Cost studies are paramount for demonstrating how resources have been spent and identifying opportunities for more efficient use of resources. The main objective of this study was to assess the actual dimension and distribution of the costs of providing antenatal care (ANC) and childbirth services in selected rural primary health care facilities in Tanzania. In addition, the study analyzed determining factors of service provision efficiency in order to inform health policy and planning.This was a retrospective quantitative cross-sectional study conducted in 11 health centers and dispensaries in Lindi and Mtwara rural districts. Cost analysis was carried out using step down cost accounting technique. Unit costs reflected efficiency of service provision. Multivariate regression analysis on the drivers of observed relative efficiency in service provision between the study facilities was conducted. Reported personnel workload was also described.The health facilities spent on average 7 USD per capita in 2009. As expected, fewer resources were spent for service provision at dispensaries than at health centers. Personnel costs contributed a high approximate 44% to total costs. ANC and childbirth consumed approximately 11% and 12% of total costs; and 8% and 10% of reported service provision time respectively. On average, unit costs were rather high, 16 USD per ANC visit and 79.4 USD per childbirth. The unit costs showed variation in relative efficiency in providing the services between the health facilities. The results showed that efficiency in ANC depended on the number of staff, structural quality of care, process quality of care and perceived quality of care. Population-staff ratio and structural quality of basic emergency obstetric care services highly influenced childbirth efficiency.Differences in the efficiency of service provision present an opportunity for efficiency improvement. Taking into consideration client heterogeneity, quality improvements are possible and necessary. This will stimulate utilization of ANC and childbirth services in resource-constrained health facilities. Efficiency analyses through simple techniques such as measurement of unit costs should be made standard in health care provision, health managers can then use the performance results to gauge progress and reward efficiency through performance based incentives. Maternal and newborn mortality and morbidity remain among the top global health challenges despite various efforts and multitude of resources directed to this field overtime. The high mortality and morbidity rates, especially in developing countries, necessitate prioritization of greater efficiency as part of efforts towards their reduction. The majority of the 40 countries with the highest maternal mortality in the world are in sub-Saharan Africa . In deveAlthough the maternal mortality ratio (MMR) has been slowly declining in Tanzania over the past years, it is still estimated to be at a staggering 454 deaths per 100,000 live births . The neoFaced with resource scarcity coupled with competing development priorities, Tanzania has strived over the years to increase its budget to health sector in its bid to increase both the quality and quantity of essential health services, including MNC services, for its population. In general, money for health in Tanzania comes from public (comprising of taxes and foreign assistance) and private (insurance and user fees) sources. MNC services are free of charge at all levels of health care in public health facilities to encourage utilization. The health spending per capita was at around 27 USD in 2009, including MNC . This reDespite the meagerness of resources allocated to health sector, including MNC, it remains paramount to have knowledge of how exactly these scarce resources are spent. Cost studies help to demonstrate how resources have been spent, what resources are needed to provide specific services, areas where costs could be reduced and where output could be increased and thus improve efficiency in the provision of health services -10. TherThis study took a health care provider perspective and accounted the actual resources used in the provision of ANC and childbirth services in eleven rural health facilities of two resource-poor districts in Tanzania. The unit costs reflected efficiency in the provision of MNC services. To understand the differences in service provision efficiency among the health facilities, regression analysis of provider and consumer side factors against unit costs was undertaken. We hope the information will help district health management teams to plan efficient resource use.This study is part of an ongoing research project that was granted ethical approval from the Muhimbili University of Health and Allied Sciences (MUHAS) ethics committee (reference number MU/RP/AEC/Vol.XIII/1) and the Faculty of Medicine of the University of Heidelberg, Germany, ethics commission (reference number S173/2008). Likewise, written informed consent was sought from all participants.This study was conducted in eleven primary health care facilities located in two southern regions of Tanzania Figures  and 2, sLindi region covers 67,000 square kilometers of mainland Tanzania and was projected to have a total population of 905,480 in 2009, the majority (76%) of whom live in rural areas, with an IMR projected at 76 per 1,000 live births  and MMR Mtwara region, the second smallest region of Tanzania, occupies 16,720 square kilometers of Tanzania mainland area. It is the south-easternmost region of Tanzania, lying in the southern border of Lindi region. Its total population in 2009 was projected to be 1,297,751 and, like its neighbor Lindi, the majority of its people (75%) live in rural areas. MMR was 116 per 100,000 live births in 2009 and IMR was projected to be at 112 per 1,000 live births in 2009 ,23. MtwaTanzania has a pyramidal health service structure. Dispensaries and health centers offer the most basic services including MNC (basic obstetric services). Complicated cases are referred to district hospitals or regional hospitals with more specialized maternal services. Ligula Hospital in Mtwara town and Sokoine Hospital in Lindi town offer comprehensive (emergency) obstetric services for Mtwara rural and Lindi rural respectively. Due to some structural challenges, however, the referral system does not work as planned.This was a retrospective quantitative cross-sectional research. Data on costs of health service provision in eleven primary health care facilities for 2009 were collected and analyzed.This study is part of a research project  funded as part of the 7th Framework Program of the European Union (grant agreement 22982), a collaboration between the Centre de Recherché en Santé de Nouna (Burkina Faso), Ghent University (Belgium), Heidelberg University (Germany), Karolinska Institute (Sweden), Muhimbili University of Health and Allied Sciences (Tanzania), and Navrongo Health Research Centre (Ghana). The selection of the facilities followed the overall project research protocol, where this study is a separate work package.As part of a baseline study of the multi-country intervention research project to improve quality of MNC, the facilities included in this study were selected as project sites based on two criteria. First, they were typical of the country and second, they were comparable in terms of medical infrastructure, equipment and staffing, corresponding to national standards . The heaA structured questionnaire was developed after a thorough identification of resources likely to be used in the provision of health care services at health centers and dispensaries according to standard national guidelines by the Ministry of Health. Between November and December 2010, data was collected through document reviews, interviews and physical inventory of resources used at the facilities. This enabled the estimation of actual purchased and donated resources used in provision of services in terms of their price and quantity in appropriate units.Wherever possible, unit prices of resources used were collected directly from health facilities, for example drugs, medical equipment and supplies, personnel  and transport. Some cost data was gathered from the Medical Stores Department (MSD), Expanded Program on Immunization (EPI) and district medical officer’s (DMO) offices. In some cases prices were imputed from market sources, for example prices of some locally obtained equipment including benches, chairs, television set, buckets etc. Building costs were based on estimated replacement cost in these rural areas.Step down cost accounting (SDCA) technique was used to estimate costs. Using this technique a range of resources needed to run a facility were identified and then assigned to chosen cost centers on an allocation basis. The costs in each cost center were aggregated together in overarching themes ,26. ThisThe allocation process went through several steps: defining the final product , defining cost centers , identifying and grouping the inputs in several categories , assigning inputs to cost centers reflecting the flow of resources in a health center or dispensary, allocating all costs to final cost centers ) and ultimately computing total and unit cost for each final cost center.Our study identified 3 cost centers for analysis. First, indirect cost centers included administration and transport units, these provided general services that were not directly related to final client services but were involved in the overall running of the health facilities. Secondly, intermediate cost centers, pharmacy and laboratory units, incorporated departments that provided diagnostic and departmental support to the final service departments. Finally, direct cost centers included final service departments, ANC, childbirth and other service departments represented the end points of the production line.Identified resources formed line items for cost categories, (1) Personnel with line items salary, pension, insurance, training, uniform and allowances for all staff, (2) Administration with line items electricity, water, stationery, local transport, communication, cleaning products, repairs and maintenance, (3) Pharmacy with line items drugs and vaccines, (4) Laboratory, (5) Transport with vehicles such as cars, motorbikes and bicycles, (6) Buildings, (7) Medical supplies/consumables and (8) Equipment- medical and office. Full costs incurred by the health facilities were established and used as a control total to ensure that all costs had been distributed to services .The end goal was to allocate all costs to departments that provided direct client care, ANC, childbirth and others. Direct allocation of inputs to cost centers and units was done wherever possible. Some costs can be assigned immediately to certain cost centers. In this case administration, pharmacy, laboratory and transport cost went directly into the respective cost centers and departments. For personnel, buildings, medical supplies and equipment, the average percentage of time spent on activities by staff was the allocation basis.Staff themselves determined the time they spent on various activities, recording the percentage distribution of their time on a range of activities at the health centers and dispensaries per week. From these reports time estimation was then undertaken for the last twelve months of the study. The health workers recorded the average percentage time spent on categorized health care services over a week’s time period and this was extrapolated to one year. Activities were categorized as administration, vaccine and drug administration, family planning, transportation, ANC, childbirth, post-natal care and “other” activities . From these data, the average time spent on each activity by personnel was calculated per facility and used as the cost allocation basis.To get the specific cost of providing final services, in our case ANC, childbirth and “other” services, the