Nationally, health in Rwanda has been improving since 2000, with considerable improvement since 2005. Despite improvements, rural areas continue to lag behind urban sectors with regard to key health outcomes. Partners In Health (PIH) has been supporting the Rwanda Ministry of Health (MOH) in two rural districts in Rwanda since 2005. Since 2009, the MOH and PIH have spearheaded a health systems strengthening (HSS) intervention in these districts as part of the Rwanda Population Health Implementation and Training (PHIT) Partnership. The partnership is guided by the belief that HSS interventions should be comprehensive, integrated, responsive to local conditions, and address health care access, cost, and quality. The PHIT Partnership represents a collaboration between the MOH and PIH, with support from the National University of Rwanda School of Public Health, the National Institute of Statistics, Harvard Medical School, and Brigham and Women’s Hospital.The PHIT Partnership’s health systems support aligns with the World Health Organization’s six health systems building blocks. HSS activities focus across all levels of the health system — community, health center, hospital, and district leadership — to improve health care access, quality, delivery, and health outcomes. Interventions are concentrated on three main areas: targeted support for health facilities, quality improvement initiatives, and a strengthened network of community health workers.The impact of activities will be assessed using population-level outcomes data collected through oversampling of the demographic and health survey (DHS) in the intervention districts. The overall impact evaluation is complemented by an analysis of trends in facility health care utilization. A comprehensive costing project captures the total expenditures and financial inputs of the health care system to determine the cost of systems improvement. Targeted evaluations and operational research pieces focus on specific programmatic components, supported by partnership-supported work to build in-country research capacity.Building on early successes, the work of the Rwanda PHIT Partnership approach to HSS has already seen noticeable increases in facility capacity and quality of care. The rigorous planned evaluation of the Partnership’s HSS activities will contribute to global knowledge about intervention methodology, cost, and population health impact. A decade after the 1994 genocide, which claimed the lives of at least 800,000 people and left 2 million homeless, Rwanda’s health system remained fragile across much of the country. Mortality rates, which had skyrocketed in the mid-1990s, did not return to pre-1994 levels until 2005 [In 2005, the Government of Rwanda (GOR) and the Clinton Foundation invited Partners In Health (PIH) to help rebuild the public health infrastructure in two of the country’s most impoverished rural districts: southern Kayonza and Kirehe. Employing a model of multilevel public sector health system strengthening used by PIH in rural Haiti, the Rwandan Ministry of Health (MOH) and PIH rapidly invested in health facility infrastructure, building or renovating two district hospitals and six health centers; recruited and trained health professionals from the limited available pool; and introduced community-based HIV care integrated with basic primary health care services .To bringMutuelle de Santé health insurance program, which provided access to basic primary health care services for 85% of its citizens by 2009 [By 2009, the Rwandan government had improved access to primary health services mainly through infrastructure development and expansion of a community-based health insurance program. Geographic access to care was relatively well distributed, with 75% of the nation’s population living within 5 kilometers of a health facility . Althoug by 2009 . Due, in by 2009 . Consist by 2009 , compare by 2009 . Concurr by 2009 .Rwanda is divided into 30 districts, and 85% of the country’s 10.8 million people live in rural areas . The arcIn 2009, the Rwanda Population Health Implementation and Training (PHIT) Partnership was established with the support of the Doris Duke Charitable Foundation’s African Health Initiative. The PHIT Partnership designed a multidimensional and integrated district-level HSS intervention that aligned with Rwanda’s 2009 National Health Sector Strategic Plan and the WHO Health Systems Framework. The partnership endeavors to improve the capacity and performance of the health system in southern Kayonza and Kirehe districts with targeted financial and technical investments focused on the health centers, coupled with quality improvement (QI) initiatives designed to improve both service delivery and strengthen monitoring and evaluation (M&E) systems. We hypothesize that the intervention will result in demonstrable improvements in population health, exceeding the already considerable health gains being made nationally.The PHIT Partnership aspires to create a replicable, evidence-based road map for district-level primary health care delivery in rural Africa and to disseminate lessons learned within and beyond Rwanda’s borders. Accordingly, the partnership has developed an integrated model of implementation, operational research, and impact evaluation to facilitate refinement and rigorous evaluation of the intervention.The PHIT Partnership is a public-private-academic collaboration comprised of six institutions. The Rwandan MOH and PIH lead the implementation and jointly fund the health system in the intervention area. The Ministry of Health sets national health policies and oversees the health management information system (HMIS) and planned national data warehouse, which provide data for both routine M&E and the impact evaluation. Harvard Medical School (HMS) and staff from Brigham and Women’s Hospital (BWH) faculty support evaluation activities, as well as capacity building for M&E and research components of the partnership. The National University of Rwanda School of Public Health (NUR-SPH) takes part in the evaluation team and leads the research capacity building program. Finally, the National Institute of Statistics of Rwanda (NISR) coordinates and implements the demographic and health surveys (DHS) and other key data collection activities, including the national census and the economic living conditions survey used for the impact evaluation.comprehensive, as enshrined in the 1978 conference on International Primary Health Care in Almaty, Kazakhstan, through the Alma Ata Declaration [integrated interventions that apply a “systems thinking” approach deliver more value than isolated vertical interventions [locally responsive, reflecting the engagement of local government leaders, civil society, and the community. Fourth, sustainability of a public health approach can only be achieved with efforts to strengthen institutions. Fifth, health systems should place a premium on equity by addressing issues of access, quality, and cost.The Rwanda PHIT Partnership is guided by five key principles that we believe are essential elements of successful HSS interventions. First, health systems interventions should be laration . Second,ventions . Third, 2 in the Eastern Province of Rwanda . Under-5 mortality remained higher in the intervention area than other rural areas (125.5 vs. 107.9) [Although the two intervention districts are poor, with only 4.4% of households having electricity and the majority of households relying on wood as the main cooking fuel, 78.8% of women and 90.7% of men were employed, predominantly in the agricultural sector . Within The Rwanda PHIT intervention employs a district-based HSS approach aimed at improving the coordination and quality of care at the health facility and community levels. The intervention aligns Rwanda’s National Health Sector Strategic Plan priority areas with the WHO Health Systems Framework  and enhaWithout adequate infrastructure — equipment, staffing, financial resources, procurement and information systems, ambulance network, and management capacity — process interventions designed to improve service delivery at health facilities are likely to fail. Therefore, we designed this intervention component to promote a flexible, evidence-based approach to improve health system readiness.The approach utilizes a health facility survey, which measures capacity in 11 key domains essential to the delivery of quality and effective services: infrastructure, medical equipment, human resources, clinical services, social services, monitoring and evaluation systems, laboratory, pharmacy, infection control, management, and referral systems Table . FollowiThe PHIT intervention emphasizes the improvement of service quality through two main pathways: the Mentorship and Enhanced Supervision of Health Centers (MESH) program and support for M&E systems, focusing on ensuring effective routine monitoring and improved data quality and utilization.Rwandan health centers are staffed almost exclusively by nurses, who typically receive didactic training and intermittent supervision from district hospital-based physicians and district health officials. The MESH program aims to improve service quality by enhancing the supervision and training of health center nurses while also addressing system-level gaps in quality . MESH isMESH assures an adequate knowledge base through didactic training in key content areas and complements this training with ongoing mentorship and supportive supervision. This is achieved through reinforcement of the existing MOH system of health center supervision: increasing the number of available staff dedicated to supervision, improving the technical skills of staff, providing staff tools for clinical and programmatic mentorship, and ensuring more supervision time per health center. Mentors with the MESH program visit each health center for two days every six weeks, conducting structured observation of nurse-delivered care, providing case-based teaching, and working with the health center leadership to identify and address system and quality gaps using continuous QI techniques. Quality of care is assessed through direct observation of patient consultations based on a checklist developed according to national protocols and making use of validated instruments where possible, as in the case of IMCI [An integrated system of ongoing routine monitoring and targeted evaluation is designed to support the quality of services, systems, and governance. The M&E system prioritizes use of routinely collected national data supplemented by targeted additional data collection activities implemented as part of the PHIT Partnership on a set of key indicators that measure inputs, processes, outcomes, and selected impacts. These indicators include use of clinical areas at health facilities, facility readiness as documented by a rapid facility assessment, stockout of tracer drugs, and quality of care as observed by trained mentors.The routine use of high quality data is vital for guiding decisions by facility managers and the intervention team. District hospital M&E staff are supported by a PHIT M&E intervention team during monthly health center visits for data quality assessments and interventions to address identified gaps. The system is designed to ensure that data are fed back to decision makers to facilitate evidence-based decisions. MOH staff are trained to use routinely collected data to determine health priorities, identify gaps for improvement, monitor health trends, evaluate programs, and identify areas for replication and dissemination.A cornerstone of the Rwanda PHIT Partnership is the strengthening of the community health system based on a network of multidisciplinary CHWs. The emphasis on a strong network of CHWs reflects the Rwandan government’s recognition of the importance of decentralizing health care delivery to the community level as a means of encouraging communities to take responsibility for their own health, as well as promoting prevention activities, early detection of illness, and increased utilization of health services. The PHIT Partnership targets three major areas of the community health system: a strong supervision system to ensure CHW quality of care and reporting; implementation of a household register to improve quality through systematic documentation of household visit activities; and the expansion of home-based care provided for chronic disease patients, including those with HIV.Under the national system, CHWs conduct monthly home visits to households in their village, providing health education, screening for specific diseases, encouraging health center visits, and monitoring child growth and development. During household visits and through routine community sensitization events, CHWs educate communities on key health messages, including hygiene and sanitation, accessing care at facilities, malaria prevention, and general health.For logistical reasons, additional support to the community health worker network is being conducted in