Evidence is lacking to inform providers’ and patients’ decisions about many common treatment strategies for patients with end stage renal disease (ESRD).The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study , (2) the Dialysis Clinic Inc , (3) the United States Renal Data System , and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry . We ascertain patient reported outcomes , morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods  to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community.The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies’ impact on clinical care and patients’ outcomes. End stage renal disease (ESRD) is a significant and growing public health problem with increasing incidence and prevalence in the United States and worldwide . PatientDespite the intensity and cost of care for patients with ESRD, little is known about the impact of many common clinical management strategies that are intended to improve health outcomes in ESRD . In the As part of its Effective Health Care Program, the Agency for Healthcare Research and Quality (AHRQ) supports the Developing Evidence to Inform Decisions about Effectiveness (“DEcIDE”) Network to conduct “studies on the outcomes, effectiveness, safety and usefulness of medical treatments and services” . In 2009The study is being conducted through collaboration of researchers at five centers (Johns Hopkins University (coordinating center), Tufts University Medical Center, Minneapolis Medical Research Foundation, the University of California, San Francisco, and the Cleveland Clinic Foundation), which are conducting several observational “sub-studies” addressing the three comparative effectiveness questions identified by AHRQ for investigation  within the ESRD community in an ongoing fashion.Four main data sources from which sub-studies derive their data comprise representative US patient populations with kidney disease that are followed through active and passive means until death. Cohorts are also linked to (or are composed of) registry data and Centers for Medicare and Medicaid Services (CMS) claims generated during the course of ESRD care. Data are linked to national death data sources to ascertain patients’ vital status and underlying cause of death. Tables  and 3.CHOICE is a longitudinal observational cohort study of 1,041 incident dialysis patients originally funded by AHRQ to measure several aspects of patients’ experiences and outcomes related to their choice of renal replacement therapy . CHOICE DCI is the largest non-profit provider of dialysis care and third largest dialysis provider in the US, serving approximately 13,000 patients at 209 dialysis facilities in 27 states. The population of patients within DCI is diverse and is demographically representative of the US dialysis population, with an overrepresentation of African Americans . InformaThe United States Renal Data System (USRDS) is a national data system  that collects, analyzes, and distributes information about ESRD in the United States. USRDS collaborates with the CMS, the United Network for Organ Sharing (UNOS), and the ESRD networks to share datasets. These data comprise several sub-files which, when linked, provide patient-level data on a) demographics, primary diagnoses, limited comorbidities and biochemical tests at dialysis initiation; b) health care services utilization and intravenous medications delivered in dialysis facilities (Form 2728); c) deaths, including cause of death (Form 2846) and d) outpatient medication use in patients receiving benefits through Medicare Part D prescription drug program . These dThe Cleveland Clinic Foundation Registry contains clinical data on over 53,000 patients with CKD based on estimated glomerular filtration rate (eGFR) or administrative billing codes obtained through clinical care in the Cleveland Clinic health care system. Data extracted from patients’ electronic health records include information on patients’ comorbid conditions, laboratory values, and health care services utilization. These data have been linked to the National Social Security Death Index as well as the USRDS data, providing additional information on patients’ vital status as well as their ESRD incidence, and ESRD-related health and health care utilization .When possible, sub-studies utilize commonly defined variables to assess patient demographic variables and comorbid conditions ascertained at studies’ baseline. Studies also attempt to incorporate similarly defined morbidity and mortality outcomes and censoring rules in main analyses.We ascertain patient demographics  through both administrative (from USRDS CMS-2728 form) and clinical data, where available. In CHOICE, some demographic data collected directly from the participants are available ,28.We utilize validated Medicare claims-based measures to assess the presence and severity of patients’ comorbid illnesses at the time of dialysis initiation and throughout the course of treatment .th revision of the International Classification of Disease (ICD-10) obtained from the National Death Index, which is commonly used to ascertain date and cause of death in population-based studies [We ascertain all-cause mortality and cause-specific mortality using cause of death information classified according to the 10 studies . We comp studies . We ascertain infectious and CVD events  and other morbidity  using Medicare and clinical data, where available. We will obtain data on all hospitalizations from Medicare claims for all three data sources. We will employ validated definitions using ICD9-CM codes to determine infectious and cardiovascular hospitalizations. Subcategories of cardiovascular events  will be explored. Health-related quality of life data are also available in CHOICE and DCI .  , effectiWe have engaged stakeholders from the ESRD community representing patients, providers, payers, and regulators to ensure the relevance of our sub-study questions and approach, and to help guide dissemination of our findings. Table  StakeholWe are studying the effectiveness of three major antihypertensive medication classes on patients’ morbidity, mortality and quality of life. Our analyses will account for several relevant potential confounders and mediators of the association of antihypertensive medication therapy choice with patient outcomes, including blood pressure control, underlying cardiovascular disease and other comorbidities, and patients’ cardiovascular volume status.We are assessing whether patients are receiving  one of three major classes of antihypertensive medications: (a) angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blocking agents (ARBs); (b) beta receptor blocking agents; or (c) calcium channel blocking agents. We are utilizing data from both clinical sources  and administrative claims  to ascertain doses of these medications prescribed to patients over time, as well as medication adherence . We are We are measuring other variables which may influence antihypertensive treatment patterns and effectiveness of antihypertensive therapy, including: (1) blood pressure and blood pressure variability, (2) patient volume status, (3) dialysis dose, (4) dialysis adherence, and (4) the presence of influential comorbid conditions such as cardiovascular disease and congestive heart failure.Study cohorts allow for descriptions of individual patient changes in anti-hypertension therapy regimens over time as well as to assess the influence of antihypertensive regimens and changes in antihypertensive regimens on proximal and distal outcomes. We have created analytic datasets assessing patient time in discrete time intervals, including 30, 60, and 90 day windows. Key exposure variables and confounders are assessed within discrete time intervals, allowing for time their varying assessment.Our main analyses attempt to identify the comparative effectiveness of distinct antihypertensive regimens (e.g. beta-blocker versus ACE or ARB containing regimens) on outcomes in longitudinal models. We are utilizing discrete time proportional hazards models to study the association of time-varying exposures and correlates with outcomes as well as marginal structural models, which provide an opportunity to account for time dependent influences of confounders on anti-hypertension treatment choice through inverse probability weighting techniques. Our analyses also attempt to capture differences in the effectiveness of antihypertensive therapies on potential acute  versus more chronic (development of cardiovascular disease) outcomes by incorporating varying lag times (ranging from no window a 90 day window) between assessments of exposures and outcomes.Defining patients’ blood pressure regimens represents a key challenge. In exploratory analyses, we identified over 100 distinct combinations of blood pressure medications used by patients receiving care in DCI. Many patients received more than one of the key antihypertensive therapies of interest, while others received numerous blood pressure combination regimens that changed over time. In order to provide decision makers with evidence they will deem usable, we will simplify our definitions of regimens to ensure they directly address key decisions clinicians would confront commonly in clinical practice .We are studying the effects of starting dialysis early versus later on patients’ of morbidity, mortality, and quality of life outcomes. Using data collected prior to patients’ dialysis initiation when possible, we will account for patients’ clinical conditions that could lead to earlier dialysis initiation . We also seek to account for the contribution of local or regional practice variations in dialysis care ,41.2 versus less than 10ml/min/1.73m2). We obtain (when available) information on GFR at dialysis initiation from provider questionnaires . For analyses among patients with pre-dialysis CKD , we obtain information on eGFR from laboratory records extracted from patients’ electronic health records.We define early versus later dialysis initiation based on pre-defined thresholds of estimated glomerular filtration rate (eGFR)  and the occurrence of medical events  in the pre-dialysis period. When data are available, we also assess the frequency of patients’ utilization of pre-dialysis nephrology care and their preparation for renal replacement therapy  prior to dialysis initiation.We are constructing cohorts to allow for descriptions of pre-dialysis factors influencing the initiation of early dialysis when possible. This includes a cohort of patients initiating dialysis who have pre-dialysis CMS claims linked to their CMS dialysis health claims (in USRDS) as well as a cohort of patients seen in nephrology clinics who have dialysis CMS claims linked to their pre-dialysis health records (in Cleveland Clinic). In cases where pre-dialysis claims are not available, we are using data collected from physicians at the time of patients’ dialysis initiation .Our analyses address limitations in previous observational studies of the comparative effectiveness of early versus later dialysis