Evaluation of tamper resistant formulations (TRFs) and classwide Risk Evaluation and Mitigation Strategies (REMS) for prescription opioid analgesics will require baseline descriptions of abuse patterns of existing opioid analgesics, including the relative risk of abuse of existing prescription opioids and characteristic patterns of abuse by alternate routes of administration (ROAs). This article presents, for one population at high risk for abuse of prescription opioids, the unadjusted relative risk of abuse of hydrocodone, immediate release (IR) and extended release (ER) oxycodone, methadone, IR and ER morphine, hydromorphone, IR and ER fentanyl, IR and ER oxymorphone. How relative risks change when adjusted for prescription volume of the products was examined along with patterns of abuse via ROAs for the products.®) Connect assessments of 59,792 patients entering treatment for substance use disorders at 464 treatment facilities in 34 states and prescription volume data from SDI Health LLC, unadjusted and adjusted risk for abuse were estimated using log-binomial regression models. A random effects binary logistic regression model estimated the predicted probabilities of abusing a product by one of five ROAs, intended ROA , snorting, injection, chewing, and other.Using data on prescription opioid abuse and ROAs used from 2009 Addiction Severity Index-Multimedia Version (ASI-MVUnadjusted relative risk of abuse for the 11 compound/formulations determined hydrocodone and IR oxycodone to be most highly abused while IR oxymorphone and IR fentanyl were least often abused. Adjusting for prescription volume suggested hydrocodone and IR oxycodone were least often abused on a prescription-by-prescription basis. Methadone and morphine, especially IR morphine, showed increases in relative risk of abuse. Examination of the data without methadone revealed ER oxycodone as the drug with greatest risk after adjusting for prescription volume. Specific ROA patterns were identified for the compounds/formulations, with morphine and hydromorphone most likely to be injected.Unadjusted risks observed here were consistent with rankings of prescription opioid abuse obtained by others using different populations/methods. Adjusted risk estimates suggest that some, less widely prescribed analgesics are more often abused than prescription volume would predict. The compounds/formulations investigated evidenced unique ROA patterns. Baseline abuse patterns will be important for future evaluations of TRFs and REMS. This article uses self-report data collected from individuals entering substance abuse treatment from a large number of treatment facilities across the country to examine the relative risks of abuse of specific prescription opioid compounds and formulations and to describe route of administration (ROAs) patterns that are characteristic of the different opioid compounds and formulations. A more comprehensive understanding of the abuse patterns of these medications is critical to inform current public health efforts intended to manage the risk for abuse of these important medications. While long-term opioid therapy for chronic noncancer pain remains controversial, such use has increased substantially over the past few decades , as has ® or other oxycodone preparation  or the hydrocodone combination products   . This l) . Simila) e.g., ,7,8).,8.® or oThe premise of this article is that it is important to differentiate the relative risks of abuse of various prescription opioid compounds and formulations as well as the characteristic ROA patterns of the various compounds. The need for such specific data has increased due to two, relatively recent developments: the advent of the so-called abuse deterrent (ADF) or tamper resistant formulations (TRF) and the Food and Drug Administration's (FDA) recent efforts to employ Risk Evaluation and Mitigation Strategies (REMS) for specific prescription opioids and formulations.Several pharmaceutical companies have begun to introduce ADFs or TRFs that are intended to decrease levels of abuse of prescription opioid medications e.g., -13). Man. Man13])The second development suggesting the need to discriminate abuse patterns of compounds and formulations are recent efforts by the FDA to subject specific prescription opioids and formulations to REMS, as well as efforts to establish a classwide REMS for extended-release opioids . CurrentThere are, to be sure, several articles that examine abuse patterns of specific compounds, formulations or products. For example, Kelly and colleagues 2008)[008[2] coAn extensive review of the public datasets administered by SAMHSA is beyond the scope of this brief review. However, two SAMHSA datasets do provide some compound and product-specific data: the Drug Abuse Warning Network (DAWN) dataset, which monitors drug-related visits to hospital emergency departments and drug-related deaths investigated by medical examiners and coroners, and the National Survey on Drug Use and Health , which p® data stream, the ASI-MV® Connect network. These authors present the relative percentages of individuals entering treatment for substance abuse at participating treatment centers across the country who report abuse specific compounds and products in the past 30 days. These data suggest that most prescription opioid abusers reported using a hydrocodone product in the past 30 days, followed closely by any oxycodone (both IR and ER), and followed more distantly by analgesic methadone, morphine, fentanyl and hydromorphone products. These authors report data showing that hydrocodone products are most always taken orally and almost never snorted or injected. Other compounds are also taken orally, but oxycodone ER products tend to be snorted and injected more often in this population of presumably hard core abusers, while morphine products are injected more often than taken orally. While these results are interesting and useful, there is no literature of which we are aware that specifically compares the relative risk of abuse of prescription opioid compounds and formulations. Nor is there a comprehensive comparison of ROA pattern differences among these compounds and formulations.The only published report, of which we are aware, that explicitly presents data on relative rankings of abuse of prescription opioid compounds and products, as well as compound-specific ROA patterns is Butler and colleagues' (2008) report oWhen considering the issue of relative abuse of compounds and formulations of prescription opioids, it is critical to consider how the raw counts of abuse cases or events are adjusted in order to compare risk of abuse across medications. In the literature on prescription opioid abuse, there is considerable discussion on this topic along with various proposals for the "best" denominator e.g., ,23,24). ,24. 23,2In the work reported here, we are interested in examining the unadjusted relative risks of abuse of seven prescription opioid compounds and, when appropriate, their immediate release and extended release formulations, similar to the relative rankings reported by Butler et al. (2008). We also®) that collects data on substances used and abused by individuals in treatment for substance use disorders within a national network of substance abuse treatment centers. The Addiction Severity Index (ASI) is a standard intake assessment designed for use on admission to drug and alcohol treatment )Another limitation of the ASI-MV Connect data is that this dataset does not draw from a probability-based sample and, while having broad, national reach, does not provide comprehensive coverage of the US. The data collected by the ASI-MV Connect system are intended to provide sentinel population surveillance of substance abuse patterns in the US, but these data are yet to achieve national representativeness. The presented results are not nationally representative and are not intended to be used for estimating national incidence and prevalence rates. Furthermore, the population represented is not randomly selected. It consists of those who seek treatment for substance abuse and who have access to a substance abuse facility. The sample utilized is a convenience sample of patients assessed at treatment facilities that are part of the ASI-MV Connect network. The sample does not represent individuals who misuse or abuse prescription opioids but are not in treatment, nor does it include those in treatment but at treatment facilities not included in the ASI-MV Connect network, and the findings may not be generalizable to all patients with substance use disorders in treatment. Approximately 60% of cases in the ASI-MV Connect data  . As geneThis study provides a comprehensive examination of the relative risks of abuse and ROA patterns of 11 compounds and formulations of prescription opioids in an at risk population of substance abusers in treatment. Using data from the ASI-MV Connect network of treatment centers across the country, relative risks of abuse were examined using unadjusted risks (based on the number of abusers of a particular compound/formulation relative to other prescription opioid abusers) and after adjusting for prescription volume. Results suggest that some drugs known to be widely abused, especially hydrocodone and IR oxycodone products, are abused less often than their prescribed volume would predict, while other drugs, such as methadone, morphine, hydromorphone, fentanyl and oxymorphone, are abused more often than their prescribed volume would predict. In addition, these data were examined to elicit ROA patterns that distinguish the various compounds/formulations, some of which  tend to be used through the intended ROA , while others  are significantly more likely to be injected than other prescription analgesics. Establishing baselines of abuse risk and ROA patterns is necessary in order to adequately test the impact of the recently approved and marketed TRFs and to evaluate the effectiveness of classwide REMS for prescription opioids.The authors declare that they have no competing interests.SFB, RB, TAC, and TD participated in the design of the study and performed the statistical analysis. SFB, RB, and SHB conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