only one of the two intervention districts: southern Kayonza. CHWs in the intervention district receive ongoing training and supervision focused on primary health care, reproductive health, family planning, and malnutrition. During routine household visits, the CHWs receive regular supervision visits in which they are given feedback on quality of care delivered and on the quality of the data recorded during the visit. In each health center catchment area, CHWs belong to a cooperative that receives modest performance-based financial incentives.The timeline of implementation and evaluation activities is presented in Figure By the end of the project’s second year (June 2011), all components of the PHIT intervention were successfully implemented. All 21 health centers and two district hospitals in the intervention area were adequately resourced, and the three core quality initiatives — the MESH program, joint M&E and data quality initiatives, and enhanced community health delivery — were operational. Based on early operational evidence of success, several intervention components are being evaluated by the Ministry of Health for potential integration into the national framework.Key implementation challenges and subsequent adaptations are outlined in Table The PHIT implementation program is complemented by a systematic evaluation designed to 1) measure the population health impact of the district-based health systems strengthening intervention; 2) assess the total cost per capita of the health system in the intervention area; 3) study the efficacy of component interventions, including targeted instrumental support to health facilities, the MESH quality improvement program, strengthening of M&E and data quality systems, and the enhanced community health program; and 4) conduct operational research on the implementation of the program  level for monitoring and evaluation activities .In both the baseline and final survey, we oversample our intervention area using national DHS methodology  to colleThe DHS data will also provide information on changes within the districts on other key indicators of population health, including stunting, wasting, and total fertility rate. The data are also the source for information on health access indicators: contraceptive prevalence, unmet need for family planning, antenatal care utilization, treatment of childhood illness, and immunization coverage.Analysis of routinely collected HMIS data will complement the DHS analysis in two ways. First, comparison of key indicators assessed through DHS and HMIS may mitigate the potential heterogeneity of DHS data when used for sub-national analysis . Second,Data from the community health center and district hospital levels are aggregated and submitted monthly by districts to a national HMIS database. We will analyze trends in service delivery and coverage at facility and community levels, comparing key HMIS-derived indicators before, during, and after the start of the intervention. HMIS data will also be used to measure trends in service volume and selected process indicators not captured in DHS, comparing intervention area facilities with those in the rural control area.The MOH has initiated a national program of routine verbal autopsy (VA) for all maternal and child deaths and is currently implementing this approach nationally, including in the intervention area. The PHIT intervention supports this effort by developing and implementing trainings in VA, and by introducing innovative methods for analyses of VA data. VA will allow for more precise analysis of trends in under-5 deaths and gain a better understanding of under-5 mortality data, which may have important programming implications.In order to control for potential external confounders, we are assessing exogenous factors expected to have an impact on population health and selected service delivery indicators. We are working with the relevant ministries to develop a database to track such catastrophic events as epidemics and humanitarian crises. Other relevant contextual factors will include sanitation, equity, women’s education, and HIV prevalence, all of which are available through the DHS. These exogenous factors will be included as potential confounders in our regression modeling of district level health outcomes.The main purpose of the economic analysis is to understand how the PHIT program contributes to local health system financing. The evaluation measures 1) the costs per capita of PHIT investment in each of the six WHO health system building blocks; 2) total cost per capita of the health system in the two intervention districts; 3) health facility spending by WHO building block; and 4) financial contributions to the local health system made by government, the PHIT Partnership, other partners, and patients. We have designed survey instruments for each facility type to measure funding sources, facility expenditure, and existing capital. Cost data have been collected for the baseline year (2010) and the surveys will be repeated annually through 2014.We will conduct trend analyses in key variables over time, including the level and trends of total health system and PHIT spending per capita in the two districts; percentage of total health expenditures contributed by PHIT, government investment, and other sources; and the level and trends of expenditure on each of the six WHO building blocks by funding source. We will use regression analysis to evaluate the impact of PHIT spending on health care provision using the provision of child health services as the outcome variable.Operational evaluations will focus on key components of the PHIT intervention — targeted instrumental support to health facility building blocks, quality improvement through the MESH program and strengthened M&E systems, and enhancements to the community health system. These evaluations will serve two purposes: use of the data for modification and improvement of the interventions throughout the implementation period and exploration of the relative contributions of each component intervention on health outcomes to inform replication and scale-up of the Rwanda PHIT intervention.As described above, a standardized health facility survey has been developed and administered before the initiation of the health center instrumental support, with plans to re-administer quarterly. Changes in domain scores and overall facility scores will be tracked and compared over time. Differences in achieving fully capacitated and high-quality systems across the sites will be explored to identify factors associated with more robust or rapid success and to identify areas where the strategy has been less effective. Multivariate models will adjust for potential confounders including site size, duration of PIH support, and remoteness of health facilities.The evaluation of the MESH program will measure the change in quality of care delivered at the health center level. The main evaluation focuses on quality of child health care delivered by MESH-supported nurses and the primary outcome is the integrated management of childhood illness (IMCI) integrated assessment index, derived from a checklist of protocol-defined assessment tasks that should be performed for all children . SecondaBecause the validity of analyses using routinely reported data depends on the quality of the data collected, we are studying the reliability of CHW data using Lot Quality Assurance Sampling (LQAS). LQAS allows for rapid classification of CHW reports as having high or low quality, defined as concordance between reports aggregated at the health center level and the original registries. This approach will provide a rapid and inexpensive methodology to target data quality improvement efforts and measure their impact .We will also measure changes in data quality of standard health facility reports. Work is ongoing to further develop mixed method evaluation of change in capacity for data interpretation, utilization of resources to address identified gaps, self-reported knowledge in data management, and interpretation.Using routinely collected data from monthly community HMIS reports, we will assess health indicators from intervention area sectors compared to other rural sectors. In a second approach, we will leverage an ongoing World Bank-sponsored study that randomized 200 community health cooperatives  to one of four different incentive models by applying its results to our interventions. We will, thus, pool data from the intervention area cooperatives and compare them to the non-PHIT cooperatives adjusting for the intervention arm assigned.In order to address a critical skills gap in Rwanda, an operational research capacity building effort has been embedded within the PHIT evaluation plan. Led by National University of Rwanda School of Public Health and Harvard Medical School, we launched an MPhil and PhD research training program, known as Rwanda PHIT Scholars, for 10 Rwandan health professionals involved in the PHIT Partnership. Candidates underwent a competitive selection process that involved the development of operational research proposals to complement the PHIT impact evaluation and intervention component evaluations. Each student has been assigned an advisory team, including a NUR-SPH advisor, an HMS faculty advisor, and a PHIT Rwanda site supervisor.Among the student-led operational projects are assessments of family planning uptake, performance of the electronic medical record (EMR) currently under development by the PHIT Partnership, the impact of Rwanda’s e-health architecture, the impact of HIV care delivery on maternal and child health services, the impact of the PHIT intervention on childhood nutritional status and health facility staff retention, and ethnographic assessment of family planning utilization.In the context of global efforts to achieve the health-related Millennium Development Goals, there is a strong and growing consensus that evidence-based interventions are needed to create “robust, responsive, and efficient health systems” . We belicomprehensive. Much as vertical, or disease-specific, interventions may paradoxically weaken primary health systems [Health systems strengthening interventions should be  systems , narrowlintegrated, adopting a “systems thinking” approach [Second, HSS interventions should be approach . Such anlocally responsive; that is, guided by both national priorities and the needs of an engaged community. The WHO Health Systems Framework acknowledges that health systems are highly context-specific and that systems strengthening interventions need to be developed accordingly [Third, HSS interventions should be ordingly . Emphasistrengthen institutions. Dr. Julio Frenk, Dean of the Harvard Medical School, highlights the importance of cultivating strong ministries of health, which can only be accomplished through long-term investment in the public sector [Fourth, in order to create sustained value, HSS interventions must c sector . Our intaccess, quality, and cost issues. Universal access to health services is both an equity issue and a sound public health principle. In Rwanda, efforts to provide universal community-based health insurance — an initiative supported by the PHIT Partnership —are already bearing fruit [Fifth, HSS interventions should address ng fruit . This fiWhile basic health infrastructure and systems inputs may be a prerequisite for quality improvement efforts, there is growing recognition that QI is a key to improved efficiency and health outcomes in global health systems ,28. The Given the financial constraints experienced by both developing country governments and external funders in a global economic downturn, the importance of smart resource allocation and value creation — defined as health outcomes per dollar spent — is difficult to overstate . The RwaThere is a critical need to promote health systems impact assessments to generate a stronger evidence base on what works in resource-constrained health systems . Only anBWH: Brigham and Women’s Hospital; DHS: Demographic health survey; EMR: Electronic medical record; HMIS: Health management information system; HSS: Health systems strengthening; HSSP-II: Health Sector Strategic Plan; IMAI: Integrated management of adult illness; IMCI: Integrated management of childhood illness; LQAS: Lot quality assurance sampling; M&E: Monitoring and evaluation; MESH: Mentorship and Enhanced Supervision of Health Centers; MOH: Ministry of Health; NISR: National Institute of Statistics of Rwanda; NUR-SPH: National University of Rwanda-School of Public Health; PHIT: Population Health Implementation and Training; PIH: Partners In Health; QI: Quality improvement; VA: Verbal autopsy; WHO: World Health Organization.The authors declare that they have no competing interests.All authors have made substantial contributions to conception and design, have been involved in drafting the manuscript or revising it critically for important intellectual content, and have given final approval of the version to be published.