initiation -46. One A key challenge we face in constructing cohorts is the problem of adequately capturing patients’ pre-dialysis health and trajectory of CKD progression prior to dialysis initiation. For instance, patients may suffer from symptoms  that could heavily influence patients’ and providers’ preferences for initiating dialysis. To address this challenge, we are attempting to capture pre-dialysis comorbidity by utilizing datasets that collect information on pre-dialysis health status as assessed in billing data and medical records. We are adapting previously validated comorbidity instruments, and trying to capture measures of the frequency or intensity of health care utilization , which we hypothesize could reflect patients’ health declines and perceived need for earlier dialysis.We are studying the safety and effectiveness of various iron dosing strategies in the care of dialysis patients. We will consider both the risk of infectious morbidity and mortality related to iron administration as well as the risk of end-organ damage . We will assess effectiveness of various dosing strategies in terms of the achievement of hemoglobin treatment goals , erythroWe are assessing cumulative iron utilized over short and longer time periods as well as the pattern of iron administration . We will ascertain iron doses from both clinical data  and administrative billing data .We are measuring other variables that may influence iron dosing patterns and effectiveness of iron therapy, including (1) the presence of inflammation or infection, (2) patient comorbidity, (3) use of other medications to treat anemia , and (4) patients’ response to anemia therapy.We are constructing study cohorts to allow for descriptions of individual patient changes in iron therapy regimens over time as well as to assess the influence of iron dose and changes in dosing regimens on proximal and distal outcomes. We have created analytic datasets assessing patient time in discrete time intervals, including 30, 60, 90, and 180 day windows. Key exposure variables and confounders are assessed within discrete time intervals, allowing for their time varying assessment.Our main analyses will compare the effectiveness of varying levels of iron dose on outcomes in longitudinal models. We are utilizing discrete time proportional hazards models to study the association of time-varying exposures and correlates with outcomes as well as marginal structural models, which provide an opportunity to account for time dependent influences of confounders on iron therapy. Our analyses will assess differences in the effectiveness of iron therapies on acute  and more chronic  outcomes by incorporating varying lag times (ranging from no window a 90 day window) between assessments of exposures and outcomes.Evaluating the short versus longer-term toxicity of iron presents a challenge. While cardiovascular events and iron deposition disorders may represent intermediate and long term outcomes, acute infectious hospitalizations may be proximally related to iron administration. Our analyses will calculate total iron exposure over varying discrete time periods  and incorporate a time lag of up to 30 days to help distinguish short versus long-term effect of iron on outcomes. Another challenge is the incorporation of laboratory values , which are measured at infrequent intervals but which influence physicians’ administration of iron. We have created longer rolling ‘windows’ over which we observe whether these laboratory values have been obtained, identifying both average values as well as most recently obtained values as they may be most influential on physicians’ iron prescribing patterns.All data sources are de-identified prior to analyses. We are performing all analyses of USRDS, CHOICE, and DCI data with the approval of the Johns Hopkins Institutional Review Board. Analyses of Cleveland Clinic data are performed at the Cleveland Clinic with approval of the Cleveland Clinic Institutional Review Board. We will work with our Stakeholder Panel to provide insight into optimal avenues and formats  for dissemination of our findings. We will also work with the Eisenberg Center within AHRQ to disseminate our study findings widely among stakeholders in the ESRD community.There is a great need for studies comparing the effectiveness of common treatment strategies employed in the care of patients with ESRD. The DEcIDE Patient Outcomes in End Stage Renal Disease Study addresses questions commonly confronted by decision makers  involved in ESRD care.Several aspects of the DEcIDE Patient Outcomes in End Stage Renal Disease Study distinguish it from other ongoing observational studies. First, our use of clinical and administrative data will facilitate our study of actual clinical practice patterns, enhancing the relevance of our findings to decision makers. Second, our data incorporate both clinical and administrative information, enhancing the specificity with which we can classify key exposures, confounders, and outcomes. Examination of four complementary cohorts will enable triangulation of results. If consistent findings are obtained, this will enhance decision makers’ confidence to act on evidence emerging from our studies. Third, our continuous engagement of stakeholders throughout the conduct of the study is novel among ESRD studies, and will enhance how the ESRD community values and integrates our findings. Fourth, our nationally representative cohorts feature some data linkages that have not previously been performed in comparative effectiveness studies among ESRD patients. Studies previously assessing cause specific mortality in ESRD have relied on dialysis physician reports in CMS reports (Form 2746). Our data linkages with the National Death Index for determination of cause specific mortality will help us validate these reports and may enhance the comparability of our findings to epidemiological studies in other areas. Finally, our use of novel strategies to overcome limitations  of prior studies may help to better inform previously unanswered questions in ESRD care.In conclusion, the DEcIDE Patient Outcomes in End Stage Renal Disease Study is funded to address gaps in evidence regarding the effectiveness of common treatment strategies employed in ESRD care. Study of these strategies in four representative US cohorts of patients with kidney disease using rigorous statistical methodology and ongoing engagement of stakeholders in the ESRD community enhances the likelihood these studies will yield findings deemed relevant and useful to decision makers in ESRD care.AHRQ: Agency for Healthcare Research and Quality; DEcIDE: the Developing Evidence to Inform Decisions about Effectiveness; ESRD: End stage renal disease; ARRA: American Recovery and Reinvestment Act; CVD: Cardiovascular disease; CKD: Chronic kidney disease; CHOICE: Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study; DCI: Dialysis Clinic, Inc; USRDS: United States Renal Data System; CMS: Centers for Medicare and Medicaid Services; UNOS: United Network for Organ Sharing; eGFR: Estimated glomerular filtration rate; ACE: Angiotensin converting enzyme; ARB: Angiotensin II receptor blocking agent.This project is supported by the DEcIDE Network AHRQ contract number HHSA290200500341I, Task Order #6. Dr. Shafi was supported by K23DK083514 from the National Institute of Diabetes and Digestive and Kidney Diseases.AHRQ Disclosure: Identifiable information, on which this report, presentation, or other form of disclosure is based, is confidential and protected by federal law, Section 903(c) of the Public Health Service Act, 42 USC 299a-1(c). Any identifiable information that is knowingly disclosed is disclosed solely for the purpose for which it has been supplied. No identifiable information about any individual supplying the information or described in it will be knowingly disclosed except with the prior consent of that individual. The authors declare that they have no competing interests.LEB contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. NT contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. PLE contributed to the conception and design of the studies, led the data acquisition, contributed to analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. JS contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. SS contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. DCC contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. TS contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. DM contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. JL contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. WLSP contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. BGJ contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. AW contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. NRP contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. SN contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. KB contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and has approved the final version for publication. DEcIDE Patient Outcomes In End Stage Renal Disease Study Authors contributed to the conception and design of the studies, analyses and data interpretation, drafting the manuscript, and have approved the final version for publication. All authors read and approved the final manuscriptDEcIDE Patient Outcomes In End Stage Renal Disease Study Authors Include: Arrigain S (arrigas@ccf.org), Collins AJ (acollins@cdrg.org), Cook C (ccook17@jhmi.edu), Coresh J (jcoresh@jhsph.edu), Gilbertson DT (dgilbertson@cdrg.org), Guo H (hguo@cdrg.org), Herzog CA (cherzog@cdrg.org), Jolly SE (jollys@ccf.org), Lui X (LiuX@ccf.org), Luly J (jluly1@jhmi.edu), McDermott A (amcdermo@jhsph.edu), Meyer KB , Michels WM (W.M.Michels@amc.uva.nl), Nally JV Jr. , Plantinga L (laura.plantinga@emory.edu), Scheel PJ (pscheel1@jhmi.edu), Schold JD (ScholdJ@ccf.org), Zager PG (pzag@unm.edu), Zhou J (jzhou9@jhmi.edu).The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/167/prepubAppendix.Click here for file