Jan Lötvall  and Marca Wauben  organized it in a very friendly way in a beautiful venue, all of which was ideal in promoting open and successful scientific exchanges. In total, 50 participants were selected from over 100 applications, based on their expertise in the field of extracellular RNA and/or vesicles  over several years. Ten percent of the participants came from Australia/Asia, with the remainder equally represented from Europe and the Americas. In addition, a WebEx access to the PowerPoint presentations was set up. This allowed for approximately 50 additional ISEV members to participate remotely in the seminar.The workshop focused on extracellular vesicle RNA (evRNA). It was organized by the International Society for Extracellular Vesicles  extracellular vesicle (EV) isolation; (2) evRNA isolation; (3) evRNA analysis by hybridization arrays, qPCR; (4) evRNA analysis by deep sequencing and bioinformatics; (5) artificial RNA loading/engineered vesicles; and (6) analysis of functional transfer of evRNA. The conclusions and/or the major issues raised during each round-table group were discussed in plenary sessions at the end of each day.Most discussed issues included (1) level of purification of EV preparations and the need to improve and share purification and separation protocols; (2) presence of RNA inside versus outside EVs and relevance of RNase treatment to address this issue; (3) absolute and relative amounts of mRNA, miRNA, and other non-coding RNA, including ribosomal RNA in EVs; (4) definite demonstration of a functional mRNA and/or miRNA transfer between cells of the same organisms via EVs (participants agreed that a transfer of virus-derived miRNA via infected cell-derived vesicles had been convincingly demonstrated).Journal of Extracellular Vesicles (JEV), in particular for phrasing recommendations for purification of EVs and analysis of their RNA cargo.From this, the participants will go on to coordinate their efforts to prepare several ISEV Position Papers, to be published in the As Secretary General of ISEV, I want to deeply thank Jan and Marca for their very efficient efforts to organize such an interactive and useful workshop. I also want to thank the other ISEV board members who attended this meeting and who participated in its smooth organization , Xandra Breakefield and Fred Hochberg who efficiently chaired two round-tables, and all the attendees for their eager and constructive participation.This event will definitely help to improve the field, by guiding and enhancing investigators to achieve the best experimental quality in their research on EVs and evRNA.INSERM U932, Institut Curie, Paris, FranceEmail: clotilde.thery@urie.frClotilde Théry


This joint statement argues for a comprehensive, integrated cholera response in Haiti. The cholera epidemic in Haiti is particularly devastating because of the vulnerability of Haiti's population after the January 12, 2010, earthquake, the long-standing weakness of its health, water, and sanitation systems, and the observed virulence of the El Tor hybrid strain. From October 19, 2010—when the first cases were confirmed in the National Public Health Laboratory—to April 4, 2011, 274,418 cases of cholera and 4,787 deaths related to cholera had been reported across all ten departments of Haiti The Haitian Ministère de la Santé Publique et de la Population  and the Direction Nationale de l'Eau Potable et de l'Assainissement  have, with the support of many nongovernmental and international groups, made great strides against cholera. Case-fatality rates have dropped to 2.1% from 7% at the outset of the epidemic (and up to 10% in certain regions); incidence has also declined across Haiti, according to recent reports Given the likelihood of case resurgence and endemicity of cholera in Haiti, this document argues for a comprehensive, integrated strategy for cholera prevention and care in Haiti. We must reduce suffering and preventable death in the short term, and we must build effective water, sanitation, and health delivery infrastructure to fortify Haiti against cholera and other diseases of poverty in the long term.The document identifies three principal goals. First, we must continue aggressive case finding and scale up treatment efforts, including oral rehydration therapy, intravenous rehydration, antibiotic therapy (for moderate and severe cases), and complementary supplementation with zinc and vitamin A. Second, we must shore up Haiti's water infrastructure by building systems for consistent chlorination and filtration at public water sources and by distributing point-of-use water purification technologies. We must also strengthen sanitation infrastructure by improving and expanding waste management facilities (such as sewage systems and latrines) and waste monitoring. Third, we must link prevention to care by bolstering surveillance, education campaigns , and water, sanitation, and hygiene (WASH) efforts. Prevention must also include advocacy for scaled-up production of cholera vaccine and the development of a vaccine strategy for Haiti. A vaccination campaign should be implemented if adequate vaccine and resources can be mobilized without undermining efforts to treat acutely ill patients or strengthen water and sanitation infrastructure.This document identifies key challenges and outlines the components of a comprehensive cholera response to aid medical and public health practitioners in Haiti and elsewhere. With leadership from the Haitian government, we must work together to bolster responses to the acute problem of cholera today and strengthen Haiti's health, water, and sanitation infrastructure to prevent similar outbreaks in the future.Long before the devastating earthquake on January 12, 2010, Haiti struggled beneath the burdens of intractable poverty and ill health. The poorest country in the Western Hemisphere, Haiti also faces some of the highest rates of maternal and infant mortality—widely used indicators of the robustness of a health system—in the world  made these rural regions vulnerable to the rapid spread of waterborne disease. While most IDP camps have been supplied with potable water, large urban slums have had to rely on existing water sources—some of them containing Public suspicion  were documented on October 19, 2010 [S4]. Within days, the National Public Health Laboratory (LNSP) in Haiti had isolated Cholera is expected to be most severe among immunologically naïve populations As of April 4, 2011, the MSPP reported 274,418 cases of cholera and 4,787 deaths attributed to cholera across all ten of Haiti's departments. The overall observed case-fatality rate was 1.7% The reduction of case-fatality rates to under 2% reflects the implementation of rapid treatment and case management efforts . Yet as During the first 2 months of the epidemic, cholera spread most rapidly in the central and northern parts of the country [S9] Overall incidence in IDP camps has remained low. (Some camps have reported mere dozens of cases.) This achievement is chiefly thanks to the work of the Ministère de la Santé Publique et de la Population (MSPP), Direction Nationale de l'Eau Potable et de l'Assainissement (DINEPA), and many partnering institutions participating in water, sanitation, and hygiene (WASH) programs. Such efforts have, among other things, made safe drinking water available—mostly for free—to camp-dwellers. Nonetheless, poor sanitation conditions among the camps could lead to rapid disease transmission if access to clean water declines, and recent doubts about the “sustainability” of free water distribution threaten to undermine such access.V. cholerae, some evidence suggests that the hybrid El Tor strains in Haiti cause more asymptomatic cases, persist longer in the environment, and exist in higher concentrations of bacteria in feces (including in asymptomatic cases) [S10] Compared with previous strains of V. cholerae, HIV, or Mycobacterium tuberculosis travel freely throughout this web. Cases traceable to the Haitian outbreak have already been reported in the Dominican Republic, Venezuela, Florida, and Massachusetts [S11] If past is prologue, there is little reason to believe that the “Haitian” cholera epidemic will remain strictly Haitian for long. Haiti is part of a web of global connections, and pathogens like A history of poverty, natural disaster, neglected public water and sanitation systems, and under-resourced health infrastructure has magnified the impact of cholera in Haiti. Some have called these conditions a “perfect storm for a massive epidemic of cholera” [S12] Ongoing efforts led by the Haitian government and local and international relief teams have already reduced incidence and case-fatality rates across the country. But many medical and public health teams lack the tools of their trade—including oral rehydration salts (ORS), intravenous solution, antibiotics, vaccines, soap, cholera cots, ambulances—and the rainy season (May–October) is approaching. We must move together to marshal the tools needed to control the epidemic and to fortify Haiti against cholera for the long term. Divisions over the respective roles of prevention and care are as senseless as those over the use (or lack thereof) of vaccines and antibiotics; in the face of cholera's challenge to Haiti and the world, we can accept nothing less than complementary and comprehensive prevention and care.Considering the observed virulence of this El Tor strain and the fragility of the Haitian health system, aggressive case finding and treatment must be scaled up. Treatments are inexpensive, effective, and can be coordinated through existing referral and communication systems. Although a network of treatment sites is in place, too many patients are unable to get the medical care they need or arrive at cholera treatment centers in time. Not only do these individuals face the debilitating symptoms of cholera (sometimes ending in death), they continue to spread infectious organisms. We must expand case finding, patient transport, and treatment and integrate such efforts into the public health system to facilitate responses to future cholera epidemics.Most of the hundreds of thousands of patients who have received care to date have not reached cholera treatment sites as a result of case-finding efforts; they have fallen ill and been brought in by their families, sometimes too late in situ care remains a bottleneck to scaling up cholera treatment, especially in rural areas. Ambulances are in short supply However, patient transport and in situ—is the key to saving lives. World Health Organization (WHO) guidelines provide a framework for managing cholera treatment based on case severity Treating dehydration—with ORS and intravenous fluids, both inexpensive and deliverable But treatment cannot stop with rehydration: patients with moderate and severe disease can still die from persistent fluid loss while receiving ORS. These patients need intravenous rehydration and antibiotic therapy. In addition, innovative therapeutics like rice-based ORS, zinc supplements, vitamin A, and deworming agents should be integrated with existing treatment efforts. Most ORS is glucose-based, but some studies have found rice-based varieties to be more effective, particularly in reducing mean stool output Given Haiti's fragile health system and the observed virulence of the hybrid El Tor strain, there is growing consensus about the urgency of making antibiotic therapy available for all moderate and severe cases