Background: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses.Objective: We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization.Methods: We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by the RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from international authorities.a) the implications of the PWG findings, particularly lymphoma diagnostic issues; b) differences between RI studies and those from other laboratories that are relevant to evaluating RI cancer bioassays; and c) future work that may help resolve some concerns.Discussion: Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not find close agreement for lymphoma/leukemia of the respiratory tract or for neoplasms of the inner ear and cranium. Here we discuss a) issues related to respiratory tract infections have complicated diagnoses at that site , as well as for neoplasms of the inner ear and cranium, and b) there is consistency and value in RI studies for identification of other chemical-related neoplasia.Conclusions: We concluded that http://dx.doi.org/10.1289/ehp.1306661Citation: Gift JS, Caldwell JC, Jinot J, Evans MV, Cote I, Vandenberg JJ. 2013. Scientific considerations for evaluating cancer bioassays conducted by the Ramazzini Institute. Environ Health Perspect 121:1253–1263;  The Ramazzini Institute (RI) is an independent nonprofit organization that has been conducting lifetime cancer bioassays in rodents since 1970. As stated by Use of animal species and strains whose basic tumorigram and kind of response to cancer stimuli is not too remote from the human counterpart …Continuing bioassays until the end of the life of an animal …Following the rules of Good Laboratory Practice as a minimum standard in experiment management …Choosing precise parameters to assess neoplastic response …Standardizing the experimental conditions for conducting experiments, parameter assessment, and data presentation.Perceived problems in RI studies have been central in European Food Safety Authority (EFSA) reviews , 2009 ofa) recent U.S. Environmental Protection Agency (EPA) and NTP efforts to investigate the issues raised by the EFSA and others related to RI chronic bioassays; b) relevant considerations for evaluating RI cancer bioassays that take into account the unique aspects of the RI study design and protocols in the context of existing international risk assessment guidelines; and c) methods and approaches that may assist in the future conduct and review of RI chronic bioassays.In this review we summarize Pathology Working Group (PWG) review. In April 2010, pathologists and technicians representing the NTP visited the RI in Bentivoglio, Italy, and conducted a preliminary review of RI pathology procedures and lymphoma/leukemia diagnoses from the RI methanol study (tertiary-butyl ether (MTBE), ethyl tertiary-butyl ether (ETBE), vinyl chloride, and acrylonitrile. A summary of the PWG results  who provided a more complete diagnosis and comparison of all lesions that were initially diagnosed by RI pathologists. A subset of slides of interest for each chemical was then selected for a PWG panel review. The most thorough reviews were for methanol  and MTBHowever, a consistent feature of the 2010 preliminary review of the RI methanol study  and the The accuracy of diagnoses of pathological lesions can be affected by autolysis of tissue cells and the fixation process used to prepare pathology slides . However, the full pathology reports for the RI methanol and MTBE studies noted that the histological quality of the sections was good and that “neither the occasional cases with tissue autolysis nor the use of alcohol fixation presented diagnostic difficulties” , 2011c.The consistency of diagnoses of lymphoma/leukemias could also have been affected by differing categorization schemes used by RI, QA, and PWG pathologists. Lymphomas encompass a spectrum of histological types, and many schemes have been developed to describe them . UpdatesRI diagnoses of neoplasms as lymphocytic, histiocytic, monocytic, and/or myeloid in origin were generally confirmed in a preliminary NTP pathology review of RI aspartame slides, but the RI’s practice of combining myeloid leukemias and histiocytic sarcomas with malignant lymphomas was not accepted because these neoplasms are considered to be of different cellular origins . The U.SDifferences in protocols used by the RI and the reviewing groups may also have affected diagnostic consistency. Both the 2010 preliminary  and 2011RI findings relative to other laboratories. in utero.” Thus, tert-amyl methyl-ether (TAME), toluene, and vinylidene chloride]. The findings of RI and non-RI cancer bioassays for these 10 lymphoma/leukemia–positive RI chemicals are summarized in Table 3. Only the RI performed cancer bioassays for DIPE, mancozeb, and TAME. For the 7 chemicals studied by both RI and non-RI laboratories, 3  have been reported to be positive for lymphomas/leukemias in non-RI laboratories. These findings include a) marginal increases in leukemias in female rats exposed to chlorinated drinking water (b) positive findings in Eppley Swiss Webster mice exposed to methanol (c) an increase in mononuclear cell leukemia in rats co-exposed to MTBE and gasoline, but not gasoline alone .In support of a chemical relationship for increased incidence of lymphoma/leukemia, Further, a simplistic examination of tumor-site concordance using differing study designs may not capture mechanistic concordance and susceptibility differences that can indicate carcinogenic potential. Other tumor types have been observed in non-RI studies for methanol [lung tumors and pheochromocytomas in rats ], formalThe diagnosis of increased lymphomas/leukemias in a minority of RI studies (~ 5%) and the consistency of diagnoses between RI and non-RI studies for some chemicals  suggest that a regular misassociation of the end point and chemical exposures has not occurred in RI studies. However, the general lack of evidence of treatment-related increases of lymphomas/leukemias reported in non-RI studies for 7 of the 10 chemicals listed in Table 3 indicates that risk assessors should carefully consider all possible explanations for the lack of tumor-site concordance, including differences in study design and laboratory protocols.Guidance and study design criteria. To identify the most relevant considerations for evaluations of RI cancer bioassay design and protocols, we reviewed existing international guidelines from a number of sources. Bioassay design issues have been discussed in guidelines by the NTP  use of sensitive animal models for end points under investigation; b) detailed characterization of the agent and administered doses; c) challenging doses and durations of exposure and observation; d) sufficient numbers of animals per dose group; e) multiple dose groups for characterization of dose–response relationships; f ) complete and peer-reviewed histopathological evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted incidence. These considerations are also cross-referenced in the guidelines cited above.Keeping in mind current standards as well as those contemporaneous with the study, the U.S. EPA carcinogenic risk guidelines  encouragAnimal models that are sensitive for end points under investigation. In the early 1970s, the RI and the National Cancer Institute (NCI) used Sprague-Dawley rats in their cancer bioassays; by the late 1970s, the NCI  switched to Fischer 344/N (F344N) rats. The RI did not switch strains, and the FDA still primarily uses the Sprague-Dawley strain to assess the effects and safety of drugs and additives . In 2009The historical databases for RI and NTP studies reflect differences in rat strain sensitivity and ability to detect certain types of cancer  . Such diCancers in laboratory animals and humans do not always occur in analogous or the same target/system; for example, rodent Zymbal gland tumors were the first and most consistent benzene-induced cancer response observed, but humans do not possess Zymbal glands. Such rodent cancer findings should not be dismissed given that growth-control mechanisms at the cellular level are generally homologous among mammals . CoherenWith regard to lymphoma/leukemia diagnoses, the types of chemically induced lymphomas reported in RI studies have also been observed in older untreated Sprague-Dawley rats in the RI colony . Howeverp < 0.001). The fraction of RI control groups  with a lymphoma/leukemia rate > 10% has increased from 3 of 43 in 1988–1989 studies to 18 of 22 in 2002–2006 studies. Possible explanations for this increase include genetic drift associated with inbreeding of the colony and a more active immune system in the non–pathogen-free RI rats. For example, successive inbreeding of Sprague-Dawley rats with chromosome 11 abnormalities has resulted in increased background levels of lymphoblastic lymphoma/leukemias in a Prague colony  rate of these tumors in RI Sprague-Dawley rats has been reported to be higher than in Sprague-Dawley rats from other sources . Using te colony . In genee colony .Detailed characterization of the agent and administered doses. Guidelines developed by regulatory agencies such as the the U.S. EPA  provide a) the MTD, b) a dose within an order of magnitude of human exposure levels, and c) an intermediate level  maximizes the number of control and treated animals available at the same age for comparisons of pathology, and b) minimizes late-developing background tumors that may limit the ability to detect chemical-induced effects  has been raised, because the RI does not always randomize the assignment of animals to treatment groups but often “assigns litters to the same dose group and uses all animals, while keeping track of litter identification information” . HoweverMultiple dose groups for characterization of dose–response relationships. Estimation of the dose–response relationship is a primary aim of carcinogen risk assessment. In general, confidence in dose–response analyses is increased for studies with additional dose groups, particularly when at least two dose levels have response rates above background . U.S. EPComplete and peer-reviewed histopathological evaluations. Organ system evaluations have been well described for U.S. EPA and FDA testing requirements  and for The recent PWG review of RI studies  represenFor any peer review of histopathological diagnoses, tissue preservation and condition can be a limiting factor. Studies conducted by or for the NTP involve removal of moribund animals to avoid autolytic tissue destruction and to prevent tissue loss through cannibalism . AlthougPairwise comparisons and analyses of trends based on survival-adjusted incidence. Existing cancer guidelines recommend trend tests and pairwise comparison tests for determining whether chance, rather than a treatment-related effect, is a plausible explanation for an apparent increase in tumor incidence . In caseFor a study with excessive premature death of animals from incidental or chemical-related causes other than tumors at the organ site of interest, animals that died early may not have been alive long enough to contribute a sufficient time at risk to that study . SimilarNTP reports typically contain appropriate statistical analyses, including survival-adjusted tumor rates and trend analyses. Recent RI reports also included pairwise comparison and trend tests, and