Recent rapid progress in plant science and biotechnology in China demonstrates that China’s stronger support for funding in plant research and development (R&D) has borne fruit. Chinese groups have contributed major advances in a range of fields, such as rice biology, plant hormone and developmental biology, genomics and evolution, plant genetics and epigenetics, as well as plant biotechnology. Strigolactone studies including those identifying its receptor and dissecting its complex structure and signaling are representative of the recent researches from China at the forefront of the field. These advances are attributable in large part to interdisciplinary studies among scientists from plant science, chemistry, bioinformatics, structural biology, and agronomy. The platforms provided by national facilities facilitate this collaboration. As well, efficient restructuring of the top–down organization of state programs and free exploration of scientists’ interests have accelerated achievements by Chinese researchers. Here, we provide a general outline of China’s progress in plant R&D to highlight fields in which Chinese research has made significant contributions. Enough food supply is always one of the most important issues for the government in China because of its huge population. On the other hand, dwindling areas of arable lands and global climate change have challenged amount of the agriculture production. Therefore, Chinese government always has strongly supported the agriculture sciences, as well as plant sciences during the state development.Plant molecular biology has come into a new phase in China  in 2012, although percentage of funding for basic research was still lower. Plant science and its related fields have been areas of concern for the government because China perennially faces the problem of ensuring sufficient food supply to its huge population. As a Chinese economic development initiative, funding for plant R&D has been increased rapidly in the last decade Fig. . The funSetaria italica   and D (Aegilops tauschii) , etc. Absolute quantitation of isoforms of post-translationally-modified proteins has been performed in transgenic organisms  for crops include: rice functional genomics and designer breeding by molecular modules, molecular biology of photosynthesis and biological nitrogen fixation, molecular mechanism of plant reproduction and their hormonal regulation, molecular basis of high-efficiency utilization of N and P by crops, molecular basis of pest resistance and stress tolerance, functional genomics of cotton fiber development and quality improvement, molecular biology of wood formation and tree breeding , plant secondary metabolism and molecular basis of quality improvement in main vegetables and fruits, molecular regulation of fatty acid biosynthesis in rapeseed, molecular improvement of Cassava, genetics of crop germplasms, etc.DEP1 dominant allele causes shorter inflorescence internodes, more grains per panicle, and a consequent increase in grain yield. Chinese groups also found that artificial selection of an amino acid substitution in PROG1 during domestication led to the transition from the wild rice plant architecture, and affected erect growth and grain yields in cultivated rice . They reported that rice architecture traits (such as tillering and panicle type) affecting yield are controlled by key components such as MOC1/LS/LAS, TAD1, and TE that form a complex involved in APC/C in the cell cycle  and a conserved, essential nuclear gene (Cox11) -related cytoplasmic–nuclear incompatibility is driven by a detrimental interaction between a newly evolved mitochondrial gene  to solve frontier issues in hormone biology. Various hormone receptors such as COI1 for jasmonic acids (Jas), D14 complex for strigolactone (SL), and PYR/PYL/RCAR and ABAR for abscisic acid have been identified  system for analysis of complex hormones such as gibberellic acids (GAs) and SLs, and to create novel identification methods. For example, Feng’s group (Wuhan University) has established a MS-based method for quantitative identification of multiple GAs (up to 11 derivatives of GAs) in one sample  and Dioscorea opposite   locus controls amylose synthesis in rice and many other species. Wx gene expression can be regulated by antisence approach or RNAi technique in transgenic rice and cassava, which have been used to regulate starch composition. Rice endosperm has been used as bioreactor to produce HSA  by transgenic rice with high expression of recombinant HAS (OsrHSA) . In medicinal plant, Artemisia annua, the content of biological active component, artemisinin, is less 1 % (dry matter), but it reached 2.8 % in some strains of transgenic plants with SQSi, which has been proved for field test .Since the new century started, the community of plant scientists has steadily enlarged in China. Correspondingly, the output of Chinese plant science research is impressive. Mainland Chinese plant researchers have published a significantly increasing share of the research articles in top journals, but breakthroughs driven by original innovations that are capable of leading new research fields and great strides in research methods are still lacking. With continuous support from the Chinese government in terms of increased funding allocations and improved infrastructure, we would like to see that Chinese plant scientists may contribute more than ever to the plant science in the world.Using the model plant Arabidopsis, Chinese plant scientists have produced high-quality, internationally acknowledged work. However, to feed the 1.3 billon people in China and supply more food to the world despite the shrinking area of arable land, always is one of the top concerns of the Chinese government and politicians, and the responsibility of plant scientists in the world. Plant scientists need to pay more attention for staple crops such as rice, wheat, corn, soybean, rapeseed and cotton. Also, we should study those crops, like potato, sweet potato and cassava, which generally are important food resources for developing regions. When we consider to continue to increase the crop yield, we also should consider to breed more crop varieties which are environmental friendly, that means less chemical fertilizers and pesticides used. With improvement of living standard in China, Chinese scientists are to pay more attention to important vegetables and fruits for improvement of nutrient composition. For identification of active component of Chinese medicinal plants, we seriously lack the knowledge about secondary metabolism for those plants. Thus, it is important to study plant development and hormone function, plant metabolism including photosynthesis, pest resistance and stress tolerance at molecular level, and clone more functionally important genes from germplasm collection. Although many Chinese plant scientists have done impressive work in the above research areas using different crops, they should integrate their research resources, they need more interdisciplinary cooperation to solve those important plant biology problems and provide more molecular breeding approaches and to resolve major agricultural challenges. We are sure that better plant science for better life of human being.


Vincent Iacopino and Stephen Xenakis review case records of nine individualsimprisoned at Guantánamo Bay which indicate that medical personnel assigned tothe US Department of Defense neglected and/or concealed medical evidence oftorture.  In the wake of the September 11, 2001 attacks on the US, the governmentauthorized the use of “enhanced interrogation” techniques thatwere previously recognized as torture. While the complicity of US healthprofessionals in the design and implementation of US torture practices hasbeen documented, little is known about the role of health providers,assigned to the US Department of Defense (DoD) at the US Naval StationGuantánamo Bay, Cuba (GTMO), who should have been in a position toobserve and document physical and psychological evidence of torture and illtreatment.We reviewed GTMO medical records and relevant case files  of nine individuals for evidence of torture and ill treatment anddocumentation by medical personnel. In each of the nine cases, GTMOdetainees alleged abusive interrogation methods that are consistent withtorture as defined by the UN Convention Against Torture as well as the morerestrictive US definition of torture that was operational at the time. Themedical affidavits in each of the nine cases indicate that the specificallegations of torture and ill treatment are highly consistent with physicaland psychological evidence documented in the medical records and evaluationsby non-governmental medical experts. However, the medical personnel whotreated the detainees at GTMO failed to inquire and/or document causes ofthe physical injuries and psychological symptoms they observed.Psychological symptoms were commonly attributed to “personalitydisorders” and “routine stressors of confinement.”Temporary psychotic symptoms and hallucinations did not prompt considerationof abusive treatment. Psychological assessments conducted bynon-governmental medical experts revealed diagnostic criteria for currentmajor depression and/or PTSD in all nine cases.The findings in these nine cases from GTMO indicate that medical doctors andmental health personnel assigned to the DoD neglected and/or concealedmedical evidence of intentional harm.Please see later in the article for the Editors' Summary Torture has been used throughout history for interrogation, coercion, andpunishment. Ingenious methods have been devised to inflict severe physicalor mental pain or suffering intentionally on an individual to obtain aconfession or information, or to punish, intimidate, or coerce. Nowadays,torture is prohibited under international law and under the domestic law ofmost countries, and is considered to be a violation of human rights. Article5 of the United Nations (UN) Universal Declaration of Human Rights, whichwas adopted in December 1948, states: “No one should be subjected totorture or to cruel, inhuman or degrading treatment or punishment.”Similarly, signatories of the Geneva Conventions, which provide protectionfor people who fall into enemy hands during conflicts, have agreed not totorture prisoners. Torture is also prohibited by the UN Convention againstTorture and Other Cruel, Inhuman or Degrading Treatment or Punishment, whichcame into force in June 1987. Implementation of this Convention byparticipating states is monitored the UN Committee against Torture.After the September 11, 2001 attacks on the United States, the US governmentredefined acts such as waterboarding (simulated drowning), sleepdeprivation, and prolonged isolation as “safe, legal, ethical, andeffective” “enhanced interrogation” techniques (EITs).These EITs were previously recognized as torture by the UN Committee againstTorture. US health professionals are known to have been complicit in thedesign and implementation of EITs. For example, the US Central IntelligenceAgency (CIA) and Department of Defense (DoD) designated“non-clinical” health professionals to monitor the use of EITsat the US detainee facility at the US Navy Base at Guantánamo Bay,Cuba (GTMO), and the active role of these individuals during interrogationshas been documented. Much less is known, however, about the role of healthprofessionals assigned to the DoD to provide medical and mental health careto the GTMO detainees. Specifically, it is not known whether these healthprofessionals accurately documented physical and psychological evidence oftorture and ill treatment among the detainees. In this case series, theresearchers review GTMO medical records and case files of nine detainees forevidence of documentation of ill treatment and torture by medicalpersonnel.The researchers—non-governmental medical experts retained by legalrepresentatives of GTMO detainees alleging torture and illtreatment—reviewed the medical records, client affidavits,attorney–client notes, and legal declarations of medical experts ofnine GTMO detainees. In each