrating mental health care into existing health systems may be the most effective and cost-efficient approach to increase access to mental health services in South Africa. Integration would also direct treatment, prevention, and screening to people with HIV and other chronic health conditions who are at high risk for mental disorders. We identify four major knowledge gaps: 1) accurate and thorough assessment of the health burdens of MNS disorders, 2) design and assessment of interventions that integrate mental health screening and treatment into existing health systems, 3) information on the use and costs of traditional medicines, and 4) cost-effectiveness evaluation of a range of specific interventions or packages of interventions that are tailored to the national context.
doi:10.3402/gha.v7.23431
PMCID: PMC4038770  PMID: 24848654
mental health; South Africa; economics; health planning; policy; costs and cost analysis
12.  Prevalence and risk factors for active convulsive epilepsy in rural northeast South Africa 
Epilepsy Research  2014;108(4):782-791.
Highlights
•Epilepsy is prevalent in rural South Africa, but less than other parts of Africa.•Most epilepsy starts in childhood.•Poor obstetric history and snoring were associated with active convulsive epilepsy.•HIV and parasitic infection were not associated with active convulsive epilepsy.
Summary
Rationale
Epilepsy is among the most common neurological disorders worldwide. However, there are few large, population-based studies of the prevalence and risk factors for epilepsy in southern Africa.
Methods
From August 2008 to February 2009, as part of a multi-site study, we undertook a three-stage, population-based study, embedded within the Agincourt health and socio-demographic surveillance system, to estimate the prevalence and identify risk factors of active convulsive epilepsy (ACE) in a rural South African population.
Results
The crude prevalence of ACE, after adjusting for non-response and the sensitivity of the screening method, was 7.0/1,000 individuals (95%CI 6.4–7.6) with significant geographic heterogeneity across the study area. Being male (OR = 2.3; 95%CI 1.6–3.2), family history of seizures (OR = 4.0; 95%CI 2.0–8.1), a sibling with seizures (OR = 7.0; 95%CI 1.6–31.7), problems after delivery (OR = 5.9; 95%CI 1.2–24.6), and history of snoring (OR = 6.5; 95%CI 4.5–9.5) were significantly associated with ACE. For children, their mother's exposure to some formal schooling was protective (OR = 0.30; 95%CI 0.11–0.84) after controlling for age and sex. Human immunodeficiency virus was not found to be associated with ACE.
Conclusions
ACE is less frequent in this part of rural South Africa than other parts of sub-Saharan Africa. Improving obstetric services could prevent epilepsy. The relationship between snoring and ACE requires further investigation, as does the relative contribution of genetic and environmental factors to examine the increased risk in those with a family history of epilepsy.
doi:10.1016/j.eplepsyres.2014.01.004
PMCID: PMC4000269  PMID: 24582322
Epilepsy; Prevalence; Case-control; Risk factors; Population-based
13.  Long-Term Survival and Outcome in Children Admitted to Kilifi District Hospital with Convulsive Status Epilepticus 
Objectives. The incidence of convulsive status epilepticus (CSE) is high in Africa but the long-term outcome is unknown. We examined the neurocognitive outcome and survival of children treated for CSE in a Kenyan hospital 3 to 4 years after discharge. Methods. The frequency and nature of neurological deficits among this group of children were determined and compared to a control group. The children were screened with the Ten Questions Questionnaire for neurodevelopmental impairment if alive and those that screened positive were invited for further assessment to determine the pattern and extent of their impairment. A verbal autopsy was performed to determine the cause of death in those that died. Results. In the 119 cases followed-up, 9 (8%) died after discharge, with the majority having seizures during their fatal illness. The 110 survivors (median age 5 years) had significantly more neurological impairments on the screening compared to 282 controls (34/110 (30.9%) versus 11/282 (3.9%), OR = 11.0, 95% CI 5.3–22.8). Fifteen percent of the cases had active epilepsy. Conclusions. This study demonstrates the considerable burden of CSE in African children. Strategies to manage children with CSE that are acceptable to the community need to be explored to improve the longer-term outcome.
doi:10.1155/2014/643747
PMCID: PMC3928879  PMID: 24627807
14.  Risk factors associated with the epilepsy treatment gap in Kilifi, Kenya: a cross-sectional study 
Lancet Neurology  2012;11(8):688-696.