indirect and intermediate costs were allocated to the direct cost centers using staff time allocation basis. Separate total costs for ANC, childbirth and “other” services were derived.Service unit costs were then calculated as a ratio of inputs to outputs for ANC and childbirth. Output data reflected service volume (utilization of services), in this case ANC visits and number of normal births in the facilities.Unit costs reflected productivity in these facilities. Since productivity is one aspect of efficiency, the unit costs therefore reflected efficiency in the provision of MNC services ,15. ThisAll costs were identified in local currency, Tanzanian Shillings (TZS), and later converted to United States Dollars (USD) according to the average exchange rate for 2009, 1 USD = 1326.83 TZS. Annuitization was applied to estimate the equivalent annual costs (EAC) for capital outlays . Health To explain observed unit cost differences between the facilities, a reflection of relative efficiency of providing ANC and childbirth services, we ran a multivariate regression analysis using demand and supply side factors as explanatory variables .Supply/provider side factors included structure and process quality and number of staff. The structure quality reflected the attribute of settings in which MNC services occurred in terms of availability of MNC infrastructure, collected through surveys of the 11 health facilities. The process quality reflected what was actually provided in the giving and receiving of MNC services  was collected through observations of 418 ANC consultations and 254 childbirths.Demand/consumer side factors included perceived quality, reflecting the women’s experience of the MNC services provided . This was obtained through ANC exit interviews carried out with 611 women, and 503 childbirth exit interviews, and catchment population size obtained through a document review.The quality variables  indicated various dimensions of quality of MNC services offered in these facilities relative to the World Health Organization (WHO) maternal health services guidelines . Separatt statistic and p-value of at least 0.100 were removed to get the most significant model. We tested several models but reported only the most significant ones.We used SPSS version 16 to perform a stepwise backward elimination process in model estimation. The method started with all independent variables (Equation 1) entered in a linear regression, and then step-by- step variables with smallest Reported average time spent per activity by staff in a health center or dispensary was the allocation basis for cost. This allowed us to gain a clear picture of the share of each resource used in the provision of health care services, the average percentage time spent on an activity per health center or dispensary and for the two districts as a whole. On average, about 8% range 3-15%) and 10% (range 4-20%) of staff time was spent on provision of ANC and childbirth services respectively. The rest of time was divided between the other activities  and were significant  predictors of ANC unit costs in these facilities  in 11 rural settings of Tanzania. It gave a clear picture of costs and their distribution. Further, it shows factors that influenced differences in ANC and childbirth unit costs between the health facilities taking into account perceived, structure and process quality, number of staff and catchment area population size. Efficiency in the provision of ANC and childbirth services was reflected by the unit costs.This study estimated that approximately 7 USD was spent to provide health care per person in both districts giving a sense of resource distribution equality between the rural districts. This figure nevertheless reflected resource scarcity for health services. The expenditure was roughly 26% of the national health expenditure per capital in 2009  to ensurPersonnel costs accounted for the largest portion of total costs in these facilities. Mtwara had a slightly higher proportion than its neighbor Lindi due to variations in staff qualifications, performance based incentives and allowances observed in this study. Similar studies -11 have Our study showed a low utilization of ANC and childbirth services and a wide variation in unit costs between the facilities. Low utilization implies that the direct costs have to be spread across fewer units of output as reflected by the unit costs . Most woAvailability of health care infrastructure has been found to have positive effect on utilization ,34. The How women perceive quality of care affects their utilization levels ,34,35. SUnlike for ANC, a woman’s perception of quality of care had no association with childbirth unit costs. Given the emergency nature of childbirth a woman’s perceived quality of care may not really play a strong role on the final decision on where to deliver. Furthermore, rural families base their decisions to utilize health care providers for childbirth, including emergency births, not only on quality criterion but also on a number of other criteria including out of pocket cost, opportunity cost, transport access and how the community perceives a woman’s health condition among other things ,33,36-43Many other studies have shown the importance of quality of care for utilization of professional assistance during pregnancy and childbirth, including the importance of availability of health workers -39,44. TOur study suggested that, improvement in quality dimensions involving number of health workers and how they provide services to women had a positive effect on efficiency however, trade-offs between quality and efficiency are inevitable especially when making investments. Costs are incurred when investments are made to improve health service provision; a case in point was the importance of investing in BEmOC regardless of the cost involved because none of the facilities under study met the criteria for proper provision of this crucial maternal service.Our study showed a wide range of time allotted to ANC and childbirth services between study facilities. Besides differences in service volume as one explanation, this study does not have more evidence to explain this variation. However, past studies have found that Tanzanian health facilities do not have an official structure for service delivery, especially for preventive services. Health workers in some facilities tend to overcrowd clients in the morning hours leaving the afternoon hours almost unoccupied ,12,45.Due to the small number of health facilities involved in this study, representativeness of the results cannot be ascertained. These results are applicable to the study districts. For countrywide health care policy-making and planning larger samples are required. The retrospective methodology used is also a limitation. A prospective approach would have been useful in capturing actual time allocation for health services by providers in addition to the recall approach used. A qualitative investigation on the acceptance and preferences of the women for explanation of the level of utilization of services would have made our study findings more robust. This would have also addressed the possible effects of unit cost from the perspective of district and facility managers and health providers.Comparing our study to a similar study conducted in Mtwara urban health facilities by Both et al.  shows thOur study has shown great variability in unit costs of ANC and childbirth service provision, reflecting room for efficiency improvement. High unit costs are mainly due to level of input costs and service utilization in these facilities. The importance of focusing on providers and consumers of health care in efforts to improve efficiency cannot be over emphasized.With our study sites having most infrastructures for provision of ANC and childbirth services, a focus should be on improving process quality and putting in place infrastructure for basic emergency obstetric care services. Restructuring of the referral system to ensure effective response to obstetric and newborn emergencies is also key.Improvement of human resources in terms of number and competency is also important. Human resources make most part of costs therefore this warrants a careful analysis of health facilities, including analysis of the health care provision structure, to identify areas with human resource improvement need.Fixed costs  make the largest share of total costs, showing opportunity for efficiency improvement. In those facilities operating below full capacity, unit costs are likely to fall with increment in MNC utilization, at least in the short run as most costs are fixed . ReductiHealth care demanders are heterogeneous and they incorporate a range of criteria in their decision to utilize ANC and childbirth services. Apart from perceived quality of care, unofficial charges, opportunity costs, transport accessibility plus a whole range of other issues are important for utilization. Keeping this in mind, focused maternal interventions are envisioned to work in increasing utilization compared to generalized interventions . CommuniThe results of this study are important for sensitization of district management towards performing and standardizing cost assessment in different health facilities in Tanzania. The routine performance of such analyses would reduce the cost for the analyses compared to the benefits expected. Efficiency analyses through simple techniques such as measurement of unit costs should be made standard in health care provision, health managers can then use the performance results to gauge progress and reward efficiency through performance based incentives. In addition, the results are important to inform the health policy on the possibilities for higher utilization of MNC services through improvements in process quality, human resources structure and involving the community.ANC: Antenatal care; BEmOC: Basic emergency obstetric care; DMO: District medical officer; EPI: Expanded program on immunization; IMR: Infant mortality rate; MNC: Maternal and newborn care; SDCA: Step-down cost accounting; URT: United Republic of Tanzania; USD: United States Dollar; WHO: World Health Organization.The authors declare that they have no competing interests.HPS acquired analyzed and interpreted data and drafted the manuscript. ED HD SM RS and SL critically revised the content. PT assisted in regression analysis. MD and GS assisted in cost data analysis and review of content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/14/96/prepub


Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation.We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia.Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases . Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC.Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27–0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure.The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned. Non-melanoma skin cancers (NMSC) comprise more than one-third of all cancers and are increasing worldwide, causing a significant economic burden at the individual and community levels Phenotype characteristics, environmental exposures, and genetic predisposition appear to be risk factors for the development and progression of NMSC. Studies on humans and animals suggest that ambient solar radiation, in particular, plays an important role in the pathogenesis of these skin malignancies A large number of people are exposed to varying levels of UV radiation at the workplace. However, the number of epidemiological studies focusing on NMSC occurrence in workers is limited and the findings are contradictory. Moreover, most studies are limited by a lack of individual exposure assessment, and are based only on census and registry data, or occupations/industries  as surrogates of exposure. Also, important confounders  and/or effect-modifiers  were not sufficiently addressed in prior work The study results are based on data collected during the Arsenic Health Risk and Molecular Epidemiology (ASHRAM) Study, a hospital-based incident case-control study conducted on White residents of three European countries , between January 2003 and September 2004. All participants provided written informed consent, and the privacy of the study participants and the confidentiality of the information were assured according to the principles of the Helsinki Declaration. The project was reviewed and approved by the Ethical Committees for participating institutions in each contributing country, including: Hungary, the Ethical Committee of the National Health Research Council and the Regional Ethical Committees of the Szentgyörgyi Albert University of Szeged and of the Kecskemét, Gyula, and Szolnok County Hospitals; Romania, the Ethical Committees of the Arad and Bihor County Public Health Departments, and of the Arad and Oradea County Hospitals; Slovakia, the Ethical Committees of the Nitra, Nove Zamky, Levice, and Ziar nad Hronom State Health Institutes, and of the Banska Bystrica, Nitra, Brezno, Nove Zamky, Levice, and Nova Bana Hospitals; and the United States, Institutional Review Board of the University at Albany, State University of New York. The primary aim of the ASHRAM Study was to investigate the carcinogenic role of arsenic exposure via drinking water related to skin, kidney, and bladder cancers.th Revision, Codes C44). All cases were confirmed by histological examination or dermatology specialist opinion. Controls were selected from general surgery in-patients , and from orthopedic or trauma patients (fractures). Controls residing in the study area for at least one year were frequency matched to cases by county of residence, sex, and 5 year age range. A detailed description of participant recruitment has been published previously Skin cancer cases, aged 30–79 years, and having lived in the study area for at least one year, consisted of NMSC newly diagnosed at county hospitals , 0.50 (medium), 1.00 (high)), jF is the frequency of exposure for the jth job (F = 0.03 (low), 0.18 (medium), 0.65 (high)), jC is the confidence factor of exposure assigned to the jth job (C = 0.25 (low), 0.50 (medium), 1.00 (high)), and jD is the duration of exposure in hours .Occupational exposure to natural and artificial UV radiation was considered using two indices: “ever” exposure and cumulative exposure over the lifetime. A subject was classified as ever exposed if any of the reported jobs involved UV radiation from the sun , or from artificial sources . If none of the jobs over a lifetime was associated with UV radiation, the subject was classified as “never” exposed. The cumulative lifetime exposure (CLE) was calculated by summing over a participant’s working lifetime the products of exposure semi-quantitative scores and the exposure duration for each job period, as presented in the following equation:The continuous cumulative exposure variable was further categorized based on tertiles of the distribution among controls with participants never exposed to workplace UV radiation defined as the reference category. Frequency distributions of exposures and demographic characteristics were characterized and compared by case status using chi-square tests.Odds ratios (OR) and 95% confidence intervals (95% CI) were used to estimate associations between occupational exposure to UV radiation and NMSC using unconditional logistic regression. Based on the literature, a number of factors possibly associated with the risk of NMSC development and the likelihood of working in agricultural or industrial settings with UV exposure were considered, including skin complexion, propensity for sunburn, cancer history, education as a proxy for socio-economic status, tobacco smoking, recreational UV exposure, arsenic exposure at work, and arsenic exposure through consumption of contaminated drinking water. Skin complexion, family history of cancer, and lifetime average exposure to arsenic in drinking water were identified as confounding factors  and were therefore included in the final multivariable regression models, along with the matching variables sex, age, and county of residence.Skin complexion is a critical modifier for the effect of UV radiation exposure on NMSC. We included skin complexion  evaluated in multivariable regression models by the inclusion of two-way interaction terms between skin complexion and UV exposure. Effect modification by skin cancer histology and anatomical location was also considered by stratified analyses.To account for the reported latency The response rate for the ASHRAM study was 81.6% for cases and 90% for controls. A total of 618 NMSC cases and 527 controls were included in the present study . Cases tA total of 5,589 job periods (4.9 job periods per subject on average), were coded based on job title and employer activity as reported during the interview. Workplace exposure to natural  UV radiation was ascertained for 511 job periods and to artificial UV radiation for 249 job periods. Out of 227 participants who were classified as ever being exposed to occupational UV radiation, 135 were exposed to sunlight only, 69 to artificial UV radiation only, and the remaining 23 had been exposed to both natural and artificial UV radiation. The small number of participants exposed to both natural and artificial UV light did not allow for a separate analysis. As anticipated, a high proportion of participants ever exposed to natural UV radiation were involved in agriculture (23%), military service (19%), construction (10.5%), transport (9.5%), and forestry (6%). The participants ever exposed to artificial UV radiation were predominantly workers in machinery manufacturing (39%), blacksmiths, toolmakers, and machinery fitters/assemblers (17%), and plumbers, welders, and sheet metal workers (10%).The lifetime prevalence of ever exposure to natural UV radiation was 13.8% for cases (N = 78) and 11.9% for controls (N = 57), while the prevalence of exposure to artificial UV radiation was only 6.6% for cases (N = 34) and 7.7% for controls (N = 35). We conducted an additional subgroup analysis of the BCC histologic type . The resThe present case-control study of more than 1,100 participants investigated NMSC in relation to natural and artificial UV radiation exposure in agricultural and industrial workplaces, in three Central and Eastern European countries. The study results suggested a weak inverse association of NMSC, mainly due to BCC, with workplace exposure to natural UV radiation, and no significant relationship with artificial UV radiation. The inverse association was limited to participants with light skin complexion.UV radiation exposure does not increase human health risks monotonically, but rather demonstrates a hormesis dose-response relationship due to biological determinants such as vitamin D levels and behavioral factors including UV exposure pattern, and amount and type of radiation. Minimum risks for adverse health effects occurs at an optimal exposure, according to skin complexion and individual UV sensitivity, while increased disease risk is observed with very low level UV or very high levels Given the substantial volume of literature corroborating solar radiation exposure as an important risk factor for skin cancer, the present findings of weak inverse associations between sun exposure at work and BCC seem contradictory. Yet, comparable results were reported in several other epidemiologic studies of UV-induced BCC at the workplace published between 1995 and 2006, and recently reviewed by Bauer et al. The lack of an increased NMSC risk from occupational exposure to natural UV radiation, and significant protective effects against NMSC among participants with a light skin complexion, may be linked to a modification of behaviors towards adopting personal sun protection measures. Although sun protection behaviors vary considerably by occupation, sex, age, education, and local sun-related habits, a number of studies reported that outdoor workers and individuals with sun sensitive skin types are more likely to employ sun safety practices such as wearing a hat or protective clothes Investigators previously reported large spatial differences in the NMSC risk among White populations, with reported incidences being about 5-fold and 7-fold higher in the U.S. than in Europe, and about 50-fold and 100-fold higher in Australia compared to Europe The present study has several limitations. First, the use of hospital controls may be of concern when the source population from which cases originate is not adequately represented. Various strategies were undertaken to minimize the potential for this type of selection bias and they were extensively discussed in a previous publication Occupational exposure to UV radiation was not self-reported, but was reconstructed by subject-matter experts using job histories. Study exposures were limited to jobs of at least one year duration; we did not capture short-term work such as summer seasonal agricultural jobs, or migration associated outdoor employment because these practices are uncommon in the communities studied. The experts, who were blinded to the disease status, assigned the exposure based on an occupational coding manual. The experts participated in several training workshops and validation exercises. As a result, any assigned exposure misclassification is expected to be similar for cases and controls and thus, will cause an underestimation of UV effects. Furthermore, it is unlikely that any systematic bias in the assignment of exposure by experts would be limited to only light-skinned participants, the group in which a decreased risk is detected, further suggesting that any exposure misclassification is likely to have been non-differential. Analysis of exposure patterns among the subset of participants with estimated high intensity UV radiation exposure would have the advantage of reducing potential exposure misclassification bias as these are important in the etiology of NMSC. However, the small number of participants with high intensity UV radiation exposure at work  precluded a subgroup analysis.This study has a number of strengths compared to studies focusing on the association between NMSC and occupational exposure to UV radiation. The large sample size and the pathological verification of 94% of the NMSC cases facilitated a subgroup analysis by histological type and by anatomical site. While this study had sufficient statistical power to detect relatively small associations, the number of cases diagnosed with tumors located on body sites usually not exposed to solar radiation was rather small. Other methodological strengths of this study include the short period of time for recruitment cases and controls (21 months), the use of incident cases, and the high participant response rate (>85%). Furthermore, the associations were adjusted for important confounding factors and were reported by skin complexion.The study results do not provide support for an increased risk of NMSC in association with workplace exposure to natural or artificial UV radiation. These findings are consistent with weak, null or inverse associations previously reported in epidemiologic studies, particularly for BCC. Our results might be attributed to the low level of UV exposure among participants, and to exposure misclassification. The protective effect we observed among participants with light skin complexion suggests that they are using adequate personal sun-protection measures. These results add to the evidence that moderate sunlight exposure might decrease the risk of some types of cancer, likely in association with sun-protection behaviors. Further investigation focusing on individual genetic susceptibility and potential interactions with other exposures at work and with low-level environmental exposures will be conducted in order to achieve a more complete knowledge of the etiology and effective prevention methods for human skin malignancies.