case, the detainee alleged abusiveinterrogation methods consistent with torture as defined by the UNConvention against Torture. The researchers report that the medicalaffidavits for all the cases indicate that the allegations of torture andill treatment were consistent with physical and psychological evidence oftorture and ill treatment documented in the medical records and inevaluations by non-governmental experts. However, the medical personnelresponsible for the detainees' routine medical and mental health carefailed to inquire about and/or document the causes of the physical injuriesand psychological symptoms that they observed. Instead, they attributedpsychological symptoms to “personality disorders” and“routine stressors of confinement”. Moreover, psychotic symptomssuch as hallucinations did not prompt consideration of abusive treatment.Importantly, psychological assessments conducted by non-governmental expertsrevealed diagnostic criteria for current major depression and/orpost-traumatic stress disorder  in all the cases.These findings indicate that health professionals assigned to the DoD toprovide medical and mental health care to GTMO detainees neglected and/orconcealed evidence of intentional harm. Because only nine cases are includedin this case series, these findings may not be generalizable to other GTMOdetainees. The findings are also limited by their reliance on medicalrecords and case files that were sometimes heavily edited and onpsychological assessments based on questionnaires rather than on directexamination. Nevertheless, these findings reveal new information about thepotential extent of medical complicity in US torture practices, and theyhighlight the need for a thorough and impartial investigation of all theavailable information, including relevant classified information.http://dx.doi.org/10.1371/journal.pmed.pmed.1001027.Please access these Web sites via the online version of this summary atPLoSMedicineEditorialThis study is further discussed in the April 2011 torture, and on the Guantánamo Bay detention camp note thatWikipedia is a free online encyclopedia that anyone can edit;available in several languages)Wikipedia has pages on Office of the UN High Commissioner for Human Rightsprovides information about the UNConvention against Torture and other Cruel, Inhuman or DegradingTreatment or Punishment and the UN Committee against Torture The Physicians forHuman Rights is a non-profit organization thatmobilizes health professionals to advance health, dignity andjustice, and promotes the right to health for all. Its Campaign against Torture seeks to restore the UScommitment against tortureAmnesty International provides information about theGuantánamo Bay detention camp Despite international recognition of torture as a crime that can never be justifiedRecent release of previously classified US documents The CIA's Office of Medical Service (OMS) and the DoD's Behavioral ScienceConsultant Teams (BSCT) designated “non-clinical” health professionalsto monitor EITs. Their active roles in acts of torture and ill treatment have beenwell documented In this case series, we reviewed GTMO medical records and relevant case files of ninedetainees for evidence of ill treatment and torture and assessed the documentationby medical personnel.As non-governmental medical experts retained by legal representatives of GTMOdetainees alleging torture and ill treatment, we reviewed a series of nine GTMOmedical records, client affidavits, attorney–client notes and summaries, andlegal declarations of non-governmental medical experts who were retained by thedetainees' attorneys. The legal declarations of non-governmental medicalexperts were filed in civilian or military court cases. A total of fivenon-governmental medical experts, including the authors, consulted on behalf of thenine detainees, only one non-governmental medical expert was partially financiallycompensated for his services. Psychological evaluations were conducted eitherin-person by the authors (two cases in GTMO), by Physicians for Human Rights (PHR)consultants (one case following release from GTMO), or by proxy evaluations (sixcases) developed by a forensic psychiatrist and former DoD consultant who wasretained as a medical expert by the detainees' legal representatives. The proxyevaluation included 22 questions on alleged trauma, 37 questions to assess symptomsof post-traumatic stress disorder (PTSD), depression, and anxiety, and a 24-itemchecklist to assess mental status. In one unclassified case, redacted interrogationplans and interrogation summaries were available as well. Classified informationthat was available to the authors is not included in this case review.In all cases, written permission by means of a consent form through legalrepresentatives was provided for the review of the relevant records and possiblepublication of de-identified case information. After cases were reviewed andfindings identified that were thought to merit submission for publication, the studywas also reviewed and approved by the Ethics Review Board of PHR. All in-personmedical evaluations of torture and ill treatment were conducted in accordance withIstanbul Protocol guidelines All of the detainees were incarcerated in GTMO in 2002 with an average incarcerationperiod of seven years. At the time of incarceration, the average age of all ninemale detainees was 33.All of the GTMO detainees alleged torture and ill treatment, inflicted over aperiod of at least several months and, in some cases, several years, to theirattorneys and to non-governmental medical experts see . The detThe GTMO medical records indicate that detainees were evaluated and treatedon multiple occasions by DoD health providers for a wide range of medicalproblems unrelated to allegations of abuse, for example: skin rashes, weightloss, diarrhea, low back pain, hemorrhoids, peptic ulcer disease, upperrespiratory infections, gingivitis, ear wax removal, and refraction for eyeglasses. The average number of medical problems among the detainees was ninewith a range of five to 12. In general, the quality of medical documentationfor these problems appeared adequate.In three of the nine cases, the GTMO medical records documented injuries thatwere consistent or highly consistent with detainee allegations of abuse:contusions (2), bone fractures (3), lacerations (2), peripheral nerve damage(1), and sciatica (2). There was no mention of any cause for theseinjuries.Several detainees indicated that access to medical care was linked tocooperation with the interrogators. In one case, a detainee was treated fora painful ankle injury two weeks after the alleged injury. In another case,medical personnel allegedly “certified” the detainee's“fitness” to continue being interrogated after several periodsof unconsciousness. Another detainee indicated that he observedinterrogators with his medical records and that his chronic back pain wasexploited by interrogators with the use of prolonged, painful stresspositions.The medical records indicate that, prior to detention in GTMO, none of thedetainees had any past psychological history or family history ofpsychological problems. GTMO medical personnel documented significantpsychological symptoms, however, among eight of the detainees including:nightmares (5), suicidal ideation (4), depression (2), audiovisualhallucinations (3), suicide attempts (2), anxiety/claustrophobia (2), memoryand concentration difficulties (1), and dissociative states (2). In eachcase, the onset of psychological symptoms was temporally related toallegations of abuse and corroborating medical information in the medicalrecords. According to the GTMO medical records, DoD mental health providerswith the Behavioral Health Service (BHS) evaluated six of the nine detaineesand diagnosed the following: depression (4), passive aggressive personality(4), borderline personality (2), adjustment disorder (3), routine stressorsof confinement (2), narcissistic traits (1), psychosis or depression withpsychotic features (2), and anxiety NOS (not otherwise specified) (2).Although BHS notes indicated that seven of the detainees had symptomssupporting a diagnosis of PTSD , BHS clinicians did not indicate inquiring aboutor documenting possible causes of these symptoms and/or the diagnosis ofPTSD. Treatment for depression consisted of medications and periodic checksfor suicidal/homicidal ideation. In one case, BHS clinical notes document adetainee's symptoms of nightmares, lapses in memory, decreasedconcentration and appetite, depressed mood, and suicidal thoughts. Themedical records indicate that he was treated with antidepressants and told,“[You]…need to relax when guards are being moreaggressive.”Nearly all BHS visits were initiated after suicide attempts and/or detaineehunger strikes. Under these circumstances, BHS notes indicate that thevisits were unwelcome and the detainees often refused to cooperate.The assessments conducted by non-governmental medical experts in each of the ninecases indicate that the specific allegations of torture and ill treatment werehighly consistent with and supported by physical and psychological evidenceobserved in all cases. The psychological component of the evaluation revealeddiagnostic criteria for current major depression and/or PTSD in all nine cases.Many of the psychological symptoms noted were content-specific for the allegedtorture and ill treatment, i.e., nightmares, avoidance behaviors, and triggersfor hyperarousal symptoms and exaggerated startle responses.There was no evidence of malingering or deception by the detainees in any of theevaluations. Each of the detainees provided highly consistent accounts ofalleged torture and ill treatment. In one case, unclassified interrogation plansand interrogation summaries provided precise corroboration of the methods oftorture and ill treatment that was alleged. There was no evidence ofover-endorsement of physical or psychological symptoms and it was clear duringthe in-person interviews that the detainees' observed affect was internallyconsistent with the content of the evaluation, for example sadness and crying inthe course of recounting shameful experiences such as sexual assault and theexpression of anger when describing threats against family members.Review of one detainee's declassified interrogation plans indicated thatBSCT psychologists identified the detainee's psychological and socialvulnerabilities; they monitored his interrogations and advised interrogators onhow to achieve the ultimate goal of breaking him down psychologically. At onepoint, the detainee was observed by an interrogator to be having auditoryhallucinations in response to extreme sleep deprivation and other abuses. Casedocuments indicate that a BSCT psychologist was informed of the hallucinationsand did nothing to mitigate obvious and profound psychological harm that he/shewas made aware of.The findings of this study demonstrate that allegations by these nine detainees oftorture were corroborated by forensic evaluations by non-governmental medicalexperts and that DoD medical and