Summary
Background
Many people with epilepsy in low-income countries do not receive appropriate biomedical treatment. This epilepsy treatment gap might be caused by patients not seeking biomedical treatment or not adhering to prescribed antiepileptic drugs (AEDs). We measured the prevalence of and investigated risk factors for the epilepsy treatment gap in rural Kenya.
Methods
All people with active convulsive epilepsy identified during a cross-sectional survey of 232 176 people in Kilifi were approached. The epilepsy treatment gap was defined as the percentage of people with active epilepsy who had not accessed biomedical services or who were not on treatment or were on inadequate treatment. Information about risk factors was obtained through a questionnaire-based interview of sociodemographic characteristics, socioeconomic status, access to health facilities, seizures, stigma, and beliefs and attitudes about epilepsy. The factors associated with people not seeking biomedical treatment and not adhering to AEDs were investigated separately, adjusted for age.
Findings
673 people with epilepsy were interviewed, of whom 499 (74%) reported seeking treatment from a health facility. Blood samples were taken from 502 (75%) people, of whom 132 (26%) reported taking AEDs, but 189 (38%) had AEDs detectable in the blood. The sensitivity and specificity of self-reported adherence compared with AEDs detected in blood were 38·1% (95% CI 31·1–45·4) and 80·8% (76·0–85·0). The epilepsy treatment gap was 62·4% (58·1–66·6). In multivariable analysis, failure to seek biomedical treatment was associated with a patient holding traditional animistic religious beliefs (adjusted odds ratio 1·85, 95% CI 1·11–2·71), reporting negative attitudes about biomedical treatment (0·86, 0·78–0·95), living more than 30 km from health facilities (3·89, 1·77–8·51), paying for AEDs (2·99, 1·82–4·92), having learning difficulties (2·30, 1·29–4·11), having had epilepsy for longer than 10 years (4·60, 2·07–10·23), and having focal seizures (2·28, 1·50–3·47). Reduced adherence was associated with negative attitudes about epilepsy (1·10, 1·03–1·18) and taking of AEDs for longer than 5 years (3·78, 1·79–7·98).
Interpretation
The sensitivity and specificity of self-reported adherence is poor, but on the basis of AED detection in blood almost two-thirds of patients with epilepsy were not on treatment. Education about epilepsy and making AEDs freely available in health facilities near people with epilepsy should be investigated as potential ways to reduce the epilepsy treatment gap.
Funding
Wellcome Trust.
doi:10.1016/S1474-4422(12)70155-2
PMCID: PMC3404220  PMID: 22770914
15.  Fosphenytoin for seizure prevention in childhood coma in Africa: A randomized clinical trial☆☆☆★★★ 
Journal of Critical Care  2013;28(6):1086-1092.
Purpose
We conducted a double-blind trial to determine whether a single intramuscular injection of fosphenytoin prevents seizures and neurologic sequelae in children with acute coma.
Methods
We conducted this study at Kilifi District Hospital in coastal Kenya and Kondele Children's Hospital in western Kenya. We recruited children (age, 9 months to 13 years) with acute nontraumatic coma. We administered fosphenytoin (20 phenytoin equivalents/kg) or placebo and examined the prevalence and frequency of clinical seizures and occurrence of neurocognitive sequelae.
Results
We recruited 173 children (median age, 2.6 [interquartile range, 1.7-3.7] years) into the study; 110 had cerebral malaria, 8 had bacterial meningitis, and 55 had encephalopathies of unknown etiology. Eighty-five children received fosphenytoin and 88 received placebo. Thirty-three (38%) children who received fosphenytoin had at least 1 seizure compared with 32 (36%) who received placebo (P = .733). Eighteen (21%) and 15 (17%) children died in the fosphenytoin and placebo arms, respectively (P = .489). At 3 months after discharge, 6 (10%) children in the fosphenytoin arm had neurologic sequelae compared with 6 (10%) in the placebo arm (P = .952).
