Around 70% neonatal deaths occur in low birth weight (LBW) babies. Globally, 15% of babies are born with LBW. Kangaroo Mother Care (KMC) appears to be an effective way to reduce mortality and morbidity among LBW babies. KMC comprises of early and continuous skin-to-skin contact between mother and baby as well as exclusive breastfeeding. Evidence derived from hospital-based studies shows that KMC results in a 40% relative reduction in mortality, a 58% relative reduction in the risk of nosocomial infections or sepsis, shorter hospital stay, and a lower risk of lower respiratory tract infections in babies with birth weight <2000 g. There has been considerable interest in KMC initiated outside health facilities for LBW babies born at home or discharged early. Currently, there is insufficient evidence to support initiation of KMC in the community (cKMC). Formative research in our study setting, where 24% of babies are born with LBW, demonstrated that KMC is feasible and acceptable when initiated at home for LBW babies. The aim of this trial is to determine the impact of cKMC on the survival of these babies.This randomized controlled trial is being undertaken in the Palwal and Faridabad districts in the State of Haryana, India. Neonates weighing 1500–2250 g identified within 3 days of birth and their mothers are being enrolled. Other inclusion criteria are that the family is likely to be available in the study area over the next 6 months, that KMC was not initiated in the delivery facility, and that the infant does not have an illness requiring hospitalization. Eligible neonates are randomized into intervention and control groups. The intervention is delivered through home visits during the first month of life by study workers with a background and education similar to that of workers in the government health system. An independent study team collects mortality and morbidity data as well as anthropometric measurements during periodic home visits. The primary outcomes of the study are postenrollment neonatal mortality and mortality between enrollment and 6 months of age. The secondary outcomes are breastfeeding practices; prevalence of illnesses and care-seeking practices for the same; hospitalizations; weight and length gain; and, in a subsample, neurodevelopment.This efficacy trial will answer the question whether the benefits of KMC observed in hospital settings can also be observed when KMC is started in the community. The formative research used for intervention development suggests that the necessary high level of KMC adoption can be reached in the community, addressing a problem that seriously constrained conclusions in the only other trial in which researchers examined the benefits of cKMC.NCT02653534. Registered on 26 December 2015 (retrospectively registered).ClinicalTrials.gov identifier: The online version of this article (doi:10.1186/s13063-017-1991-7) contains supplementary material, which is available to authorized users. Globally, around 15% of newborns are born with low birth weight (LBW) as a result of preterm birth or intrauterine growth retardation or both, and up to 70% of neonatal deaths occur in these infants , 3. The KMC is an effective way to reduce mortality among LBW babies. It helps to meet babies’ needs for warmth, breast milk, protection from infection, safety, and love . KMC as Prolonged SSC has been shown to provide effective thermal control for preterm and LBW babies. The review cited above showed a 76% relative reduction in the occurrence of hypothermia by hospital discharge or 40–41 weeks corrected gestational age –15. A meThe evidence summarized above comes from studies where KMC was initiated in the hospital . There hIn most developing countries, only a small proportion of LBW infants can be hospitalized for care. In these settings, a large proportion of deliveries still take place at home, and even if born in facilities, newborns are discharged early. It is therefore crucial to evaluate cKMC in a well-conducted efficacy study.We are undertaking a randomized controlled trial to evaluate the impact of cKMC on newborn survival. In preparation for this study, we undertook intensive formative research to develop the cKMC intervention package to assure ourselves that there would be a high rate of cKMC adoption by families.Proportion of infants exclusively breastfed at 1 and 3 months of ageWeight, length, and head circumference gain at 1, 3, and 6 months of ageIncidence of infections and hospitalizations in the neonatal period and between 1 month and 5 months of ageRecognition of illness and early care seeking by the family from appropriate sourcesIn a subsample, neurodevelopment at 6 and 12 months of ageThis paper describes an efficacy trial in which the primary objective is to determine the impact of promoting cKMC for LBW infants on postenrollment neonatal mortality and on mortality from enrollment up to 6 months of age. The secondary objectives of the study are to determine the impact of promoting cKMC on the following:The protocol has been prepared according to the Standard Protocol Items: Recommendations for Interventional Trials . In the formative research conducted prior to trial initiation, qualitative research methods such as in-depth interviews, focus group discussions, and observations were used to ascertain practices around birth and to assess the feasibility and acceptability of cKMC. A prototype intervention package and delivery strategy were designed, and household trials were conducted to ascertain adoption rates among mothers of LBW babies .The study is ongoing in Palwal and Faridabad districts in the State of Haryana, India. In this region with a population of around 2 million, the median family size is 6 (IQR 4–9) . The birThe common sources of drinking water are hand pumps (approximately 40%), piped water supply (approximately 30%), public taps (approximately 20%), and others (10%). Around 60% of the population uses open fields for defecation. A high proportion (92%) of families has electricity in their homes. Care of ill children is most often (60%) sought from private practitioners within and outside the villages.auxiliary nurse midwife (ANM) [http://nrhm.gov.in).The government-owned primary health center (PHC) is the most basic structural and functional unit of the health system. Apart from regular medical treatment, PHCs focus on maternal-child health promotion, including family planning as well as safe water supply access and basic sanitation. A PHC caters to a population of approximately 30,000. Under each PHC, there are 4 to 5 subcenters, each of which caters to a population of approximately 5000. Each subcenter is managed by a female health worker commonly known as the fe (ANM) . Her rolfe (ANM) . Each ANASHAs are community health workers employed by the government and cater to a population of approximately 1000. They are local women trained to act as health educators and promote universal immunization, timely referral, and escorting women and children for reproductive and child health and other health care programs in their communities .http://icds-wcd.nic.in/icds/icds.aspx). One AWW caters to a population of approximately 1000.Besides these workers, Anganwadi workers (AWWs) operate from Anganwadi centers (AWCs). An AWC is a government-sponsored child care and maternal care center in India. It caters to children in the 0–6 years age group. This center is the focal point for delivery of all services under the Integrated Child Development Services program to children and women  and their mothers are screened within 3 days of delivery. Babies born at home and babies born in health facilities are included if KMC was not initiated in the facility. Infants who are unable to feed, have breathing problems, have gross congenital malformations, or are less than normally active  are referred to hospitals. Those mothers intending to move away over the next 6 months or who do not consent to participate are also excluded.Approximately 12% of infants in the study area weigh between 1500 g and 2250 g . AssuminSurveillance workers conduct door-to-door surveys in the study areas. Surveys are redone at least quarterly. The details of all pregnant women are communicated to a study coordinator who allocates them to the relevant worker for follow-up.All identified pregnancies are allocated to the pregnancy follow-up and screening and enrollment (PSE) team. Each PSE team member covers a fixed geographical area comprising 3500–5000 households. These workers keep in touch with pregnant women through phone contacts or home visits  monthly in the initial months, twice weekly in the third trimester, and daily as the time of delivery approaches. The study is explained to families, and they are asked to inform the study team when the woman delivers. Outcomes of pregnancies—abortions, stillbirths, and live births—are documented. If a woman delivers at home, the team visits the household as soon as possible after delivery and weighs the infant. Workers keep in touch with families of women who deliver in the hospital, and women are visited as soon as possible after discharge. Prior to screening, consent for participation is taken. If the weight of the baby is <1800 g, families are counseled to visit health facilities as mandated by the Indian government .Infants who are identified as being ill are referred, and contact with the family is maintained. Hospitalization is facilitated by putting the family in touch with the ASHA in their area. The baby is screened for enrollment when discharged from the hospital if still within the 3-day enrollment window.The randomization list was prepared using random permuted blocks of variable block size by an offsite statistician from the WHO in Geneva who is not otherwise involved with the trial. Once an infant meets the inclusion criteria, has no exclusion criteria, and the family consents to participation, the PSE worker calls the coordinator in charge for allocating the participant an identification number. The coordinator opens a sequentially numbered, opaque sealed envelope (SNOSE) next in serial order and communicates the participant identification number to the worker. These procedures are identical for intervention and control participants, and PSE workers are not aware of the group allocation.For twins, triplets, or multiple children , the same intervention is allocated, and the participant identification number is suffixed with letters B and C, respectively. Similarly, if the mother has another eligible baby from a subsequent pregnancy, the same identification number is allocated, and a suffix is added. Only if the previously enrolled infant is in the control group is a new SNOSE opened. This strategy is being followed to give the second infant a chance of getting the intervention.Under the national program, all infants (in the intervention or control group) are to be visited on days 1, 3, 7, 14, 21, 28, and 42 for counseling on essential newborn care, identification of illnesses, and referral of ill infants . The natchaati se chipkana—or “sticking the baby to the chest.” The team uses photographs, helps the mother place the baby in the KMC position, and observes breastfeeding. The mother is advised to do SSC in the position in which she is most comfortable: semireclining or supine. Family members, including husband and mother-in-law or other relatives in the home, are also taught the procedure and encouraged to do SSC during the periods when the mother is not doing so or by helping with the household work so that the mother is free to be with the baby.The coordinator informs the intervention delivery team whenever an infant is allocated to the intervention group. This team comprises workers with educational and work experience backgrounds similar to those of government ANMs and