mental health providers at GTMO failed to documentphysical and/or psychological evidence of intentional harm.In each case we reviewed, detainees alleged forms of abuse that are highly consistentwith torture as defined by the UN Convention Against Torture as well as the morerestrictive US definition of torture that was operational at the time The “enhanced interrogation” techniques that the detainees reported wereauthorized and implemented by the US in at least three theaters of operation,including GTMO. These acts have been recognized historically as torture and decadesof literature have demonstrated the severe physical and mental health consequencesof EITs The medical affidavits in each of the nine cases indicate that the specificallegations of torture and ill treatment are highly consistent with physical andpsychological evidence documented in the medical records and evaluations bynon-governmental medical experts. Using international standards The medical evaluations in this case series revealed evidence of severe physical andsevere and prolonged psychological pain as stipulated in the Bybee definition oftorture. But, according to the Bybee definition of torture, even if the requisitepain thresholds had been exceeded, the infliction of such pain had to be theinterrogator's “precise objective” to constitute torture. Thecondition of “specific intent” for torture is not only inconsistent withinternational law The medical doctors and mental health personnel who treated the detainees at GTMOfailed to inquire and/or document causes of the physical injuries and psychologicalsymptoms they observed. Psychological symptoms were commonly attributed to“personality disorders” and “routine stressors ofconfinement.” Temporary psychotic symptoms and hallucinations did not promptconsideration of abusive treatment.The documentation of torture and ill treatment in medicolegal evaluations conductedby non-governmental medical experts indicates that each of the detainees continuesto experience severe, long-term and debilitating psychological symptoms that arelikely to persist for many years, and possibly a lifetime.The failure of “non-clinical” medical monitors of interrogations and DoDclinical health providers to document medical evidence of torture is not surprising.OLC attorneys Jay Bybee and John Yoo attempted in 131 pages of legal memos The commission and/or concealment of acts of torture should never be justified by anyhealth professionals—clinical, non-clinical, military, or non-military. As theDeclaration of Tokyo states “The physician's fundamental role is toalleviate the distress of his or her fellow human beings, and no motive, whetherpersonal, collective or political, shall prevail against this higher purpose”The findings of this case series indicate that policy makers did not act in“good faith” to ensure “safe, legal, ethical, and effective”EITs as they have claimed The cases selected for review included only those for which the authors wereconsulted. The findings included in this commentary may not be generalizable toother GTMO detainees. The findings are based on medical records and case fileswhich, in some cases, are heavily redacted. Also, psychological evaluations inthe majority of cases consisted of proxy assessments. Despite these limitations,non-governmental medical evaluators had sufficient information to form theirmedicolegal assessments and to qualify any uncertainties related to limitedaccess to case information.The findings in these nine cases indicate that medical doctors and mental healthpersonnel assigned to the US Department of Defense neglected and/or concealedmedical evidence of intentional harm. The full extent of medical complicity inUS torture practices will not be known until there is a thorough, impartialinvestigation including relevant classified information. We believe that, untilsuch time as such an investigation is undertaken, and those responsible fortorture are held accountable, the ethical integrity of medical and other healingprofessions remains compromised.


Enabling innovation and access to health technologies remains a key strategy in combating infectious diseases in low- and middle-income countries (LMICs). However, a gulf between paying markets and the endemicity of such diseases has contributed to the dearth of R&D in meeting these public health needs. While the pharmaceutical industry views emerging economies as potential new markets, most of the world’s poorest bottom billion now reside in middle-income countries--a fact that has complicated tiered access arrangements. However, product development partnerships--particularly those involving academic institutions and small firms--find commercial opportunities in pursuing even neglected diseases; and a growing pharmaceutical sector in BRICS countries offers hope for an indigenous base of innovation. Such innovation will be shaped by 1) access to building blocks of knowledge; 2) strategic use of intellectual property and innovative financing to meet public health goals; 3) collaborative norms of open innovation; and 4) alternative business models, some with a double bottom line. Facing such resource constraints, LMICs are poised to develop a new, more resource-effective model of innovation that holds exciting promise in meeting the needs of global health. Please see Additional fileInfectious diseases remain a significant contributor to the burden of disease in low- and middle-income countries (LMICs). Leading communicable diseases from AIDS, tuberculosis and malaria to diarrheal diseases, measles, and lower respiratory infections claim upwards of eleven million lives in these countries each year. The burThe attainment of the Millennium Development Goals (MDGs) is closely entwined with progress in reducing the burden of infectious diseases. MDG 6 focuses on combating HIV/AIDS, malaria and other diseases while steps towards meeting MDG 4 , MDG 5  and MDG 7C (improving basic sanitation and sustainable access to safe drinking water) also relate to the treatment of infectious diseases. MDG 8E From triple therapy for AIDS and directly-observed therapy for TB to oral rehydration salts and vaccines for childhood killers like diarrhea and pneumonia, the past decade has witnessed significant advances. Between 2000 and 2010, 45 global health technologies were introduced for use in resource-limited settings, and the current R&D pipeline for global health includes 365 medical products at various stages of development[t over the past decade[Still many of these technologies remain out of reach to millions who might benefit. For LMICs as a group, the annual health expenditure per capita is just under US$200 as of 2010. While mt decade, less tht decade. This let decade,10. Sucht decade. Applying a systems thinking perspective, more might be done to reshape the enabling environment for innovating such health technologies. Meeting these twin goals of innovation and access is key to bringing technologies from bench to bedside. Focusing on the pharmaceutical value chain might offer insights on how best to ensure technology innovation and access appropriate to disease-endemic countries. Delivering effective artemisinin combination therapy for malaria provides a case example where several interventions along the value chain shape the availability and affordability of this treatment.Delivering Existing Health Technologies to Those in Need--Artemisinin Combination Therapy for Malaria""The Affordable Medicines Facility-Malaria (AMFm) has sought to stem irrational treatment approaches to malaria. AMFm worked to negotiate for lower prices of artemisinin combination treatment (ACT) with manufacturers, subsidize the purchase of ACTs through copayments, and support interventions that encourage rational use of ACTs. By sharply reducing the retail prices of ACTs, the initiative hoped to displace oral artemisinin monotherapies and other medicines, such as chloroquine and sulfadoxine-pyrimethamine, to which resistance had emerged. UNITAID, the Gates Foundation and DFID supported the piloting of this intervention with US$216 million while the Global Fund complemented this, committing up to US$127 million towards supporting interventions for scaling up ACT use effectively [.The premise and preliminary findings behind this pilot illustrate the complexity of delivering even existing innovations to those in need. Early findings from the Health Action International pricing survey in six African countries showed that the AMFm price bested the originator brand and the lowest-priced generic, approaching but not yet consistently beating the prices of irrational alternatives, like chloroquine and sulfadoxine-pyrimethamine [. In less than a year though, six out of eight pilot countries met or exceeded benchmarks for availability, price and market share of quality-assured ACTs, both in rural and urban areas [. Efforts in Tanzania showed that accredited drug dispensing outlets could complement these upstream interventions by increasing access to and dispensing of subsidized artemisinin combination therapy [. However, the volatility in artemisinin supply upstream has caused significant price fluctuations in the pricing of the active pharmaceutical ingredient of this drug. Though it may not offset entirely the greater demand for artemisinin from an expanded AMFm, the anticipated advent of artemisinin, sourced from microbial production, by late 2012 is a technology that may help stabilize and secure the supply of this critical drug for ACT [.thamine . In lesn areas . Efforttherapy . Howevefor ACT .Innovation can take several forms. For disease-endemic countries, the technology challenge may not only be one of novel invention, but also local adaptation of an existing technology. Such adaptation might be to target locally endemic strains, as for meningococcal or pneumococcal vaccines, where the introduction of such technologies in LMICs has lagged. Or such health technologies might require being lyophilized, kept in cold chain storage, or perhaps soon stabilized in silk films for tranOf course, encouraging innovation for disease-endemic countries is not necessarily the same as engaging disease-endemic countries in the process of innovating health technologies for their settings. Looking at industry-supported phase 3 clinical trials conducted by the twenty largest U.S.