Few studies describe system-level challenges or facilitators to implementing population-based colorectal cancer (CRC) screening outreach programs. Our qualitative study explored viewpoints of multilevel stakeholders before, during, and after implementation of a centralized outreach program. Program implementation was part of a broader quality-improvement initiative.During 2008–2010, we conducted semi-structured, open-ended individual interviews and focus groups at Kaiser Permanente Northwest (KPNW), a not-for-profit group model health maintenance organization using the practical robust implementation and sustainability model to explore external and internal barriers to CRC screening. We interviewed 55 stakeholders: 8 health plan leaders, 20 primary care providers, 4 program managers, and 23 endoscopy specialists , and analyzed interview transcripts to identify common as well as divergent opinions expressed by stakeholders.The majority of stakeholders at various levels consistently reported that an automated telephone-reminder system to contact patients and coordinate mailing fecal tests alleviated organizational constraints on staff’s time and resources. Changing to a single-sample fecal immunochemical test (FIT) lessened patient and provider concerns about feasibility and accuracy of fecal testing. The centralized telephonic outreach program did, however, result in some screening duplication and overuse. Higher rates of FIT completion and a higher proportion of positive results with FIT required more colonoscopies.Addressing barriers at multiple levels of a health system by changing the delivery system design to add a centralized outreach program, switching to a more accurate and easier-to-use fecal test, and providing educational and electronic support had both benefits and problematic consequences. Other health care organizations can use our results to understand the complexities of implementing centralized screening programs. Colorectal cancer (CRC) is the third most common non-skin cancer, and the second leading cause of cancer-related death, in the U.S. . The earDespite the proven benefits, CRC screening at regular intervals for age-appropriate populations remains sub-optimal in the U.S.. Although more than half of adults aged 50 and older in the U.S. have ever received a CRC screening test, millions of Americans are not receiving CRC screening at all, or are not repeating screening tests at recommended intervals . PopulatWe conducted a qualitative case study -18 to exWe conducted our qualitative study between 2008 and 2010 at Kaiser Permanente Northwest (KPNW), a not-for-profit group model health maintenance organization (HMO) with about 485,000 members in Southern Washington and the Portland, Oregon, metro area. KPNW regional electronic databases capture >95% of all medical care and pharmacy services members receive, and data are linked through each member’s health record number. A full electronic medical record (EMR) has been in place since 1996. The study design and procedures were approved by KPNW’s institutional review board, and interview participants provided written informed consent.Our qualitative study was designed to take advantage of an already in-process change in care practices at KPNW. In 2008, the organization implemented a new CRC screening-reminder program and related quality-improvement initiatives. The reminder program used automated phone calls to encourage CRC screening for average-risk, age-appropriate members who were coming due, all identified through diagnosis and procedural codes in the electronic medical record. Details on the design and outcomes of this program are reported elsewhere . BrieflyOther quality-enhancement efforts within the organization included heightened training of providers  highlighting CRC screening importance and methods. The organization also implemented staff financial incentives for meeting organizational target goals in CRC screening rates.The guiding framework for our study was the practical robust implementation and sustainability model , and 20 primary care providers (PCPs).n = 4) to a 90-min focus group, occurring after the intervention; all of them participated.We identified health plan leaders and managers based on their role in the organization as a resource and program decision-maker, and/or their role in designing and implementing the CRC screening program. We invited all health plan leaders through an organizational e-mail to participate in a 45-min face-to-face interview, and provided lunch for participants. All of them agreed to participate. We interviewed four of them prior to the intervention and four of them after the intervention, to obtain perspectives over time on the anticipated and realized successes and challenges of the implementation. We also invited four managers designing and implementing the centralized CRC screening program  within the organization. We obtained permission to conduct a 30-min focus group with the gastroenterologists during a regional staff meeting; attendance at the meeting was mandatory but participation in the focus group was optional (with informed consent obtained). All 15 gastroenterologists present at the meeting participated. We conducted a similar but separate focus group for the general surgeons; 8 out of 11 general surgeons present actively participated, while 3 listened but did not share in the discussion. These focus groups occurred toward the end of the intervention phase.n = 246). We identified “lower” (<20th percentile) and “higher” (>80th percentile) performers based upon their 2008 CRC screening-performance rates ascertained through routine HEDIS quality measures by the health plan. We further divided the list into those who used more stool tests and those who used more endoscopy, based on proportion of completed tests. From this process, we identified a total of 102 PCPs and sent out 67 individual recruitment emails to a representative subgroup of the identified list to reach a total of 20; both PCPs and the staff recruiting and conducting the interviews were blinded to whether they fell into the “lower” or “higher” screening performance groups. Forty-one participants provided no response to the email invitation, and 6 participants indicated scheduling conflicts or lack of time as their reason for not participating.We identified and interviewed 20 PCPs ,30 who hA trained, third-party qualitative methodologist not known to the participants [JS] conducted interviews, and interviews were audio-recorded and professionally transcribed for analysis. Focus groups were facilitated by both EL and JS, with notes taken manually by JS. Interview and focus group questions elicited information about stakeholders’ perspectives regarding barriers and facilitators to CRC screening in general, and specifically within the organization; overall reaction to the organization’s CRC screening program, including to the use of automatic reminder calls and stool tests. Questions also elicited advice on improving the CRC screening program. The research team developed and refined interview and focus group guides using an iterative approach, whereby team members regularly met to discuss themes generated by prior interviews and to consider areas of exploration for subsequent interviews -32. CoauThe most commonly perceived external  barrier expressed was that expert opinions about the best screening option for low- or average-risk patients were inconsistent. Internal CRC screening recommendations had changed over the course of 5 years, with an emphasis on sigmoidoscopy initially, followed by an emphasis on stool testing, followed by allowance of multiple options. Health plan leaders/managers stated that there were too many screening options in the system , with limited guidance for providers and patients about which test to choose. Specialists and health plan leaders/managers alike perceived that PCPs, influenced by training or work culture, may promote primarily screening colonoscopies rather than stool tests or sigmoidoscopy as options for average/low-risk patients. Similarly, PCPs and some of the specialists expressed discomfort with the previous years’ focus on stool tests and flexible sigmoidoscopy as preferred screening options, rather than colonoscopy, because this emphasis did not match community norms and expectations. Primary care providers expressed that they received a “mixed-message” from the organization by being allowed to refer patients to colonoscopy to screen for CRC in average-risk patients, but then were not always supported by health plan leaders or specialists for doing so. They also said that frequent changes in the emphasis on screening options for patients created confusing expectations Table .Table 1Stakeholders also uniformly expressed concern about limited availability of trained specialists for conducting screening colonoscopies. Surgery and gastroenterology specialists said that inappropriate referrals for colonoscopy further strained already limited colonoscopy resources. Primary care providers reported that resource constraints created challenges with patient rapport, due to having to explain and negotiate the long wait for access to a screening colonoscopy. They described as challenging working in an environment that had undergone numerous shifts in how the organization allocated CRC screening resources.PCPs felt specialists lacked appreciation or awareness of the time constraints and pressures they are under during a 20-min office visit, making it challenging to always thoroughly discuss with patients CRC screening importance, risk/benefits, and various screening options. The challenge of offering patients a choice in the discussion of CRC screening options compounded the problem. PCPs felt a lack of support in ensuring that patients followed through with screening completion. They felt the communication from support staff to patients about how to return completed stool test kits was inconsistent and confusing. Additionally, PCPs felt the referral process for a screening colonoscopy involved too many steps and departments, leaving room for miscommunication, misunderstanding, and lack of follow-up with the patient. Specialists acknowledged that they had historically tended to have a limited role in shaping the organizations CRC screening program.Health plan leaders and managers described a historical focus on quality and prevention in the organization’s mission as a facilitator of continued efforts to improve CRC screening rates. They were spurred on by the fact that the local organization’s quality performance numbers for CRC screening had historically been lower than those in other regions, who had demonstrated improvement by adopting a more formalized and centralized outreach program. They also reported prior successes in improving screening rates for other prevention measures  through a centralized reminder program as a strong motivator to continue to innovate. Health plan leaders cited this example as inspiration that a sustainable and cost-effective population-based CRC screening program acceptable to both providers and patients was possible Table .Table 2Health plan leaders cited their confidence in the abilities of key leaders, managers, and implementation groups within the integrated health system. PCPs emphasized the importance of experts in the system to facilitate CRC screening knowledge and programs. They also cited a strong trust in the skill level, training, and recommendations of endoscopy specialists in the organization. They also valued having a PCP champion within the system who could help colleagues both navigate and integrate new CRC research with organizational goals and patient preferences. Some PCPs also found that the EMR tools that alert them when CRC screening is due, or show indications of prior completed screenings, were facilitators in their screening efforts. Lastly, PCPs reported that use of support staff  trained in educating and motivating patients on screening and follow-up helped them to screen more patients.Specialists identified the importance of increasing future access to colonoscopy and discussed solutions such as having general surgeons and other staff trained in conducting colonoscopies. Specialists described being motivated to support the program’s efforts because they see firsthand the consequences of colon cancer for patients. PCPs perceived a subtle organizational shift in recent years that had allowed them to more easily refer patients for screening colonoscopies, particularly if that was the patient’s preference. This, along with decreasing the wait time for screening colonoscopies, and adjusting the organization’s CRC guidelines to be more in line with the U.S. emphasis on colonoscopy, were also perceived by PCPs as important organizational changes that facilitated CRC screening.Health plan leaders felt the reminder calls had helped to improve the