ASHAs, and therefore they are designated as study ANMs and study ASHAs. A pair of workers makes the first visit to explain KMC and support the mother to do it. KMC is promoted using the local term identified during formative research—As described above, the visits are made daily for the first 3 days, on days 5 and 7, twice in week 2, and once each in weeks 3 and 4. ANMs and ASHAs visit together on the first 3 days. Subsequently, the ANM visits if the mother is having problems in doing KMC or needs counseling for breastfeeding. Visits end at 28 days or earlier if the baby no longer wants to be kept in KMC position as evidenced by the baby trying to wriggle out. At each visit, the ASHA documents how much KMC has been given since the last visit.Enrolled infants in both the intervention and control groups are visited by an independent outcome ascertainment team. An attempt is made to keep the team blinded as far as possible to whether the baby belongs to the intervention or control group. Weight, length, and head circumference are measured by a pair of workers. A baseline form containing socioeconomic and demographic characteristics is completed. Outcomes are also ascertained at 1, 3, and 6 months of age. At each of these visits, child care practices, prevalence of illness, and details of treatment-seeking and hospitalizations are ascertained. Additionally, at the month 1 visit, information is sought on whether any SSC was given and, if so, the number of days and the number of hours each day SSC was given by the mother or any other family member. Weights and length measurements are taken using a digital hanging weighing scale  and an infantometer , respectively; head circumference is measured with head-measuring tape . At their scheduled visits, the outcome ascertainment team also documents visits made by government workers for all enrolled infants.A member of a separate team well trained in verbal autopsy techniques visits each household as soon as possible after learning of the death of a study infant. A verbal autopsy questionnaire is completed; this technique is used to ascertain the cause of death . An inteActivities conducted by different teams are observed by the process evaluation team. These include counseling by the intervention delivery team, pregnancy surveillance, pregnancy follow-up, screening and enrollment, and anthropometric measurements. All main activities and individual team members are covered. Feedback is given to the person concerned, and corrective action is taken if necessary.All staff were trained in study objectives, overall strategy, and good clinical practice . Each teFor the outcome measurement team, weight, length, and head circumference inter- and intraobserver standardization exercises were conducted before study initiation and are repeated every 6 months. Weighing scales and infantometers are calibrated periodically using standard weights and length measurement rods.All data are captured electronically on phones or tablets. Range and consistency checks are built in. Queries are returned to the respective teams and resolved within 1 week of data collection. Data are transferred monthly to the WHO for offsite data quality checks.The primary analyses will be conducted on an intention-to-treat basis. Analyses will be performed with both person time  and number of babies as the denominator. Random effects models and robust standard errors will be used to account for clustering of deaths for twins, triplets, and other study babies living in the same household. Data cleaning will be completed and the databases locked before the data analysis workshop. The code will be broken after the analysis has been carried out and we interpret the findings, aiming to reduce the risk of prejudice.The flow and number of participants through assessment of eligibility, randomization, follow-up, and analysis will be documented Fig. . ReasonsSummary values  for background characteristics in the intervention and control groups will be presented in a baseline table. These data will represent maternal age, parity, maternal education, wealth index of the household, place of delivery, singleton or multiple birth, sex of infant, birth weight, and age at enrollment. As per the Consolidated Standards of Reporting Trials (CONSORT) guidelines, we will not perform significance tests to compare baseline characteristics between the study arms , 38. AltFor the primary outcome , data will first be analyzed using person time as the denominator. Hazard Ratios (HRs) and 95% CIs will be calculated using a Cox regression model to compare the effect of the intervention (cKMC) with the control condition on infant deaths. We will also estimate the effect of cKMC using the number of enrolled infants as the denominator to deduce risk ratios (RRs) using generalized linear models (GLMs) of the binomial family with a log-link function. However, if these regression models do not converge, the delta method for nonlinear combinations of estimated parameters from the coefficients computed in logistic regression shall be used . The perThe effect of KMC on secondary outcomes  will be assessed using linear or logistic regression, as appropriate, adjusting for clustering in case of twins or another enrolled baby subsequently born to the same woman, as well as other potential confounders, and taking clustering into account as in the primary analysis. Though an extended cost-effectiveness analysis is planned, it is beyond the scope of this paper and will be described in a separate paper.We will undertake subgroup analyses for infants according to birth weight categories, sex, timing of initiation of KMC, and duration of KMC. The relative measures of effect within each of these subgroups will be estimated.A DSMC has been constituted to review the data twice a year with at least one face-to-face meeting every year to monitor the progress of the trial and assess