sometimes survival-adjusted analyses , but earT), with the result that even some animals living ≥ 2 years could contribute relatively little weight to the incidence denominator representing the animals at risk; this approach may yield erroneous findings  tumors for which traditional survival analysis methods may not be valid. The poly-3 adjustment technique used by the NTP for survival-adjustment of 2-year bioassay data  is generfindings . A reweiominator  would beGLP. Studies conducted under GLP provide highly detailed protocols, strictly monitor animal health, and extensively document both measurable and observational results  , whereasMicrodissection techniques have been developed to select single cells or groups of cells from a heterogeneous tissue sample for molecular analyses. Laser capture microdissection (LCM) uses low-energy infrared laser pulses to selectively adhere visually targeted cells and tissue fragments to a thermoplastic membrane. This technique has been used to distinguish noncancer and cancer tissues and has been an important tool in lymphoma research of human tissues . The majAfter investigating the issues identified by the EFSA and others, we conclude that RI bioassay results for cancer end points other than respiratory tract lymphoma/leukemia and inner ear and cranium neoplasms are generally consistent with those of the NTP and other laboratories. Concerns regarding a possible link between respiratory infections and the development of lymphomas have been considered . HoweverIn regard to the evaluation of RI cancer bioassays, we have identified several considerations to support interpretation of RI results (summarized in Table 4) that take into account the unique aspects of RI study design within the context of relevant international guidelines. We have also suggested approaches that may assist in the future conduct and review of RI chronic bioassays. Although the PCR and microdissection assays discussed here have the potential to help resolve some of these concerns for past RI studies, the future resolution of these diagnostic issues will be influenced by the ability of the RI to maintain its GLP certification and adhere to OECD guidelines regarding the monitoring and control of infectious agents, including regular serological testing, and diligent sacrifices of moribund test animals.The protocols characteristic of RI studies can cause interpretive challenges, but aspects of the RI design, including gestational exposure, life span observation, and larger numbers of animals and dose groups, may impart advantages that provide chemical risk assessors with valuable insights for the identification of chemical-related neoplasia not obtained from other bioassays. We conclude that RI studies may be informative for health risk assessment when reviewed on a case-by-case basis, with consideration given to the unique aspects and issues discussed here that can impact RI bioassay results and interpretations.(344 KB) PDFClick here for additional data file.


The ‘Recalcitrant Cancer Research Act of 2012’ defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. Cancers specifically mentioned in the act are lung and pancreatic cancers. In addition to recalcitrant tumors, rare tumors are often neglected in the drug discovery arena. Sarcomas are ~1% of cancers. The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are 3 SPOREs focused on pancreatic cancer, 7 SPOREs focused on lung cancer and 1 SPORE focused on sarcoma. Through the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The current effort is on sarcoma, SCLC and pancreatic lines. The DTP functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors. The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes. The DTP maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms. In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases. The cancer research community has witnessed and participated in the recent grassroots efforts of advocacy groups lobbying the US Congress, the nation’s most visible bully pulpit, to provide focused research efforts directed toward improving patient survival of some of the most deadly cancers. The ‘Recalcitrant Cancer Research Act of 2012’ defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. The cancers specifically mentioned in the act are lung and pancreatic cancers. Pancreatic cancer is the 5th leading cause of cancer death in the US. Over 33,000 newly diagnosed cases and the same number of deaths are expected in the US each year with a 5-year survival rate of 5%. The American Cancer Society estimated that there were 221,130 new cases of lung and bronchus cancer and 156,060 deaths in the year 2011. The most aggressive type of lung cancer is the small cell lung carcinoma. Approximately 31,000 new cases of small cell lung carcinoma were diagnosed in the US in 2011  frequently recurs after conventional cytotoxic chemotherapy. SCLC is a neuroendocrine subtype of lung cancer and affects >200,000 people worldwide every year. In the US, SCLC represents 13–15% of all lung cancer cases and is the most aggressive form of lung cancer with nearly as many deaths as diagnoses per year. Although initially a chemotherapy and radiation-sensitive disease, SCLC recurs rapidly . Althougsurvival . The aposurvival ,17. SCLCsurvival .Sarcoma includes widely varied tumors now divided into types and subtypes. Sarcoma occur in patients of all ages with frequency spread evenly over the human age range. Sarcomas represent a heterogeneous group of cancers from soft tissue (muscles and fat tissue), bone, cartilage, peripheral nerve sheets, or from other connective tissues. Many of these tumors affect children and young adults accounting for 15% of all pediatric cancers. The incidence for individual sarcoma types is rather low and all combined amount to ~13,000 new cases per year . Bone anhttp://trp.cancer.gov/). In addition, a component of NCI Developmental Therapeutics Program’s mission is to improve the treatment of recalcitrant, rare and neglected cancers through the discovery of potential therapeutic targets, the screening of new agents, the identification of genomic and epigenetic vulnerabilities, and the identification of potential therapeutic combinations using state-of-the-art drug discovery, molecular characterization, and mechanism-of-action techniques and through interactions collaboration with the cancer research community and other NCI laboratories. To achieve these goals, the NCI operates the classic NCI60 cell line screen, a target validation and screening laboratory, a functional genomics laboratory, a tumor microenvironment laboratory, a drug mechanism group, a cell characterization laboratory and a translational support laboratory. This effort is currently focused on sarcoma, small cell lung cancer and pancreatic cancer, and has collections of 70–80 human sarcoma cell lines, 70–80 human small cell lung cancer cell lines and 21 human pancreatic cancer cell lines.The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are currently 3 SPOREs focused on pancreatic cancer and 7 SPOREs focused on lung cancer. The first and only sarcoma SPORE so far was awarded in 2010  gene/exon expression; ii) microRNA expression; iii) mutations; iv) subpopulations; v) response to standard and investigational anticancer agents; vi) protein expression and activated pathways; and vii) cell surface and intracellular markers. These data will be offered as a resource to the cancer research community. The panels and the characterization data will be used to identify targets and target combinations from which to generate new drug discovery endeavors at NCI and in the cancer research community. Currently, the sarcoma and SCLC lines are being screened in 9-point concentration response in triplicate to all of the FDA approved anticancer agents and to ~400 investigational agents, characterized genetically by exon array and microRNA array, characterized for cell surface protein expression and assessed for metabolic alterations. The drug discovery process is agnostic with respect to therapeutic approach using the best therapeutic strategy, small molecule or protein to approach each target.New therapeutic approaches are needed to improve long-term survival in these diseases. The challenge of sarcoma is that it is 50–100 unique diseases, each with relatively small patient populations. Growing many types of sarcoma as xenografts has been difficult making NCI’s widely recognized classic 60-cell line screen has nine cancers, including leukemia, melanoma, non-small cell lung, colon, brain, ovary, breast, prostate and kidney –23. ThesThrough the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The screening laboratory is equipped with extensive robotics, high content imaging, an Octet system for label-free quantitation of molecular  interactions, and maintains human sarcoma, SCLC and pancreatic cancer-focused cell line banks. This laboratory also has a BD FACSAria III flow cytometer, which is used to identify and map cell surface and intracellular markers and targets as well as to sort cell subpopulations. The current effort is to identify targets and characterize subpopulations within the sarcoma, SCLC and pancreatic lines. The FACSAriaIII is also used to assess response of cells to varied alterations in genes and response to exposure to varied chemical entities. The screening laboratory is a central focus for initiating projects and is the hub for carrying out screens with a goal to identify potential drug targets and unexpected sensitivities and to design screens to identify starting chemical matter for medicinal chemistry campaigns. A fragment library has been added to the compound screening sets to facilitate fragment-based drug design.The Developmental Therapeutics Program functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, RNA interference, methylation assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors –29. ThesThe Developmental Therapeutics Program tumor microenvironment laboratory focuses on the discovery of targets and development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes –38. This18/O16), 2D-PAGE, multiple reaction monitoring (MRM), and drug conjugate (e.g. GSH) and metabolite analysis. Compounds prioritized by the DTP Biologic Evaluation Committee and compounds from the DCTD NExT Discovery Projects are assessed in experiments directed toward identifying molecular target(s) and mechanism(s) of action.The Developmental Therapeutics Program maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms –47. The et al, unpublished data). In collaboration with the biological testing group, >2000 xenograft tissues collected were processed by snap-freezing, formalin-fixing and isolation of RNA and DNA in a study to provide a resource to the cancer research community. This laboratory conducts detailed combination studies in cell lines.The Developmental Therapeutics Program translational science laboratory contributes broadly to collaborative projects. For example, detailed cell-based studies including experiments with endothelial cells to assess antiangiogenic potential, cancer cell and normal cells to assess potential for therapeutic benefit that contribute to the evaluation of varied natural product and synthetic compounds are performed regularly (48–51; Hollingshead In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases.