EHP 120(4):577–582; van den Berg et al.][.Although insecticides have helped lower worldwide rates of infectious disease, the use of these chemicals must be monitored and controlled to avoid pest resistance and minimize associated risks to human health and the environment. Researchers have conducted a comprehensive assessment of trends in the global use of insecticides for vector-borne disease control over the last decade and found that the potential for overuse of pyrethroids could result in a loss of the effectiveness of long-lasting insecticidal nets (LNs), which have been one of the most successful tools for controlling malaria to date The research team analyzed data from 125 countries that used organochlorines, organophosphates, carbamates, and pyrethroids for vector control between 2000 and 2009. Application methods were classified as residual spraying , space spraying (spraying exterior spaces), treatment of nets , and larviciding (treating aquatic breeding sites of mosquitoes with insecticides). The team conducted 2 analyses of insecticide use for each country, covering a 10-year and an annual average.The main diseases targeted by insecticide use were malaria, dengue, leishmaniasis, and Chagas disease. The organochlorine DDT was by far the most used insecticide in terms of quantity (71%), with India accounting for most applications (82%) and African countries accounting for the rest. Globally the use of DDT has not changed substantially since the Stockholm Convention on Persistent Organic Pollutants was established in 2004, although use increased sharply in Africa until 2008.Pyrethroid use in residual and space spraying accounted for the greatest surface or area covered (81%), with most use occurring in the Americas, although an increase occurred in African countries. Global pyrethroid use has increased steadily since 2004, mainly due to increased use for residual spraying, a factor the authors warn could promote resistance among mosquitoes, negatively affecting the long-term effectiveness of treated bed nets. They warn that “in areas where resistance genes have already spread, immediate implementation of resistance management is required to preserve the effectiveness of available tools, including LNs.”The main limitation of the study is countries’ potential lack of capacity for reporting insecticide use, especially regarding dengue control . Even so, the data collected can help guide global strategies on vector control and resistance management.


The prevalence of inadequate zinc intake in a population can be estimated by comparing the zinc content of the food supply with the population’s theoretical requirement for zinc. However, assumptions regarding the nutrient composition of foods, zinc requirements, and zinc absorption may affect prevalence estimates. These analyses were conducted to: (1) evaluate the effect of varying methodological assumptions on country-specific estimates of the prevalence of dietary zinc inadequacy and (2) generate a model considered to provide the best estimates.r = 0.57–0.99, P<0.01). A “best-estimate” model, comprised of zinc and phytate data from a composite nutrient database and IZiNCG physiological requirements for absorbed zinc, estimated the global prevalence of inadequate zinc intake to be 17.3%.National food balance data were obtained from the Food and Agriculture Organization of the United Nations. Zinc and phytate contents of these foods were estimated from three nutrient composition databases. Zinc absorption was predicted using a mathematical model (Miller equation). Theoretical mean daily per capita physiological and dietary requirements for zinc were calculated using recommendations from the Food and Nutrition Board of the Institute of Medicine and the International Zinc Nutrition Consultative Group. The estimated global prevalence of inadequate zinc intake varied between 12–66%, depending on which methodological assumptions were applied. However, country-specific rank order of the estimated prevalence of inadequate intake was conserved across all models (Given the multiple sources of uncertainty in this method, caution must be taken in the interpretation of the estimated prevalence figures. However, the results of all models indicate that inadequate zinc intake may be fairly common globally. Inferences regarding the relative likelihood of zinc deficiency as a public health problem in different countries can be drawn based on the country-specific rank order of estimated prevalence of inadequate zinc intake. Adequate zinc nutrition is essential for adequate growth, immunocompetence and neurobehavioral development of young children and normal pregnancy outcomes Two previous analyses, conducted in 2001 and 2005, have used this ecological approach, estimating the global prevalence of inadequate zinc intake at 48.9% and 20.5%, respectively. The difference between estimates was due primarily to changes in methodological assumptions regarding food processing methods and updated information regarding zinc requirements and the fractional absorption of dietary zinc The objectives of the current analysis were to (1) update the country- and region-specific estimated prevalence of dietary zinc inadequacy, focusing on four major sources of uncertainty in this analysis and evaluating the effects of different assumptions on estimates of the prevalence of inadequate zinc intake, and (2) generate a model considered to provide the best estimate of the prevalence of inadequate zinc intake, given the current state of knowledge. The different input parameters for the model are as follows:Alternative global and regional nutrient composition databases to estimate the amount of zinc and phytate in the national food supplies, recognizing that reported zinc and phytate values of foods may vary substantially by agricultural conditions, plant cultivar and methods of laboratory analysis.Different age- and sex-specific estimates of average physiological requirements for absorbed zinc, as well as requirements for total dietary zinc intake, as developed by the Food and Nutrition Board of the Institute of Medicine (FNB/IOM) and the International Zinc Nutrition Consultative Group (IZiNCG). Both sets of estimates were used because of a lack of consensus regarding zinc requirements.Different methods to estimate the fractional absorption of zinc (FAZ), using either mathematical modeling, based on zinc and phytate contents of the food supply, or P:Zn molar ratio cut-offs.Alternative assumptions regarding inter-individual variation in dietary zinc intake, ranging from 20–30%, due to limited data from nationally representative surveys in populations of interest.The following steps were completed to estimate the prevalence of inadequate zinc intake on a country-specific basis, for each country with available data:Calculation of country-specific data on the average daily per capita availability of major food commodities;Calculation of the zinc and phytate contents of each food commodity;Estimation of the absorbable zinc content of the daily food supply on a per country basis;Calculation of the theoretical mean daily per capita physiological and dietary requirements for zinc, based on the age and sex distribution of the national population;Comparison of the absorbable or total dietary zinc content of the food supply with the population’s theoretical mean physiological requirement or dietary requirement for zinc, respectively; andEstimation of the prevalence of inadequate zinc intake in a population and calculation of country-specific rank order by estimated prevalence.Each of these steps is further explained in the following paragraphs.The FAO publishes annual food balance sheets (FBS), which provide country-specific data on the quantities of foods available for human consumption. To smooth differences in within-country inter-year variability, the present analyses are based on the mean availability of commodity foods from 2003 to 2007, encapsulating the latest five years of data currently available in the public domain. Data were downloaded for 210 countries and territories with available information for the period from 1998–2007 The FAO FBS report 95 ‘standardized’ food commodities, the majority of which are created using one of two methods. The first standardization method aggregates similar foods into one commodity . The second standardization method reverts processed foods back to the original commodity . The FAO provides definitions and a listing of possible foods included in each standardized commodity .As mentioned above, the first standardization method aggregates similar foods into one standardized food commodity. A previous review of the zinc and phytate contents of the individual foods included in each of the FAO standardized food commodities created by this standardization method concluded that there was limited intra-category variability in the amounts of these two food components The second standardization method reverts processed foods back to the original primary commodity. For FAO standardized food commodities created according to this standardization method, zinc and phytate values were assumed to be those of either the representative whole-grain non-fortified flour for cereals or the non-processed primary food for all other commodities .a priori that when the percent difference in either zinc or phytate content for any aggregated food commodity was greater than 25% between databases, or the amount of zinc or phytate from a single aggregated food commodity accounted for greater than 5% of the daily availability of that food component for human consumption in any region, attempts would be made to resolve the differences between databases and create best estimates. However, 80% of the food commodities which contained either zinc or phytate met the aforementioned criteria; therefore all food commodities were re-evaluated. KRW reviewed the available reference data underlying the nutrient values for the NDSR and IML databases. Data for the new composite database were obtained from the two aforementioned databases, the USDA Nutrient Database for Standard Reference, Release 23 (USDA SR23) Food Phytates, edited by Reddy et al.et al., when available; all values were checked for internal and external consistency. The zinc and phytate values for each of the aggregated food commodities, as well as documentation of data sources, are available as online supporting material for each database . The subsequent analyses were conducted using each of the three nutrient databases  to examine the effects of different estimates of zinc and phytate contents of the food commodities on the estimated prevalence of inadequate zinc intake.In