the safety of the intervention. The members include an epidemiologist, a statistician a neonatologist and an expert on community interventions. The DSMC examines deaths, rate of enrollment and compliance to the intervention every 6 months. An interim analysis will be conducted when approximately 50% of the infants have been enrolled. This analysis will be conducted in a blinded manner (treatment groups X and Y). The randomization code shall be broken following the recommendation of the DSMC if there is clear evidence of a difference in mortality between the two groups. The committee will advise the study team on study continuation, modification or termination based on preestablished stopping rules.The study is running from July 2015 to September 2019  than community-level health workers such as ASHAs. The follow-up support could be provided by ASHAs. In this trial, therefore, local workers equivalent to government ANMs were selected for initiation of the intervention. Well-trained community health workers equivalent to the government ASHAs provide follow-up support, with the ANM visiting for problems. Because this is the first time cKMC is being implemented in a community setting, a design using well-trained study workers is considered to be most appropriate, owing to there being a need to estimate the efficacy of the intervention.On the basis of standard KMC guidelines, mothers and other caregivers in this trial are advised to continue KMC until 28 days of age or until the baby no longer wants to stay in the KMC position , 33. TheWe believe that contamination between the mother-infant pairs randomized to cKMC promotion and those in the control families is unlikely. The households with babies meeting the inclusion criteria are far away from each other. Further, babies born in households where a baby has previously been treated with KMC is not randomized and will be provided KMC. Besides, we did not encounter any resistance to the practice from community members or health workers during formative research, which would have necessitated the need for community awareness generation activities. Because promotion of cKMC requires hands-on demonstration, intensive counseling, and high-level motivation, it is unlikely that mothers or other family members will practice KMC without adequate support.Although it may be deemed that we are implementing cKMC with high intensity in our trial, we believe that the intervention is scalable in similar settings because the workers delivering the intervention are similar in terms of education and experience to their government-employed counterparts. Moreover, there will be relatively few babies who need KMC, so it should be possible to manage them with the existing number of government services. The process evaluation activities will provide insights into barriers and facilitating factors. These will be valuable sources of information for later scale-up and adaptation to other settings.The trial is ongoing. Participant recruitment is expected to be completed by mid-2019.


Distinguished pioneer John Bukovac and Antonio Heredia reflect on more than half a century of cuticle research.An influential figure in plant cuticle research, John Bukovac began research in the 1950s following graduation from Michigan State University (MSU) , where he majored in Horticulture. He had gone into military service, but Harold Tukey, chair of the department and a well known horticulturist/botanist, encouraged him to return and at the end of his service in 1953 he took up a ‘special research assistantship’ available in a grant from the Atomic Energy Commission. Even though Tukey was busy with administrative responsibilities, he served as his mentor, and Sylvan Wittwer, a relatively new faculty member who was actively researching foliar absorption of mineral nutrients, provided considerable additional guidance.John worked at MSU for his entire career and was elected to the US National Academy of Sciences in 1983. During the 1970s and 80s, his lab became a focal point for young researchers, many from abroad, interested in the plant cuticle . When they moved back to their home countries, they established their own research groups in different basic and applied research topics related to the cuticle, and many senior researchers from these countries could now also be considered disciples of his pioneering work. As a fitting flourish, in 1995 John received a senior Humboldt Award and went to Bonn (Germany) to work on fruit abscission in apple, going back to his horticultural beginnings. He was selected to receive an honorary doctorate. ‘Retiring’ in 1996, he returned to MSU and retained a small lab for several more years (as would so many research scientists given the chance), continuing a research programme on chemical control of flowering and fruit abscission in apple and cherry.Antonio obtained his PhD at the University of Málaga in 1982 with a thesis in quantum chemistry. He began his research on the plant cuticle in 1988 at MSU with John Bukovac; his research over nearly three decades back at Málaga has kept that focus, revealing biophysical, structural and molecular aspects.Phaseolus vulgaris). The Atomic Energy Commission (AEC) provided me with soil samples collected on an atoll in the Pacific where atomic weapons were being tested: the contaminated samples were rich in Sr90 and Cs137. For root absorption, I labelled the soil media with a quantity of the radioactive soil. For foliar absorption, the AEC provided me with a solution of a soil extract, which I applied as various treatments to the surface of designated leaves. I followed penetration and translocation to the remainder of the plant, specifically the pods and seeds. These studies were not mechanistic.My research focused on absorption of atomic fission products by edible plants, mostly the common bean  of phenoxyacetic and benzoic acids on penetration through