In patients with co-morbid obsessive–compulsive disorder (OCD) and posttraumatic stress disorder (PTSD), repetitive behavior patterns, rituals, and compulsions may ward off anxiety and often function as a coping strategy to control reminders of traumatic events. Therefore, addressing the traumatic event may be crucial for successful treatment of these symptoms.In this case report, we describe a patient with comorbid OCD and PTSD who underwent pharmacotherapy and psychotherapy.Case Report. A 49-year-old Dutch man was treated for severe PTSD and moderately severe OCD resulting from anal rape in his youth by an unknown adult man.The patient was treated with paroxetine (60 mg), followed by nine psychotherapy sessions in which eye movement desensitization and reprocessing (EMDR) and exposure and response prevention (ERP) techniques were applied. During psychotherapy, remission of the PTSD symptoms preceded remission of the OCD symptoms.This study supports the idea of a functional connection between PTSD and OCD. Successfully processing the trauma results in diminished anxiety associated with trauma reminders and subsequently decreases the need for obsessive–compulsive symptoms. The psychopathology of obsessive–compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) shares the need for control as a core theme. OCD patients are obsessed with absolute certainty and try to control their anxiety provoking thoughts with repeated acts or rituals. PTSD patients try to regain control after experiencing an uncontrollable event by avoiding triggers of the event  treatment and pharmacotherapy.Albert, a 49-year-old Dutch man who lives with his male partner, was referred to our department by his company doctor after 6 months of sickness absence from his work as a teacher. At intake, he met DSM-IV criteria for PTSD and OCD with daily trauma recollections, obsessions, and compulsions of cleaning and ordering for many hours a day. The trauma took place at the age of 14 when a 32-year-old man raped Albert. The PTSD symptoms started at the age of 21, when he first discussed what had happened with his partner. His OCD symptoms started at the age of 34, when he told a therapist about the trauma. Trauma recollections then evoked thoughts in his mind about feeling “dirty” (including his own body and surroundings). He tried to get rid of them by repeatedly showering, cleaning, exercising, and meticulously arranging things in his house.After intake, paroxetine was started and increased to 60 mg, which improved his sleep and made him feel less anxious, though the diagnoses of PTSD and OCD remained. After 3 months, Albert received Eye Movement Desensitization and Reprocessing (EMDR) therapy in a randomized clinical trial (Nijdam, Gersons, Reitsma, de Jongh, & Olff, Albert's symptom course was closely monitored by means of widely used, reliable and valid instruments, as displayed in This case report demonstrates a successful treatment of comorbid OCD and PTSD, which hitherto has not been described in literature. We report on an outpatient with moderately severe OCD and severe PTSD, whose obsessive–compulsive symptoms commenced after revealing a sexual assault and were maintained by recollections of the trauma. The OCD and PTSD symptoms disappeared completely following a combined treatment with paroxetine and nine sessions of EMDR and ERP.Our treatment strategy was based on the hypothesis that OCD symptoms serve as a strategy to cope with reminders of the trauma, which has been put forward by previous studies (Gershuny et al., To sum up, the current study supports the idea of a functional relationship between PTSD and OCD and suggests that trauma-focused psychotherapy may be useful in cases of concurrent PTSD and OCD originating from a traumatic event. By successfully processing the trauma, anxiety to trauma reminders decreases which may facilitate ERP treatment for OCD. This can lead to a shortened treatment trajectory and possibly an improved long-term treatment outcome. The findings are too preliminary to support widespread dissemination. Therefore, further research is encouraged to confirm these findings.


Increasing drug resistance among many infections of public health importance has created an urgent need for new and effective antimicrobial agents. However, existing economic incentives for research and development appear to be insufficient to meet the anticipated need for new antimicrobial drugs. U.S. Food and Drug Administration approval of new antibacterial agents has decreased by 56% in the past 20 years (1998–2002 vs. 1983–1987), and only 6 of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies are new antibacterial agents -plus pilot projects in low- and middle-income countries, projects that modify typical DOTS strategy in light of issues (such as the use of second-line drugs) specific to areas with a high prevalence of multidrug-resistant tuberculosis.The Medicines for Malaria Venture manages a portfolio of projects that are conducted by academic and pharmaceutical partners. Criteria for products to treat uncomplicated malaria include efficacy against drug-resistant strains, cure within 3 days, low propensity to generate rapid resistance, safety in children <6 years old and pregnant women, appropriate formulations and packaging, and low cost.The Accelerating Access Initiative, a joint project of UNAIDS, other international organizations, and several HIV-drug–producing pharmaceutical companies, has developed what it calls a common approach to accelerating access to HIV/AIDS care and treatment in developing countries. The approach calls for political will and commitment of governments; strengthened national healthcare capacity; safe, secure, and efficient distribution systems; involvement of all sectors of society; substantial additional funding from national and international sources; and continued investment in research and development by the pharmaceutical industry.


Both autism spectrum conditions (ASCs) and schizophrenia spectrum conditions (SSCs) involve altered or impaired social and communicative functioning, but whether these shared features indicate overlapping or different etiological factors is unknown. We outline three hypotheses  for the possible relationship between ASCs and SSCs, and compare their predictions for the expected relationships between autistic and schizotypal phenotypes using the Autism Spectrum Quotient and the Schizotypal Personality Questionnaire-Brief Revised from a large non-clinical sample of undergraduate students. Consistent with previous research, autistic features were positively associated with several schizotypal features, with the most overlap occurring between interpersonal schizotypy and autistic social and communication phenotypes. The first component of a principal components analysis (PCA) of subscale scores reflected these positive correlations, and suggested the presence of an axis (PC1) representing general social interest and aptitude. By contrast, the second principal component (PC2) exhibited a pattern of positive and negative loadings indicative of an axis from autism to positive schizotypy, such that positive schizotypal features loaded in the opposite direction to core autistic features. These overall PCA patterns were replicated in a second data set from a Japanese population. To evaluate the validity of our interpretation of the PCA results, we measured handedness and mental rotation ability, as these are established correlates of SSCs and ASCs, respectively. PC2 scores were significantly associated with hand preference, such that increasingly ‘schizotypal’ scores predicted reduced strength of handedness, which is consistent with previous research. PC1 scores were positively related to performance on the mental rotation task, suggesting trade-offs between social skills and visual-spatial ability. These results provide novel evidence for an autism-positive schizotypy axis, and highlight the importance of recognizing that psychological variation involving reduced social interest and functioning may have diverse causes. The relationship between autism spectrum conditions (ASCs) and schizophrenia spectrum conditions (SSCs) has been subject to ongoing, unresolved investigation since Kanner Impairments in social reciprocity, communication, and behavioural flexibility are central features of the autism spectrum Since the delineation of autism from schizophrenia in the DSM-III In a non-clinical sample of college students, Hurst and colleagues Del Giudice and colleagues Using the same self-report measures as Hurst et al. In a related investigation, Wouters and Spek Using the AQ and the SPQ in a group of adolescents with and without ASCs, Barneveld and colleagues Russell-Smith et al. Wakabayashi et al. These previous studies provide empirical support for phenotypic overlap between ASCs and SSCs at the psychometric and behavioural levels in both clinical and non-clinical populations. Some studies have reported overlap of autistic features with manifestations of positive schizotypy In this study we used two of the primary measures of ASCs and SSCs, the Autism Spectrum Quotient and a revised version of the Schizotypy Personality Questionnaire-Brief, to evaluate hypotheses for the relationship between these sets of conditions. Given that various perceptual, cognitive, and affective alterations underlie the behavioural abnormalities expressed in ASCs and SSCs, we also measured two phenotypic correlates of autism and schizophrenia, mental rotation ability and strength of handedness, in order to provide validation of our interpretation of the questionnaire data analyses. First, previous research has demonstrated enhanced visual-spatial abilities, such as superior performance on mental rotation tasks, in individuals with autism and in individuals with autistic features Second, atypical patterns of cerebral asymmetry appear to play a role in schizophrenia etiology, and multiple studies have reported decreased cerebral lateralization, as indexed by a handedness preference leaning toward mixed and non-right handedness, in both schizotypy and schizophrenia Most studies comparing ASCs with SSCs using psychometric data have focussed on single, specific predictions, rather than testing a set of alternative hypotheses. Here, we use autism and schizotypy questionnaires in addition to data from mental rotation performance and handedness preference to evaluate three hypotheses for the relationship between the autism spectrum and the schizophrenia spectrum. This approach allows us to validate our interpretations of the relationship between autistic and schizotypal features in in order to build explicit models of how the two disorder spectra may be related to one another at both etiological and phenotypic levels.Firstly, observations of distinct developmental trajectories for autism and schizophrenia Secondly, shared phenotypes between autism and schizotypy could reflect overlapping etiologies; as also suggested by recent genetic evidence interpreted as indicating shared risk factors between autism and schizophrenia Thirdly, Crespi and Badcock We evaluated predictions from the independent, overlap and diametric models through (1) examining the bivariate correlations between subscales of the AQ and a revised version of Raine and Benishay’s Data was collected from 605 undergraduate students  at both University