the previous analysis conducted by this group, zinc and phytate contents of each food commodity were obtained from the WorldFood System International Mini-list (IML) . Due to the relatively limited number of countries implementing mandatory national zinc fortification programs prior to 2007, no assumptions were made regarding the zinc fortification of flour Whole-grain cereals typically contain more zinc and phytate than decorticated grains and low extraction (i.e. refined) flours, due to higher concentrations of zinc and phytate in the bran and germ as compared to the endosperm. In addition, food processing techniques, such as soaking, fermentation and nixtamalization, can reduce the phytate contents of cereals and legumes, thus affecting the bioavailability of zinc in the processed foods. We attempted to locate country- and/or region-specific data on the methods and rates of extraction and processing of cereals and legumes, as well as the effects of extraction and processing on the zinc and phytate contents of the food commodities. However, such information is lacking and may be highly variable within and between countries. To re-evaluate and improve previously developed regional estimates, we solicited information from international research centers, experts in the field, and current literature searchable through ScienceDirect, Agricola and PubMed. The regional processing and extraction assumptions that were ultimately used for each region, and the effects of extraction and processing on zinc and phytate contents of the aggregated food commodities, are provided as online supporting material The proportion of dietary zinc that is absorbed is determined primarily by the total zinc and phytate content of the diet. The fractional absorption of zinc  decreases with increasing zinc intake, although the total absorption of zinc  increases. Phytate, a phosphorus storage molecule in plants, is a strong chelator of zinc; the phytate: zinc complex passes through the intestinal tract unabsorbed. The inhibitory effect of phytate on zinc absorption is dose-dependent Theoretical mean daily per capita requirements for zinc can be calculated based on either estimated average physiological requirements for absorbed zinc or estimated average dietary requirements for total zinc intake. These latter requirements are termed the “estimated average requirements” (EAR) by the Dietary Reference Intakes (DRI) of the FNB/IOM; however, for the purpose of this analysis they will be referred to as “dietary requirements”. Due to a lack of consensus regarding zinc requirements, we conducted separate analyses using both the physiological and dietary requirements.The FNB/IOM, WHO/FAO/IAEA, and IZiNCG have each proposed different age- and sex-specific physiological requirements for absorbed zinc. Although all methods use the same general factorial approach, estimated requirements reflect different criteria for inclusion of studies in the analyses , different reference body weights, and different statistical methods with or without weighting studies by sample size . The IZiNCG dietary requirements account for the effects of phytate on total zinc intake requirements, whereas the FNB/IOM dietary requirements do not consider the effects of phytate. To categorize countries according to diet-type, so as to apply the appropriate dietary requirement, as developed by IZiNCG, we first calculated phytate: zinc (P:Zn) molar ratios to estimate zinc absorption categorically . The theoretical mean daily per capita dietary requirement was calculated using the aforementioned weighting method based on the age and sex distribution of the population. The subsequent analyses were conducted using both the FNB/IOM and IZiNCG population mean theoretical dietary requirements, in conjunction with the composite nutrient database and availability of zinc in the food supply (mg/capita/d), to investigate the effects of differing dietary requirements on the estimated prevalence of inadequate zinc intake.As an alternative strategy, given the aforementioned uncertainties surrounding the phytate contents of food commodities, and lack of consensus regarding physiological requirements, we also used age- and sex-specific estimated average dietary requirements for total zinc intake put forth by the FNB/IOM To calculate the percentage of the mean physiological requirement for zinc that is available in the national food supply, we divided the estimated absorbable zinc content of the national food supply by the theoretical mean national requirement for absorbed zinc. We also divided the estimated daily per capita availability of zinc (mg/d) by the theoretical mean national requirement for dietary zinc intake to calculate the percentage of the mean dietary requirement for zinc that is available in the food supply. We obtained six estimates of the percentage of the mean requirement for zinc that is available in the national food supply, using different combinations of methodological assumptions, as indicated in We then applied a method akin to the Estimated Average Requirement (EAR) cut-point method described by the IOM Due to the numerous methodological assumptions inherent in this analysis, and the lack of consensus regarding zinc requirements and nutrient composition of food commodities, we also ranked countries by estimated prevalence of inadequate zinc intake and examined the conservation of rank among models based on different assumptions.As noted previously, we attempted to identify the most appropriate assumption at each step in the methodological process, given the current state of knowledge regarding nutrient composition of foods, zinc requirements, the effects of zinc and phytate intakes on zinc absorption, and inter-individual variability in intake. We then used the totality of these assumptions to generate a “best-estimate” model to determine the prevalence of inadequate zinc intake, which is comprised of zinc and phytate data from the composite nutrient database, IZiNCG physiological requirements for absorbed zinc, the Miller equation to estimate the fractional absorption of zinc and a 25% CV in inter-individual variation in intakes.P value <0.05 was considered statistically significant.Regional classifications are based on the reporting regions of the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study, and are grouped according to geographical location and dietary patterns Regional data, based on the “best-estimate” model for the estimated prevalence of inadequate zinc intake in the population are presented in , due to dissimilarities in the reported zinc and phytate contents, and P:Zn molar ratio, of rice among databases. However, although the estimated prevalence of inadequate zinc intake varied, country-specific rank order of estimated prevalence of inadequate intake was highly conserved when different databases were used to estimate zinc and phytate contents .Holding assumptions regarding physiological zinc requirements (IZiNCG) and absorbed zinc (Miller equation) constant, the IML and NDSR databases provide estimates of the global prevalence of inadequate zinc intake of 20.9% and 13.8%, respectively, compared with the 17.3% estimated by the composite database  (Holding assumptions regarding the nutrient composition database (composite) and absorbed zinc (Miller equation) constant, FNB/IOM physiological requirements estimate a global prevalence of inadequate intake of 66.1%, compared to the 17.3% estimated when applying the IZiNCG physiological requirements Table 3.). However, there was considerable variability in the two sets of results for individual countries . Among countries with a P:Zn molar ratio≤18, the mean estimates were similar, although the range of estimates was much greater when IZiNCG dietary requirements were applied than when the physiological requirements were used (9.4% (0.34–77.5%) vs. 11.1% (2.3–34.9), respectively). However, among countries with a P:Zn molar ratio >18, both the mean and range of estimates of the prevalence of inadequate zinc intake were dissimilar when IZiNCG dietary requirements were applied (IZiNCG dietary requirement: 40.8% (2.5–99.9%) vs. IZiNCG physiological requirement: 26.8% (13.1–54.3)). The prevalence of inadequate zinc intake was greater with IZiNCG dietary requirements than with the physiological requirements in all regions except Central Asia, North Africa and the Middle East, where total zinc availability was high enough to compensate for the higher dietary requirements. IZiNCG dietary requirements are based upon IZiNCG physiological requirements and were calculated based on a FAZ of ∼30% and ∼22% (a difference of 8%) when the P:Zn molar ratios are≤18 and >18, respectively. By contrast, with the Miller equation, the difference in estimated mean FAZ between countries with a P:Zn molar ratio≤18 and >18 was only 2.2% . However, the Miller Equation captured considerable inter-country variability in the FAZ , which was not accounted for in the establishment of the IZiNCG dietary requirements. Nevertheless, country-specific rank order of estimated prevalence of inadequate zinc intake was conserved between estimates generated using IZiNCG physiological and dietary requirements  . The global estimate of the prevalence of inadequate zinc intake based upon IZiNCG dietary requirements was similar to that generated based upon IZiNCG physiological requirements  Table 3; ). The fractional absorption of zinc as estimated by the Miller equation and used to calculate the estimated prevalence of inadequate intake in relation to physiological requirements was 24.3±3.6% ; however, FNB/IOM dietary requirements are based on a fixed fractional absorption of zinc of 41%, irrespective of dietary intake. Due to the universal application of a single FAZ estimate, country-specific rank order improved in countries with higher P:Zn molar ratios relative to those with lower P:Zn molar ratios; overall country-specific rank order was only moderately conserved  .All country- and region-specific, as well as the global, estimated prevalence of inadequate zinc intake based upon FNB/IOM physiological requirements were dramatically higher than those based upon FNB/IOM dietary requirements  ; . The fraHolding all other model assumptions constant , varying the assumed inter-individual CVs from 20 to 30% resulted in a global estimates of the prevalence of inadequate zinc intake ranging from 13.1 to 21.0%, respectively.The present analyses suggest a high prevalence of inadequate zinc intake, particularly in the regions of South Asia and Sub-Saharan Africa; however, the absolute prevalence estimates vary depending on the assumptions applied with regard to nutrient composition of commodity