enzymatically isolated tomato fruit cuticle – this was published in On my return to MSU, I focused on two areas: one on spray application and use of plant growth regulators to control flowering and fruiting in tree fruits (primarily cherry and apple), and a second on the structure, permeability and factors that affect sorption and penetration of the cuticle. This latter programme was designed to improve the horticultural use and performance of plant growth regulators.I was very fortunate in having many dedicated and capable students and postdocs. Too many to cover individually here. But it would be nice to mention my first postdoc, Yasuyuki Yamada. Early in my career (1958) I was invited to lecture at a UNESCO course held at Tokyo University. The primary purpose was to train scientists from southeast Asia in the use of radioisotopes in plant research. At the end of the course my host arranged for me to visit with a student who I had corresponded with (Yasuyuki) earlier. He was working on urea penetration. After graduation (1962) he joined our lab for three years and worked on penetration, binding and effects of urea on ion penetration. He was a very talented and pleasant colleague. On return he was the first to produce a rice plant from a protoplast. He also became the president of the Nara Institute of Science and Technology (NAIST) and the youngest member of the Japanese Academy of Sciences.Another one to mention is Jörg Schönherr, who worked on factors that control stomatal entry, aqueous pores, ion exchange properties and diffusion kinetics. On his return to Germany he devoted his entire career to studies on the cuticle and, with a student, Lukas Schreiber, wrote a book on the permeability of plant cuticles . In the The discovery of plant growth regulators/herbicides like 2,4-D, and related chemicals, initiated a keen interest in foliar penetration studies. The ability to visually observe and quantify a response following foliar application resulted in numerous publications documenting factors affecting foliar absorption, namely spray volume, concentration, surfactants and leaf characteristics (e.g. waxy vs pubescent). It was possible to obtain such data with limited technology and the results led to a rapid acceptance of foliar application, particularly in use of herbicides in agricultural practice.With advances in technology after the late 1960s, research focused on the cuticle as a barrier to penetration, and our understanding of the cuticular membrane increased remarkably. With radioisotopes, it was possible to make quantitative measurements of sorption, desorption and penetration, and imaging of absorption and transport with autoradiography. With GC-MS (gas chromatograph coupled to mass spectrometer) chemical constituents of the cuticle could be identified. And with developments in microscopy there were many new findings: with the electron microscope, detailed transverse structure; with the scanning electron microscope, transverse and surface fine structure of the cuticle, epicuticular wax structure and density, deposition and surface distribution of many plant growth regulator deposits ; and with a stereo-scanning microscope, structure of the stomatal pore and the depth to which water of varying surface tension would penetrate.Probably the most pressing questions were how to increase penetration of 2,4-D and related bioactive compounds, how the cuticle limits penetration, and how this can be overcome. Many researchers contributed to the general understanding by a variety of studies including spray retention, dosage, use of surfactants, surface wax abrasion and temperature. These were relatively simple studies, often using visual rating of plant injury or other visible symptoms.per se soon led to studies on cuticle development, composition, embedded waxes and the cuticle cell/wall interface.Another question was whether stomata serve as a pathway for penetration. Schönherr’s work defining the role of surface tension and the architecture of the stomatal pore provided convincing information on how a liquid may enter via stomata . InteresLast, are their cuticular pores that serve as pathways for penetration of polar and non-polar compounds? Studies by First, the discovery of 2,4-D and other bioactive compounds, primarily plant growth regulators . This had dramatic potential for agriculture. The bio-response induced could be quickly seen, and observed visually (recorded or photographed) or measured using simple devices. Individuals working with foliar nutrition did not have this advantage.Other breakthroughs allowed research to flourish. Isolation of the non-living cuticle from many leaves and fruit of economic plants without (significant) loss of properties was very important. Further, the isolated cuticle could be stored and used later for analysis or permeability studies. Thus, the initial isolation of the cuticle with pectinase was most significant .14 labelling of many herbicides, plant growth regulators and mineral nutrients, and automated counting systems, made for quantitative analysis of sorption, desorption and penetration under many conditions. Advances in instrumentation continued to have an impact during my career, just as they do today.And returning to technology, it is important to re-emphasize the importance of radioisotope technology. CBy the end of the 20th century, researchers had made significant advances in our knowledge of cuticle structure, composition and permeability, and on factors that affected sorption/desorption and trans-cuticular penetration, such as pH, concentration, molecular structure of the penetrant, and role of spray additives .During this period the agricultural chemical industry grew tremendously in the US, UK, France, Germany, Switzerland and Japan in parallel with cuticle research. Companies capitalized on use of the plant growth regulators which had been discovered and introduced