of cholera . Policy has shifted in this direction: most global public health policymakers—including the WHO and the Pan American Health Organization (PAHO), CDC, MSPP, and the International Centre for Diarrhoeal Disease Research, Bangladesh —now recommend antibiotics for all moderate and severe disease First, antibiotics have been shown to shorten the duration of symptomatic cholera and therefore limit life-threatening dehydration. The current strain in circulation in Haiti is susceptible to doxycycline and azithromycin, resistant to nalidixic acid and sulfisoxazole (a marker for co-trimoxazole resistance), and has reduced susceptibility to ciprofloxacin Second, antibiotic use brings public health benefits by reducing transmission. Antibiotic treatment can cut stool volume in half Third, expanding access to antibiotic treatment for all moderate and severe cases would mitigate the strain on the health system by decreasing the severity of illness and duration of inpatient care  In addition to providing antibiotic treatment for all moderate and severe cases, we suggest launching a closely monitored study about the efficacy of these drugs for mild cases and for prophylactic use among certain vulnerable populations, such as family members, health care workers, and cellmates of infected prisoners. Some evidence from past epidemics in Tanzania and Ecuador suggests that chemoprophylaxis may lead to bacterial resistance without compensatory gains in survival A triage system of independent treatment sites—cholera treatment centers (CTCs) and cholera treatment units (CTUs)—has been deployed in Haiti There are substantial delivery challenges in both urban and rural Haiti. On the one hand, densely populated urban areas, including slums and IDP camps, are a volatile setting for fecal–oral bacterial transmission. On the other hand, many populations in well-managed camps have better access to treated drinking water  Rural regions, where the majority of cholera cases have been recorded, face many delivery challenges, including large distances between patients and treatment centers, poor infrastructure, inadequate transport services, and insufficient health personnel [S18]. Médecins Sans Frontières, an international nongovernmental organization (NGO) that has provided health care in rural Haiti for decades, has stressed that rural communities are at high risk of recurrent cholera outbreaks One of the greatest obstacles to the effective delivery of health services in Haiti is the lack of health personnel. Haiti faced a shortage of health care workers prior to the cholera epidemic, and in early December 2010, PAHO called for an additional 350 doctors, 2,000 nurses, 2,200 support staff, and 30,000 community health workers (CHWs) to respond to the outbreak in situ, including in rural areas As the epidemic lingers in Haiti, CHWs should be the main line of defense against case resurgence. CHWs have been an integral part of effective community-based tuberculosis and HIV/AIDS prevention and care in Haiti Training initiatives have contributed to declining incidence and case-fatality rates. Cholera management skills must now be integrated into the regular training package for all health workers.The cholera epidemic is a symptom of Haiti's long history of water insecurity.Although some NGOs have put resources into local water projects over the years, private projects cannot replace a robust public sector water system [S20]. But political instability and crippling debt, among other factors, have kept the Haitian government from providing a safe supply of drinking water for its citizens. Almost a decade before the 2010 earthquake, Haiti was ranked last of 147 countries on the Water Poverty Index (a measure of water security) Haiti's fragile water infrastructure received another blow in the January 2010 earthquake. One month after the outbreak, 521 of 1,356 IDP camps listed by the United Nations (UN) shelter cluster had no water or sanitation services Current efforts to prevent transmission of cholera in Haiti must be continued at the same time that treatment and filtration systems at public water sources are strengthened in the long term. In the short term, point-of-use treatment and filtration technologies should also be rolled out to improve immediate access to clean water on a household level. Furthermore, working in conjunction with DINEPA and the Ministère des Travaux Publics Transports et Communications  would allow NGO projects to build the capacity of municipal water systems and therefore improve Haiti's long-term water security.On the health provider end, ORS must be prepared and stored in sanitary conditions or it can do more harm than good. One study in Guinea-Bissau found that ORS prepared in an open tub was highly susceptible to bacterial contamination. Storing ORS in a narrow-mouthed spigot container and rinsing vessels with chlorinated water reduced such contamination [S23] On the household end, point-of-use water purification tools can help prevent diarrheal illness, even in settings of poverty and water insecurity. For example, household water treatment and safe storage (HWTS) technologies offer families an independent means of water treatment and storage, and they have been shown to reduce waterborne disease transmission—even during epidemics. Studies estimate 30%–40% reductions in diarrheal disease due to improved household drinking water quality at the point of use [S24] V. cholerae contamination Boiling and solar disinfection can be difficult to deliver in Haiti due to high costs and infrastructural constraints. Point-of-use filtration/disinfection units and sachets combining flocculation , chlorination, and safe storage are affordable, deliverable in resource-poor areas, and produce enough safe water for multiple households [S25] Although household-based purification systems should be deployed widely, strengthening Haiti's public water system remains the best way to improve water security in the long term. As noted, 70% of Haiti's population lacked access to potable water before the earthquake Some have suggested that household-based interventions are more effective at preventing diarrheal disease than interventions at the source [S30] V. cholerae in excrement As noted, close patient contacts  are at particularly high risk of infection because of the hyperinfectious state exhibited by First, hand-washing with soap can decrease the risk of contracting most diarrheal diseases [S31] Second, better sewage systems and latrines would help curb cholera transmission. Pit latrines are a good option for rural areas, as they would strengthen sanitation infrastructure. In the crowded and concrete streets of Port-au-Prince, above-ground sewage tanks are the best available short-term solution. As part of the city's reconstruction, however, permanent underground sewage systems must be put in place to decrease the likelihood of fecal–water contamination and transmission of waterborne disease [S32] V. cholerae O1 and vibriophages—signaled a cholera outbreak 1 month in advance, facilitating the rapid implementation of prevention measures [S33] Third, waste monitoring can decrease the spread of waterborne disease and also improve outbreak prediction. A study in Peru found that waste and water surveillance—including weekly sewage analysis for Fourth, safe disposal of cadavers must also be integrated into the broader waste management system. Cadaver management poses many challenges, including honoring cultural practices related to dying and death, disinfecting cadavers, and identifying burial sites that are acceptable to the community and will not contaminate the waterbed [S34] The existing arsenal of tools for effective treatment (from rehydration to antibiotics) and prevention  should be delivered in the context of comprehensive care to strengthen Haiti's health system. As incidence declines, long-term prevention measures, including rolling out vaccination campaigns and strengthening water and sanitation infrastructure, should be implemented. But prevention should not come at the expense of acute care: the biggest priorities remain case finding and treatment. Rather, additional resources should be secured so that immunologically naïve populations can be vaccinated while acutely ill patients are being treated.Past epidemics have been curbed without vaccines, but we believe that vaccination has a significant role to play in Haiti given the vulnerability of the post-earthquake health, water, and sanitation systems and the observed virulence of the El Tor strain. Any rational vaccine strategy must be coordinated by local authorities. However, the MSPP is currently wary of NGOs haphazardly delivering vaccine because uneven access could trigger social frictions and interfere with other cholera prevention and treatment efforts. The MSPP has called for nothing less than a universal vaccination campaign—an end goal this document endorses.If sufficient vaccine and resources were mobilized, large-scale immunization could bring a more rapid end to the current epidemic and help prevent a resurgence of cases. However, there is insufficient vaccine currently available to cover the 10 million people in Haiti (20 million doses); a scale-up strategy that first targets vulnerable groups (like children under 5) is needed. Antiretroviral therapy roll-out in Haiti showed that pilot projects demonstrating the utility of an intervention can boost consensus, political will, resources, and manufacturing for that intervention. Pilot vaccination projects for cholera could do the same.Recent estimates suggest that 4 million vaccine doses could be available by March 2012, and this figure will only increase as implementation begins . Indeed, in November 2010, experts estimated 200,000–400,000 doses could be available in 1 year; by early February 2011, they estimated 4 million [S35] Concerns about the cost-effectiveness and feasibility of implementation have hindered progress on vaccination in Haiti, but these concerns are fading There are two oral cholera vaccines on the market, both feasible for use in Haiti. Dukoral, produced by Crucell and licensed in over 60 countries, contains recombinant cholera B subunit, which stimulates anti-toxic and antibacterial immunity [S40] A closely related bivalent oral cholera vaccine is licensed as Shanchol in India and mORCVAX in Vietnam. The latter is produced by VaBiotech and currently intended for domestic use in Vietnam, while Shantha Biotechnics (acquired by Sanofi-Aventis) is applying for WHO prequalification to produce Shanchol for international use.  