foods, estimated zinc requirements, and inter-individual variability in zinc intake.However, all models suggest that inadequate zinc intake may be fairly common. With one exception, the new estimates of the global prevalence of inadequate zinc intake ranged from 12–21% among models, and are generally consistent with our previous estimate of 20.5% Because of the multiple sources of uncertainty in in these food balance sheet models which estimate the prevalence of inadequate zinc intake, considerable caution needs to be used in the interpretation of the prevalence figures, and they should not be considered as numeric absolutes. However, when countries are ranked according to the estimated prevalence of inadequate intake in their population, the country-specific rank order is fairly consistent across assumptions, except for the comparison between FNB/IOM physiological and dietary requirements. Thus, by using the information on rank order, inter-country inferences can be drawn regarding the relative likelihood of zinc deficiency as a public health problem. Countries at high-risk can be targeted for further assessments of population zinc status using measurements of plasma zinc concentration and dietary zinc intake as part of nationally representative nutritional assessment surveys.The estimate based on FAO FBS is advantageous in the preliminary identification of countries deemed to be at high risk of zinc deficiency relative to other countries, insofar as it uses relevant national food balance data that are routinely collected, standardized and presently available in the public domain. However, there are several potential limitations of this method that need to be recognized in the interpretation and subsequent use of the results, as described in the following paragraphs.Attempts were made in the present analysis to identify outliers and to impute values when data were missing or considered implausible; however, inaccuracies may continue to exist in the national food balance data as reported to the FAO. Moreover, the type and extent of processing applied to food commodities are not reported in the FAO food balance sheets. However, in previous analyses of the impact of applying different assumptions regarding the processing of wheat and maize, these differences had relatively little effect on the estimated percentage of the mean physiological requirement available in the national food supply (8). In addition, food balance sheets supply data on annual food availability, and the present analysis does not account for, inter- and intra-household differences in the distribution of food to individuals, or food wastage within the household, all of which may substantially affect dietary zinc intake, or seasonal variation in food supply which may differentially affect zinc status throughout the year When the composite, IML or NDSR nutrient composition databases were applied to the model, holding all other assumptions constant, the global prevalence of inadequate zinc intake ranged from 13–21%. The largest differences in estimates occurred in Asian regions, largely due to the different values for zinc, phytate and resulting P:Zn molar ratios, of rice in the three databases . Overall, we found large variations in the reported zinc and phytate contents of individual foods among different regional and universal food composition databases, and within the scientific literature. Inter-database variation may be due to actual differences in the zinc and phytate contents of similar foods, possibly related to differences in genetics or environmental conditions Additional information is needed on the prevalence of country- and region-specific food processing methods, and the impact various practices have on the total zinc and phytate contents of the foods and zinc bioavailability. In the present analyses, we focused on decortication, milling, fermentation and nixtamalization of cereals, and fermentation of starchy roots. However, we recognize that there is a serious lack of published information, and that inter-individual, national and regional differences in the type, order and duration of processing methods can dramatically influence the resultant zinc and phytate contents of the food commodities. For example, research has shown that extent of decortication of millet in Sahelian West Africa are highly dependent on the woman operator of the mortar and pestle From 2003–2007, very few countries had implemented mandatory national programs for the zinc fortification of wheat and/or maize flour The WHO/FAO/IAEA, FNB/IOM, and IZiNCG have each proposed different physiological requirements for absorbed zinc, as well as dietary requirements for total zinc intake All analyses using physiological requirements applied the Miller equation, a physiologically based mathematical model using saturation kinetics that considers the effects of zinc and phytate intakes on Zn absorption The FNB/IOM dietary requirements likely underestimate the prevalence of inadequate zinc intake, due to an assumed fractional absorption of zinc (41%) that is much higher than that predicted by the Miller equation in this analysis (24%). FNB/IOM dietary requirements are based on zinc absorption data from low-phytate or phytate-free diets, and thus their application does not seem justifiable for the global estimation of the prevalence of inadequate zinc intake. IZiNCG proposed higher dietary requirements for total zinc intake among individuals consuming diets with low zinc bioavailability (P:Zn molar ratios >18), in a preliminary attempt to address the impact of phytate intake on zinc absorption. In the present analysis, the estimated prevalence of inadequate zinc intake in the global population was similar when IZiNCG physiological or dietary requirements were applied and country-specific rank order was well conserved. However, the IZiNCG dietary requirements are based on limited data and the dichotomous categorization by diet type. This simplification, compared to results obtained when the Miller equation is used to calculate FAZ based on country-specific zinc and phytate dietary intakes, results in a wider range of estimates of the prevalence of inadequate zinc intake, and potentially overestimates dietary zinc inadequacy in those consuming diets with low zinc bioavailability.Our estimate of the prevalence of inadequate zinc intake is based on a method akin to the EAR cut-point method, the theoretical aspects of which have been previously described The following information is necessary strengthen the present analysis: (1) further development of national and regional food composition tables, with the inclusion of phytate data; (2) information on local food processing methods, focusing on major sources of zinc and phytate; (3) additional modeling of data on zinc absorption among different populations and population subgroups of varying age and dietary practices; (4) consensus on the estimation of physiological and estimated average dietary requirements, accounting for phytate intake; and (5) information from nationally representative dietary surveys on inter-individual variability in intakes. As this information becomes available, the estimates put forth in this analysis can be easily updated and modified. In addition, national estimates of the prevalence of inadequate zinc intake obtained from analyses of the food balance sheets should be validated against direct indicators of a population’s risk of zinc deficiency, including nationally representative dietary data and plasma zinc concentrations, as this information becomes available.These analyses indicate that the prevalence of inadequate zinc intake may be fairly common. However, there is considerable variability in the estimates based on the application of different model assumptions, most strikingly between different theoretical mean physiological requirements for zinc. Given the current state of knowledge, we generated a model considered to provide the best estimate of the prevalence of inadequate zinc intake. This “best-estimate” model, comprised of zinc and phytate data from the composite nutrient database, IZiNCG physiological requirements for absorbed zinc, the Miller equation to estimate total zinc absorption, and a 25% CV in inter-individual variation in intakes, indicates that the zinc content of national food supplies may be inadequate to meet zinc requirements for ∼17% of the world’s population. This model owes it strength to the thoroughness of this analysis’ review of food composition databases, regional food processing techniques, and zinc requirements and absorption. However, based on the current state of knowledge, we do not believe that this approach using FAO food balance sheets can be used to estimate the true prevalence of inadequate zinc intake. Nevertheless, because country-specific rank order was highly conserved across most estimates, information obtained from these analyses can be used to draw inferences regarding the relative likelihood of zinc deficiency as a public health problem in different countries. These results suggest that the prevalence of zinc deficiency is greatest in South Asia and Sub-Saharan Africa; further assessment of zinc status, using plasma zinc concentration and/or dietary zinc intake as part of nationally representative nutritional assessment surveys should be a priority in these regions.Table S1Nutrient composition data for standardized food commodities, as defined by the Food and Agriculture Organization of the United Nations and obtained from different nutrient composition databases. Individual foods were aggregated into standardized food commodities and weighting factors were applied based on the number of foods defined for each commodity. The zinc and phytate contents of the individual foods are provided, as appropriate, for the USDA Nutrient Database for Standard Reference, Release 23 (USDA SR23), Nutrition Data System for Research (NDSR), WorldFood System International Mini-list (IML) and composite database created for the purposes of this analysis.(XLS)Click here for additional data file.Table S2Regional extraction and processing assumptions for cereals, starchy roots and legumes, and the effects of extraction and processing on the zinc and phytate contents of the standardized food commodities.(XLS)Click here for additional data file.Table S3Documentation of sources used in the regional extraction and processing assumptions for cereals, starchy roots and legumes, and the effects of extraction and processing on the zinc and phytate contents of the standardized food commodities.(DOCX)Click here for additional data file.Table S4Regional classifications.(DOCX)Click here for additional data file.