organization’s CRC screening rates, and said that calls are an effective, sustainable resource for supporting the organization’s efforts to screen a large population. They described the reminder calls as acceptable to patients, patient-centered, friendly, and easy to follow. PCPs said the reminder program helped to decrease workload for providers and health care teams by decreasing the need for individual providers to conduct their own outreach. Challenges to successful implementation of the centralized, automated reminder program identified by health plan leaders and managers centered on the interface of the program with the electronic medical record, with Medicare and Medicaid regulations, and with population health services sending kits to patients. They recommended involving the information technology (IT) department early in order to optimally integrate automated calls with the EMR. Health plan managers identified the challenge of being adequately staffed to quickly enter orders in the EMR and get them mailed to patients who wanted a stool test. This constraint initially decreased interest and compliance in completing or returning the stool test kits. They recommended streamlining the ordering of the stool test for patients due to receive a reminder call so the order would already be in the EMR, ready to be acted upon. They also suggested automatically sending stool test kits to every person who is due for screening following the receipt of a reminder call Tables a, b.TablHealth plan managers felt that implementation of FIT increased patient compliance with the stool test method of screening; instructions for completing FIT were perceived as being easier for patients to follow. Yet, both health plan leaders and PCPs felt there was room for improving the readability of instructions and protocols for distribution of kits; for example, some kits distributed in clinic were returning to the lab without proper patient identification labels. Health plan leaders felt that the transition to FIT further increased the organization’s CRC screening rate from prior years. PCPs and health plan managers described how ease of FIT completion made discussion about CRC screening easier and more efficient. Additionally, PCPs said that increased test sensitivity of FIT has raised their enthusiasm for, and trust in, stool test screening. Specialists expressed enthusiasm about having a centralized screening program, but also ambivalence about prioritizing fecal testing over colonoscopy.All three stakeholder groups felt the organization had improved its communication so to provide a unified message to providers to encourage and discuss FIT screening as an option, and offer screening colonoscopy if the patient preferred this option. Nonetheless, all stakeholder groups felt there were still some providers who believed that colonoscopy is the only acceptable method for CRC screening for average-risk patients. Health plan leaders and PCPs both felt the organization continues to lack effective and clear methods to communicate the organization’s CRC screening approach to all providers. Specialists said there was a need for communication to help staff see the screening program as an integrated service involving input and effort from multiple departments such as surgery, gastroenterology, primary care, and oncology. PCPs and health plan leaders identified the helpfulness of education on resource stewardship and on feedback of providers’ screening tendencies. Yet, health plan leaders expressed the desire for more effective ways to communicate and educate providers about resource stewardship issues and evidence-based outcomes as they pertain to CRC screening.There was concern from all three stakeholder groups that the current CRC program may be creating some screening duplication, contributing to inefficient use of resources. Health plan leaders endorsed the multimodal approach to offering screening options to patients  and via automated calls (outreach) as important attributes of improved screening rates. Yet, health plan leaders and PCPs identified that the lack of integration or documentation of the reminder calls in the EMR created challenges by increasing providers’ chances of duplication of effort or service. PCPs desired clearer prompting through the EMR about patient screening status  during the clinic visit. Specialists felt strongly that improving EMR alerts and directions for providers/support staff could also prevent patients who had a recent normal colonoscopy from receiving a FIT. PCPs and specialists found overall documentation of prior colonoscopy results to be inconsistent and confusing, as they could not always discern what were recommended next steps for future screening. Specialists were frustrated that some patients were still inappropriately screened, such as the very elderly or hospice patients. Concern about screening duplication generated questions where evidence-based practices and policies were unclear. For example, specialists and health plan leaders described a lack of clarity on protocols for patients with a negative FIT who requested a screening colonoscopy within the same year.PCPs and health plan leaders both underlined the need to improve patient education regarding CRC screening importance and options. PCPs requested more consistent educational tools to help patients navigate screening information and options . Specialists emphasized the need to proactively educate patients about all available CRC screening choices. PCPs and health plan leaders agreed on the need to increase and standardize training of support staff in order to expand staff roles in CRC screening, since support staff are often the ones who see patients first and place the screening order in the system; they suggested enabling preordering of the screening test during rooming procedures.The greatest challenge to implementing FIT, as identified by health plan leaders and specialists, was unintentionally creating resource and access issues with colonoscopy services due to the increased compliance with, and sensitivity of, the test. Health plan leaders and PCPs felt that there is still a need for additional highly trained staff to provide endoscopy services, including colonoscopies. PCPs advocated for the organization to train more mid-level providers to conduct colonoscopies to assist with issues of access. Specialists emphasized their desire for patients to be able to self-refer for CRC screening, similar to the breast cancer screening program already in place. Self-referral would allow the patient to choose any of the tests available and have direct access to scheduling, rather than requesting a referral from a primary care provider. At the time of this publication, the health system does not offer self-referral for endoscopy.Prior studies have evaluated implementation of colorectal cancer screening programs within medically underserved populations in the U.S. -37, wherUnique to this study setting was a preexisting sophisticated electronic medical record (EMR), which integrates data from all departments and all sites of care. Stakeholders attributed screening increases in part to implementation of clinical decision support in the EMR, which allowed notification in the chart of patients who appeared overdue for screening, and enabled distribution of FIT kits from different points of clinical care. While outreach efforts from clinic support staff (through reminder letters) were already underway prior to the implementation, the addition of the centralized automated telephone outreach program enabled multimodal communication with, and reminding of, patients, which has been shown to enhance screening rates in prior studies -44. Yet,Participants stated that changing from guaiac fecal occult blood test cards to the FIT test, a single-sample fecal immunochemical test with implementation of a centralized outreach program, provided much-needed clarity about organizational priorities. Prior to implementation, administrators expressed that it was difficult to know which screening test to prioritize for promotion across the system. U.S. guidelines do not strongly recommend one test over another ,6. Even An unintended consequence of program implementation was more screening duplication. Stakeholders reported that the ease of access and ubiquitous distribution of FIT led to some waste of fecal test kits and also to some over-screening. This finding is a downside to the benefit of achieving high screening rates by using multimodal reminders. PCPs and health plan managers reported that some patients received several kits at different points of care, because of electronic alerts indicating that he/she was overdue for screening. Those with low screening adherence would sometimes lose kits or would keep more than one at home, incomplete. Prior studies have targeted non-adherent patients by employing tailored navigation through telephone outreach by a nurse or medical assistant, though success of this approach has been variable, and widespread implementation would need to consider cost-benefit tradeoffs ,49. ScreLastly, in spite of the focus of the program being fecal tests, stakeholders at all levels discussed the ongoing need to expand colonoscopy resources, namely, increasing the number of endoscopists and the dedicated facilities and staff for offering this procedure. Both administrators and specialists had concerns about limitations in colonoscopy resources, and how the organization should manage these resources while still offering screening to all eligible patients. Resource constraints are likely to remain an ongoing concern in colorectal cancer screening programs ,57.Our study could not discern whether stakeholders’ responses represent the feelings of non-interviewed clinicians, specialists, and health plan managers across the Kaiser Permanente system. However, responses were sufficiently consistent that we could identify themes and patterns across different groups. Another limitation may be that the lessons learned in this system, which has internal practice guidelines and a sophisticated electronic medical record, may be difficult to apply in systems lacking those attributes. However, ~80 million people in the U.S. receive care from an HMO, which likely have similar organizational attributes as those described here. Two strengths of this qualitative study are that we obtained a variety of viewpoints through multiple interviews, and that we elicited responses at a variety of time points relative to the quality interventions. We also used a prespecified interview guide, a trained interviewer, and a repeated, iterative process of reliability-checking among members of the research team.Our analyses of multiple stakeholder viewpoints about quality-improvement efforts to raise CRC screening rates yielded valuable information about successes, and remaining challenges, to successful implementation of a reminder program in a highly integrated U.S. managed health care system. CRC screening rates improved 10% during program implementation and continue to rise. The implementation program capitalized on historical facilitators , while also removing some historical barriers to screening . Success was due in large part to the activation of three different domains within the PRISM framework: changing the delivery system design through centralizing screening efforts (implementation infrastructure); switching to a more accurate and feasible fecal test ; and providing educational and electronic support (recipients of intervention). The combination of these actions resulted in a successful and sustained improvement in CRC screening rates.Health plan leaders, PCPs, specialists, and support staff in other health systems can use our results to address remaining barriers to raising CRC screening rates. All the stakeholders we interviewed acknowledged the complexity of understanding and applying the scientific evidence for CRC screening, and expressed a need for ongoing education of both providers and patients about organizational emphases on CRC screening. They also wanted to understand, and have input into, the scientific reasoning informing an organization’s choices in recommending one test over others for people at average risk of colon cancer. Further refinement of the stool test distribution system should focus on reducing duplication of test dissemination, and installing new procedures for identifying and documenting prior endoscopies done outside of the system. Perhaps the greatest challenge to the system we studied is that increases in FIT testing, and the greater sensitivity of FIT, have led to greater demand for colonoscopies. Ultimately, decision-makers will need to re-examine the relative benefits of joint informed decision-making  and weigh them against the benefits of centralized screening efforts through a single test , and concentrate their resources accordingly.