A 5-year efficacy trial in Kolkata, India, is ongoing, but an interim analysis after 2 years indicated an overall protective efficacy of 67% against culture-confirmed cholera among those who received two doses [S42] These vaccines have been shown to be effective at preventing both El Tor cholera in endemic settings and the newly emergent El Tor hybrid strains, with protective immunity expected to begin about 1 week after the last dose [S43] Dukoral is manufactured at a cost of US$6 per dose and has a retail price in North America of US$50 to US$75 per dose While there are currently fewer than 400,000 vaccine doses ready for shipment from their manufacturers Models suggest that vaccination campaigns that target vulnerable populations  can be equally cost-effective as other prevention methods Finally, existing vaccination and treatment delivery channels provide an infrastructure for cholera vaccine administration. Unlike more complex medical interventions, oral vaccines can be implemented rapidly and effectively by CHWs. A cholera vaccination campaign could therefore leverage existing health worker networks without taking doctors and nurses away from the provision of acute care [S49] We recognize that there is insufficient vaccine today for an immediate mass campaign, and that the current epidemic could be curbed before such a supply becomes available. Without significant investment in Haiti's weakened health system, there will continue to be insufficient human and financial resources to deliver a mass vaccination campaign. Nonetheless, we believe a rational vaccine strategy should be pursued immediately. Although the 1 million doses available would provide a complete vaccine course to only 500,000 people (about 5% of Haiti's population), targeting vulnerable populations could help to reduce transmission, decrease the likelihood of resurgence, and put gears in motion toward amassing a global stockpile—an outcome that would be beneficial for this epidemic and the next.Coupling community education about cholera transmission with the provision of necessary supplies could improve hygienic behavior and reduce social stigma. Numerous public education campaigns have disseminated information about cholera transmission, diagnosis, and treatment, including the location of treatment sites and transport options. These efforts have targeted populations in slums, IDP camps, schools, and other public fora, urban and rural, around the country. In the first 2 months of the epidemic, camp management teams implemented 670 cholera risk-reduction activities in IDP camps and their surrounding communities; UN education cluster partners distributed cholera prevention and water treatment protocols in schools across the country; phone companies, along with the International Federation of the Red Cross and Red Crescent Societies, the International Organization for Migration, and others, sent public health warnings via SMS; and radio stations dedicated broadcasts to education programs, provided updates from the MSPP, and answered caller questions Yet the success of these efforts has been limited. Surveys to assess IDP camp residents' awareness of cholera management protocols—where to access clean water, obtain ORS, and dispose of cadavers—reveal serious gaps, particularly concerning where to obtain ORS. Continued surveillance of education programs could help improve message targeting and efficacy The more important reason for the failure of education and behavioral campaigns is that, like other diseases of poverty, cholera's spread is dictated less by bad behavior than by a chronic shortage of tools and resources. People may defecate near public water supplies if they lack decent sanitation and sewage systems; they may draw water from contaminated sources if there is no alternative; and they may not wash their hands if soap is too expensive or inaccessible. The structures of poverty mediate risk of cholera infection, and therefore information can only keep cholera at bay if vulnerable populations are furnished with necessary resources and supplies.As noted, proper hand-washing can significantly reduce transmission of cholera and other waterborne diseases. Yet without adequate access to soap and clean water, public health messages about hand-washing are futile. As late as December 7, 2010, UN officials reported soap shortages in IDP camps, urban slums, and rural communities Public health messaging has also sought to address cholera-related stigma. Health workers have encountered resistance to building treatment sites because local residents fear that these facilities could bring cholera to the community. OCHA and many Haitian media groups have reported lynchings of individuals thought to have used witchcraft to spread cholera [S50] Laudable efforts are underway to collect and compile surveillance data on the national level and to map health facilities and care capacity. But these efforts must be expanded to avoid a resurgence in cases in the coming months and years. Haiti's existing national surveillance system regularly aggregates reported case data: local MSPP officials send hospital and clinic case counts to central authorities who aggregate and transmit the information to the central government; the MSPP then posts all non-hospitalized and hospitalized cases daily on a public Web site Additional sentinel sites and greater resources for surveillance efforts could help anticipate, treat, and prevent the further spread of cholera and other preventable diseases. Surveillance is a key part of treatment and prevention, and simple but effective models exist. For example, a four-symptom diagnostic method  has helped identify transmissible diseases in one IDP camp [S51] That the country's early warning system was able to rapidly detect the first cases of cholera highlights the strong leadership of the MSPP, PAHO, and the CDC. However, some have suggested that cases are being underreported, particularly in rural areas. For example, many children die before they reach treatment sites, and therefore their deaths may not be captured by current monitoring techniques . Poor coordination among health providers has further hindered the MSPP's case data collection Cholera is likely to become endemic in Haiti, and it presents a threat to other countries in the region and around the world. Surveillance must be part of a comprehensive response to the immediate epidemic and a cornerstone of the country's health infrastructure. Education, supply chain, treatment, and prevention channels can be coordinated to feed information to a central source; early results of antibiotic scale-up and vaccine pilots should guide future implementation; the MSPP should coordinate all monitoring to strengthen its national surveillance systems for cholera and other notifiable diseases.The comprehensive, integrated strategy described in this document should be implemented to mitigate the current cholera epidemic and strengthen the Haitian health system in the long term. Scaled-up delivery of ORS, intravenous therapy, antibiotics, vaccine, soap, and other tools for cholera prevention and care should be linked to the provision of primary health care services to strengthen supply chains countrywide. CTCs, CTUs, ORPs, and other cholera-specific facilities and infrastructure should be integrated into the public health system. We can build on the extensive national HIV treatment network to establish permanent cholera treatment sites at hospitals and health centers. Cholera caregivers should also be trained to identify and treat other diarrheal diseases and illnesses of poverty. In other words, cholera-specific interventions should be used as a wedge to bolster primary health care services and strengthen the Haitian health system.The Haitian government must lead the ongoing response to cholera in order to promote collaboration between the multiplicity of donors, aid groups, and NGOs offering assistance in Haiti—all of which have disparate protocols and goals. Even with the best intentions, these groups can impose significant burdens on a stressed public health system. Only a well-coordinated response with clear leadership from the MSPP and DINEPA will be able to address the acute challenges of the current outbreak while also building robust health, water, and sanitation systems to prepare for future epidemics.The goal of this paper is to highlight the priorities of a comprehensive, integrated, and long-term cholera response; the next and even more important goal is the implementation of this strategy. Implementation will require political will and substantial, long-term financial commitments from global health authorities, donors, and health providers. In a December 2010 report to the UN General Assembly, Secretary-General Ban Ki-moon asked nations to help Haiti respond to the cholera epidemic [S53] The months following the earthquake on January 12, 2010, were among the most trying in Haiti's history. Continued international assistance can prevent suffering and death in the near term and help Haiti to rebuild better in the long term. But the response to cholera must be comprehensive, linking prevention to care and coordinating Haitian and non-Haitian partners. In the last two decades, a period of economic stagnation and frequent political turmoil, comprehensive and integrated community-based prevention and care reduced infant mortality rates in Haiti by two-thirds and cut the AIDS epidemic in half. This model has since been adopted across the developing world. We have the opportunity to do the same with cholera.Debates about prevention versus care are misguided. We must integrate population-based prevention measures with medical treatment to contain the outbreak and save thousands of lives. Haiti faces both urgent and entrenched challenges that require solutions combining speed in the short-term and sustainability in the long-term.Our objectives in Haiti should be no different than those we would set in the Dominican Republic, the United States, or any other neighboring country. This “Haitian” epidemic is part of a global pandemic that claims over 100,000 lives each year. The presence of cholera in Haiti highlights the volatility of transmission in an era of global migration and trade, and it threatens to spread the pathogen in the Caribbean and across the Western Hemisphere. All nations share a common interest in eliminating cholera wherever it occurs: a world in which the burden of cholera follows the burden of poverty is not just inequitable, it is dangerous, even to rich nations.We, a group of 44 medical and public health researchers, policymakers, funders, and practitioners, working for research universities, government agencies, NGOs, international multilateral organizations, and the private sector in Haiti, the US, and many other countries around the world, strongly support a comprehensive, integrated, and long-term response to cholera in Haiti. We stand behind the government of Haiti and are committed to helping implement this strategy together and in the months and years ahead.Text S1Supplemental references.(DOC)Click here for additional data file.