Conclusion
A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma.
doi:10.1016/j.jcrc.2013.09.001
PMCID: PMC3835934  PMID: 24135012
Coma; Child; Seizure; Prophylaxis; Anticonvulsants
16.  Socio-Cultural Determinants of Health-Seeking Behaviour on the Kenyan Coast: A Qualitative Study 
PLoS ONE  2013;8(11):e71998.
Background
Severe childhood illnesses present a major public health challenge for Africa, which is aggravated by a suboptimal response to the child's health problems with reference to the health-seeking behaviour of the parents or guardians. We examined the health-seeking behaviour of parents at the Kenyan coast because understanding impediments to optimal health-seeking behaviour could greatly contribute to reducing the impact of severe illness on children's growth and development.
Methods and Results
Health-seeking behaviour, and the factors influencing this behaviour, were examined in two traditional communities. We held in-depth interviews with 53 mothers, fathers and caregivers from two rural clinics at the Kenyan Coast. Biomedical medicine (from health facilities and purchased over the counter) was found to be the most popular first point of treatment. However, traditional healing still plays a salient role in the health care within these two communities. Traditional healers were consulted for various reasons: a) attribution of causation of ill-health to supernatural sources, b) chronic illness (inability of modern medicine to cure the problem) and c) as prevention against possible ill-health. In developing an explanatory model of decision-making, we observed that this was a complex process involving consultation at various levels, with elders, but also between both parents, depending on the perceived nature and chronicity of the illness. However, it was reported that fathers were the ultimate decision makers in relation to decisions concerning where the child would be taken for treatment.
Conclusions
Health systems need to see traditional healing as a complementary system in order to ensure adequate access to health care. Importantly, fathers also need to be addressed in intervention and education programs.
doi:10.1371/journal.pone.0071998
PMCID: PMC3832523  PMID: 24260094
17.  Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study 
Lancet  2013;382(9905):1646-1654.
Summary
Background
Epilepsy is associated with high rates of premature mortality, but the contribution of psychiatric comorbidity is uncertain. We assessed the prevalence and risks of premature mortality from external causes such as suicide, accidents, and assaults in people with epilepsy with and without psychiatric comorbidity.
Methods
We studied all individuals born in Sweden between 1954 and 2009 with inpatient and outpatient diagnoses of epilepsy (n=69 995) for risks and causes of premature mortality. Patients were compared with age-matched and sex-matched general population controls (n=660 869) and unaffected siblings (n=81 396). Sensitivity analyses were done to investigate whether these odds differed by sex, age, seizure types, comorbid psychiatric diagnosis, and different time periods after epilepsy diagnosis.
Results
6155 (8.8%) people with epilepsy died during follow-up, at a median age of 34·5 (IQR 21·0–44·0) years with substantially elevated odds of premature mortality (adjusted odds ratio [aOR] of 11·1 [95% CI 10·6–11·6] compared with general population controls, and 11·4 [10·4–12·5] compared with unaffected siblings). Of those deaths, 15·8% (n=972) were from external causes, with high odds for non-vehicle accidents (aOR 5·5, 95 % CI 4·7–6·5) and suicide (3·7, 3·3–4·2). Of those who died from external causes, 75·2% had comorbid psychiatric disorders, with strong associations in individuals with co-occurring depression (13·0, 10·3–16·6) and substance misuse (22·4, 18·3–27·3), compared with patients with no epilepsy and no psychiatric comorbidity.
Interpretation
Reducing premature mortality from external causes of death should be a priority in epilepsy management. Psychiatric comorbidity plays an important part in the premature mortality seen in epilepsy. The ability of health services and public health measures to prevent such deaths requires review.