P. falciparum malaria.Yoel Lubell and colleagues consider ethical and economic perspectives on mass drug administration of primaquine to limit transmission of Please see later in the article for the Editors' Summary Rapidly achieving falciparum malaria elimination could require mass antimalarial treatment of asymptomatic individuals to eliminate the parasite reservoir that sustains malaria transmission.Plasmodium falciparum gametocytes, but it is associated with a dose-dependent risk of haemolysis in G6PD-deficient individuals.Primaquine is the only licenced antimalarial that kills mature We discuss ethical and economic considerations pertaining to mass primaquine administration in malaria elimination programmes, which go beyond those encountered in other public health interventions. These include the lower direct benefit for individuals at higher risk, the increasingly available diagnostic tests for G6PD deficiency, and the economic implications of testing.We propose a research agenda to assist informed and rational policy decision making in the rollout of primaquine mass drug administration that is pragmatically and economically viable and within acceptable ethical standards.P. falciparum undermining these gains. The potential benefits of malaria elimination are substantial, including the direct burden averted and economic growth through improved educational attainment and productivity; these gains were estimated recently to far outstrip the costs required to achieve them Following a decade of gains in malaria control, two divergent prospects are emerging: malaria elimination in many endemic countries, and spreading artemisinin-resistant Much of the international investment in malaria control, approximating US$2.5 billion annually, is allocated to distributing insecticide treated nets (ITN) and improved diagnosis and treatment of clinical cases. While these contributed to the declining burden of malaria, avoiding the spread of artemisinin resistance and a final push to elimination could require additional interventions, notably population-wide antimalarial treatment.There is a qualitative difference between interventions such as ITN and improved case management, offering immediate health gains to recipients, and the treatment of asymptomatic, often uninfected individuals for a broader community gain, which offers little or no direct benefit and may even harm recipients. An unfavourable individual risk/benefit ratio could deter both policy makers from adopting what could be a critical component of an effective elimination campaign, and health providers from supporting its effective implementation.Mass drug administration (MDA) could, however, be essential to malaria elimination. This is because of the substantial proportion of malaria infections that are asymptomatic and chronic at densities lower than detection thresholds for microscopy or malaria rapid tests, even in areas of low malaria transmission. These infections still produce gametocytes, and in low-endemic settings are estimated to account for 20%–50% of transmission episodes P. falciparum gametocytes, but safety concerns in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd) have deterred its use to interrupt transmission on a large scale Primaquine is the only licenced antimalarial that kills mature P. falciparum transmission, and there have been occasional reports of significant haemolysis following the 0.75 mg base/kg gametocytocidal dose hitherto recommended. The WHO recently adjusted its guidelines for the management of falciparum malaria in low-transmission settings to allow for a single, low dose of primaquine (0.25 mg base/kg) without G6PDd testing, except for pregnant women and infants <1 year of age Over two hundred million people have received primaquine, but in the majority of cases primaquine was given in a two-week course (0.25 mg base/kg/day) to prevent relapses of vivax malaria. This carries a substantially greater risk than single-dose administration to prevent transmission of falciparum malaria. Excluding Chinese data for which denominators are unclear, it has been estimated that the risk of death associated with use of primaquine is one in 621,428 individuals treated, with an upper 95% CI boundary of one in 407,807 Previous public health interventions, such as the smallpox and polio eradication campaigns, posed comparable risks to vaccinated individuals, as does the use of sulfadoxine–pyrimethamine and other antimalarials in intermittent preventive treatment often provided to children and pregnant women in malaria-endemic regions P. falciparum gametocytocide in MDA contentious. Firstly, the use of primaquine offers no curative or prophylactic effect to the individuals receiving it , but it does expose them to risk of harm . Asymptomatic carriers targeted by the programme are less likely to benefit from the programme because of their immunity to malaria.Ethically, there are two additional aspects that make use of primaquine as a Secondly, the technology to identify G6PD-deficient individuals and exclude them from treatment is increasingly available. While intuitively appealing, this involves significant trade-offs – it would lower gametocytocidal treatment coverage, jeopardising the campaign and therefore increasing the probability of a rebound in malaria cases; and it requires significant resources to prevent what is likely be a very low degree of harm. Assuming a cost of US$2 per test, the above estimated mortality of 1–2 million, and a life expectancy of 20 years, would result in a cost per DALY averted in the range of US$50,000 to US$100,000, far exceeding what is normally considered cost-effective in low-income settings. The substantially lower estimated risk associated with single-dose primaquine would imply an even higher cost per DALY averted. This investment, from a consequentialist perspective, might be unethical, if these resources could be used elsewhere to generate far greater health benefits; but from other ethical perspectives and given the unique context, use of the tests could still be considered an ethical obligation.Taken together, the decision to implement MDA with primaquine introduces challenges both within public health ethics and between public health ethics and those of clinical practice At the core of public health ethics is the ambition of improving the health of populations whilst minimising potential risks to the liberty or autonomy of individuals Despite a favourable consequentialist assessment, an unequal distribution of risk amongst different ethnic groups and marginalized communities with poorer access to medical care to manage adverse events poses further challenges. The confluence of malaria transmission, marginalized communities, and in some instances higher prevalence of G6PDd is a reality in many endemic areas P. falciparum to India and Africa could undermine the recent global gains in malaria morbidity and mortality From the public health planners' perspective, the question of consent on the part of recipient communities is paramount. There is a distinction between medical research, which usually necessitates an opt-in informed consent process, and public health interventions where an opt-out approach might be more appropriate In considering these challenges, reference should be made to relevant national and international legal frameworks and ethics guidelines. Such laws, embedded in national constitutions and legislative mechanisms, as well as conventions and customary obligations under international law, guarantee specific legal entitlements to individuals subjected to medical interventions, even where these are at the expense of the “greater good” Although health providers administering treatments in an MDA programme might be committed to reducing malaria transmission in the population, their primary concern is likely to be the well-being of individuals in their care. Indeed, health-care professionals have a legal and moral duty to act in the best interests of the patient. In practical terms, this means that health-care professionals exercising their duty of care will generally administer medication only where the risk of harm is minimal or where the individual benefit outweighs the risk of harm prima facie at odds with the administration of a potentially harmful drug to an asymptomatic or even uninfected individual for the benefit of the wider community. Much depends, however, on the degree of risk involved. For therapeutic interventions the obligation to ensure informed consent is proportional to the risk involved This is Even if implicit informed consent is normatively acceptable, ensuring its validity will be challenging. Will individuals comprehend the difference between a public health intervention and an individual curative treatment Considering these challenges, how best to proceed? One option is to continue minimising the burden of clinical cases without pushing forward with an aggressive elimination campaign. This will spare the resource-intensive phase required in stamping out final infections and avoiding re-importation, as well as potential harm associated with measures such as primaquine MDA. The risk here is that the spread of artemisinin resistance undermines our ability to effectively treat clinical cases coupled with a rebound in transmission, resulting in a large increase in morbidity and mortality. The global impact could be enormous.With a more ambitious objective of interrupting transmission, an alternative strategy targeting asymptomatic infections and circumventing the ethical challenges in MDA is to screen for parasitaemia and treat only positive individuals, offering a clearer benefit to drug recipients. The malaria tests available for wide-scale screening, however, often fail to identify low levels of parasitaemia Given these limitations, MDA with single dose primaquine might be the only option for successful elimination campaigns. The risk associated with this low dose is small, even in G6PD-deficient individuals, and while its existence raises ethical questions both in relation to public health and to clinical care, these can be managed with careful consideration. On this basis it is our view that MDA programmes that include the use of primaquine are justifiable, but will require carrying out a significant programme of research together with implementation see . A reseaA number of MDA studies with single-dose primaquine and other drug regimens have been carried out or are underway; further studies are needed to inform on the impact on transmission and establish the regimens' safety profiles in different age groups and in G6PD normal and deficient subgroups.These findings can be used in economic–epidemiological models to estimate the costs and benefits of MDA with or without gametocytocidal drugs and the probability and timeframe to elimination. Such models can also estimate the minimal coverage required for successful elimination, and explore the impact of excluding G6PD-deficient individuals from gametocytocidal treatment.If exclusion of G6PD-deficient individuals is predicted to critically compromise the programme's effectiveness or the cost is prohibitive, further assessment should be undertaken to explore whether provision of primaquine without G6PD testing would comport with national and international legal obligations and comply with ethical standards.Qualitative research is required to provide insight into the practical ethical challenges that may arise for health professionals and for community members. For example, it is important to understand community views about taking drugs when ill and when not; attitudes towards Western medicine; and previous experience with MDA programmes and any challenges associated with them.Drawing on these findings, programme designs should be trialled to identify those that achieve the highest levels of coverage while complying with ethical and legal standards.