-based pharmaceutical companies, a third of such studies are now being conducted solely outside of the United States, and a majority of study sites now reside outside of the United States. Much ofIn considering access, several related dimensions--each corresponding to a different part of the value chain of delivering technologies--matter. The primary focus for technology innovation is therapeutic access, which refers to whether diagnostics, drugs or vaccines are under research and development or not in the pipeline. Financial and structural access issues also play important roles in enabling diffusion of such technologies. The failure to deliver existing technologies, like AIDS treatment or oral rehydration salts for children with diarrhea, illustrates the challenges of financial and structural access barriers, respectively. Therapeutic access refers to how well the R&D pipeline works, financial access to the market, and structural access to the delivery system.By deaths and DALYs, the focus on HIV/AIDS, tuberculosis and malaria on the global health landscape is understandable: the “Big Three” diseases account for over 4.3 million deaths per year. While tIn a survey of R&D projects focused on neglected diseases, BioVentures for Global Health found 218 R&D projects on AIDS, tuberculosis and malaria--over four times the number of projects on diarrheal diseases  and pneumococcal disease. By contrast, these other diseases of poverty, specifically various causes of diarrheal disease and pneumococcal infection, claim 3.8 million deaths each year. The numTraditional distinctions among Type I diseases  and Type II diseases  and Type III diseases (endemic only in developing countries) depend on the size of potential paying markets for these diseases. Such distinctions may help bound likely contributions and interest from the private sector in these areas of pharmaceutical discovery and R&D. Where there are no paying markets, market failures result.Bridging this gulf, public sector investments can play an important role in driving this innovation. Between 2007 and 2010, the G-Finder survey found that 97 percent of the research funding backing neglected disease research projects originates from high-income countries. Nearly As a market, emerging economies have caught the attention of the global pharmaceutical industry. On the one hand, the industry eyes the growing middle and upper classes of these emerging economies as potential paying customers. On the other hand, 960 million of the bottom billion in the world live in middle-income countries. This is in sharp contrast to two decades ago when over 90 percent of the poorest of the poor lived in low-income countries. Most of these poor people live in countries such as India, Pakistan, Indonesia, and Nigeria, which have graduated from low- to middle-income status.This has implications for pharmaceutical innovation and access. For example, in establishing tiering schemes that give preferential access, from licensed technology to product prices, this tension has made firms reluctant to offer such breaks to middle-income countries. This is reflected in the challenges that the Medicines Patent Pool faces in recruiting companies to license voluntarily their HIV/AIDS drugs for generic production as part of fixed-dose combinations. Similarly, the anchoring of the GlaxoSmithKline-initiated Pool for Open Innovation Against Tropical Neglected Diseases and WIPO Re:Search Consortium--both efforts to pool building blocks of knowledge and to license them royalty-free to those working on neglected diseases--places limits on geographic coverage to only least developed countries as a starting condition.This underscores the different circumstances facing emerging economies and other developing countries. The stark reality is that less than a quarter of all biomedical research publications and less than a third of all clinical trials in Africa even relate to diseases that comprise nearly 50 percent of the burden of disease on the continent. The samMobilizing public and private sector resources, product development partnerships (PDPs) have stepped in to address the market’s failure to bring forward treatments for neglected diseases. A study of 63 neglected disease projects at the end of 2004 tells an interesting story. Half ofA survey of product developers engaged in drug and vaccine R&D for neglected diseases suggested, however, that only 40 percent of such projects involved a PDP, with thEmerging economies may play an increasingly strategic role in this space. Already India and China are making significant investments in domestic R&D efforts. Among BRICS countries , foreign assistance to other developing countries has risen at near double-digit rates from 2005 to 2010.i), a product development partnership, to bring to market a new fixed-dosed artemisinin-based combination treatment, ASMQ, the first ACT with a three-year shelf life in tropical climates[For Brazil, health has been a significant component of the country’s foreign assistance budget. Brazil contributed approximately US$130 million to WHO and PAHO between 2005 and 2009 and pledclimates. FarmangInnovation for neglected diseases, more often than not, is viewed less as an exemplar to emulate and more as an exception. Just because pharmaceutical and biotechnology firms contribute to neglected disease projects, some might argue that this does not translate to new models of R&D collaboration from which broader, more generalizable lessons might be derived for more commercially viable therapeutic areas.The perception is, by value, that markets in LMICs are considered small; and the diseases, are typically classified as Type II or III. After all, over three-quarters of global expenditures on pharmaceuticals are spent on 16 percent of the world’s population living in high-income countries. HoweverSpurred initially by the struggle for affordable medicines to treat HIV/AIDS, a decade-long policy process--beginning with the WHO’s Commission on Intellectual Property, Innovation and Public Health, continuSeveral developments may shape and nurture the direction this approach to innovation emerging from developing countries takes. Important elements of this enabling environment include 1) access to building blocks of knowledge; 2) strategic use of intellectual property and innovative financing to meet public health goals; 3) collaborative norms of open innovation; and 4) alternative business models, some with a double bottom line.Access to the building blocks of knowledge is key to innovation and technology transfer. Journal subscription costs pose barriers to accessing the latest developments in research. In response, WHO has supported the Health InterNetwork Access to Research Initiative (HINARI). Working with publishers, HINARI provides tiered access to journal articles for low- and middle-income countries. This approach has been imperfect, with all BRICS countries, Indonesia, Thailand and other middle-income countries ineligible for the discounted subscription arrangements despite sizable poor populations and under-resourced research institutions in these countries.While such voluntary agreements provide work-around solutions to improved access to the research literature, industrialized countries have made significant strides to advancing an open access model for sharing journal publications. Departing from the traditional model of subscription-supported publication, open access journals raise revenues from other sources, ranging from endowments and membership dues to advertising and upfront submission or publication fees. As a result, published articles in open access journals are made available freely on-line without subscription barriers. A growing number of leading universities, from Harvard University to the Massachusetts Institute of Technology, have also established institutional, open access repositories where faculty may deposit their publications. Funders like the NIH and the Wellcome Trust have taken steps to require grantees to make available their journal publications in publicly accessible archives. The model of open access publication not only may have more universal applicability, both North and South, but also enables users to assemble relevant publications from multiple journals, without the barrier of subscription costs to each journal.The past decade has witnessed shortfalls in the supply of influenza vaccine to meet the H1N1 pandemic and heightened concerns over the spread of emerging infectious diseases like SARS and avian flu. Not wishing to be last in queue for a vaccine or treatment, developing countries have sought assurances from WHO’s Global Influenza Surveillance and Response System (GISRS) that the sharing of virus samples would result not just in vaccines for industrialized countries, but also affordable access for such technologies in their settings as well. The Pandemic Influenza Preparedness Framework lays out a standard material transfer agreement, a system for benefit sharing and for contributions from pharmaceutical manufacturers and public health researchers, and hortatory measures encouraging Member States to urge manufacturers to set aside vaccines for influenza strains with pandemic potential for stockpiling and use by developing countries, to engage in technology transfer efforts, and to make such vaccines and antivirals available under tiered pricing arrangements. WhetherAnticipating the need to scale up this technology, WHO has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or enhance their capacity to produce pandemic influenza vaccine. The Netherlands Vaccine Institute was not only enlisted to provide training, but also to support an influenza vaccine technology platform or hub to facilitate the transfer of technology to these countries. Building upon a “robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production,” next steps are being planned for work under this technology platform. Such teThe strategic management of intellectual property rights is central to securing access to these building blocks of knowledge. Even whPlasmodium falciparum, is such an example. This deposit into the pool of the European Bioinformatics Institute’s ChEMBL database and the U.S. NIH PubChem database provides wide access under a Creative Commons CC0 license (work dedicated to the public domain with waiver of copyright)[With varying degrees of resulting access and other forms of success, a patchwork of ad hoc tiering and pooling arrangements have emerged. Both policy instruments have their place in ensuring broader access to research inputs. Collaborating with the Medicines for Malaria Venture, GlaxoSmithKline’s release of the chemical structures and assay data of over 10,000 compounds with activity against the malaria parasite, pyright). Tieringpyright).As with open access initiatives, funders can set norms supportive of sharing knowledge and also lower the risks of crossing the valley of death from pre-clinical to clinical testing. The NIH recently launched the National Center for Advancing Translational Sciences (NCATS). Created to “catalyze the generation of innovative methods and technologies” that might bring diagnostics and therapeutics to first-in-human trials, NCATS provides a spectrum of intramural and contracted services that enable small firms and academic research institutions to secure needed preclinical support. FundersEstablishing collaborative norms of open innovation has deep roots in public sector funding of science. The Wellcome Trust and the U.S. National Institutes of Health (NIH) engaged leading centers involved in the Human Genome Project to agree to the Bermuda Rules, whereby investigators pledged to deposit gene sequences of every 1000 base pairs within 24 hours of completion into GenBank. The intIncreasingly, the