Funding
Wellcome Trust, the Swedish Prison and Probation Service, and the Swedish Research Council.
doi:10.1016/S0140-6736(13)60899-5
PMCID: PMC3899026  PMID: 23883699
18.  Value of Plasmodium falciparum Histidine-Rich Protein 2 Level and Malaria Retinopathy in Distinguishing Cerebral Malaria From Other Acute Encephalopathies in Kenyan Children 
The Journal of Infectious Diseases  2013;209(4):600-609.
Background. The diagnosis of cerebral malaria is problematic in malaria-endemic areas because encephalopathy in patients with parasitemia may have another cause. Abnormal retinal findings are thought to increase the specificity of the diagnosis, and the level of histidine-rich protein 2 (HRP2) may reflect the parasite biomass.
Methods. We examined the retina and measured plasma HRP2 levels in children with acute nontraumatic encephalopathy in Kenya. Logistic regression, with HRP2 level as an independent variable and World Health Organization–defined cerebral malaria and/or retinopathy as the outcome, was used to calculate malaria-attributable fractions (MAFs) and retinopathy-attributable fractions (RAFs).
Results. Of 270 children, 140 (52%) had peripheral parasitemia, 80 (30%) had malaria retinopathy, and 164 (61%) had an HRP2 level of >0 U/mL. During 2006–2011, the incidence of HRP2 positivity among admitted children declined by 49 cases per 100 000 per year (a 78% reduction). An HRP2 level of >0 U/mL had a MAF of 93% for cerebral malaria, with a MAF of 97% observed for HRP2 levels of ≥10 U/mL (the level of the best combined sensitivity and specificity). HRP2 levels of >0 U/mL had a RAF of 77% for features of retinopathy combined, with the highest RAFs for macular whitening (99%), peripheral whitening (98%), and hemorrhages (90%).
Conclusion. HRP2 has a high attributable fraction for features of malarial retinopathy, supporting its use in the diagnosis of cerebral malaria. HRP2 thresholds improve the specificity of the definition.
doi:10.1093/infdis/jit500
PMCID: PMC3903374  PMID: 24041795
attributable fractions; cerebral malaria; children; histidine-rich protein-2; malaria retinopathy
19.  The Performance of Children Prenatally Exposed to HIV on the A-Not-B Task in Kilifi, Kenya: A Preliminary Study 
The aim of the study was to investigate early executive functioning in young children from 6–35 months of age. The study involved 319 randomly selected children from the community, 17 HIV exposed but uninfected children and 31 HIV infected ARV-naive children. A variation of the A-not-B task was used. While there were no group differences in total correct, perseverative errors, nor maximum error run, a significant percentage of children were unable to complete the task as a consequence of the children becoming overtly distressed or refusing to continue. In a multivariate analysis we observed that the significant predictors of non-completion were HIV exposure (both infected and exposed) and being under 24 months of age. These patterns of results indicate that future work with a broader array of tasks need to look at the association of HIV and EF tasks and potential contribution of factors such as emotion regulation, persistence and motivation on performance on EF tasks.
doi:10.3390/ijerph10094132
PMCID: PMC3799506  PMID: 24008985
HIV; executive functions; A-not-B task; Kenya; children
20.  Plasma and Cerebrospinal Proteomes From Children With Cerebral Malaria Differ From Those of Children With Other Encephalopathies 
The Journal of Infectious Diseases  2013;208(9):1494-1503.