Plants being sessile in nature are often challenged to various abiotic stresses including temperature fluctuations, water supply, salinity, and nutrient availability. Exposure of plants to such environmental perturbations result in the formation of reactive oxygen species (ROS) in cells. To scavenge ROS, enzymatic and molecular antioxidants are produced at a cellular level. ROS act as a signaling entity at lower concentrations maintaining normal growth and development, but if their levels increase beyond certain threshold, they produce toxic effects in plants. Some developmental stages, such as development of reproductive organs are more sensitive to abiotic stress than other stages of growth. As success of plant reproductive development is directly correlated with grain yield, stresses coinciding with reproductive phase results in the higher yield losses. In this article, we summarize the redox control of plant reproductive development, and elaborate how redox homeostasis is compromised during abiotic stress exposure. We highlight why more emphasis should be given to understand redox control of plant reproductive organ development during abiotic stress exposure96to engineer crops with better crop yield. We specifically discuss the role of ROS as a signaling molecule and its cross-talk with other signaling molecules such as hormones and sugars. The entire life cycle of flowering plants is a succession of distinct growth phases, where plants depict various developmental stages. The growth phase between seed germination and vegetative maturity is termed as “vegetative-phase”; and the subsequent phase including formation of reproductive organs, sexual reproduction, and seed set is termed as “reproductive-phase.” Plant performance in these growth phases, and transition from vegetative to reproductive phase is under tight control of genetic network  and gynoecium . The detailed structure of plant reproductive organs and the sequence of events leading to fertilization are described in the legend of Figure roxy1 mutant, deficient in CC-type GRXs (glutaredoxins: glutathione dependent oxidoreductases) displays reduced petal number and male-sterile phenotype. A deeper analysis revealed that this mutant lacks ability to enter meiotic phase  mutant phenotype of maize, confirming that excess ROS formation was mainly responsible for male sterility  mutant which is impaired in glutathione (GSH) synthesis shows poor pollen germination, indicating that GSH is essential for pollen development  double mutant of Arabidopsis, which lacks the ability of ROS burst shows severe reduction in pollen tube tip growth  mutant lacking MSD1 activity shows defects in embryo sac development. The sperm cell release from pollen tube is a redox (ROS) dependent process. It is regulated through FERONIA (FER) receptor kinase which induces the production of high ROS levels, especially hydroxyl radicals, at the entrance of female gametophyte to facilitate the rupture of pollen tube in a calcium dependent manner  and NO (nitric oxide) mediated redox signaling is involved in pollen-pistil interactions  was observed at the receptive papillae, while pollen still retain high NO levels  in enhanced seed production subjected to chronic heat stress was illustrated in One of plant's remarkable strategy to deal with stress is to escape the stressful environment via reproduction. Hence, proper timing of transition from vegetative to reproductive phase determines the success of reproduction. The OXS2 (OXIDATIVE STRESS 2) is a member of zinc-finger transcription factor family, which is involved in maintaining vegetative growth, stress tolerance, and stress-induced reproduction (Blanvillain et al., Two contrasting hypothesis have been proposed to explain the effects of redox status on meiosis and germline formation. The “reductive hypothesis” proposes that reduced ROS levels are required for successful meiosis (Kelliher and Walbot, Arabidopsis as a model organism, future research should input judicious use of major crop species ensuring yield robustness in meeting continual demands of an ever increasing human population.The redox control of plant reproductive development has been the long standing dilemma of plant scientists. Understanding the reproductive cost of oxidative stress requires a targeted molecular approach for engineering transgenes responsible for stress resilience in plant's reproductive system. But our knowledge is demarcated by methods to intertwine regulatory networks underlying reproductive development. Although much of the studies now focus on GZ and AK conceived the idea and outline for the prescribed article and thereafter compiled and incorporated the different sections contributed by co-authors. All the authors read and approved the final version before submission.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.


Wind turbine noise exposure and suspected health-related effects thereof have attracted substantial attention. Various symptoms such as sleep-related problems, headache, tinnitus and vertigo have been described by subjects suspected of having been exposed to wind turbine noise.This review was conducted systematically with the purpose of identifying any reported associations between wind turbine noise exposure and suspected health-related effects.A search of the scientific literature concerning the health-related effects of wind turbine noise was conducted on PubMed, Web of Science, Google Scholar and various other Internet sources.All studies investigating suspected health-related outcomes associated with wind turbine noise exposure were included.Wind turbines emit noise, including low-frequency noise, which decreases incrementally with increases in distance from the wind turbines. Likewise, evidence of a dose-response relationship between wind turbine noise linked to noise annoyance, sleep disturbance and possibly even psychological distress was present in the literature. Currently, there is no further existing statistically-significant evidence indicating any association between wind turbine noise exposure and tinnitus, hearing loss, vertigo or headache.Selection bias and information bias of differing magnitudes were found to be present in all current studies investigating wind turbine noise exposure and adverse health effects. Only articles published in English, German or Scandinavian languages were reviewed.Aeq of 35 dB. Of the many other claimed health effects of wind turbine noise exposure reported in the literature, however, no conclusive evidence could be found. Future studies should focus on investigations aimed at objectively demonstrating whether or not measureable health-related outcomes can be proven to fluctuate depending on exposure to wind turbines.Exposure to wind turbines does seem to increase the risk of annoyance and self-reported sleep disturbance in a dose-response relationship. There appears, though, to be a tolerable level of around L In recent years suspected health-related effects of exposure to wind turbine noise have attracted much public attention. Whether or not this exposure can result in an array of described symptoms and disorders has been widely debated. It has been reported that noise from wind turbines can lead to such symptoms as dizziness, nausea, the sensation of ear pressure, tinnitus, hearing loss, sleeping disorders, headache and other symptoms. Additionally, the term “Wind Turbine Syndrome” has been coined to describe the association of these symptoms to wind turbine noise exposure In order to shed light on the question of causation, researches frequently seek a statistically significant dose-response relationship. Statistically significant relationships between exposure and symptoms may not be shown to be causal without knowing if there is a dose-response relationship. The aim of the present study is to systematically analyse the literature and conclude if there is any evidence to support these theories of adverse health effects caused by exposure to wind turbines.Noise from wind turbines is generated to a lesser degree by the rotory hub; however, virtually all other wind turbine noise is generated by the downward movement of the rotating blades which result in the characteristic audible swishing pulses Aeq) during a certain period of time. To then calculate Lden, 10 dB is added to the A-weighted equivalent sound pressure levels (LAeq) during the night and 5 dB is added to these noise levels during evening periods. If LAeq is constant throughout the day and night, Lden can be calculated by the addition of 6.4 dB to the measured LAeqden is measured at a height of 10 meters, and it is dependent on the wind speed, the landscape and the turbine type Aeq at 35–44 dB, depending on the given wind speed and the special noise sensitivity in areas with low levels of background noise max, corresponding to a LAeq of 42–44 dB or 37–39 dB in noise sensitive areas, is dependent on the wind speed (8 or 6 m/s respectively) Noise is often measured as A-weighted equivalent sound pressure levels (LpALF) of 20 dB Infrasound is considered to be sound of frequencies below 20 Hz, and low-frequency sound is considered to be sound between 20–200 Hz. Infrasound originates from many different sources in the environment including compressors, ventilation and traffic noise The supporting PRISMA checklist is available as supporting information; See The objective of the present study was to analyze the literature systematically, and to determine if there was any statistical evidence of adverse health effects from exposure to wind turbine noises. The literature reviewed here included literature from both peer-reviewed scientific sources as well as internet sources which were not necessarily peer-reviewed. All types of studies investigating any relationship between wind turbine noise exposure and health-effect outcomes were included in the systematic review. Furthermore, with the purpose of aiding in the analysis and interpretation of the findings of the systematic review, a separate review of issues related to wind turbine exposure was also conducted. Focus was given in particular to finding additional technical information with respect to the size and character of wind turbine noise, as well as information regarding documented community opinions of wind turbines.th of June 2014, and included all relevant reports published up until that time. No limits in language were used in the database searches.A PubMed search was conducted using the search string: wind turbines OR wind turbine OR wind farm OR wind farms. Additionally, a Web of Science search was conducted using the search string: (wind turbines OR wind turbine OR wind farm OR wind farms) AND  . Both daDuplicates of articles were removed, and the titles and abstracts of all records were screened. Articles were then selected for full-text review, dependent upon whether the content of the article concerned wind turbines and related health effects on humans. Of the articles selected for full-text review, reported health effects included noise annoyance and psychological aspects related to the opinions of communities regarding wind turbine noise, as well as specific studies exploring noise exposure from wind turbines. Only articles in English, German and Scandinavian languages were selected for full-text review. Articles containing specific environmental issues and problems related to biology and wild life, as well as more technical articles regarding wind turbine mechanics, were not selected for full-text review.http://scholar.google.dk/) was searched with the same search string previously used for the Web of Science search  and the low-frequency noise was between 26.7–29.1 dB(A). The highest octave band was found to be 250 Hz, and this means that low frequencies play an important role regarding the noise measured in neighbouring areas of wind turbines. Half of the measured room/wind turbine combinations actually demonstrated that the low-frequency limit of 20 dB set by Danish legislation was exceeded Sound pressure levels of nine wind turbines (2.3–3.6 MW) were measured in