Maximizing the quality and benefits of newly established chiropractic services represents an important policy and practice goal for the US Department of Veterans Affairs' healthcare system. Understanding the implementation process and characteristics of new chiropractic clinics and the determinants and consequences of these processes and characteristics is a critical first step in guiding quality improvement. This paper reports insights and lessons learned regarding the successful application of mixed methods research approaches—insights derived from a study of chiropractic clinic implementation and characteristics, Variations in the Implementation and Characteristics of Chiropractic Services in VA (VICCS). Challenges and solutions are presented in areas ranging from selection and recruitment of sites and participants to the collection and analysis of varied data sources. The VICCS study illustrates the importance of several factors in successful mixed-methods approaches, including (1) the importance of a formal, fully developed logic model to identify and link data sources, variables, and outcomes of interest to the study's analysis plan and its data collection instruments and codebook and (2) ensuring that data collection methods, including mixed-methods, match study aims. Overall, successful application of a mixed-methods approach requires careful planning, frequent trade-offs, and complex coding and analysis. There is growing consumer interest in complementary and alternative medicine (CAM) in the USA and internationally –3. HealtChiropractic care is often described as sitting at the crossroads of CAM and mainstream medicine , and itsThe establishment of chiropractic clinics within VA was challenged by the rarity of existing models in other healthcare systems and by the widely varying perception of chiropractic services by medical physicians and other stakeholders . VA convBy the end of 2005, VA had successfully complied with the requirement of establishing a minimum of one chiropractic clinic within each VISN. This initiative was loosely coordinated by VA Central Office (VACO), leaving much of the details to individual facilities. Over the following years, the use of chiropractic services at these initial facilities dramatically increased. This growth, along with interest from Veterans and providers at other VA facilities, stimulated the expansion of chiropractic clinics into other VA facilities. From fiscal year 2005 to fiscal year 2011, without further Congressional mandate, the number of VA chiropractic clinics increased from 24 to 43, and the number of Veterans receiving care at these clinics increased from just under 4,000 to over 81,000. Also during this time, VACO established central leadership for the chiropractic program in the Office of Rehabilitation Services which began to monitor and assess the ongoing uptake and expansion of services . Do. Do27]. require establishment of a clinic at a given facility or did facility leadership voluntarily establish a clinic?) and other key features of the healthcare setting prior to chiropractic clinic implementation. The data collection framework also distinguished several distinct phases in the clinic planning, implementation, and maintenance process and several distinct categories of variables describing the clinic context, chiropractic clinic itself, and key outcomes and measures of performance at each clinic.The VICCS data collection framework was designed to include several key categories of variables. These included features of each site and the background and motivation for the establishment of each chiropractic clinic. For example, information was collected on the initial impetus for each clinic , organizational alignment, and physical features of the clinic, the formal relationship, and extent of integration or collaboration with other facility programs and stakeholders.Care processes include characteristics of healthcare services provided, features of case management or care pathways, and quality of services.Impacts/outcomes include the status of clinic access and use, patient-based outcomes, system perception of value, and external stakeholder opinions.Semistructured interview guides were developed for each type of stakeholder. Interview subjects included VA facility leaders, chiropractors, chiropractor supervisors, chiropractic clinic support staff, other clinicians from various departments, administrative planners, VA patients with musculoskeletal pain complaints (from both chiropractic and nonchiropractic clinics), and external stakeholders . Interview guides were adapted from existing instruments employed in similar studies, augmented by new questions and content specific to this study. Questions to measure stakeholder satisfaction and views were informed by existing instruments such as the Chiropractic Satisfaction Questionnaire , the MeaMixed-methods research is increasingly used in the social, behavioral, and health sciences. The VICCS mixed-methods approach employed an explicit conceptual framework identifying key variables and data sources relevant to the study's primary aims. This approach improves the quality and completeness of data in health care research to study issues as varied as health disparities, cultural differences, behavioral factors contributing to disability and health, processes and factors involved in implementation of health research findings, and much more. The increasing use of mixed methods reflects growing recognition of the value of qualitative and other social science research methods, collaborative interdisciplinary research teams  , 38, andCreswell et al.  documentn = 99) during two-day site visits at seven facilities. The remaining interviews were completed by telephone  with VA facility staff unavailable during the site visit and with external stakeholders. Documents were collected during site visits and received via fax and e-mail prior to and following site visits.The VICCS study data included extensive notes from one hundred eighteen interviews. Most interviews were conducted in person  was invaluable given his expertise and experience in administrative and subspecialty matters. However, to avoid potential coercion or bias, AJL did not participate in the site selection decision-making process, recruitment, or interviews with any chiropractic staff .facility geographic location ;facility type ;administrative alignment (facility service line overseeing the clinic);chiropractor characteristics ;clinic establishment (how long the clinic had been in existence);involvement with academic affiliate(s).Sites were selected to ensure diversity on key dimensions, including:At the time of site selection, forty-one (41) VA facilities offered on-site chiropractic services. Two (2) sites involved the study's co-PI as a staff member and were thus excluded. Two (2) other sites were deemed ineligible because they functioned as independent outpatient clinics and were not directly linked administratively to VA. Another site was ineligible because there was no chiropractor on staff at the time of site selection. Therefore, a total of thirty-six (36) sites were eligible for recruitment.We set a sample size of seven sites, including one pilot site. A total of 12 sites were invited to participate until we reached our sample of seven, for a total site response rate of 58%. Of the five (5) sites that declined, 3 declined due to workload or other time conflicts, and 2 declined because facility leadership determined that local IRB review would be required , thus disqualifying them from meeting the study's timeline. Facilities invited but declining to participate in this study remain confidential to those outside of the study team as well as to the study's co-PI, as per the study's recruitment protocol and a confidentiality feature designed to minimize coercion.facility leadership ;key department heads ;chiropractors;clinicians  ;chiropractic clinical and administrative support staff;VA back or neck pain patients ;external stakeholders .At each site, we targeted a variety of stakeholders for interviews:Prior to data collection, all study team members attended interview training and observed at least two pilot interviews. Two or three members of the study team attended each site visit, with one or two members conducting each interview. All subjects orally consented prior to participation. For respondents who agreed to be audio-recorded, these interviews were transcribed. Patients were not audio-recorded as per our protocol, but copious notes were taken and debriefing sessions occurred immediately afterwards to ensure that as much verbatim information was retained as possible. Excluding the 18 patients interviewed, 96 of the remaining 100 interview subjects agreed to be audio-recorded. To ensure confidentiality of sites and subjects, all identifiers were removed and replaced with study-generated consecutive identification codes prior to data coding and analysis.Between December 2010 and November 2011, 118 semistructured interviews were conducted at seven sites, including one pilot site. Interview subjects included sixty-two non-DC clinicians (53%), eighteen patients (15%), eleven leaders (9%), seven chiropractors (6%), six chiropractic support staff (5%), five staff involved in planning chiropractic clinics (4%), four chiropractic supervisors (3%), three former federal chiropractic advisory committee members (3%), and two academic affiliates (2%). Participation response rates for subjects and sites were 43% and 58%, respectively.Documents reviewed and analyzed included significant chiropractic care-related policy documents obtained from the study sites, including VA regional (VISN) policies, local facility policies, local service agreements, chiropractor clinician privileges, and other public documents such as congressional bills/resolutions related to VA chiropractic services.Content analysis of interviews and documents assessed a priori hypotheses derived from prior literature, as well as new themes emerging from transcript review. The codebook for the interviews and documents was developed and refined throughout the coding process using top-down (deductive/a priori hypothesis testing) and bottom-up (inductive/emerging hypothesis generating) methods.k = 0.8) among coding team members. Data were coded in a two-phased process utilizing high level codes first (double coded) for general themes and variable domains and then more specific detailed codes for subthemes and individual variables.Data collected from both interviews and documents were coded using NVivo  and Excel (Microsoft) software, respectively. We observed high interrater agreement .The VICCS study was approved by four separate institutional review boards (IRBs): VA Greater Los Angeles Healthcare System, VA Connecticut Healthcare System, Western IRB, and US Army Medical Research and Materiel Command.Most of the methodological challenges in the VICCS study fall into 4 main categories: (1) subject selection and recruitment, (2) site selection, (3) data collection instruments and logistics, and (4) analysis of and interpretation of diverse types of data related to the study's multiple research questions and goals.The site selection process was designed to ensure wide variability of chiropractic clinics and their internal structures and processes. However, because participation of sites and stakeholders at each site was voluntary, some bias may have been introduced that will limit any generalizations outside of VA.Recruitment of busy healthcare professionals (both clinicians and administrators) is a well-recognized challenge to conducting research in healthcare settings . BecauseVA and related federal regulations on patient survey/interview research allow small numbers of patients to be sampled in all IRB-approved studies, but, for studies attempting to recruit larger numbers of patients (>9), additional approval of the Office of Management and Budget is required. Because OMB approval is lengthy, we sampled a smaller number of patients directly and attempted to gather additional patient perspectives indirectly through provider interviews.In partnership research involving program leaders who serve as research team members, research subjects  may be concerned that they are being evaluated on their performance and actions rather than studied for the purpose of scientific knowledge development. Therefore, issues of possible coercion and sensitivities may affect the validity of data collected.Staff turnover and limited memories also threaten data validity  when studying program development and evolution in a retrospective manner. Archival records are limited, and thus we relied heavily on VA staff (where still available) and their memories.n = 99). To minimize data security and privacy concerns with IRBs, patients were recruited for interviews onsite and only first names were used.To improve the validity and integrity of data