Clinical signs and symptoms of cerebral malaria in children are nonspecific and are seen in other common encephalopathies in malaria-endemic areas. This makes accurate diagnosis difficult in resource-poor settings. Novel malaria-specific diagnostic and prognostic methods are needed. We have used 2 proteomic strategies to identify differentially expressed proteins in plasma and cerebrospinal fluid from children with a diagnosis of cerebral malaria, compared with those with a diagnosis of malaria-slide-negative acute bacterial meningitis and other nonspecific encephalopathies. Here we report the presence of differentially expressed proteins in cerebral malaria in both plasma and cerebrospinal fluid that could be used to better understand pathogenesis and help develop more-specific diagnostic methods. In particular, we report the expression of 2 spectrin proteins that have known Plasmodium falciparum–binding partners involved in the stability of the infected red blood cell, suppressing further invasion and possibly enhancing the red blood cell's ability to sequester in microvasculature.
doi:10.1093/infdis/jit334
PMCID: PMC3789566  PMID: 23888081
proteomics; P. falciparum; cerebral malaria; spectrin; platelet activation
21.  Traditional Healers and Epilepsy Treatment on the Kenyan Coast 
Epilepsia  2008;49(9):1638-1639.
doi:10.1111/j.1528-1167.2008.01580_1.x
PMCID: PMC3672948  PMID: 18782213
Intervention Studies; Pediatric Epilepsy; Healthcare Providers; African Traditional Medicine
22.  Co-morbidity of epilepsy in Tanzanian children: a community-based case-control study 
Purpose
To define the prevalence and associations of co-morbidity and school attendance in older children with epilepsy (CWE) from a rural district of Tanzania by conducting a community-based case-control study.
Methods
Children aged 6 -14 years old with active epilepsy (at least two unprovoked seizures in the last five years) were identified in a cross-sectional survey in Tanzania. Co-morbidities were assessed and cases were compared with age-matched controls.
Results
Co-morbidity was very common amongst cases (95/112, 85%), with 62/112 (55%) having multiple co-morbidities. Co-morbidities consisted of cognitive impairment (72/112, 64%), behaviour disorder 68/112 (61%), motor difficulties 29/112 (26%), burns and other previous injuries (29/112, 26%). These complications were significantly more common in cases than in controls (Odds Ratio 14.8, 95%CI 7.6–28.6, p<0.001). Co-morbidity in CWE was associated with structural cause, abnormal electroencephalogram and early onset seizures. Cognitive impairment was very common in CWE (64%) and was not associated with Phenobarbital use but was associated with motor difficulties, early onset and recurrent seizures. Poor school attendance was found in 56/112 (50%) of CWE, but not in the controls: it was associated with the presence of multiple co-morbidities, especially with motor difficulties in CWE.
Conclusion
Children with epilepsy in a rural area of sub-Saharan Africa had a high level of co-morbidity. Cognitive impairment and poor school attendance were very common. These associated difficulties in CWE in the region need to be addressed to reduce the negative impact of epilepsy on these children.
doi:10.1016/j.seizure.2011.10.011
PMCID: PMC3672980  PMID: 22130004
epilepsy; Africa; children; co-morbidity; cognitive impairment; education
23.  New classification of acute papilledema in children with severe malaria 
Raised intracranial pressure is a feature of cerebral malaria in children living in Africa. We investigated specific clinical optic disc features of papilledema to establish their prognostic significance in this encephalopathy. We developed a classification of acute papilledema and tested it against disease outcome. Kenyan children admitted with severe falciparum malaria (cerebral or impaired consciousness) underwent dilated fundal examination using direct and indirect ophthalmoscopy. Clinical features of the optic disc were systematically recorded and compared to the child’s outcome. Poor outcome defined as death or neurological impairment on discharge was used to construct and test a clinical classification of papilledema. Forty-five children were examined (26 cerebral malaria, 17 severe malaria with an impaired conscious level or prostration) of whom seven had a poor outcome (three died, four had residual neurological impairment). Loss of the optic disc cup and marked optic disc elevation were significantly correlated with a poor outcome (P < 0.05). Increasing severity in the proposed classification of acute papilledema was positively correlated with a poor outcome (P < 0.05, chi-square test for trend). Loss of the optic disc cup and marked elevation of the optic disc head appear to be correlated with poor outcome in children with severe malaria whereas the presence of dilated veins suggests a good outcome. The proposed classification of acute papilledema is useful as a prognostic indicator and may be applicable to other encephalopathies with raised intracranial pressure.
doi:10.3233/JPN-2009-0317
PMCID: PMC3672988  PMID: 23750109
Optic disc; papilledema; malaria; coma
24.  Hematological and Genetic Predictors of Daytime Hemoglobin Saturation in Tanzanian Children with and without Sickle Cell Anemia 
ISRN Hematology  2013;2013:472909.