This integrative review synthesises research studies that have investigated the perceptions of nurse practitioners and medical practitioners working in primary health care. The aggregation of evidence on barriers and facilitators to working collaboratively and experiences about the processes of collaboration is of value to understand success factors and factors that impede collaborative working relationships.An integrative review, which used systematic review processes, was undertaken to summarise qualitative and quantitative studies published between 1990 and 2012. Databases searched were the Cochrane Library, the Joanna Briggs Institute Library, PubMed, Medline, CINAHL, Informit and ProQuest. Studies that met the inclusion criteria were assessed for quality. Study findings were extracted relating to a) barriers and facilitators to collaborative working and b) views and experiences about the process of collaboration. The findings were narratively synthesised, supported by tabulation.27 studies conducted in seven different countries met the inclusion criteria. Content analysis identified a number of barriers and facilitators of collaboration between nurse practitioners and medical practitioners. By means of data comparison five themes were developed in relation to perceptions and understanding of collaboration. Nurse practitioners and medical practitioners have differing views on the essentials of collaboration and on supervision and autonomous nurse practitioner practice. Medical practitioners who have a working experience with NPs express more positive attitudes towards collaboration. Both professional groups report concerns and negative experiences with collaborative practice but also value certain advantages of collaboration.The review shows that working in collaboration is a slow progression. Exposure to working together helps to overcome professional hurdles, dispel concerns and provide clarity around roles and the meaning of collaboration of NPs and MPs. Guidelines on liability and better funding strategies are necessary to facilitate collaborative practice whether barriers lie in individual behaviours or in broader policies. A nurse practitioner (NP) in primary health care collaborates on average with 4.4 medical practitioners (MPs) and most of these MPs work on-site with the NP . In mostCollaboration, as described in the literature, involves trust, mutual respect, shared decision-making and equality ,16. CollNo matter what form of collaboration is in place, a number of factors can influence the functioning or failure of collaborative practice between NPs and MPs. Literature reviews -26 and pTherefore, this literature review aims at summarising the existing evidence about the views and experiences of NPs and MPs with collaborative practice in primary health care settings. The findings of the review will provide information about health professionals’ understanding of collaboration, the perceived barriers and facilitators to collaborative practice and their attitude about working in collaboration. Since this review aims to aggregate data of qualitative and quantitative evidence and not to re-interpret findings, an integrative synthesis was the method chosen for this literature review . The steA number of methods are available for the synthesis of qualitative and quantitative evidence ,38-42. AStudies were included in the review if they focused on a population of NPs  and The following databases were searched: Cochrane Library, Joanna Briggs Institute Library of Systematic Reviews, PubMed/MEDLINE, CINAHL, ProQuest (Dissertation and theses) and Informit . The review also contains grey literature such as theses and dissertations.When available medical subject headings or index terms were used in each database. An example of a typical search is shown in the Additional file Results from all databases were combined in Endnote®, duplicates deleted and the results screened by title and abstract for suitability for the literature review. One reviewer examined the full text of potentially relevant papers for final inclusion or exclusion in the review. Reference lists of included papers were screened for eligible studies.A separate appraisal tool was used for each included study type . The fol•For cross-sectional studies – 11 Questions to help you make sense of descriptive/cross-sectional studies •For surveys – CEBMA Appraisal Questions for a Survey •For qualitative studies – JBI Qualitative Assessment Research Instrument (QARI) •For mixed methods research – Scoring System for appraising mixed methods research No articles were excluded from the review based on their methodological quality to not exclude valuable insights from weaker studies , unless Firstly, study details such as the methodology, the population and the context of the study were extracted from each study and organised in an evidence table ,Results from quantitative studies were juxtaposed with qualitative findings within each descriptive theme and outlined in a descriptive summary, supported by tabulation of data . Since tThe literature search identified 3635 papers. After excluding duplicates and papers published before 1990 there were 2256 papers for review. The flow chart in Figure There was an almost equal number of papers reporting qualitative studies (n = 14) and surveys (n = 13), whereas there were only two mixed methods study papers and one paper reporting data from a cross-sectional design as part of one of the mixed methods studies. However, most of the surveys applied a mixed-methods design, using open-ended and closed questions. A meta-analysis of quantitative results was not possible because only one study investigated effects of an intervention on perceived collaboration.The evidence of this review is based on studies including a total of 1641 MPs and 380 NPs (among those were 4 APNs with a similar level of authority than NPs). The majority of studies were undertaken in the US (11) followed by Canada and the UK (6 each) with one study undertaken in each of the Netherlands, Sweden, Ireland and New Zealand.Overall, studies were of moderate quality with some information difficult to assess due to weaknesses in reporting  & Professor of Public Health, Australian Catholic University; Adjunct Professor, University of Adelaide. AG: PhD MPH RN; Professor of Nursing, Australian Catholic University; Adjunct Professor, James Cook University.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/132/prepubMedline search, Table with Medline search strategy.Click here for fileEvidence table, Table that provides details of all included studies.Click here for fileQuality appraisal, Table that outlines the quality appraisal of included studies.Click here for file


Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed. Human genome sequencing, the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined, was the most significant technical challenge of the Human Genome Project. Completed in 2003, the 13-year project identified 20,000 to 25,000 genes and determined the sequence of the 3 billion chemical base pairs that make up human DNA as well as the regions that control them. Since then, improvements in sequencing speed, reliability, and cost have been the ongoing goals. Hence, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. With the numerous advances in genomic sequencing, there has been a dramatic increase in the number of clinical trials now using this technology to study key disease outcomes [The objective of this review is to familiarize the translational investigator with genomic sequencing technologies as they apply to clinical trials. We describe the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. To illustrate the recent impact and widespread movement of genomic sequencing into clinical and translational research, we provide a summary of the types and distribution of clinical studies that are using genomic sequencing to enhance the understanding of complex pathophysiology and identify important biomarkers of both rare and common diseases. We provide some key examples of clinical trials in which translational researchers are utilizing this technology to better identify and individualize the management of high-risk patients, and to achieve major breakthroughs in drug development.So rapid are the advances in genomic sequencing technology that the methods are commonly referred to as first- and next-generation sequencing (NGS). Sanger sequencing, developed in the 1990s, was the earliest method used to sequence human DNA. In fact, it was Sanger technology that was used to sequence the human genome in the Human Genome Project. It is often referred to as "first-generation sequencing" because it revolutionized how a single lab could sequence millions (rather than thousands) of base pairs. Sanger sequencing is a multi-channel capillary approach that allows relatively rapid DNA sequencing. Even though the newer platforms are much faster and cheaper, Sanger sequencing remains in many respects the "gold standard" for smaller validation studies, and remains the only widely used platform that can sequence relatively long sequences of DNA--up to 1,000 nucleotides in length , and Applied Biosystems (ABI) SOLiD. These platforms are able to generate more sequence and are substantially less expensive than the original Sanger methods Table . They caTable There are currently three widely adopted approaches to sequencing: whole genome, exome, and transcriptome sequencing. The specific approach being used for any given study will determine which NGS platform is used. For example, due to its significant expense, whole genome sequencing, in which the entire genome is sequenced, is an arduous and costly methodology to adopt. However, for collecting large amounts of DNA sequence data from individual human subjects, the more expensive Sanger sequencing is still widely used because of its capacity for longer read lengths . An impoBRCA1 mutations, and the identification of MYO1E mutations in childhood familial focal segmental glomerulosclerosis.[Recent whole genome studies have used NGS to gain insight into genomic markers of disease. An excellent example using whole genome sequencing was reported by Mardis et al, in which 12 somatic mutations within coding sequences and 52 somatic point mutations in conserved regions of patients with acute myeloid leukemia (AML) were identified . Investiclerosis.-20MYH3 gene mutation by sequencing four individuals with the disease. Since then, exome sequencing has been used as a popular approach to identify rare Mendelian disorders [Exome sequencing has been used to gain insight and determine genetic abnormalities in congenital defects. This approach has been favored for a number of reasons. First, this technique requires only about 5% as much sequencing as a whole genome. In total, there are about 180,000 exons found in the human genome. It is estimated that the protein coding regions of the human genome constitute about 85% of the disease-causing mutations. A pivotal study reported in 2006 identified a point mutation in Freeman-Sheldon Syndrome . After eisorders -24. Thesisorders  familialisorders ,27 Parkiisorders ,29 and aisorders ,31.ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumor removed at diagnosis 9 years earlier; six  were present at lower frequencies (1-13%); 19 were not detected in the primary tumor, and two were undetermined [SRP9 and COG3. Taken together, these data show that transcriptome sequencing was useful in identifying single nucleotide mutational heterogeneity, which can be a property of low or intermediate grade primary breast cancers, and that significant evolution can occur with disease progression. Most recently, researchers have used transcriptome sequencing approaches to identify functional microRNA involved in endometriosis, and diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer [Transcriptome sequencing encompasses experiments including small RNA profiling and discovery, mRNA transcript expression analysis  and the sequencing and analysis of full-length mRNA transcripts. Transcriptome investigation has included the areas of novel gene discovery, gene space identification in novel genomes, assembly of full-length genes, SNPs, and insertion-deletion and splice-variant discovery. Transcriptome sequencing has evolved as a robust technique for evaluating gene expression changes from either healthy individuals who develop disease, or within diseases themselves, such as breast cancer and malignant metastases within the same patient . One apptermined . The come cancer -36.Perhaps the best resource for identifying and tracking the growing number of studies now using genomic sequencing is ClinicalTrials.gov . This weThere is a wide range of studies that are now utilizing genomic sequencing technology. The list of conditions and diseases involved is a clear indicator of the growing interest in understanding the role of genetic predisposition in human disease. According to ClinicalTrials.gov, genomic sequencing technologies have been incorporated into studies on 16 categories of disease conditions. Table According to our search, there were six recently completed clinical studies that have proposed genomic sequencing as an outcome measure at the time of this review. In France, an observational study of molecular and metabolic markers in oligodendrogliomas was recently completed with tumor collection from 189 pediatric and adult patients (NCT00213876). Researchers will use these tumor samples to identify diagnostic molecular and metabolic markers that could be used as a signature to characterize benign versus more aggressive tumor histologies. Genomic sequencing and serial analysis of genomic expression results will be correlated to survival and clinical features of oligodendrogliomas, medulloblastomas, and gliomas. A recently completed epidemiological study on the distribution of insulin-like growth factor-1 (IGF-1) deficiency in children with idiopathic short stature will investigate candidate genes and DNA changes that are potentially associated with short stature. DNA regions identified during genome-wide scan will be further mapped at higher resolution using DNA-sequencing (NCT00710307).in situ gene expression induction with the drug by RNA microarray technology (NCT00144976). In an international phase II trial of Lapatinib in patients with relapsed or refractory inflammatory breast cancer, researchers will study tumor cell growth and survival by quantitative immunohistochemistry and by direct and genome-wide methods  in tumor tissue collected prior to and following 28 days of lapatinib monotherapy (NCT00105950). In the Dominican Republic, a Phase III randomized, double-blind, placebo-controlled study was completed in 2008 (200 infants) to investigate horizontal transmission of human rotavirus vaccine strain (Rotarix) (NCT00396630). Investigators are using genomic sequencing to analyze mutations in the vaccine strain after transmission.Genomic sequencing has also been incorporated as a secondary outcome measure in a few recently completed experimental studies: Investigators in France conducted an open label trial to evaluate the biological effect of Tarceva for patients with epidermoid carcinoma. A frozen tissue bank was generated for genomic sequencing study of tumorous epidermal growth factor receptor (EGF-R) structure and for modification of Thirteen of the 35 studies were designed with genomic sequencing results as a primary outcome measure Table . The mosThere are a few large-scale epidemiological studies that have begun to incorporate genomic sequencing as a major part of their observations. For example, the largest U.S. sample registered at the time of this review, sponsored by the National Cancer Institute (NCI), has enrolled 3,000 patients to study gene expression of lymphoma, leukemia, and multiple myeloma NCT00339963). In this trial, DNA sequencing methods are being used to analyze base changes in the genome of the cancer cells. While there are several reports that have described the sequencing of whole genomes from a few patients, the much larger number of cases in this trial will allow researchers to identify biologically relevant patterns in humans 9963. In -41. The As the cost of NGS technology is becoming less of a limitation, several inherent challenges remain that must not be overlooked. Of utmost relevance to the translational investigator are the ethical, legal and social issues surrounding genomic sequencing. In a recent study conducted by Allen and Foulkes, 30 cancer genome sequencing studies were assessed to evaluate how these issues are being handled across different jurisdictions . While tWith the vast amounts of high-quality, complex data now being processed through NGS, an ongoing challenge for translational researchers remains: How do we deal with the computational complexities of analyzing this data? NGS can miss parts of the genome that may be clinically important. It detects mainly small polymorphisms, though it could be used to detect larger copy number variations. Multiple comparison and sample size issues remain an ongoing problem. In general, the computational complexities of properly handling genomic sequencing data have lagged behind the development of the technology. Such challenges may only be addressed through the development of innovative bioinformatic approaches, and through strategic collaboration and knowledgeable study design and implementation by translational investigators. Computerized technological advances are rapidly becoming in high demand . Two proIn summary, rapid advances in genomic sequencing have paved the way for the incorporation of NGS into clinical applications. With NGS technology there is much improved cost-effectiveness and more rapid turnover, two critical success factors that are highly appealing to clinical and translational investigators. In the past, studies that implement gene sequencing have been concentrated around major academic institutions, but this is not expected to continue in the future. With more readily available and cost-effective markets now capitalizing on complete human genome sequencing and analysis as an outsourced service, the use of this technology is likely to become more automated, with significant impact on national and international economies . As illuAIDS: Acquired Immune Deficiency Syndrome; AML: Acute Myeloid Leukemia; CAP: Community Acquired Pneumonia; ChIP: Chromatin Immunoprecipitation; CNV: Copy Number Variant; DNA: Deoxyribonucleic Acid; EGF-R: Epidermal Growth Factor Receptor; EMR: Electronic Medical Record; GA: Genome Analyzer; HIV: Human Immunodeficiency Virus; IGF: Insulin-like Growth Factor; mRNA: messenger Ribonucleic Acid; NCI: National Cancer Institute; NGS: Next-Generation Sequencing; NHGRI: National Human Genome Research Institute; NIAID: National Institute of Allergy and Infectious Disease; NICHD: National Institute of Child Health and Human Development; RNA: Ribonucleic Acid; SNP: Single Nucleotide Polymorphism.The authors declare that they have no competing interests to disclose. Dr. Mestan receives career development funding from NHLBI (K23 HL093302).KM conducted the research on the Distribution and Types of Clinical Trials, and was primarily responsible for preparing the initial draft of this manuscript for submission, revisions, and for final editing. LI conducted the literature search on Genomics in Human Disease and prepared this section of the manuscript, in addition to critically revising the manuscript for important intellectual content. SM conducted the research on Human Genomic Sequencing and prepared the tables and written sections pertaining to NGS technology. SL is responsible for initiating the topic of this review, overseeing the conception and design, and critically revising for important intellectual content. All authors read and approved the final manuscript.


India with a population of 1.2 billion is changing rapidly with increasing literacy, declining sex ratio, huge urban growth, high population density and a rising proportion of young people. Some communicable diseases show a declining trend while others show an upward trend. The proportion of deaths and burden of disease due to chronic disease risk factors are on the rise.Resource limited countries like India face several practical problems, the most prominent being the difficulty to convince policy makers that non-communicable diseases are silent killers. The size and diversity of the population necessitates large cohorts resulting in significant cost escalation. In addition infrastructure, manpower and resource limitations preclude the availability of quality data. The operational and management challenges include consistency of data capture across diverse regions, building and sustaining clinical infrastructure, long term data storage and ethical issues. The scientific requirements in undertaking population based cohort studies in India include identification of susceptible individuals, tracking of migrants and qualitative studies to supplement quantitative data. Mechanisms to ensure community participation like need based benefits for the community, proper feedback and networking with non-governmental organizations and private health care providers are also important.In addition to the information available from routine surveillance, medical records and national programmes, a well planned cohort study can provide incidence rates, predictors of diseases, sub-clinical infections, individual, family and community parameters, in-migration and out-migration, early indications of impending outbreaks, health and treatment seeking behaviour and impact of individual or community level clinical or behavioural interventions. Senior level health managers and experts have identified non-communicable diseases as a public health research priority next only to maternal and child health and it is necessary to initiate population based cohort studies and plan interventions accordingly.