collected, this study performed most interviews in person during a two-day site visit (with two to three research team members) at each of the seven sites; 84% of all interviews were conducted in person . Patients in clinic waiting areas were recruited systematically. No one was missed or avoided. And, because of the study's IRB-approved minimal risk status, this study was granted a waiver of documentation of informed consent; thus all subjects orally consented to participate in this study.n = 98) were subjects who did not respond to these initial or follow-up e-mails requests for participation.Interviews at each site were scheduled to fill target quotas for each of the various roles (respondent groups) needed. After each site's chiropractor and facility leaders approved participation in the study, lists of providers by department (or service line) were compiled. Recruitment involved sending individual invitations to VA employees to fill the two-day site visit schedule. Initial invitations were sent by e-mail describing the study and announcing the planned site visit dates, and up to five follow-up contacts were attempted per person. Relatively low subject response rates (45.6%) may have resulted partly from the limited two-day interview timeframe scheduled at each site. Of those who did not participate, 69.5% . In part, the distinction here is between data collection approaches designed to develop new insights and frameworks for understanding and describing the phenomena of interest, versus applying a priori frameworks to collect predefined data and test aspects of these frameworks. Similar problems result from the use of observation guides or protocols lacking adequate specificity and a firm foundation in a priori hypotheses and clearly identified variables: such protocols often produce inconsistent data by (1) encouraging the observer to record events as they unfold and to record a wide range of attributes of the situation under study (whether or not they are deemed relevant to the hypotheses of interest), (2) limiting the likelihood that the observer will note the significance of events that do not occur, and (3) limiting the likelihood that the observer will collect complete, consistent data required for direct comparisons across observation samples.Considerations of validity, intrusiveness or subject reactivity (Hawthorne effects), and triangulation (to minimize bias) are also too often neglected in deductive applications of qualitative methods. Distinctions between subjective and objective data and between formal and informal organizational structures and processes are also frequently neglected, threatening the validity of study conclusions.Avoiding these problems requires careful design of data collection plans, based on study goals and hypotheses, involving use of systematic tables or other methods for specifying key variables and suitable, multiple measures. Depending on the importance of each variable and the validity of available measures, two or more data sources are typically needed in qualitative research. Data planning tables listing concepts or variables, definitions, and data sources are effective in ensuring appropriate rigor; data collection instruments  can be developed directly from these tables.Rigor and validity are also enhanced through development and use of data collection instrument specifications and training protocols, including variable and measure definitions and instructions in instrument use. When used in research examining health care delivery organizations, such protocols should include plans and instructions for approaching sites, making contacts, arranging interviews/visits, identifying and obtaining documents, following up , managing informed consent and confidentiality, and so forth. Adequate pilot testing helps ensure the appropriateness of data sources and measures although data collection protocols must be flexible and allow for changes in data collection plans and strategies, when pilot testing fails to reveal valuable new data sources or validity problems that eventually emerge during the main study period.Finally, study validity is further enhanced through development of data analysis protocols and plans together with the actual instruments, rather than after the completion of data collection. Data planning tables created to guide data collection activities can be used to develop data reporting templates and specifications for translating raw data into variables and preparing for analyses; data from organizational studies are often reported in a standardized “organizational profile” or other comparative formats. These profiles store raw data and summary variables from all data sources, which are then converted into tables for analysis. Additional challenges arise in studies pursuing inductive and deductive study aims simultaneously. For deductive studies with a rigid a priori framework, the number of variables to be measured should be relatively small and easily managed. Inductive, exploratory work involves open-ended questions and unlimited data and is thus more challenging to plan and conduct.The field of health services research has benefited from several insightful, comprehensive discussions of qualitative research methods and their appropriate use . ProponeFor qualitative research, patterns of observed individual and organizational practices, behaviors, and outcomes are highly variable (across time and site) and are subject to wide variations and interviewer/observer bias and interpretation. This heterogeneity challenges those designing the research to find and describe consistent patterns and topics within the findings. The patterns and topics identified are heavily influenced by idiosyncratic factors, such as an individual leader's personal views or situation or unrelated pressures or events within a site. Also, each site's situation  is influenced by a very large number of factors, whose combined and interacting effects lead to highly variable outcomes . Data collection relying on interviews with individuals entails potential bias, limited validity, and inaccuracies due to challenges in recall and differing perspectives and views of events and differential access to information. Therefore standard challenges in qualitative/case study research also apply here.Another challenge arises from the limitation that data for many key variables are not always reliably available or are difficult to access, in addition to having questionable validity in some instances. This study also examined a long chain of causal links and multiple determinants and outcomes (independent and dependent variables). Overall, the mixed-methods approach employed here was challenging because dual inductive and deductive research is inherently demanding, for example, deciding how to allocate limited interview time to measure variables identified a priori (for deductive) versus open-ended interviewing to maximize the likelihood of learning something new and interesting (for inductive). Lastly, the lack of available standardized, validated measures, concepts, definitions, and so forth was a significant challenge to this study. These challenges are especially common to pilot studies.However, there are steps to minimize these biases, including adequate training of data collection staff; comprehensive plans for data collection, validation, and storage; and frequent reviews of data quality and interpretation. While data validity and completeness can be enhanced through the recording of interviews, other methods should also be paired with the traditional recording of interviews such as use of paired interviewers, postinterview debriefing, and other methods. Quality assurance methods should be considered and operationalized for each instrument and data sources. Problems such as incomplete, missing, unusable data should be identified and resolved during the data collection phase rather than after its completion.Ronald J. Chenail:Take a pragmatic posture to creating studies that marry the most fitting design and methodology choices with the focus of your research curiosity… remain true to your interests and then explore a variety of research approaches which can help in the designing and conducting studies to meet your needs. The bottom line is to be pragmatic in creating the design, but remain curious so every reasonable methodological option is considered. However, like taking too many medications can lead to adverse effects to your body, using too many methodologies might produce negative side effects which could be unhealthy for your study. To help remedy this potential risk, please remember this simple research commandment: Thou shall not select an additional methodology for a study, until thou is sure the first methodology selected cannot manage all of the design issues .Finally, analysis plans are relatively quantitative in most conventional health care studies that often pursue narrow, explicit aims and test explicit, confirmatory hypotheses. However, mixed-methods studies that address both inductive and deductive study questions and employ methods features, such as randomized sampling, that are more typically associated with experiments—combined with open-ended interviews more typically associated with qualitative research—offer what is termed by Morse “alternative forms of evidence” , p. 86. To our knowledge, VA's introduction of chiropractic services represents the most extensive introduction of any nontraditional medical service into the largest integrated US healthcare system. This is likely to present future research areas of interest to multiple stakeholders. VA policy makers may seek data to inform efforts to best assess and improve the delivery of chiropractic services to meet Veterans' needs. Stakeholders in the chiropractic profession may look to VA's experience as an indicator of future opportunities and integration into other healthcare systems. Other CAM disciplines seeking inclusion into VA and other systems may be interested in the policy and practice implications of VA's chiropractic program. At a broader level, beyond the unique chiropractic and/or CAM implications, our study may have implications for researchers to assess the introduction of any new healthcare service into VA or other large healthcare systems.For these types of inquiries, research-practice-policy partnerships facilitate research that can be more useful to decision makers . Decision maker involvement increases the likelihood that (1) useful questions are answered by developing methods and data analyses relevant to service delivery and (2) the interpretation and reporting of results will inform future policy.Analysis of qualitative observational data in studies combining deductive and inductive aims should be guided by prespecified, model-based hypotheses and detailed analysis plans developed at the outset of the study. Unfortunately, while quantitative analysis methods are well established and accepted, methods for analysis of qualitative data are subject to variability and lack of consensus. Analyses of qualitative data are too often informal, ad hoc, and emergent, with low reliability and validity. These threats can be countered through the use of formal table approaches, in which key variables relevant to each hypothesis are listed in tables and manipulated in a blinded fashion, using qualitative pattern identification and nonparametric quantitative techniques. The analysis tables summarizing and synthesizing information from diverse sources in a standardized format may also serve as reporting tools, in papers and reports. Combining the use of qualitative methods for hypothesis testing and interpretive, inductive applications in this manner represents a powerful application of these methods, using their strengths to enhance management studies and other empirical research in important ways.In conclusion, qualitative case study research allows for the collection of rich data for deep understanding of the phenomenon of interest. Yet data collection relying on interviews with individuals entails potential bias, limited validity, and inaccuracies due to challenges in recall and differing perspectives and views of events and differential access to information. Also, data for many key variables may be unavailable or difficult to access, in addition to having questionable validity in some instances. Researchers who are not trained in qualitative methods  are less likely to be interested in applying qualitative methods in inductive or interpretive research but can—and should—be interested in applying qualitative methods to enhance the data available for more conventional deductive forms of empirical research. The use of mixed methodology can enrich health services research testing a priori study hypotheses and narrowly defined research questions and can also help suggest detailed causal explanations and generate important new exploratory questions and findings as well.