of Alberta and Simon Fraser University. As part of a larger collaborative project approved by Human Research Ethics at University of Alberta and by the Simon Fraser University Research Ethics Board, data was collected in single sessions held over the course of two semesters at each institution. All students gave written consent before participating in the study.social skills; 2) communication; 3) attention to detail; 4) attention switching; and 5) imagination. For the social skills and communication domains, either poor social skills and communication or the preference to be in non-social situations increases the participant’s score. Attention shifting tends to be less flexible in autism We used the Autism Spectrum Quotient (AQ) cognitive-perceptual schizotypy, interpersonal schizotypy, and disorganized schizotypy; these factors map onto the positive, negative, and disorganized dimensions of schizophrenia as described above magical thinking; unusual perceptions; and ideas of reference. For interpersonal (negative) schizotypy, the subscales include constricted affect and social anxiety. The disorganized factor includes eccentric behaviour and odd speech. This measure was chosen because it is brief, sensitive, and covers a broad range of schizotypal features.Schizotypy was assessed using the Schizotypal Personality Questionnaire-Brief Revised (SPQ-BR) We also gave subjects the Mental Rotation Test (MRT) a priori chose to use the correlation matrix rather than the covariance matrix in the PCA; therefore, the factor loadings are expected to be lower and more similar to one another compared to output using covariance matrix and additional rotations. All analyses were performed in R.Data from Wakabayashi et al. Data were analyzed from 605 participants  with a mean age of 19.4 years. The majority of study subjects identified their ethnicity as Western European descent (87%) and ethnicity did not show significant effects in any of the following analyses. A summary of descriptive statistics and sex differences for the four measures  is presented in attention to detail was negatively correlated with SPQ-BR odd speech in females only, and imagination was negatively correlated with SPQ-BR magical thinking in males and in both sexes when analyzed together.Total AQ score was positively and significantly correlated with total SPQ-BR score in males, females, and in both sexes when analyzed together . This poprcomp function on the correlation matrix of scores for the five subscales of the AQ  and the seven subscales of the SPQ-BR . Given that the AQ is scored on a smaller scale than the SPQ-BR, we chose to standardize the data by using the correlation matrix rather than the covariance matrix. We included the seven subscales of the SPQ-BR in the PCA rather than their higher-order factors  because collapsing the subscales together would obscure the contributions of specific subscales  that demonstrated unique associations with the AQ in the correlation tests; this decision allowed for a finer-grained analysis in addition to providing output that builds upon the factor analysis on AQ and O-LIFE data in Russell-Smith and colleagues A principal components analysis (PCA) was performed using the R males = 0.33, xfemales = −0.14; t = 3.15, df = 472.92, p = 0.002). Females scored slightly higher than males on PC2  but this difference did not approach statistical significance .The patterns and strengths of loadings for PC1 and PC2 were directly interpretable, so we did not perform any rotations on the components . social skills and communication) and for four of the SPQ-BR subscales . PC2 included relatively strong negative loadings from two of the AQ subscales  and especially strong positive loadings from two of the seven SPQ-BR subscales . Most of the AQ subscales and SPQ-BR subscales were positively related and a few were negatively related. The positive correlations between several of the AQ and SPQ-BR subscales are reflected in the PCA output; PC1 demonstrated positive loadings from several domains, with the strongest loadings from subscales related to social and communicative functioning . These results are inconsistent with independence between autistic and schizotypal features as assayed by these metrics.PC1 demonstrated relatively strong positive loadings for two of the AQ subscales  and positively associated with total SPQ-BR score . social skills, attention switching, and communication and for SPQ social anxiety, constricted affect, no close friends. The second component accounted for 16.8% of the variance and demonstrated negative loadings for all AQ subscales (except for attention to detail). As in social skills and imagination, contrasting with relatively strong positive loadings for subscales belonging to positive/cognitive-perceptual and disorganized schizotypy .PCA results for the AQ and SPQ data from Wakabayashi et al. social skills, positively predicted MRT score in both sexes, though the positive correlation between MRT and total AQ score was driven by males  and magical thinking  , given that previous research has provided evidence for enhanced MRT performance in individuals with autism and in individuals with autistic features by males . AQ atten males) . PC1 demn males) .interpersonal/negative, disorganized, and cognitive-perceptual/positive) were significantly and negatively associated with strength of handedness (Because one of the four study cohorts did not complete the Waterloo Handedness Questionnaire (WHQ), the sample size for all analyses using this data is n = 504 . The distribution of WHQ scores was strongly skewed, so we used a Kendall’s rank correlation test for all following analyses. Consistent with previous research, total SPQ-BR score as well as all three subtypes of schizotypy  schizotypy, followed by disorganized schizotypy. These positive correlations were evident in PC1: this component included relatively-strong positive loadings from subscales of both the AQ and the SPQ-BR, and the strongest loadings were found for social skills, communication, social anxiety, constricted affect, eccentric behaviour, and ideas of reference. Consistent with both the overlapping and diametric models, we interpreted PC1 as a factor indicating general social-communicative disinterest, impairments and abnormalities. The subscale attention to detail demonstrated a different pattern of loadings in comparison to the other AQ subscales . According to Baron-Cohen et al. attention to detail measures a person’s tendency and preference to focus on and recall local rather than global details . Detail-oriented attention may represent a separate dimension of autism, relatively independent of its other features, as also reported by Hoekstra et al. In accordance with results from several previous studies The overlap between autistic and schizotypal features evidenced in PC1 is consistent with the high degree of conceptual, diagnostic, and phenotypic overlap observed between the broader social phenotypes of autism and schizophrenia, especially between Asperger’s syndrome and schizoid personality in childhood and/or schizotypal personality disorder (SPD) The diametric model and the overlapping model do not diverge in their predictions with respect to PC1, but the models differ in their explanation for the causes underlying the similarity: the overlapping model suggests that shared causal factors underlie the social traits common to both the autism spectrum and schizophrenia spectrum, whereas the diametric model suggests that opposite causal factors lead, to some degree, to general social phenotypes that present similarly enough to show strong correlations. Under the diametric model, the overlap evidenced by the bivariate correlations and PC1 need not reflect shared causal factors, but rather may indicate that autism and schizotypy involve social deficits and abnormalities due to different causes. By this hypothesis, social deficits and abnormalities in autism may represent central, underlying causes of the autism-related traits, whereas social deficits and abnormalities in schizotypy  may predominantly represent effects of the neuropsychological alterations that characterize the schizophrenia spectrum, including paranoia, alterations to regulation of affect, social ambivalence, social anhedonia, delusions with social content, and ideas of reference, as well as impaired social cognition due to general cognitive deficits and disorganized thought processes. Some of these psychological alterations, especially paranoia, delusions, and ideas of reference, involve aspects of hyper-mentalizing Consistent with a prediction specific to the diametric model, we found evidence consistent with a phenotypic axis of autism-positive schizotypy (PC2), after removing apparent general social-deficit and abnormality variation measured by both questionnaires and quantified by PC1. Based on the pattern of PC2 loadings, this autism-schizotypy axis appears to reflect a diametric pattern between autistic features and positive aspects of schizotypy (including both ‘positive’ and ‘disorganized’ dimensions), most strongly manifesting in magical thinking and unusual perceptions. The presence of such as axis was consistent with the finding that PC2 was negatively associated with absolute strength of handedness across individuals, such that increased PC2 scores  predicted reduced lateralization. This effect was small, though it is similar in magnitude to many other findings in handedness research attention switching ; total AQ score ; interpersonal (negative) schizotypy; and disorganized schizotypy. Taken together, these results suggest that enhanced mental rotation skills are associated with reduced social-communicative functioning; this is an interesting finding that may be explicable in the context of trade-offs between different types of cognitive systems We compared questionnaire scores to performance on a mental rotation task, and did not find a relationship between MRT skill and PC2 scores, as we would expect under the diametric model. However, PC1 was significantly and positively related to MRT score across the entire sample, though analyzing the sexes separately indicated that males drove this effect. Autistic and schizotypal subscales that also positively predicted MRT included: social skills; Our study has several limitations. First, undergraduate samples may not be characteristic of the population at large, especially with regard to children and mature adults. Second, some of the correlation coefficients are low in magnitude, although statistically significant. Third, whether or not the results that we obtained through comparing AQ scores to SPQ-BR scores are generalizable to other widely-used psychometric instruments for assessing autism and schizotypy, such as the Social Responsiveness Scale (SRS) per se in phenotypes, novel phenotypes, or increased expression of phenotypes, in contrast to negative phenotypes, which comprise general deficits, absences, unspecified abnormalities, or reductions Given current findings, as discussed here, the degree to which the overlapping social phenotypes of autism spectrum traits and schizotypy stem from diametric or overlapping causes, or both, remains an important question for future research. Generally, our results suggest that social-deficit and social-abnormality phenotypes, as assessed by scales such as the AQ and SPQ-BR, may have less usefulness in distinguishing between different psychological and psychiatric conditions than do positive phenotypes: differences