Denmark, and the distances which equalled LVibrations from low-frequency sounds are reported to be the cause of vibro-acoustic disease (VAD) Noise annoyance is not directly studied as a primary outcome in most of the case studies; however, it is evident from these studies that many subjects complain about noise from wind turbines Several reasons can explain why wind turbine noise probably causes more annoyance than other sound sources. Wind turbines are often placed in areas where background noise levels are low. People living in these areas may have sought out tranquillity and have likely accustomed themselves to the silence, which may influence their annoyance level regarding unwanted sounds in their environment As shown in Additionally four studies ranging from 23 to 93 households were conducted near four different specific wind farms in Australia  [50]–[52den was calculated from the measured LAeq reported in the original studies den an average correction factor of 4.7 dB was used as earlier suggested by van den Berg (2008) to account for differences in wind conditions and different terrains in the different studies. By calculation of Lden this study could compare the degree of annoyance in relation to Lden and this value could be compared to other well-known sources of environmental noise such as road traffic noise and noise from airports. The meta-analysis showed that noise from wind turbines was perceived as more annoying compared to noise from road traffic, airports and trains at similar values of LdenThe studies from Sweden and the Netherlands were used in a meta-analysis where LExperimentally it has been shown that wind turbine noise does not differ substantially from traffic noise when the wind turbine noise is not known of in advance den by as much as 50 dB and that 440.000 inhabitants were exposed to Lden above 29 dB. Of these 440.000 inhabitants, 1500 were expected to be severely annoyed It was calculated that 330 dwellings in the Netherlands were exposed to wind turbine noise exceeding LWhereas most studies collected only subjective information about sleep disturbance, some studies attempted to also collect objective longitudinal sleep data over several nights. By using an Actigraph, sleep was monitored and related to noise measurements in the sleeping room. The study had a limited sample size; however, and no difference in objective sleep quality in relation to the noise exposure was observed in the 11 subjects exposed to wind turbines compared to the 10 unexposed subjects.Noise from various environmental factors can affect sleep if the noise is pronounced at night Noise annoyance, self-reported sleep disturbance and psychological stress were all related to increasing sound pressure levels of wind turbines Another general health questionnaire (SF-36) was used to measure mental and physical component scores in wind turbine noise exposed subjects Associations between A-weighted sound pressure levels and subjective tinnitus and diabetes were demonstrated in one of the previous Swedish studies by Pedersen et al. Case series studies of wind turbine noise exposed subjects often report headache, vertigo, tinnitus and hearing loss as frequent symptoms It is hypothesized that sound may affect the vestibular organ in the inner ear even at subaudible levels It has been further speculated that rotating wind turbine wings passing through the sunlight can induce epileptic attacks in sensitive subjects because the sunlight will be seen to flicker on the horizon. This phenomenon is known in the field of aviation medicine and can actually disqualify a pilot at the aeromedical health check-up due to the risk assessment associated with flying a turbo prop plane or helicopter. If light flickers at a frequency around 3 Hz there is a known risk that this can induce an epileptic attack in sensitive subjects Noise from wind turbines results in significant annoyance for neighbours of wind turbines, and the level of annoyance is related to the A-weighted sound exposure Annoyance was significantly related to psychological distress and the mental component scores of SF-36 were significantly affected in wind turbine exposed subjects in some studies The quality of the studies included in this review is quite varied. There are five cross-sectional studies of reasonable sample size from which a dose-response relationship between sound exposure and health outcomes, particularly in relation to annoyance and sleep disturbance, was demonstrated Several studies investigated sleep disturbance and psychological distress in relation to an unexposed or low exposed control group Several case reports have raised concerns that wind turbine noise may lead to various symptoms such as tinnitus, vertigo and headache. Until now, however, of these suspected symptoms, only tinnitus has been shown to have an association with A-weighted sound exposure, and that only in a single study out of three similar studies Aeq or Lden based on model assumptions of sound propagation from wind turbines over distance Most studies investigating a dose-response relationship between sound exposure and annoyance have used calculated values of LOne study has already measured objective sleep parameters in relation to sound exposure, but the sample size of the study was a limiting factor in reaching any conclusions It is currently known that traffic noise exposure may increase the risk of cardiovascular disease and diabetes Furthermore, it should also be acknowledged that some patients might have symptoms of a functional somatic syndrome, describing persistent bodily complaints for which no objective findings supporting the symptoms can be found Aeq of 35 dB. Logically, accepting higher limits in legislations may lead to increased numbers of annoyed subjects. It therefore seems reasonable to conclude that a cautious approach is needed when planning future wind farms. Furthermore, there is an indication that noise annoyance and sleep disturbance are related and that disturbed sleep potentially can lead to adverse health effects. These conclusions are, however, affected by a potential risk for selection and information bias even in the larger cross-sectional studies providing the current best evidence. The evidence for adverse health effects other than sleep disturbance is primarily supported by case-series reports which certainly may be affected by various sources of bias. Larger cross-sectional surveys have so far been unable to document a relationship between various symptoms such as tinnitus, hearing loss, vertigo, headache and exposure to wind turbine noise. One limitation causing this could be that most studies so far have only measured LAeq or Lden. An additional focus on the measurement of low-frequency sound exposure as well as a more thorough characterisation of the amplitude modulated sound and the relationship between objective and subjective health parameters could lead to different conclusions in the future. Finally, in regards to the objective measurement of health-related disorders in relation to wind turbine noise, it would be valuable to demonstrate if such health-related outcomes fluctuate depending on exposure to wind turbine noise.At present it seems reasonable to conclude that noise from wind turbines increases the risk of annoyance and disturbed sleep in exposed subjects in a dose-response relationship. There seems to be a tolerable limit of around LChecklist S1PRISMA 2009 checklist.(DOC)Click here for additional data file.


The processing of facial identity and facial expression have traditionally been seen as independent—a hypothesis that has largely been informed by a key double dissociation between neurological patients with a deficit in facial identity recognition but not facial expression recognition, and those with the reverse pattern of impairment. The independence hypothesis is also reflected in more recent anatomical models of face-processing, although these theories permit some interaction between the two processes. Given that much of the traditional patient-based evidence has been criticized, a review of more recent case reports that are accompanied by neuroimaging data is timely. Further, the performance of individuals with developmental face-processing deficits has recently been considered with regard to the independence debate. This paper reviews evidence from both acquired and developmental disorders, identifying methodological and theoretical strengths and caveats in these reports, and highlighting pertinent avenues for future research. The human face conveys information regarding a person’s identity e.g., , emotionOne way to approach this question is to examine the type of basic visual information  and perceptual processes  that are used to make identity and expression judgments. Studies examining the effect of spatial frequency  do not show a strict dissociation between expression and identity judgments: although certain spatial frequency bands may be more conducive to identification or detection of individual emotions e.g., , or may Current face-processing models support the segregation of identity and expression mechanisms. Functional models posit that identity and expression information is processed independently, although some interaction may be mediated by the wider cognitive system e.g., . AnatomiEarly evidence supporting the proposed independence of identity and expression processing (hereon termed “the independence hypothesis”) came from a double dissociation between two neurological disorders. One half comes from individuals with prosopagnosia, who cannot recognize familiar people yet have preserved processing of facial expression e.g., . The othSince the publication of One half of the neuropsychological double dissociation traditionally believed to support the independence hypothesis comes from individuals with prosopagnosia. This condition typically results from occipitotemporal lesions , and is However, since 2005, further instances of prosopagnosia with preserved expression recognition have been described. Converging evidence comes from patient HJA, who acquired damage to the ventral occipital and temporal lobes and was unable to recognize facial identity or static facial expressions at normal levels , potentiWhile increasing evidence supports independent mechanisms for dynamic and static facial information, there is less agreement about the stage at which this split occurs. There are fewer reports of acquired deficits in expression processing and it is not always clear whether facial identity recognition has been preserved. There is also some variation in lesion location (which is sometimes under-specified), with early studies reporting expression recognition difficulties following diffuse bilateral damage , right  or left The studies reviewed above mostly relied on categorization performance rather than examination of processing strategy. One exception is Other criticisms suggest this half of the double dissociation has been over-simplified . EvidencDespite these issues, several studies have investigated the independence hypothesis in developmental prosopagnosia. This disorder is typically viewed as a parallel condition to acquired prosopagnosia, and is similarly characterized by a severe and relatively selective deficit in facial identity recognition e.g., . HoweverEvidence of selectively impaired expression recognition has been reported in socio-developmental disorders (SDDs), but findings are mixed. Many studies fail to find group-level deficits, with individuals falling into both typical and atypical ranges (for reviews, see More consistent findings suggesting atypical processing of facial expression have been observed in studies that examine the use of diagnostic facial information in SDDs. Several reports suggest that, during expression recognition, high-functioning individuals with autism look less at the eye region e.g.,  or the iWhile patient-based evidence supporting the independence of facial identity and expression processing was almost entirely discounted by 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.