Antenatal care (ANC) is one of the recommended interventions to reduce maternal and neonatal mortality. Yet in most Sub-Saharan African countries, high rates of ANC coverage coexist with high maternal and neonatal mortality. This disconnect has fueled calls to focus on the quality of ANC services. However, little conceptual or empirical work exists on the measurement of ANC quality at health facilities in low-income countries. We developed a classification tool and assessed the level of ANC service provision at health facilities in Zambia on a national scale and compared this to the quality of ANC received by expectant mothers.We analysed two national datasets with detailed antenatal provider and user information, the 2005 Zambia Health Facility Census and the 2007 Zambia Demographic and Health Survey (DHS), to describe the level of ANC service provision at 1,299 antenatal facilities in 2005 and the quality of ANC received by 4,148 mothers between 2002 and 2007.We found that only 45 antenatal facilities (3%) fulfilled our developed criteria for optimum ANC service, while 47% of facilities provided adequate service, and the remaining 50% offered inadequate service. Although 94% of mothers reported at least one ANC visit with a skilled health worker and 60% attended at least four visits, only 29% of mothers received good quality ANC, and only 8% of mothers received good quality ANC and attended in the first trimester.DHS data can be used to monitor “effective ANC coverage” which can be far below ANC coverage as estimated by current indicators. This “quality gap” indicates missed opportunities at ANC for delivering effective interventions. Evaluating the level of ANC provision at health facilities is an efficient way to detect where deficiencies are located in the system and could serve as a monitoring tool to evaluate country progress. Every day, approximately 800 women die from preventable causes related to pregnancy and childbirth. In 2008Although the percentage of women attending ANC (for at least one visit) generally tends to be satisfactory even in low-income countries, maternal and neonatal mortality remain high. In Zambia, for example, 94% of women attend ANC at least once, while maternal mortality is estimated at 591 maternal deaths per 100,000 live births, and neonatal mortality at 34 neonatal deaths per 1,000 live births. This weDonabedian proposed a framework for assessing quality of care which distinguishes between the attributes of the health care setting (structure), the actual care delivered (process) and the end result of the interaction between an individual and the health care system (outcome)-22. MaxwTools to capture several dimensions of quality of ANC received by mothers have been developed for high-income settings,27, but Little conceptual work has been done on measurement of ANC quality at health facilities, althougPossible reasons for this neglect or inadequate measurement of quality of care, besides the conceptual difficulties in capturing the multiple dimensions of quality, include the weakness of routine health information systems, and the subsequent dependence on household surveys, which lack appropriate information on technical aspects of quality of care, as pointed out by Graham and Varghese. Only feIn Zambia, both a national Health Facility Census from 2005, and a national household survey (Zambia DHS 2007) are available, presenting a unique opportunity to illustrate how the barriers to the measurement of quality of ANC can be overcome methodologically. We draw upon these datasets to comprehensively assess and describe the quality of ANC in Zambia at that point in time, which can serve as a baseline to show any improvements against. The specific objectives were to: (i) assess various quality of care dimensions for ANC facilities in Zambia; (ii) ascertain how many of Zambia’s ANC facilities met developed criteria for optimum and adequate level of service provision, and (iii) assess and compare level of service provision at health facilities with the quality of ANC received by expectant mothers in Zambia.The Health Facility Census (HFC), developed by the Japan International Cooperation Agency, is a national-level assessment of the functionality of health system assets, providing extensive information useful for health system planning. There iThe 2007 Zambia Demographic and Health Survey (DHS), a nationally representative household cluster survey, interviewed 7,146 women aged 15–49 years and 6,500 men aged 15–59 years across Zambia. All women who had given birth in the five years preceding the survey were asked a range of questions about maternal care. Detailed information about antenatal care was only collected for the last live birth in that period[We adopted a definition of quality based on the frameworks of Donabedian-22 and MInformation collected on ANC provision in a health facility included the availability of the service, the number of ANC days per week, performance of screening tests for anaemia, syphilis, urine protein and urine sugar, tetanus toxoid vaccination, folate/iron supplementation, intermittent presumptive treatment (IPT) of malaria, voluntary counseling and testing (VCT) for HIV, prevention of mother-to-child transmission (PMTCT) of HIV, routine discussion of family planning with pregnant women, and ANC outreach services. Based on the recommended interventions for pregnancy care, initialWe first evaluated the level of service provision for four core ANC quality attributes individually  and then combined them to assess the overall level of ANC provision at all Zambian ANC facilities. TableA facility was considered to provide an optimum level of ANC service if providing at least three days of ANC per week, performing at least three screening tests including urine protein testing, offering all five key ANC functions and having three or more skilled health workers registered at the facility, in addition to offering Emergency Obstetric Care (EmOC) referral and delivery services. A facility was classified as providing an adequate level of service if failing in any of the criteria for optimum level but providing at least one day of ANC per week, performing at least one screening test, at least three ANC functions and having at least one registered skilled worker. Failing in any of these criteria, a facility was considered offering an inadequate level of ANC services.The 2007 Zambia DHS collected details on ANC received in the five years prior to the survey for all last births to the mothers interviewed. InformaHaving received “good quality ANC” was defined as having attended at least the recommended four ANC visits with a skilled provider and received at least eight antenatal interventions, while our definition of “moderate quality ANC” required four visits with a skilled provider and five to seven antenatal interventions.Out of the 1391 health facilities with information on the availability of ANC in the Health Facility Census (HFC) dataset, 1299 (93%) were recorded as providing ANC. Of these, 71 (5.5%) were health posts, 950 (73%) rural health centers, 207 (16%) urban health centers, 52 (4%) first-level hospitals, 18 (1.4%) second-and-third-level hospitals, and one ANC facility was unclassified. The majority of ANC facilities were run by the Zambian government (85%) and by churches or NGOs (9%).Of the 1299 ANC facilities in Zambia in 2005, 42% provided ANC once a week, 30% twice a week and 27% three days or more per week. For 12 ANC facilities “zero” days of ANC per week were recorded. Five of the latter provided ANC outreach services; another reason for this seemingly contradictory statement could be that ANC is provided less frequent than weekly in these facilities.TableTableApplying our classification framework for assessing levels of service provision Table, only 45FigureWhile 98% of the 4148 women in the Zambia DHS 2007 attended ANC at least once and 94% attended at least once and saw a skilled health worker, only 60% had the recommended four antenatal visits and 58% received the recommended ANC of at least four visits with a skilled health worker. Only 19% of mothers who attended ANC had their first ANC visit in the first trimester, while 74% attended for the first time during the second trimester. Most mothers (72%) attended ANC at a health center and the vast majority (91%) received care from a nurse or midwife .ANC: Antenatal care; DHS: Demographic and Health Survey; EmOC: Emergency Obstetric Care; HFC: Health Facility Census; HIV: Human Immunodeficiency Virus; IPT: Intermittent Presumptive Treatment; MDG: Millennium Development Goal; PMTCT: Prevention of Mother-To-Child Transmission; VCT: Voluntary Counselling and Test; WHO: World Health Organization.The authors declare that they have no competing interests.NK analysed the data and drafted the manuscript. SG identified and cleaned the data, supervised data analysis and contributed to writing the manuscript. CC provided country-specific input and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/12/151/prepub


Arabidopsis thaliana. Due to membrane heterogeneity, hydrophobicity, and low relative abundance, analysis of the PM proteome has been a special challenge. Various experimental techniques to enrich PM proteins and different protein and peptide separation strategies have facilitated the identification of thousands of integral and membrane-associated proteins. Numerous classes of proteins are present at the PM with diverse biological functions. PM microdomains have attracted much attention. However, it still remains a challenge to characterize these cell membrane compartments. Dynamic changes in the PM proteome in response to different biotic and abiotic stimuli are highlighted. Future prospects for PM proteomics research are also discussed.The plasma membrane (PM) regulates diverse processes essential to plant growth, development, and survival in an ever-changing environment. In addition to maintaining normal cellular homeostasis and plant nutrient status, PM proteins perceive and respond to a myriad of environmental cues. Here we review recent advances in the analysis of the plant PM proteome with a focus on the model plant  The plasma membrane (PM) is the cellular interface that regulates the exchange of molecules and information between cells and their environment. The PM is involved in a range of plant physiological processes including growth and development, ion and metabolite transport, perception of environmental changes, and disease resistance  in a given fraction relative to other subcellular markers, it was possible to confidently assign PM localization to a number of previously unknown PM proteins in Arabidopsis  but later it became clear that 2DGE was not an ideal technique for separation of membrane proteins . Early efforts in For most researchers, liquid chromatography-tandem MS (LC-MS/MS) “bottom-up” shotgun proteomics has emerged as the method of choice for large-scale identification and quantification of proteins, especially membrane proteins Figure . PM protAfter digestion, peptides can be separated in one or more dimensions, typically involving reverse phase (RP) and/or strong cation exchange (SCX) chromatography for increased resolution and improved detection of low abundance peptides , where extracted proteins are first subjected to one dimensional SDS-PAGE to separate by size and then regions of the gel lane are excised, digested, and subjected to LC-MS/MS separately  or aquaporin family which function mainly as water channels but can transport other small molecules  family, whose members can be relatively abundant on the PM  has uncovered novel modes of protein regulation during immunity  treatment   experiments have been instrumental in identifying interacting partners of the PAMP receptors FLS2 and EFR, the nucleotide binding-leucine repeat immune receptor RPS2, and the immune regulator RIN4 (Heese et al., Proteomic approaches have also been instrumental in identifying Arabidopsis PM proteome over the last 15 years has uncovered many new insights into plant cell membrane structure and function. Recent studies have greatly advanced our understanding of PM microdomain behavior and receptor kinase-mediated signaling in Arabidopsis (Tang et al., Analysis of the Increases in the speed and sensitivity of the mass spectrometer instrument will soon facilitate virtually complete analysis of the PM proteome in a single experiment. Combining LC-MS/MS with cell biology approaches to survey PM responses to diverse stimuli will undoubtedly play an integral role in systems biology approaches for understanding complex cellular signaling events. Furthermore, combining quantitative proteomics with transcriptomics, metabolomics, and protein–protein interaction datasets will generate a wealth of testable models that will contribute to a holistic view of cell function.