Low hemoglobin oxygen saturation (SpO2) is common in Sickle Cell Anemia (SCA) and associated with complications including stroke, although determinants remain unknown. We investigated potential hematological, genetic, and nutritional predictors of daytime SpO2 in Tanzanian children with SCA and compared them with non-SCA controls. Steady-state resting pulse oximetry, full blood count, transferrin saturation, and clinical chemistry were measured. Median daytime SpO2 was 97% (IQ range 94–99%) in SCA (N = 458), lower (P < 0.0001) than non-SCA (median 99%, IQ range 98–100%; N = 394). Within SCA, associations with SpO2 were observed for hematological variables, transferrin saturation, body-mass-index z-score, hemoglobin F (HbF%), genotypes, and hemolytic markers; mean cell hemoglobin (MCH) explained most variability (P < 0.001, Adj r2 = 0.09). In non-SCA only age correlated with SpO2. α-thalassemia 3.7 deletion highly correlated with decreased MCH (Pearson correlation coefficient −0.60, P < 0.0001). In multivariable models, lower SpO2 correlated with higher MCH (β-coefficient −0.32, P < 0.001) or with decreased copies of α-thalassemia 3.7 deletion (β-coefficient 1.1, P < 0.001), and independently in both models with lower HbF% (β-coefficient 0.15, P < 0.001) and Glucose-6-Phosphate Dehydrogenase genotype (β-coefficient −1.12, P = 0.012). This study provides evidence to support the hypothesis that effects on red cell rheology are important in determining SpO2 in children with SCA. Potential mechanisms and implications are discussed.
doi:10.1155/2013/472909
PMCID: PMC3649307  PMID: 23691341
25.  Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors: cross-sectional and case-control studies 
Lancet Neurology  2013;12(3):253-263.
Summary
Background
The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region.
Methods
We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007–July 31, 2008); Agincourt, South Africa (Aug 4, 2008–Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009–Oct 30, 2009); Ifakara, Tanzania (May 4, 2009–Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010–April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status.
Results
586 607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7·8 per 1000 people (95% CI 7·5–8·2) in Kilifi, 7·0 (6·2–7·4) in Agincourt, 10·3 (9·5–11·1) in Iganga-Mayuge, 14·8 (13·8–15·4) in Ifakara, and 10·1 (9·5–10·7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged <18 years), the greatest relative increases in prevalence were associated with difficulties feeding, crying, or breathing after birth (OR 10·23, 95% CI 5·85–17·88; p<0·0001); abnormal antenatal periods (2·15, 1·53–3·02; p<0·0001); and head injury (1·97, 1·28–3·03; p=0·002). In adults (aged ≥18 years), the disorder was significantly associated with admission to hospital with malaria or fever (2·28, 1·06–4·92; p=0·036), exposure to T canis (1·74, 1·27–2·40; p=0·0006), exposure to T gondii (1·39, 1·05–1·84; p=0·021), and exposure to O volvulus (2·23, 1·56–3·19; p<0·0001). Hypertension (2·13, 1·08–4·20; p=0·029) and exposure to T solium (7·03, 2·06–24·00; p=0·002) were risk factors for adult-onset disease.
Interpretation
The prevalence of active convulsive epilepsy varies in sub-Saharan Africa and that the variation is probably a result of differences in risk factors. Programmes to control parasitic diseases and interventions to improve antenatal and perinatal care could substantially reduce the prevalence of epilepsy in this region.
Funding
Wellcome Trust, University of the Witwatersrand, and South African Medical Research Council.
doi:10.1016/S1474-4422(13)70003-6
PMCID: PMC3581814  PMID: 23375964

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