numerous additional bioactive products. They further extended and optimized the findings of the researchers and developed useful and effective formulations of compounds for specific agricultural applications. Last, they modified the genetics of some plants, including corn and soybean, to permit a specific herbicide to kill weeds without affecting the crop itself.Antonio began his research on the plant cuticle in 1988 at MSU with John Bukovac .John Bukovac was an authority in the plant cuticle field. Not only because of his experience, but also the way he approached his subject from different angles and his ability to combine different perspectives. His kind and warm character and his attitude towards colleagues, students and staff have always been inspiring to me. Before his retirement, we applied for a NATO Collaborative Research Grant (1990–1994) that allowed a fruitful continuation of the research I started in his lab.The areas that he has mentioned are still open – his research is very relevant in the field of applied agricultural science. There are a good number of researchers in agricultural companies and academia who worked and collaborated with John and who are currently involved or working on these topics. His lab was characterized by a combination of basic and highly applied research, and this imparted a broad perspective to the scientists ‘formed’ there.Research has certainly changed in the last two decades. The current acceleration of society is also affecting the way we do science and there is a lot of pressure, especially for young students and researchers. At the same time the techniques and methodologies for doing science have evolved tremendously, allowing us to do things we could only dream of just a few years ago. Essential questions about our research subject, the plant cuticle, still remain but the way they are being addressed has changed considerably. We have more precise and sophisticated equipment but we must continue to pursue the appropriate question for each approach to improve and increase our knowledge. There is so much information at our fingertips these days that the big challenge is to integrate all the information coming from different disciplines in order to improve our understanding of a research topic.More recent research, from this new century on, has been very fruitful. Some colleagues have focused their attention on biophysical properties. There has been noticeable progress in understanding the hydrodynamics, mechanics and thermodynamics of the cuticle, together with physiological implications. At the same time a lot of progress has been made in elucidating the complex architecture and structure of plant cuticle, an extraordinary, complex biopolymer. Moreover, during the past two decades there have been tremendous advances in understanding its molecular biology. Advances in the field of genetics and the development of collections of mutants have allowed the identification of many genes involved in the synthesis and regulation of cuticle components and more recently in cutin assembly. In this context, it is important to remember the pioneering work carried out in the 1970s and 80s by Pappachan Kolattukudy on the biochemistry of plant cuticle components, with special emphasis on the proteins involved in the synthesis of waxes, cutin monomers and the cutin polymer. Continuing with the more recent past, the switch in focus from Arabidopsis  to the inclusion of several crops has added a plant breeding dimension to cuticle studies. Nevertheless, the research carried out with Arabidopsis is of great importance since it has given new perspectives to our understanding of the cuticle.


Patients are becoming increasingly involved in research which can promote innovation through novel ideas, support patient-centred actions, and facilitate drug development. For rare diseases, registries that collect data from patients can increase knowledge of the disease’s natural history, evaluate clinical therapies, monitor drug safety, and measure quality of care. The active participation of patients is expected to optimise rare-disease management and improve patient outcomes. However, few reports address the type and frequency of interactions involving patients, and what research input patient groups have. Here, we describe a collaboration between an international group of patient organisations advocating for patients with atypical haemolytic uraemic syndrome (aHUS), the aHUS Alliance, and an international aHUS patient registry .The aHUS Registry Scientific Advisory Board (SAB) invited the aHUS Alliance to submit research ideas important to patients with aHUS. This resulted in 24 research suggestions from patients and patient organisations being presented to the SAB. The proposals were classified under seven categories, the most popular of which were understanding factors that cause disease manifestations and learning more about the clinical and psychological/social impact of living with the disease. Subsequently, aHUS Alliance members voted for up to five research priorities. The top priority was: “What are the outcomes of a transplant without eculizumab and what non-kidney damage is likely in patients with aHUS?”