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Beneficial effects of fish consumption on early cognitive development and cardiovascular health have been attributed to the omega-3 fatty acids in fish and fish oils, but toxic chemicals in fish may adversely affect these health outcomes. Risk–benefit assessments of fish consumption have frequently focused on methylmercury and omega-3 fatty acids, not persistent pollutants such as polychlorinated biphenyls, and none have evaluated Great Lakes fish consumption.Objectives: The risks and benefits of fish consumption have been established primarily for marine fish. Here, we examine whether sufficient data are available to evaluate the risks and benefits of eating freshwater fish from the Great Lakes.Methods: We used a scoping review to integrate information from multiple state, provincial, and federal agency sources regarding the contaminants and omega-3 fatty acids in Great Lakes fish and fish consumers, consumption rates and fish consumption advisories, and health effects of contaminants and omega-3 fatty acids.Data synthesis: Great Lakes fish contain persistent contaminants—many of which have documented adverse health effects —that accumulate in humans consuming them. In contrast, data are sparse on omega-3 fatty acids in the fish and their consumers. Moreover, few studies have documented the social and cultural benefits of Great Lakes fish consumption, particularly for subsistence fishers and native communities. At this time, federal and state/provincial governments provide fish consumption advisories based solely on risk.Conclusions: Our knowledge of Great Lakes fish has critical gaps, particularly regarding the benefits of consumption. A risk–benefit analysis requires more information than is currently available on the concentration of omega-3 fatty acids in Great Lakes fish and their absorption by fish eaters in addition to more information on the social, cultural, and health consequences of changes in the amount of fish consumed. The relationship between the risks and benefits of fish consumption is complex. Consumption of fish and fish oils may be beneficial to early cognitive development and improve cardiovascular health in adults, but fish can also be an exposure route for toxic chemicals such as polychlorinated biphenyls (PCBs) and methylmercury, which confer risks for these same health outcomes  and otheRecommendations and advisories on fish consumption for both mercury and persistent organic pollutants (POPs) are often conflicting and can be confusing to consumers. The U.S. Food and Drug Administration (FDA) issued consumption advice for mercury in fish, but only for young children and women who are or might become pregnant or are nursing (U.S. FDA 2004). Health Canada advises different rates of consumption for the general population (150 g/week), for women who are or might become pregnant (150 g/month), for children 5–11 years of age (125 g/month), and for children 1–4 years of age (75 g/month) . To add Fish consumption advice has received considerable publicity in the popular press, and this has led to changes in consumption patterns. After the dissemination of advice by the U.S. FDA in 2001 recommending that women of childbearing age should avoid consuming specific long-lived predatory fish high in mercury and limit fish and shellfish meals, pregnant women in eastern Massachusetts decreased their total fish consumption, resulting in an estimated decline of 17% to 1.4 servings per month . A natioThe five Great Lakes have abundant fish stocks harvested by native peoples, recreational anglers, and commercial fishing enterprises. More than 160 aboriginal communities situated around the Great Lakes Basin have historically depended on local fish for a substantial proportion of their diet. Recreational Great Lakes sport fishing is a $7 billion annual industry in the United States . In addiCurrently, fish consumption advisories exist for some fish in all of the Great Lakes . In the United States, the Great Lakes states have developed a uniform fish consumption advisory approach that provides information on the amounts of fish that should be consumed over a particular period based on contaminant level, size, species, and location , 2007. SWhile a fair amount of information on contaminant concentrations in Great Lakes fish is available, little is known about the omega-3 fatty-acid content of these fish, creating significant uncertainty about how to balance the risks and benefits of eating Great Lakes fish. Indeed, most of our knowledge on the nutritional benefits of fish consumption is based on marine fish, which generally have higher concentrations of omega-3 fatty acids than freshwater fish . SeveralWe used a scoping approach  to conteHistorical and current contaminants in Great Lakes fish. The Great Lakes are contaminated with many bioaccumulative pollutants including PCBs, polychlorinated dibenzo dioxins and furans (PCDD/Fs), polybrominated diphenyl ethers (PBDEs), methylmercury, and chlorinated pesticides such as dichlorodiphenyltrichloroethane (DDT) and its metabolites. Most of these contaminants are lipophilic and therefore are found in higher concentrations in fatty, older, and piscivorous fish. Levels of methylmercury are also higher in older and predatory fish, but because methylmercury binds to protein, it bioaccumulates in muscle tissue rather than fatty tissue.Contaminant levels measured in edible portions of a variety of Great Lakes fish are monitored by the OMOE , by the U.S. states that border the Great Lakes, and by some tribal nations and are used to issue fish consumption advisories. In addition, the U.S. EPA and Environment Canada have ongoing, long-term efforts to monitor whole-body contaminant levels of top predator fish species  in order to track trends in contaminants over time . Many ofIn general, fish from Lakes Michigan, Ontario, and Huron have the highest levels of PCBs, DDT, and dieldrin; fish from Lake Superior have the highest levels of toxaphene; and those from Lake Ontario have the highest levels of mirex . Contamip-dioxin  in lake trout from the Canadian Great Lakes have also been reported  for details on individual species]. Although there are considerable data on omega-3 fatty acids in numerous species of fish from marine and freshwater systems , only thOmega-3 fatty acids in Great Lakes fish consumers. Consumption of fish, and fatty fish in particular, is correlated with serum levels of omega-3 fatty acids. For example, both fish and fish oil consumption were related to plasma DHA and EPA in a cohort of 4,949 men and women from the United Kingdom . function . Consumpfunction , althougfunction . Fish coSubstantial evidence suggests that increased fish consumption has important cardiovascular benefits . SeveralConsumption of Great Lakes fish is of particular concern for several population groups. Consumption rates in women and children are important because of known developmental effects of pollutants. In addition, potentially larger pollutant exposures are possible in persons exposed through recreational, cultural or subsistence fishing. Because all fish carry some levels of pollutants, it is necessary to consider total fish consumption rates, including commercial and sport-caught fish from the Great Lakes and other bodies of water.In surveys of Great Lakes states populations, 7–8% of adults, or 4.2–4.7 million persons, reported consumption of Great Lakes sport-caught fish in the previous year, and 830,000 persons ate ≥ 24 Great Lakes sport-caught fish meals annually . Adults in utero toxicant exposures may pose a greater risk for adverse neurodevelopmental and other health outcomes than exposure after birth  coexposures to multiple toxic pollutants from fish and other sources, including methylmercury, lead, and POPs; b) dietary intakes of nutrients such as omega-3 fatty acids, selenium, and other antioxidants—either from fish or from other sources—that could possibly counteract the negative effects of contaminants; c) sex differences in exposure or susceptibility; and d) the social environment. An investigation of the neurodevelopmental impact of fish consumed from all sources found that simultaneous adjustment for both methylmercury and fish intake strengthened estimates of both benefits related to fish consumption and risks of mercury exposure  PDFClick here for additional data file.


In 2007, UNAIDS and AVAC developed the Good Participatory Practice (GPP) Guidelines with the aim of ensuring community and stakeholder engagement in HIV prevention research. The second edition, launched in 2011, provides the first standardized framework for GPP compliance. Five years after initial publication, it is possible and necessary to evaluate milestones in adoption of the guidelines at trial site, sponsor, country, and international levels in order to gauge progress and next steps.A systematic review of 1) articles citing or mentioning GPP; 2) GPP-specific trainings requested and/or carried out by AVAC partners; 3) national and international forums in which GPP was mentioned, adopted or presented shows that GPP is gaining currency and relevance as key in guiding not only prevention research but all research involving human subjects.Support for and awareness of GPP have increased dramatically over the past five years. There is, however, a continued need for technical support for implementation. Common gaps in practice included low levels of documentation of engagement activities, planning around possible contentious issues and trial results, and stakeholder input in trial protocols. National level implementation activities provided initial steps in requirement of GPP. For example, GPP was presented to US President Obama’s Commission for Bioethics, and subsequently cited as recommendation for community engagement in the Commission’s official report. This effort secured international recognition and expanded relevance beyond HIV prevention research. Additional action is necessary for requirement and monitoring of practices.While stakeholder engagement has long been accepted practice in HIV prevention research, findings from multiple implementation processes suggest the value and power of applying a systematic framework to practices. Awareness of GPP has increased, however meaningful implementation within and outside of HIV prevention research necessitates sustained commitments, new resources and action on the part of national, international and community-level stakeholders.