Regulation of protein trafficking between the nucleus and cytoplasm represents a novel control point for antineoplastic intervention. Several proteins involved with cellular growth and survival depend on precise and timely positioning within the cell to fulfill their functions, and the nuclear membrane defines one of the most important compartmental barriers. Chromosome Region Maintenance 1, or exportin-1 (CRM1/XPO1), is involved with the export of more than 200 nuclear proteins, and has intriguingly been shown to have an increased expression in several tumor cell types. Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (SINE) to be developed for clinical use. Preclinical data has demonstrated antineoplastic activity of SINE compounds in many human solid and hematologic malignancies. The clinical development of Selinexor provides an excellent model for translational research. There are many ways in which neoplastic cells can gain a selective survival advantage over their non-cancerous counterparts. While traditional chemotherapeutics target the end result of cell division caused by many transformative events, more recent ‘targeted therapies’ have aimed to selectively block specific aspects of neoplastic cells that allow them to compete for resources and grow without restraint. For the most part, targeted therapies include those that 1) block external signals that can lead to cell growth, 2) interrupt intracellular signal transduction or enzymatic pathways that mediate growth and/or metabolism within neoplastic cells, or 3) thwart the cancer cell’s ability to evade signals and intracellular process such as apoptosis that would otherwise lead to self destruction. Many of these therapeutic strategies target cancer cells through antibody recognition or small molecule interaction with specific proteins that mediate pro-survival processes. Other strategies  seek to more globally manipulate the expression and longevity of the proteins that lead to the selective advantage of tumor cells.Regulation of protein trafficking between the nucleus and cytoplasm represents a novel control point for antineoplastic intervention. Several proteins involved with cellular growth and survival depend on precise and timely positioning within the cell to fulfill their functions, and the nuclear membrane defines one of the most important compartmental barriers. Although molecules smaller than 40 kDa can passively move between the nucleus and cytoplasm, larger molecules depend on active transport mediated by karyopherin chaperones . Once suSelinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (SINE) to be developed for clinical use. By interacting directly with CRM1, this drug prevents its interaction with potential cargo and traps in the nucleus proteins that would otherwise have been destined for export to the cytoplasm. Preclinical data has demonstrated antineoplastic activity of SINE compounds in many human solid and hematologic malignancies including renal cell carcinoma , mantle Journal of Hematology & Oncology, Gravina et al. explore mechanisms by which SINE compounds can affect the growth and spread of prostate cancer tumor lines [in vivo models. In one model, the authors orthotopically transplanted PCa cells into the prostate glands of SCID mice. Direct growth of the orthotopic tumor and extension into the peritoneum were both inhibited by KPT-330 given at two different dose levels and dosing schedules. In two models of bone metastasis, the authors injected PCa cells into the heart or directly into the tibiae of SCID mice. Both models showed decreased growth of osteolytic lesions upon treatment with SINE, as well as a decrease in markers of bone resorption and increased survival of the treated mice. To further demonstrate the antimetastatic potential of these inhibitors, the authors demonstrated decreased migratory potential across Boyden chambers, decreased metalloprotease production and decreased survival of cells detached from their microenvironment when treated with Selinexor. Perhaps even more intriguingly, they found that Selinexor can inhibit markers of angiogenesis and osteoclast differentiation induced by contact with media conditioned by PCa cells. In sum, these results suggest a multitude of ways that SINE can affect the biology and natural history of prostate cancer, from direct inhibition of cell growth to alterations in the microenvironment that mitigate not only metastasis, but destructive lesions fostered by nearby tumor growth.In this issue of or lines . The autwww.clinicaltrials.gov), and early reports of these trials are showing activity in various tumor types. At the 2013 annual meeting of the American Society of Hematology (ASH), updated results from the hematologic malignancy phase 1 trial demonstrated activity in patients with multiple myeloma, Waldenstrom’s macroglobulinemia, AML, CLL and various subtypes of NHL [The clinical development of Selinexor provides an excellent model for translational research. In 2012, first-in-man phase 1 trials of KPT-330 were begun in both solid (NCT01607905) and hematologic (NCT01607892) malignancies (s of NHL ,17,18. Ps of NHL . Once agin vivo experience presented here, we might expect to see direct decreases in osseous metastasis as well as decreases in lytic lesions caused by disruption of osteoclastogenesis in the microenvironment. This could alleviate one of the most vexing adverse effects of PCa – the pain that comes from bony lesions – even if tumor burden is not measurably decreased. Of course, the results reported also portend hope of improving the total disease burden, but it is too early to tell how deep or durable these responses can be with single-agent therapy. While these are compelling results for a new class of agents, we anxiously await results that will guide the optimal dosing schedule, mitigation of SINE-induced adverse effects, and best combination treatments to pursue.It will be very interesting to follow prostate patients on the phase 1 and subsequent trials that allow their inclusion. The model presented in this issue of JHO might predict numerous potential benefits for such patients. If the effects in humans reflect the


Despite the evidence showing the promise of HIV treatment as prevention (TasP) in reducing HIV incidence, a variety of ethical questions surrounding the implementation and “scaling up” of TasP have been articulated by a variety of stakeholders including scientists, community activists and government officials. Given the high profile and potential promise of TasP in combatting the global HIV epidemic, an explicit and transparent research priority-setting process is critical to inform ongoing ethical discussions pertaining to TasP.We drew on the Arksey and O’Malley framework for conducting scoping review studies as well as systematic approaches to identifying empirical and theoretical gaps within ethical discussions pertaining to population-level intervention implementation and scale up. We searched the health science database PubMed to identify relevant peer-reviewed articles on ethical and implementation issues pertaining to TasP. We included English language articles that were published after 2009  by using search terms related to TasP. Given the tendency for much of the criticism and support of TasP to occur outside the peer-reviewed literature, we also included grey literature in order to provide a more exhaustive representation of how the ethical discussions pertaining to TasP have and are currently taking place. To identify the grey literature, we systematically searched a set of search engines, databases, and related webpages for keywords pertaining to TasP.Three dominant themes emerged in our analysis with respect to the ethical questions pertaining to TasP implementation and scale-up: (a) balancing individual- and population-level interests; (b) power relations within clinical practice and competing resource demands within health care systems; (c) effectiveness considerations and socio-structural contexts of HIV treatment experiences within broader implementation contexts.Ongoing research and normative deliberation is required in order to successfully and ethically scale-up TasP within the continuum of HIV care models. Based on the results of this scoping review, we identify several ethical and implementation dimensions that hold promise for informing the process of scaling up TasP and that could benefit from new research. The role of antiretroviral therapy (ART) in preventing the onward spread of HIV is now widely accepted as a crucial component within comprehensive HIV prevention efforts  based ona. This raises questions about the kinds of efforts that will be required within these large-scale programs to identify and engage HIV positive individuals into long-term care and treatment. As a result, questions related to an individual’s autonomy and the potential for coercive seeking and testing strategies during implementation warrant examination [Given the high profile and potential promise of TasP in combatting the global HIV epidemic, an explicit and transparent research priority-setting process is critical to meaningfully inform ongoing ethical discussions pertaining to TasP. This strategy requires a comprehensive and systematic synthesis of the key ethical issues and concerns related to the implementation and scaling up TasP as expressed by both scientists and community stakeholders. For example, within the TasP approach, clinical treatment guidelines within many settings now recommend ART for all individuals living with HIV, regardless of their individual CD4 count or based on an expanded set of parametersmination . Moreovemination . Despitemination . Nonethemination .In this paper, we draw on concepts and approaches from the field of population and public health ethics to critically interrogate TasP approaches in order to more fully consider and negotiate a balance of individual and collective interests and health outcomes . Our aimHIV, HIV infections, treatment as prevention, TasP, HIV prevention, and ethics. We included review articles, and used citation tracking to identify other relevant sources. We included only articles that included a discussion of the ethical issues pertaining to the implementation and/or scaling up of TasP. Articles that only discussed issues pertaining to TasP research  were excluded, as well as articles that focused exclusively on other HIV prophylaxis regimes . Empirical studies that did not engage with implementation/scale up or ethical issues were excluded.We drew on the Arksey and O’Malley framework for conducting scoping review studies ,14 as weSearches yielded 374 results in PubMed. We reviewed all abstracts for content, removed duplicates, and included those articles related to the ethical and implementation issues related to TasP, resulting in a total of 19 articles. We also hand searched the references of relevant articles and special journal issues within this field, and co-authors searched their own library archives, resulting in additional articles, for a total of 8 peer-reviewed articles. Finally, one article was added via citation chasing and one from the library of a reviewer, resulting in a total of 29 articles.The Centre for Reviews and Dissemination[Given the tendency for the exclusion of grey literature within systematic reviews , as wellemination. This inCo-authors BP and RK screened the search results for eligibility. Data containing ethical discussions of TasP advanced within the peer-reviewed and grey literature were extracted and managed in Microsoft Excel. Tables Using these questions as a rubric, we were guided by both deductive and inductive approaches as we employed techniques from thematic analysis to identify patterns and themes within the literature . The co-b. Three dominant themes emerged in our analysis with respect to the ethical questions pertaining to TasP implementation and scale-up: (a) balancing individual- and population-level interests; (b) power relations within clinical practice and competing resource demands within health care systems; (c) effec tiveness considerations and socio-structural contexts of HIV-related experiences within broader implementation contexts.Our search resulted in 29 peer-reviewed articles and 19 grey literature sources that were included in data extraction and literature mapping. Figure The ethical implications of initiating individuals on ART regardless of their CD4 count emerged as the most salient and contentious question related to the ethical implementation of TasP . This deIndividualistic  frameworks tend to prioritize individual autonomy against a set of communitarian frameworks that emphasize the interests of the broader population . Applicanot to seek early treatment was also described as an important ethical consideration regarding the successful scaling up of TasP [Questions about the ethics of early initiation of ART have also been closely embedded in matters of agency. If the individual freely chooses to initiate TasP , then TasP meets the ethical criteria set out within applied medical ethics – regardless of the potential for individual or population-level harms/benefits ,21. Howe of TasP ,25.Communitarian and utilitarian framings, on the other hand, offer a view that more strongly features the potential for TasP to prevent future cases as a primary consideration, counter-positioning previous HIV prevention approaches as ‘status quo’ and insufficiently equipped to decrease the spread of HIV . These ‘The second dominant theme that emerged in the analysis related to power relations within patient-physician interactions and health care systems more broadly . For exaversus prevention [Questions also have been raised in the literature around the prioritization and distribution of limited resources. Indeed, in the context of scarce resources, issues related to TasP have led some to question the extent to which efforts should be focused on treatment evention . For exaevention  – particevention ,35. Stilevention . Moreoveevention . Ultimatevention ,33.Issues related to the scarcity of HIV prevention and health promotion resources have also led to a set of arguments around targeting efforts at specific population sub-groups considered most at-risk for transmitting HIV for cost-specific reasons , though Others have suggested that explicit criteria be used in order to determine who should be prioritized to receive treatment. In general, children and monogamous sex partners (those least likely to transmit the virus) are characterized as low priority groups for TasP, whereas those who are the most likely to spread HIV should be high priority  . These aTasP is most widely referred to as one strategy within a set of HIV prevention programs, often referred to as a continuum, cascade or combination prevention strategy ,36,40,41The third emergent theme centered on questions related to the external validity of randomized controlled trials supporting the role of TasP, leading to concerns about whether existing trial data is sufficient to justify the widespread implementation of TasP ,37,43. WIt also has been postulated that effectiveness studies could reveal TasP as having unintentional inequity-enhancing consequences. For example, effectiveness trials might demonstrate the potential for a skewing of beneficial impacts among various population sub-groups  ,44. UninThe issue of adherence in ‘real world’ settings was widely discussed in the literature, with many suggesting that the levels of adherence attained in clinical trials cannot be attained within most settings globally – particularly within resource-poor settings that present a set of geographical and sociocultural challenges ,44,47,48Given these concerns, the social determinants of health were often cited as a key priority within the literature. For example, organizations such as UNAIDS and the World Health Organization recommend comprehensive approaches to HIV treatment and prevention that also acknowledge and respond to the underlying and upstream causes of HIV infection, including gender inequality and access to health care, employment and housing ,52. In sSome of the most impassioned arguments in the literature related to the socio-structural contexts of HIV-related experiences, with some authors characterizing TasP’s commitments to addressing the distal causes of HIV as rhetoric . For theIn the current scoping review, a variety of normative ethical theories were either implicitly or explicitly used to ground the arguments advanced in the literature regarding the implementation of TasP. Specifically, we explored three key themes that have important ethical and implementation implications: (1) Effectiveness considerations and socio-structural contexts of HIV-related experiences; (2) Power relations within clinical practice and competing resource demands within health care systems; and 3) Balancing individual- and population-level interests. While conflicting interests associated with various ethical frameworks may not be fully resolvable , ongoing discussion and deliberation in this area will help provide progress towards a reflective equilibrium in which a degree of ethical coherence and acceptability is acquired. Below we outline where priorities for empirical research will advance these ethical discussions. Based on the results of this scoping review, we identify several areas that hold promise for informing the ethical implementation and scale up of TasP and that could benefit from new research  as well as on population subgroups  . OngoingThere also is an urgent need to support new empirical research that characterizes how interactions between TasP and its various implementation contexts affect the health and social well being of individuals as well as populations. Limited data exist on issues pertaining to risk compensation behavior and the capacity for non-adherence or early initiation to lead to drug resistance  . While wIn addition, effectiveness studies offer opportunities to embrace heterogeneous experiences associated with TasP implementation as well as the social and structural factors that shape HIV-related experiences – particularly among vulnerable and socially disadvantaged population sub-groups. While clinical trials have provided information related to heterosexual sero-discordant couples, additional information related to men who have sex with men and other vulnerable population sub-groups  is urgently required in order to advance these discussions. Highly-controlled clinical trial settings with primarily homogenous samples do not have sufficient capacity to detect the diversity of pathways and mechanisms through which TasP might be implemented across contexts; thus, relying exclusively on information regarding implementation and ethical considerations gleaned from controlled trials may point us in unrealistically uniform future directions. Furthermore, homogenous samples effectively limit (by default) forms of variability that are important considerations in ethical implementation, including behavioural characteristics, cultural and ethnic traditions and gender norms. Building capacity in effectiveness studies also could enhance the likelihood of undertaking international comparative studies to further determine the extent to which context-based heterogeneity  shape or respond to the ethical and implementation dimensions of TasP.Many authors argued that if an individual is fully informed and has the capacity to consent  to the early initiation of TasP, public health practices associated with TasP are ethically justifiable. However, many questions arose as to whether all individuals exposed to TasP will have the capacity to be fully autonomous given the power relations manifest in many clinical interactions – particularly among vulnerable or disadvantaged population sub-groups. In addition, while the literature reviewed here does not surface concerns that clinicians might make a set of idiosyncratic ‘choices’  about who should or should not be offered TasP, these concerns have been identified in another body of literature  – that pdispersion of benefits. TasP represents an important area in which more research, evidence and philosophical deliberation may provide some resolution pertaining to the ethical implications of targeted public health practices. In order to provide moral guidance in this area, ongoing empirical and philosophical work should aim to characterize the extent to which a burden negatively impacts individuals and population sub-groups targeted for TasP.Within the realm of public health, there is concern that features of various targeted public health interventions (whereby a particular subgroup of population is targeted for an intervention or enhanced intervention focus) may exacerbate health inequity ,60, raisPerhaps one of the most salient and complex moral dilemmas that arises relates to issues around resource distribution within the context of scarcity and various global austerity measures. Based on our analysis of the literature included in the current scoping review, we suggest it would be productive to move beyond the ongoing ‘treatment versus prevention’ debate and focus energies on developing new empirical estimations regarding the costs (including opportunity costs) of scaling up TasP. To make informed decisions globally and locally about ethical scaling up of TasP, it will be important to understand the degree to which investments in TasP efforts may imply opportunity costs (or have a multiplier effect) within a broader comprehensive spectrum of care and more upstream prevention.Within these efforts, interdisciplinary and collaborative approaches are required to engage in normative assessments of various sets of evidence. Indeed, based on these finding, techniques associated with implementation and social science  and moral frameworks from the field of population and public health ethics  will play an important role in leveraging the successful and ethical implementation of TasP. Finally, in order to mitigate some of the conflicting arguments in this area, we suggest the source origins of both the methodological and philosophical frameworks should be addressed to the fullest extent possible, along with clear, transparent rationale with respect to how the empirical and normative interacted to arrive at a moral conclusion. Indeed, the evaluation of data in this area should continue to engage in critical approaches, given the inherent difficulty of transforming complex research findings  into moral conclusions .This scoping study was limited in its capacity to reveal all ethical issues that will arise within this area . In addition, articles in languages other than English were not included. Moreover, this study did not appraise the quality of ethical arguments  nor the quality of the evidence base on which various arguments rest. However, by drawing on both peer-reviewed and grey literature, our review does provide illustrations of some dominant ethical issues that demand new empirical work that could inform the ethical implementation and scaling up of TasP.New research and normative deliberation is required in order to successfully and ethically treat and prevent HIV through the inclusion of TasP within HIV continuum of care models. From an ethical and implementation perspective, the process of scaling up TasP should not be conceptualized or practiced as linear, but rather as a constant feedback loop in which new evidence constantly informs morally robust practices within and during its implementation.aBefore the use of ART for TasP, the CD4 count (a measure of white blood cells in units of cells/mm3) at which individuals were recommended to begin ART was generally accepted to be at approximately 350 cells/mm3 or less [3[3). In other settings , ART may be altogether unavailable for prevention purposes [ or less . Since t or less  with resr less [3 and somepurposes -69.bWhile there are similarities between the methods associated with systematic reviews and the methods and techniques of scoping reviews with respect to ‘mapping’ the extent, range and nature of various substantive areas , there are also important differences . As a result, we have modified the PRISMA flow chart to reflect our inclusion/exclusion processes.The authors declare that they have no competing interests.RK and WS developed the study design and protocol. BP carried out the literature search. BP and RK screened the literature collected for inclusion/exclusion criteria. KT provided analytic contributions to the (re) analysis of data and revisions to the manuscript upon important feedback from reviewers. All authors contributed to the thematic analysis and drafting of the findings. All authors reviewed and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6939/15/54/prepub