pharmaceutical sector has recognized the value of open innovation. From MeMycobacterium tuberculosis genome. Their collective efforts made this possible in just four months. Supported with government funding, participants submit projects for open peer review, contribute to on-line efforts under a system of microattribution, and agree to sharing their work under a click-wrap license. In not pursuing a conventional path to drug discovery, OSDD hopes to “bring down the cost of drug discovery significantly by knowledge sharing and constructive collaboration” and “to discover new chemical entities and to make them generic as soon as they are discovered, thus expediting the process of drug discovery”[Taking this a step further, fledgling efforts to conduct open source innovation in biomedicine have also begun. By contrast, open source innovation involves openness and transparency with the goal of shared research collaboration, but also prevents third parties from acquiring proprietary rights over what is generated by the community. Notably, India’s Council for Scientific and Industrial Research has embarked on the Open Source Drug Discovery (OSDD) initiative, initially focused on TB drugs. Using a web-based platform, hundreds of volunteers at a network of universities, both in India and elsewhere, have collaborated on re-annotating the scovery”.For many neglected diseases, the case for an alternative business model is clear. On the demand side, the need to provide affordable health technologies responsive to public health needs and the local context of low- and middle-income countries is urgent. On the supply side, high volume, closer to marginal cost pricing might match this need. Fortunately, there is growing capacity among developing countries to respond. Developing country vaccine manufacturers already supply 64 percent of vaccines procured by UNICEF; and morjugaad innovation, a Hindi word meaning “an innovative fix; an improvised solution born from ingenuity and cleverness; resourceful” captures, in part, the spirit of such efforts[Bridging the supply and demand side, there is need for a more efficient model for R&D innovation. This will likely require innovation of both products and processes. Described by various names, the idea of  efforts. Others  efforts. However efforts.Working under the constraints of a resource-limited environment, such innovation must be resource-effective, but not substandard. This efficient use of resources is reflected in the Innovation Efficiency Index scoring of countries like China and India compared to developed countries. This index compares outputs from innovation against the constraint of available inputs for innovation in a country, and by this measure, China and India come out first and second in the world. PerhapsThe enabling environment for resource-effective innovation will likely accelerate not only health technologies for infectious diseases, but also for the growing burden of non-communicable diseases. Technologies like echocardiography have clinical value whether the valvular heart disease traces to rheumatic fever, drugs or atherosclerosis. The process of technology transfer, the clinical trial platforms, and the training of scientists also build towards the common purpose of bringing these new health technologies from bench to bedside.What is exciting for global health is that the world--both North and South--has much to benefit from these new approaches to innovation. Under increasing budget constraints themselves, industrialized countries might welcome cost-effective interventions born out of the genius of innovation under resource constraint. Such innovation might be potentially disruptive, in that a product targeted at the base of the economic pyramid--an initial market marginalized by competitors--might migrate “up market” displacing established technologies. From poi: Drugs for Neglected Diseases Initiative; G-FINDER: Global Funding of Innovation for Neglected Diseases; GISRS: Global Influenza Surveillance and Response System; H1N1: A subtype of the influenza A virus, also called swine flu; HINARI: Health InterNetwork Access to Research Initiative; HIV: Human immunodeficiency virus; LMIC: Low- and middle- income countries MDG:Millennium Development Goals NCATS:U.S. National Center for Advancing Translational Science NIH:U.S. National Institutes of Health OSDD:Open Source Drug Discovery PAHO:Pan-American Health Organization PDP:Product development partnership R&D:Research and development SARS:Severe acute respiratory syndrome TB:Tuberculosis UNAIDS:Joint United Nations Programme on HIV/AIDS UNITAID:An intergovernmental organization that works through market interventions to make life-saving products better and more affordable UNICEF:United Nations Children’s Fund U.S.:United States US$:U.S. dollars WHO:World Health Organization WIPO:World Intellectual Property Organization.ACT: Artemisinin-combination therapies; AIDS: Acquired immune deficiency syndrome; AMFm: Affordable Medicines Facility - malaria; ARV: Antiretrovirals; ASMQ: An ACT fixed-dose combination of artesunate and mefloquine; CC0: The “no rights reserved” Creative Commons licensing; ChEMBL: A database of drug-like small molecules affiliated with the European Molecular Biology Laboratory; BRICS: Brazil, Russia, India, China, and South Africa; DALY: Disability-adjusted life years; DFID: United Kingdom Department for International Development; DNDi).The Program on Global Health and Technology Access, of which ADS serves as the Program Director and QRE an Associate in Research, provides consultancy services on intellectual property management for a product development partnership, the Drugs for Neglected Diseases Initiative (DNDADS led in the conceptualization and design behind the overall organization of the manuscript and substantively contributed to the collection of information and data presented in this manuscript. ADS also substantially wrote the majority of the manuscript and also gave the approval of the final submitted version of the manuscript. QRE contributed to the analysis and research that provided the evidence and examples given in this paper. QRE also assisted ADS with the drafting of the manuscript. All authors read and approved the final manuscript.ADS is a Professor of the Practice of Public Policy and Global Health at Duke University in the Sanford School of Public Policy. He is also the founder and the Director of the Program on Global Health and Technology Access. Key focus areas of the Program's interdisciplinary work include developing alternative biopharmaceutical R&D models from precompetitive collaboration to public financing of R&D and evaluating models of innovation and access to health technologies. Dr. So has led the Strategic Policy Unit for ReAct, an independent global network for concerted action on antibiotic resistance; advised the Thematic Reference Group for Innovation and Technology Platforms for Infectious Diseases of Poverty, a working group of WHO’s Special Programme for Research and Training In Tropical Diseases; and served as a member of the U.S. Institute of Medicine's Committee on Accelerating Rare Disease Research and Orphan Product Development. He has authored works on innovation for global health R&D, including a commissioned paper for the Institute of Medicine on “Sharing Knowledge for Global Health” and a paper on “Approaches to Intellectual Property and Innovation that Meet the Public Health Challenge of AIDS” for the Global Commission on HIV and the Law. This year, Dr. So was named one of the Robert Wood Johnson Foundation’s Investigators in Health Policy Research. Previously, Dr. So was Associate Director of the Rockefeller Foundation’s Health Equity program, where he co-founded a cross-thematic program on charting a fairer course for intellectual property rights, shaped the Foundation’s work on access to medicines policy in developing countries, and launched a multi-country program in Southeast Asia, “Trading Tobacco for Health,” focused on enabling countries to respond to the public health challenge of tobacco use. QRE is an Associate in Research for the Program on Global Health and Technology Access, helping lead analyses for the global health policy research projects of the Program.Multilingual abstracts in the six official working languages of the United Nations.Click here for file


Safe water and sewage systems must be constructed to prevent future epidemics. After epidemic cholera emerged in Haiti in October 2010, the disease spread rapidly in a country devastated by an earthquake earlier that year, in a population with a high proportion of infant deaths, poor nutrition, and frequent infectious diseases such as HIV infection, tuberculosis, and malaria. Many nations, multinational agencies, and nongovernmental organizations rapidly mobilized to assist Haiti. The US government provided emergency response through the Office of Foreign Disaster Assistance of the US Agency for International Development and the Centers for Disease Control and Prevention. This report summarizes the participation by the Centers and its partners. The efforts needed to reduce the spread of the epidemic and prevent deaths highlight the need for safe drinking water and basic medical care in such difficult circumstances and the need for rebuilding water, sanitation, and public health systems to prevent future epidemics. Vibrio cholerae serogroup O1 or O139, which produce cholera toxin. Symptoms and signs can range from asymptomatic carriage to severe diarrhea, vomiting, and profound shock. Untreated cholera is fatal in ≈25% of cases, but with aggressive volume and electrolyte replacement, the number of persons who die of cholera is limited to <1%. Since 1817, cholera has spread throughout the world in 7 major pandemic waves; the current and longest pandemic started in 1961  for polio, measles-rubella, and diphtheria-tetanus-pertussis vaccines , and only one fourth of seriously ill persons are taken to a health facility  camps, while an estimated 600,000 persons moved to undamaged locations.V. cholerae . On November 5–6, Hurricane Tomas further complicated surveillance and response efforts, and many persons fled flood-prone areas. By November 19, cholera was laboratory confirmed in all 10 administrative departments and Port-au-Prince, as well as in the Dominican Republic and Florida  to monitor the epidemic spread and to position cholera prevention and treatment resources across the country. In the first week of the outbreak, MSPP’s director general collected daily reports by telephone from health facilities and reported results to the press. On November 1, formal national cholera surveillance began, and MSPP began posting reports on its website . The training-of-trainers graduates subsequently led training sessions in their respective departments; 521 persons were trained by early December.CDC developed training materials (in French and Creole) on cholera treatment and on November 15–16 held a training-of-trainers workshop in Port-au-Prince for locally employed clinical training