. This led directly to the initiation of an ongoing analysis of the data collected in the Registry on patients with kidney transplants.This collaboration resulted in several topics proposed by the aHUS Alliance being selected as priority activities for the aHUS Registry, with one new analysis already underway. A clear pathway was established for engagement between a patient advocacy group and an international research network. This should ensure the development of a long-term partnership which clearly benefits both groups. In recent years, patients have become increasingly active in managing their own healthcare, in terms of both treatment decision-making processes and research participation. Thus, many patient organisations are actively engaging with clinical investigators and pharmaceutical companies. This new model has been shown to promote innovation, support patient-centred actions, and facilitate the development of new treatments . While mIn the case of rare diseases, the development of effective treatment strategies can be hampered by a lack of knowledge of the condition. Issues include a lack of basic research on the natural history of the disease and difficulty in recruiting sufficient patients for effective clinical trials. Furthermore, the research that is performed may not answer the questions considered most important by patients . PatientPatient engagement in research can be interpreted in several ways, such as information sharing amongst rare disease groups and the use of patient-driven registries to facilitate data collection. However, such activities do not give patients input to the research process; for a successful registry, providing a voice for patients to help recruitment, encourage active participation and influence the research agenda is key. Although there may occasionally be reluctance on the part of patients and academics to engage in partnerships with industry, the significant effort and costs of a patient registry are best met through public/private partnership , 8. TherAtypical haemolytic uraemic syndrome (aHUS) is a rare genetic, life-threatening, chronic disease of children and adults caused by unregulated activation of the alternative complement pathway leading to systemic thrombotic microangiopathy (TMA) , 10. A cwww.ClinicalTrials.gov Identifier NCT01522183) is an observational, non-interventional, multicentre registry of patients with aHUS, and is a product of a partnership between worldwide academia, patients with aHUS and Alexion Pharmaceuticals, Inc. The aims of the Registry are to assess the long-term patient outcomes, and collect and evaluate safety and effectiveness data specific to the use of eculizumab, fulfilling post-marketing regulatory requirements. The Global Registry is open to patients of all ages with a clinical diagnosis of aHUS; an identified complement gene mutation or factor H autoantibody is not required. Patients with secondary aHUS are eligible and physicians can record the potential precipitating cause. Patient data are collected following a research protocol and in accordance with International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. Clinical and patient reported data (e.g. a fatigue score completed by the patient) are collected at study enrolment and every 6 months thereafter. The methodology of the aHUS Registry and characteristics of the first 516 patients enrolled (from 16 countries) have recently been published [The Global aHUS Registry  for evaluation by the SAB.Scientific oversight, governance and coordination of the Global aHUS Registry are provided by an independent scientific advisory board (SAB). The SAB includes members with expertise in key specialties related to management of aHUS  as well as representation from Alexion Pharmaceuticals. Also, as a result of the engagement process described here, a patient representative is now included on the SAB. Data collected by the Global aHUS Registry are accessible to participating and nonparticipating physicians who may request data access or specific analyses by submitting a concept sheet via the aHUS Registry website . One of the Alliance’s aims, listed in the inaugural “Declaration of Collaborative Aspirations”, was to work with international clinical aHUS research networks. In order to identify and prioritise areas of interest, the aHUS Alliance devised a questionnaire to conduct a global survey of patients with aHUS in 2014. The survey was available in English, French, Spanish, German, Italian and Dutch, and contained 28 questions seeking details of basic patient characteristics plus feedback on six issues commonly raised by patients with rare diseases; diagnosis, treatment, expert centres, research, registries and availability of information [In January 2013, representatives of patient organisations from six European countries advocating on behalf of aHUS patients met and agreed to collaborate as the aHUS Alliance . Since then a further 6 organisations have become affiliated to the aHUS Alliance , and in 2016 only 1% of respondents did not wish to participate Fig. . Around When asked what would encourage greater patient participation in research studies or clinical trials, three options were selected by approximately half of the respondents Fig. . All theIn total, 24 ideas for research were generated. The ideas were then classified under seven categories  to active (patient is a researcher), [In order to promote changing the role of the patient in a registry from passive (archer),  the partThe Dialogue Model  has beenCompletion of a robust systematic evidence assessment review of the knowledge gap needs to be reviewed by the SAB as well as the Alliance, to arrive at an agreed list of specific patient research priorities, which then must be integrated with the Registry’s other research agendas from clinicians and industry. With an integrated list of research topics finalised, it will then be possible to move to a sequential programming of topics for direct study by the SAB, or indirectly, through encouragement of external investigators to use the Registry data for other priority topics.The ongoing participation of patient advocacy groups in the activities of the Global aHUS Registry will help the Registry achieve its aims of establishing a robust database of patients with aHUS, characterising the long-term natural history of the disease, and enhancing the understanding of aHUS by publishing analyses of registry data. Engagement of patients with rare diseases in clinical research may promote research efforts directed to relevant clinical questions and patient-centred health outcomes.