Compelling evidence indicates that alterations of intestinal homeostasis, such as “leaky” epithelial barrier and changes in microbiota composition, can be associated with pathological adaptations of brain functions  receptors that have been engineered to be remotely operated. Genetics provides then a means to express such switchers within the circuits. Switchers activated by drugs are collectively defined as chemogenetics , a systemic administration of a designer drug therefore directly modulates the activity of transduced cells  has already shown to be suitable for manipulating neuronal activity in cell types as diverse as glia, pancreatic β-cells, hepatocytes, fibroblasts, and induced pluripotent stem cells. This technology allows the expression of designer receptors whose affinity for endogenous ligands is lost, while affinity for an otherwise inert designer ligand is gained Figure . For exavia viral systems, including adeno-associated viral vectors that express DREADDs only following Cre-mediated recombination, thus facilitating the targeting of genetically defined cell populations . The most common and best characterized opsins used in optogenetics are: (i) channelrhodopsin 2 (ChR2), able to elicit action potentials time locked to blue light pulses; (ii) halorhodopsin, a yellow light-gated ion pump that moves chloride ions into the cell; and (iii) archaerhodopsin, a green light-driven proton pump that moves protons out of the cell. Halorhodopsin and archaerhodopsin variants have the net effect of silencing active neurons by enabling hyperpolarization of membranes and reducing the likelihood of action potential generation  can modulate cell activity in a “non-physiological” manner—this caveat is particularly true when activation strategies are used. Despite the availability of reversible inhibitory chemo- and opto-genetic tools, long-term and cell-specific loss of function approaches are often crucial to test the physiological meaning of a given system . In this respect, a number of approaches allow permanent inactivation of cell functions. Specific subset of neurons can be genetically manipulated to express the diphtheria toxin (DT) receptor. DT-expressing neurons are ablated by systemically administering DT : an intricate network of over 100 million neurons grouped in the Auerbach and the Meissner plexi. Enteric fibers projecting to Peyer's Patches and in close vicinity of immune cells control inflammation by means of neurotransmitters, neuropeptides or other signaling molecules  was used to study intestinal motility by evoking glial CaThe selectivity and wide range of manipulations that are now possible with these technologies offer an unprecedented and fascinating opportunity to expand our understanding of the gut-brain axis, the behavioral effects associated with intestinal homeostasis alterations and the gut responses following discrete manipulation of defined neuronal networks.All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


PreDREM is a database of DNA regulatory motifs and motifs modules predicted from DNase I hypersensitive sites in 349 human cell and tissue samples. It contains 845–1325 predicted motifs in each sample, which result in a total of 2684 non-redundant motifs. In comparison with seven large collections of known motifs, more than 84% of the 2684 predicted motifs are similar to the known motifs, and 54–76% of the known motifs are similar to the predicted motifs. PreDREM also stores 43 663–20 13 288 motif modules in each sample, which provide the cofactor motifs of each predicted motif. Compared with motifs of known interacting transcription factor (TF) pairs in eight resources, on average, 84% of motif pairs corresponding to known interacting TF pairs are included in the predicted motif modules. Through its web interface, PreDREM allows users to browse motif information by tissues, datasets, individual non-redundant motifs, etc. Users can also search motifs, motif modules, instances of motifs and motif modules in given genomic regions, tissue or cell types a motif occurs, etc. PreDREM thus provides a useful resource for the understanding of cell- and tissue-specific gene regulation in the human genome.Database URL:http://server.cs.ucf.edu/predrem/. Identifying motifs of regulatory proteins and their cofactors in diverse cell or tissue types is critical for the global understanding of gene transcriptional regulation. A major type of regulatory proteins is sequence-specific DNA binding transcription factors (TFs), which modulate expression of their target genes by binding to short DNA segments called transcription factor binding sites (TFBSs) . TFBSs oet al. and Kheradpour and Kellis  sequencing (DNase-seq) provides an unprecedented opportunity to discover motifs of potentially all active sequence-specific DNA binding TFs under experimental conditions . DNase-set al. . The front-end pages are implemented by JSP to provide a dynamic and functional web interface. A SQLite format database file is made available for download, which mainly contains the position frequency matrix of each motif and the datasets each motif occurs. It can be used directly for query or manipulated in R using TFBSTools .The PreDREM database includes 845–1325 adjusted motifs in each of the 349 DHS datasets. It also contains 2684 non-redundant motifs resulted from clustering similar adjusted motifs across datasets. Based on the validation using known motifs, the reference information of each motif and the corresponding TFs are reported. For each motif, the reference information includes the corresponding UniProtKB entry , the claUsers can browse motifs and motif modules discovered in each dataset and in any given genomic region. Users can also search sequence-specific DNA binding TFs to see which tissue or cell types the TFs may be active and with which cofactors they may work in these tissues or cell types. Users are able to search TFBSs of motifs and motif modules in specified genomic regions in diverse cell or tissue types. Moreover, users can download adjusted motifs, non-redundant motifs, known motifs similar to predicted motifs, TFBSs of each motif, the enrichment of TFBSs of a motif in certain types of genomic regions, motif modules, motif modules supported by known TF-TF interactions, etc. See the download page in PreDREM for the full list of items that can be downloaded.The ‘Browse’ page of the PreDREM interface allows users for a quick navigation of tissues, datasets and non-redundant motifs included in the database. Users can view a list of datasets related to a cell or tissue type, or browse all motifs discovered in one dataset by selecting the dataset, or directly visit the information page of any non-redundant motif.P-values; iv) The list of motif modules that contain this motif and are validated by known TF interaction in eight resources. The preferred order of TFBSs of two motifs in a validated motif module is also listed, including how many times motif A are found to occur before motif B and vice versa. A significance P-value is given to each module to facilitate users to choose motif modules for further studies. Each module also has a corresponding link to its detailed information, which contains the information of the motifs in the module, and a visual chart of all occurrences of this motif module in DHSs  can be at any place of the keyword. The search result will contain all possible motifs that match the keyword in all datasets. ‘Match’ is defined as meeting any of the following three criteria: i) ID of any of the most similar TFs in three external motif databases  is identical to the input keyword; ii) name of any of the most similar TFs in the three motif databases contains the input keyword; iii) consensus of the motif matches the input keyword.Users can also search validated motif modules in the same page by selecting the ‘search modules’ option. If only one ID or name is input as the search keyword, the output will be all validated motif modules containing at least one motif matching the keyword. If two or more IDs/names are used in the search keyword, the search result will be motif modules that are composed of motifs matching two of the input IDs/names. In the case of searching motif modules containing NFKB1 and SP1, users simply need to input ‘NFKB1 SP1’ or the corresponding identifiers in the three repositories . The module search result will only contain validated motif modules by known interacting TFs currently. The full list of motif modules, which are the supersets of the validated modules, can be found in the download page.The ‘Search TFBSs/Modules’ page allows users to query TFBSs of the selected motifs in specified genomic regions in one of the 349 DHS datasets. After users select a dataset, all motifs discovered in this dataset will be listed in the ‘Motif Selection’ panel. Users can then choose multiple motifs of interest. To obtain more information about each motif, users can hover the mouse pointer over any motif, and the names of the corresponding motifs in HOCOMOCO, JASPAR and TRANSFAC will be shown. Users can also filter motifs by inputting identifiers or TF names following similar keyword criteria as those in ‘Search Motifs/Modules’. Only motifs related to the searching keyword will be left in the ‘Motif Selection’ panel. Upon the submission of a query, users will receive the list of TFBSs related to the selected motifs in restricted genomic regions as a file in BED format.Users can also search TFBSs of motifs in validated motif modules by changing the query type to ‘Module’ and follow the same selection method as that to search TFBSs. Several new features will be added to PreDREM in the near future. An enforced search of TFBSs and modules will be added, allowing searching in multiple datasets and multiple genomic regions. Also, the algorithm to cluster motifs is under constant refinement to further improve the quality of non-redundant motifs. In addition, we will enable to search all predicted motif modules instead of the subset of the predicted motif modules that are validated by TF interactions. Finally, computationally predicted target genes of TFBSs and motif modules will be added to replace the current information of closest upstream and downstream genes listed in the TFBS information page for each motif.The PreDREM database allows users to browse and search predicted motifs and motif modules of potentially active sequence-specific DNA binding TFs in 349 cells and tissues. The predicted motifs are ranked and validated with known motifs in other databases, and the predicted motif modules are validated with known TF interactions to facilitate further research. PreDREM provides a unique resource for the understanding of gene transcriptional regulation in different cell and tissue types.National Science Foundation . Funding for open access charge: The National Science Foundation .This work is supported by the Conflict of interest. None declared.