staff working at PEPFAR sites across all 10 departments. These materials were also posted on the CDC website , supported through the Haitian government and other organizations, staffed local first aid clinics, taught health education classes, and led prevention activities in their communities. Training materials for CHWs developed by CDC were distributed at departmental training sessions, shared with other nongovernmental organization (NGO) agencies, and used in a follow-up session for CHWs held on March 1–3, 2011 (see pages 2162–5). The CHW materials discussed treating drinking water by using several water disinfection products; how to triage persons coming to a primary clinic with diarrhea and vomiting; making and using ORS; and disinfecting homes, clothing, and cadavers with chlorine bleach solutions. Materials were posted on the CDC website as well.Supply logistics were daunting as cholera spread rapidly across Haiti. Sudden, unexpected surges in cases could easily deplete local stocks of intravenous rehydration fluids and ORS sachets, and resupplying them could be slow. The national supply chain, called Program on Essential Medicine and Supplies, was managed by MSPP, with technical assistance from the Pan American Health Organization, and received shipments of donated materials and distributed them to clinics.Early in November the USG provided essential cholera treatment supplies through the US Agency for International Development’s Office of Foreign Disaster Assistance (OFDA) to the national warehouse and IDP camps. CDC staff also distributed limited supplies to places with acute needs. To complement efforts by MSPP and aid organizations to establish preventive and treatment services, OFDA provided emergency funding to NGO partners with clinical capacity.When surveillance and modeling suggested that the spread of cholera across Haiti could outpace the public health response, the USG reached out to additional partners to expand cholera preventive services and treatment capacity. PEPFAR clinicians were authorized to assist with clinical management of cholera patients and participated in clinical training across the country. In December, CDC received additional USG emergency funds and awarded MSPP and 6 additional PEPFAR partners $14 million to further expand cholera treatment and prevention efforts through 4,000 CHWs and workers at 500 community oral rehydration points. Funds were also used to expand cholera treatment sites at 55 health facilities. In addition, CDC established the distribution of essential cholera supplies to PEPFAR partners through an existing HIV commodities supply chain management system.To increase access to treated water and raise awareness of ways to prevent cholera, a consortium of involved NGOs and agencies, called the water, sanitation, and hygiene cluster, met weekly. Led by Haiti’s National Department of Drinking Water and Sanitation and the United Nation’s Children’s Fund, the members of this cluster targeted all piped water supplies for chlorination, and began distributing water purifying tablets for use in homes throughout Haiti. CDC helped the National Department of Drinking Water and Sanitation monitor these early efforts with qualitative and quantitative assessments of knowledge, attitudes, and practices. Emergency measures, especially enhanced chlorination of central water supplies, were expanded in the IDP camps because of the perceived high risk. OFDA and CDC provided water storage vessels, soap, and large quantities of emergency water treatment supplies for households and piped water systems. Distributing water purifying tablet supplies to difficult-to-reach locations remained a challenge.Beginning October 22, MSPP broadcast mass media messages, displayed banners, and sent text messages encouraging the population to boil drinking water and seek care quickly if they became ill. Early investigations affirmed the public’s need for 5 basic messages:1) drink only treated water; 2) cook food thoroughly ; 3) wash hands; 4) seek care immediately for diarrheal illness; 4) and give ORS to anyone with diarrhea. In mid November, focus group studies in Artibonite indicated that residents were confused about how cholera was spreading and how to best prevent it, but they understood the need to treat diarrheal illness with ORS, how to prepare ORS, and how to disinfect water with water purification tablets . On NoveCompared with Haiti’s experience, the epidemic has been less severe in Dominican Republic. Though the countries share the island, conditions in Dominican Republic are better than in Haiti: the IMR is one third that of Haiti, gross domestic product per capita is 5× greater, and 86% of the population has access to improved sanitation. Within 48 hours of the report of cholera in Haiti, the Ministry of Health in the Dominican Republic and CDC established the capacity for diagnosing cholera at the national laboratory; the first cholera case was confirmed on October 31. Dominican officials quickly planned for cholera treatment centers in at least 70 hospitals, trained staff in primary care clinics and prison dispensaries, and stocked medical supplies sufficient to treat 20,000 cases. By December, 75% of doctors had received training in the management of cholera. Chlorination levels and water quality were monitored in municipal water systems across the country. The border with Haiti was not closed, and no major trade disruptions occurred. Sanitation improvements were instituted in border markets, schools, institutions, and mass gatherings. Public education in the first 3 months included dissemination of 4,300 mass media messages, nearly 3 million flyers, 50,000 classroom booklets for teachers, and a volunteer effort to visit 1 million homes. A survey of the knowledge, attitudes, and practices of residents of Santo Domingo showed that 89% had received cholera prevention messages. Transmission was limited, but sustained, in mid December and continued at low levels through the spring. One large outbreak affected guests at a wedding in January 2011, including some visitors from Venezuela and the United States (see pages 2172–4). From October 21, 2010, through July 30, 2011, a total of 14,598 suspected cases of cholera were reported; 256 persons died   as it did in 2011. The lack of a history of cholera in the Caribbean makes prediction a challenge because cholera seasonality varies from place to place. Other unknown factors are what proportion of the population has now been immunized by natural infection and how long this immunity might last. In a setting in which the population has poor access to clean water and sanitation, endemic transmission could persist for years if the epidemic strain finds long-term reservoirs in brackish coastal waters. Antimicrobial drug resistance may emerge in toxigenic Whether the epidemic will spread beyond Hispaniola is also uncertain. With the highest IMR in the Western Hemisphere , Haiti is uniquely susceptible. Other countries in the Caribbean region have an IMR less than half that of Haiti , which suggests less risk for sustained transmission. If shipmasters leaving Haitian ports would exchange their ships’ ballast water at sea, they could help prevent the transfer of epidemic cholera from harbor to harbor.The origin of cholera in Haiti also raises questions. It has been suggested that United Nations peacekeeping troops from Nepal may have introduced cholera into Haiti (A continuing challenge facing Haiti is how to manage cholera treatment with limited resources. Cholera training for doctors and nurses should be added to clinical curricula. By increasing use of ORS and expanding the antimicrobial drug treatment of hospitalized patients, intravenous fluid needs might be decreased, without posing an undue risk for antimicrobial drug resistance. Focusing on supply chain logistics is critical to ensuring the maintenence of tenuous buffer stocks of supplies.Residents of IDP camps have been largely spared from the outbreak because of safer water supplies and improved sanitation in the camps, but preserving that protection as persons move on to homes without piped water or sewage systems will be a challenge. Encouraging and empowering residents to disinfect drinking water in their homes, schools, and clinics by using chlorine products has been effective in many African and Latin American countries and is a practical interim solution for Haiti (The role of oral cholera vaccine in the immediate postepidemic period continues to be evaluated (The existing PEPFAR program that provided support for clinical care delivery and public health infrastructure was a powerful framework that sustained the national cholera response in Haiti. Through additional USG funding for PEPFAR partners, an expanded cadre of Haitian clinicians and CHWs received cholera training, resulting in expanded access to cholera treatment throughout Haiti. In addition, the postearthquake enhancement of diagnostic laboratory testing capacity for reportable diseases enabled health officials to quickly confirm the cholera outbreak and monitor antimicrobial drug susceptibility of the bacterial strains.The Haitian epidemic shows that as long as cholera exists anywhere in the world, many who drink untreated water and live in areas of poor sanitation are at risk. The epidemic also shows how cholera can emerge where it is least expected. Despite heightened efforts to detect acute watery diarrhea among persons in urban IDP camps, cholera appeared first in rural Haiti, just as in Mexico in the 1990s, where it first emerged unexpectedly in a remote mountainous region (The Haitian experience also shows the continued success of the rehydration treatment strategies first developed in Bangladesh and refined over the past 40 years. With training and adequate supplies and treatment facilities, hospitalized case-fatality ratios of <1% were achieved. If the improvements in ORS use in treatment of diarrheal illness are sustained, these actions could reduce childhood deaths permanently.The more moderate course of the epidemic in the Dominican Republic and the relative sparing of the IDP camps in Haiti illustrate how safer water and better sanitation can prevent transmission. Without these basic public health bulwarks, the risk for recurrent cholera and other major waterborne diseases remains high. In the interim, safe water and handwashing practices should be integrated into household and community settings (Global experience with cholera suggests that the epidemic in Haiti could last for years. Although case counts decreased in early 2011, cases again increased with the onset of the rainy season, and conditions that permit waterborne transmission persist. Improving Haiti’s water and sanitation infrastructure is critical to achieving the same profound health gains brought by improved water and sanitation infrastructure elsewhere (The World Health Organization estimates that meeting the global Millennium Development Goal for improving access to safe water and improved sanitation would have a huge return on investment worldwide (