Although Aboriginal people make up a small percentage of the worlds population, they are disproportionately affected by poverty and neglected tropical diseases (NTDs). Unless prioritized, Aboriginal populations may be the last to receive access to essential medicines as part of global NTD elimination efforts.An estimated 370 million people are today classified as belonging to Indigenous or Aboriginal groups PLOS Neglected Tropical DiseasesAboriginal populations are also disproportionately affected by infectious diseases, especially infections of the skin , eye , and ear , dental caries, respiratory and urinary tract infections, and diarrheal diseases The Asia-Pacific region hosts the largest concentration of Aboriginal peoples, accounting for 70 of the global Aboriginal population Entamoeba moshkovskii) Plasmodium falciparum infection is common among the Orang Asli and an important cause of morbidity and mortality [Plasmodium knowlesi, is endemic [The term Orang Asli applies to more than a dozen Indigenous groups, comprising a population of approximately 150,000 people living in peninsular Malaysia. Although Malaysia has sustained high levels of economic growth over the last few decades, the growth has not always included Malaysias rural population, especially the Orang Asli –21. Amonortality –18, and  endemic –21. In cAncylostoma duodenale is also widespread, as are intestinal protozoan infections Staphylococcus aureus (MRSA) Burholderia pseudomallei' infection) is also common during the wet season among Australias Aboriginal population Australia hosts a large Aboriginal population of approximately 0.5 million people. New South Wales and Queensland are the states with the largest overall population, but the Northern Territories has the highest percentage of Aboriginal people compared to other states. Significant numbers of Australias Aboriginal population (approximately one-third) now also live in major cities. Some of the major NTDs affecting the impoverished populations of Oceania, including Australias Aboriginal population, were reviewed previously According to the Pan American Health Organization there are an estimated 40 million Indigenous people in the Latin American and Caribbean region , with the nations of Peru, Guatemala, Bolivia, and Ecuador having the highest percentage of Indigenous populations compared to other countries , 34. In Tunga penetrans, which may be transmitted from dogs often living within communal houses The Yanomami are a group of more than 10,000 extremely isolated rainforest people living in large communal houses in two Amazonian states of Brazil (Roraima and Amazonas) and in neighboring Venezuela Trichinella nativa) and associated with prolonged diarrhea, eosinophilia, and toxoplasmosis The Inuit are comprised of Aboriginal peoples in adjacent areas of Canada, the United States (Alaska), Greenland, and eastern Russia. Their major NTDs were reviewed previously A large number of Indigenous peoples live in sub-Saharan Africa, including up to 500,000 Pygmy  in the Central African rainforests of Cameroon, Central African Republic, Congo, Gabon, and elsewhere Although the worlds Aboriginal populations are vulnerable to and suffer from a variety of different and often unrelated NTDs, several themes emerge that suggest an opportunity for common approaches to disease control and elimination. Important among these is the concept of mass drug administration (MDA) for NTDs that might be specifically relevant to indigenous groups, including their neglected tropical skin diseases Strongyloides stercoralis and other intestinal helminths and Onchocerca volvulus. Thus, MDA with ivermectin would have important health benefits for Aboriginal populations in Australia affected by high rates of strongyloidiasis and also for two populations highly vulnerable to onchocerciasis and/or loiasis, namely the Yanomami and African Pygmy groups. Ivermectin could also have a significant impact on ectoparasitic infections, such as scabies or tungiasis, which are widespread in these populations and therefore have indirect benefits to combat secondary streptococcal infections and post-streptococcal sequelae Ivermectin targets a number of invertebrate pathogens, including 'Equally important are the potential benefits of MDA with azithromycin, particularly for reducing trachoma rates among Australias Aboriginal populations and the Yanamami. There is also recent evidence for the beneficial effects of azithromycin MDA on reducing the prevalence of yaws Overall, the worlds Aboriginal populations may lack access to essential medicines for NTDs used for mass treatments, including ivermectin and azithromycin as outlined above, as well as deworming medicines for intestinal helminth infections and schistosomiasis. For instance, the benefits of MDA with albendazole for the control of hookworm among Aboriginal populations in the Northern Territories were recently reported MDA is not the solitary approach to controlling and eliminating NTDs. Such measures are a key component of more broad and encompassing measures that include sanitation, access to clean water, good food, integrated vector control and management, childhood immunizations, and personal and family hygiene


Smiles for Life: A National Oral Health Curriculum as a knowledge framework that nurse faculty can use for faculty enrichment and competency development in oral health across the life cycle. A variety of teaching-learning strategies and resources are provided to assist nurse faculty with integrating oral-systemic health into existing nursing curricula.Nurses are positioned to play a significant role in oral health promotion and disease prevention across the life cycle. Oral health has not been a high priority in nursing practice, and educating nurses about oral health has been inadequate particularly regarding the interrelationship between oral health and overall health. The first step for developing a nursing workforce with core competencies in oral health promotion and disease prevention is to prepare nurse faculty with the requisite knowledge, skills, attitudes, and best practices in oral-systemic health. The purpose of this paper is to present  Nurses are positioned to play a significant role in oral health promotion and disease prevention across the life cycle, and in expanding access to preventive care services especially for vulnerable and underserved populations across health care settings –5. Oral  Historically, oral health has not been a high priority in nursing practice . EducatiSmiles for Life: A National Oral Health Curriculum [The initial step for developing a nursing workforce with core competencies in oral health promotion and disease prevention is to prepare nurse faculty with the requisite knowledge, skills, attitudes, and best practices in oral-systemic health. The purpose of this paper is to present rriculum  as a knoSmiles for Life (SFL) is a comprehensive oral health curriculum developed by a national steering committee of physicians and dentists formed within the Society of Teachers of Family Medicine, and specially tailored for primary care clinicians and educators [http://www.smilesforlifeoralhealth.org/) has been accessed by individual users including physicians, nurses, physician assistants, and dental hygienists [Smiles for Life curriculum has received numerous endorsements from medical and nursing organizations, including American Academy of Family Physicians, American Academy of Pediatrics, Society of Teachers of Family Medicine, American Academy of Physician Assistants, Association of Faculties of Pediatric Nurse Practitioners, National Association of Pediatric Nurse Practitioners, and Gerontological Advanced Practice Nurses Association.ducators . Since igienists . The curgienists , 10. SmiSmiles for Life is an evidence-based curriculum covering oral health across the life cycle. The curriculum is presented in an interactive, web-based format and consists of eight courses: (1) The Relationship of Oral to Systemic Health, (2) Child Oral Health, (3) Adult Oral Health, (4) Acute Dental Problems, (5) Oral Health and the Pregnant Patient, (6) Fluoride Varnish, (7) The Oral Examination, and (8) Geriatric Oral Health. Smiles for Life curriculum is approved for continuing nursing education by New York University College of Nursing's Center for Continuing Education in Nursing, an accredited provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. Each individual course is approved for 1.0 contact hour and is available free to individual users.SFL curriculum and complete the online courses at their own pace. New users are advised to complete the registration information before launching a course. Each course will take approximately one hour to complete. Clinical cases corresponding to each course are included as optional learning activities. Each case will take approximately 10 minutes to complete. Clinicians are recommended to review the clinical cases before completing the post-assessment. Only registered users will be eligible to complete the post-assessment, obtain a certificate of completion, and receive continuing education credit. Individual clinicians can access the SFL website homepage. Nurse educators can readily access educational materials for integration into existing nursing curricula and professional development programs. Each individual course is downloadable and includes course description, educational objectives, PowerPoint slides, presenter notes, clinical cases, test questions, instructional videos, and implementation guide. Additional SFL resources, described in the next section, are available for integration into clinical teaching and practice settings. A special link for educators is located on the Smiles for Life offers a multitude of educational and practice resources for educators and clinicians. Reference guides such as lab coat “pocket cards” can be downloaded to assist students and nurses in delivering patient care. For example, the Adult Oral Health Pocket Card provides clinicians with evidence-based recommendations for the prevention of periodontal disease (gum disease) and caries (tooth decay), and treatment of xerostomia (dry mouth) in adult patients. Patient education handouts and posters are available in English and other languages, including Spanish, Vietnamese, Cambodian, and Russian. The handouts can be printed and made available to patients, and the posters can be displayed in patient care areas such as waiting and examination rooms. Brief instructional videos are available on the website and can be downloaded into PowerPoint presentations. Instructional videos include lap-to-lap child oral exam, application of fluoride varnish, palpation of the temporomandibular joint, and palpation of the floor of the mouth. The SFL website also provides a selected annotated bibliography for clinicians and educators. Oral health topics include (a) engaging primary care medical providers in preventing dental disease, (b) diabetes and oral health, (c) prenatal/perinatal oral health, (d) cardiovascular disease and oral health, (e) seniors and oral health, and (f) other oral systemic health connections. The SFL website offers clinicians and educators direct links to peer-reviewed internet sites for oral health information and resources.Smiles for Life curriculum provides a knowledge framework for nurse faculty enrichment and competency development in oral health across the life cycle. SFL knowledge framework, educational strategies and resources are identified for nurse faculty enrichment. Teaching-learning strategies are described for integration into existing nursing curricula. The SFL course, The Relationship of Oral to Systemic Health, provides nurse faculty and students with a core knowledge base in oral-systemic health interactions. This foundational course addresses the linkage between oral health and systemic health, and discusses the role of clinicians in promoting oral health and preventing oral diseases. At the completion of the first course, nurse faculty and students will be able to (a) discuss the prevalence and sequelae of oral disease, (b) recognize the interrelationships between oral and systemic disease, and (c) highlight the role of professional nurses in promoting oral health. Most learners will take approximately one hour to complete the first course. It is recommended that learners complete the two optional clinical cases included in the oral-systemic health module, review the selected annotated bibliography for references addressing the association between periodontal disease and systemic diseases, and navigate the recommended oral health websites. The first Oral Health in America, is a good starting point for understanding the meaning of oral health and the link between oral health and overall health. The report described the mouth as a “mirror” of health and disease and emphasized that oral health encompasses a broader scope than healthy teeth [ The US Surgeon General's landmark report released in 2000, hy teeth . Over a hy teeth , 5.Healthy People 2020 outlined a national agenda with goals and objectives for improving health for all Americans and identified oral health as one of the leading health indicators [Healthy People 2020 website  is an excellent resource for information about the oral health impact on overall health, oral health disparities in the United States, and evidence-based recommendations on oral health. The World Health Organization (WHO) established a strategic Global Oral Health Programme focused on developing global policies addressing oral health promotion and disease prevention [http://www.who.int/oral_health/en/) is an important resource for strategies and approaches on oral health promotion and disease prevention. The WHO defined oral health as “a state of being free from chronic mouth and facial pain, oral and throat cancer, oral sores, birth defects such as cleft lip and palate, periodontal (gum) disease, tooth decay and tooth loss, and other diseases and disorders that affect the oral cavity. Risk factors for oral diseases include unhealthy diet, tobacco use, harmful alcohol use, and poor oral hygiene” [ Improving oral health is a national priority and a global challenge. dicators . The Heaevention . The WHOhygiene” . This de Strategies that actively engage learners and integrate knowledge of oral-systemic health interactions are recommended for teaching nursing students about the oral-systemic health connection. A variety of effective teaching-learning methods can be used to integrate knowledge about oral-systemic health into professional nursing practice, such as clinical case presentations, clinical simulations, and unfolding case studies. Clinical case presentations are effective in illustrating the oral manifestations of systemic diseases or oral-systemic interactions. Clinical case examples may include patients with diabetes mellitus and periodontal disease, eating disorders and oral disease, sexually transmitted diseases including HIV/AIDS and oral manifestations, depression and oral impact of medications, and impact of cancer treatments (radiation and chemotherapy) on oral health. Clinical simulation scenarios can be designed to address the role of professional nurses in the assessment and monitoring of the oral health impact of systemic conditions and treatments. Case scenarios focused on oral health promotion and disease prevention can include counseling mothers about good oral hygiene during pregnancy, teaching children proper tooth brushing, and providing oral care to patients with disabilities or special needs. Nurse faculty can develop unfolding case studies to correlate patient's oral manifestations of systemic disease and pathophysiology, and to plan and evaluate interventions for an oral-systemic interaction. Unfolding case study examples may include patients with xerostomia related to HIV treatment, poor glycemic control associated with chronic periodontal disease, and poor nutritional status and edentulism. Additional teaching-learning strategies are outlined in Smiles for Life is a comprehensive oral health curriculum for health professionals and serves as a knowledge framework for nurse faculty enrichment and competency development in oral health across the life cycle. Articulating the importance of oral health to overall general health is essential in promoting oral health and preventing oral disease. Nurse faculty and educators are called to develop a nursing workforce that understands oral-systemic health associations and demonstrates the core competencies of oral health promotion and disease prevention. To attain this goal, strategies and resources are recommended for nurse faculty enrichment. Teaching-learning strategies that actively engage nursing students about the oral-system connection will contribute to the integration of knowledge about oral-systemic interactions into professional nursing practice.


Humans and their ancestors are unique in being a fire-making species, but ‘natural’ (i.e. independent of humans) fires have an ancient, geological history on Earth. Natural fires have influenced biological evolution and global biogeochemical cycles, making fire integral to the functioning of some biomes. Globally, debate rages about the impact on ecosystems of prehistoric human-set fires, with views ranging from catastrophic to negligible. Understanding of the diversity of human fire regimes on Earth in the past, present and future remains rudimentary. It remains uncertain how humans have caused a departure from ‘natural’ background levels that vary with climate change. Available evidence shows that modern humans can increase or decrease background levels of natural fire activity by clearing forests, promoting grazing, dispersing plants, altering ignition patterns and actively suppressing fires, thereby causing substantial ecosystem changes and loss of biodiversity. Some of these contemporary fire regimes cause substantial economic disruptions owing to the destruction of infrastructure, degradation of ecosystem services, loss of life, and smoke-related health effects. These episodic disasters help frame negative public attitudes towards landscape fires, despite the need for burning to sustain some ecosystems. Greenhouse gas-induced warming and changes in the hydrological cycle may increase the occurrence of large, severe fires, with potentially significant feedbacks to the Earth system. Improved understanding of human fire regimes demands: (1) better data on past and current human influences on fire regimes to enable global comparative analyses, (2) a greater understanding of different cultural traditions of landscape burning and their positive and negative social, economic and ecological effects, and (3) more realistic representations of anthropogenic fire in global vegetation and climate change models. We provide an historical framework to promote understanding of the development and diversification of fire regimes, covering the pre-human period, human domestication of fire, and the subsequent transition from subsistence agriculture to industrial economies. All of these phases still occur on Earth, providing opportunities for comparative research. Debate over the concept of ‘background’ natural processes (i.e. independent of humans) and over the role of humans in driving global environmental change requires an understanding of the influence of anthropogenic fire on ecological systems . Humans Homo species by enabling the cooking of food as early as the Lower Pleistocene  temporal or spatial changes in fire activity and vegetation apparent from palaeoecological proxies see , (2) a dThe separation of the anthropogenic effect from ‘natural’ background fire regimes remains a source of debate in both academic and management communities. To many people, the concept of ‘natural’ fire regimes can only be applied to regions in the period prior to human colonization and settlement. But this use is problematic for fire regimes in Africa, where humans evolved. Confusingly, the term is sometimes used to describe all prehistoric fire regimes, whether or not they were dependent on human or lightning ignitions. For example, the USA Landscape Fire and Resource Management Planning Tools (LANDFIRE) includes Native American burning patterns within natural fire regimes. In the USA and Canada, forest fires ignited by lightning that do not threaten human populations or infrastructure are sometimes allowed to burn freely to allow the maintenance of ‘natural’ disturbances in these ecosystems. The intertwined relationships between humans, landscapes and fire throughout human history argue against a clear distinction between natural and anthropogenic fires. The notion of ‘restoring natural fire regimes’ without anthropogenic influence is neither possible nor useful. However, understanding the relative influences of climate, human ignition sources, and cultural practices in particular settings underpins efforts to minimize damage from fire to human health, property, and ecosystems, and to limit greenhouse gas fluxes to the atmosphere.Fire regimes can be thought of as a spatially variable template of fire intensity, severity, type, frequency, spatial scale and seasonality, within which biotas have co-evolved . Humans Although there is a general relationship between human population density and fire activity in some regions, these variables are not necessarily linearly related, being strongly influenced by the environmental setting  to another is a key to understanding the dynamics of human and fire interactions, and the consequences that have cascaded through Earth systems and human societies . For insad 2001 and 2003, demonstrating that about one-third of all agricultural fires occurred within the Russian federation. Because all pyric phases in our model  are stilDisentangling the influence of human land uses on background fire regimes is a major research challenge, requiring detailed comparative palaeoecological analyses of the effects of past fire activity by contrasting human land use regimes within similar biomes . Such co2 may change the mass or combustibility of different fuel types, owing to altered growth rates and competitive abilities, influencing fire regimes and vegetation patterns  influences in the management of fire is essential for evaluating the costs and benefits of contrasting fire regimes within individual landscapes and biomes. For example, Indonesia's decision in the 1980s and 1990s to promote the drainage of carbon-rich peatlands has led directly to catastrophic carbon releases, conservatively estimated at 2–3 Gt , but cli