Aggressive behaviors are highly prevalent in children. Given their negative consequences, it is necessary to look for protective factors that prevent or reduce their progress in early development before they become highly unshakable. With a sample of 147 children, the present study aimed to assess the relation between parental education and inhibitory control in the aggressive behavior of children aged from 7 to 10 years. The participants completed a go/no-go task to assess inhibitory control, whilst their parents reported their education level, and their teachers rated the aggressive behavior of the children through the Teacher Rating Scale (TRS) of the Behavior Assessment System for Children 2 (BASC-2). The results showed that both parental education and inhibitory control determined aggressive behavior in children. In addition, inhibitory control partially mediated the associations between parental education and aggressive behavior after accounting for age. However, a moderated mediation model revealed that lower parental education was associated with higher levels of aggressive behavior, which, in girls occurred independently of inhibitory control. In contrast, inhibitory control mediated this relation in boys. These results suggest the importance of parental education and inhibitory control in the aggressive behavior of children, supporting the idea that both constructs are relevant for understanding these conduct problems in schools, particularly in boys. The clinical implications of these findings are discussed, along with possible future lines of investigation. The high prevalence of aggressive behavior in children and its negative consequences for individuals and society make it a relevant topic on which to focus . When weThe General Aggression Model GAM;  providesGiven the prevalence and undesirable consequences of aggression, looking for protective factors that prevent or reduce its progress during childhood is an essential goal. There is already some evidence to suggest that certain variables could be important in reducing these behaviors, such as parental education and the capacity for inhibitory control, both of which have been linked to aggressive behaviors, particularly in adolescents .Parental education refers to the level of academic studies achieved by the parents of the children in question. According to the structure of the GAM, parental education belongs to the first stage as a person variable. It has been related to a variety of outcomes such as academic performance, diet, and mental health . It has Inhibitory control is the ability to control or stop pre-potent and automatic actions or thoughts, allowing for more flexible and goal-directed behaviors . This abA link has also been found between both of these variables . In particular, higher levels of parental education appear to be related to a greater level of inhibitory control . This reFurther, inhibitory control also appears to be influenced by gender. Specifically, higher scores on inhibitory control are usually found in girls  from 2 yFigure 1). We chose to study these effects in childhood given that this is a critical period for modifying maladjusted behaviors before they become highly unshakable. Given the previous findings reported in the literature, we firstly hypothesized that parental education and inhibitory control would be negatively related to aggression. Secondly, we expect inhibitory control to mediate the relation between parental education and aggressive behavior. Finally, we expect to find a moderator effect of gender when analyzing this mediator role of inhibitory control.On the basis of these considerations, the aim of the present study was to assess the relation between parental education and inhibitory control in the aggressive behavior of children. In particular, we intend to analyze the role of inhibitory control as a mediator in the relation between parental education and aggression, as well as the moderator role of gender in this mediator effect . Inclusion criteria were the absence of any  disability or cognitive/language deficits. The parents were informed about this research and no compensation, reward, or incentive was offered in exchange for participation in the study. Of the 155 families who were asked for their consent to participate in the study, 147 (95%) answered positively and completed the questionnaires.The sample was composed of 147 children from various Spanish public schools (50% boys), with an age range between 7 and 10 years  provided written informed consent. The Research Ethics Committee of the University of Málaga approved the study protocol as part of the projects SEJ-07325 and PSI2012-37490. Trained undergraduate researchers collected information relevant to the study from parents, children, and qualified teachers throughout the course of 1 week. Specifically, the parents provided data on their own levels of education, which could be classified as primary, secondary, or university level. The children were assessed on inhibitory control through the go/no-go task. Finally, the teachers completed the aggressive behavior scale of the Behavior Assessment System for Children (BASC) and the time given to complete it was the same for each teacher.Parental education was classified according to the classification system of the Spanish National Institute of Educational Evaluation , which dThe Go/no-go task was employed in order to provide a measure of inhibitory control. Our experimental paradigm consisted of a serial presentation of screen-centered blue and red colored circles for the Go stimuli and green and yellow colored circles for the No-go stimuli. The No-go trials were preceded by sequences of 0, 1, 2, 3, 4, 5 Go trials . The stiThe Behavior Assessment System for Children 2 BASC-2; , TeacherFigure 1), we used Model 14 in PROCESS to develop and analyze the gender role in our previous mediational model.All statistical analyses were carried out using the SPSS package . Preliminary analyses were conducted to compute descriptive statistics. The analysis of the relation between age, gender, parental education, inhibitory control and aggressive behavior scores was conducted with Pearson’s coefficients and Kendall’s Tau-b. To investigate the validity of parental education and inhibitory control for determining aggressive behavior, we conducted three-step hierarchical regression analyses. We also conducted regression analyses to examine the role of inhibitory control as a mediator of the link between parental education and aggressive behavior, based on the recommendations of Table 1. For all variables except aggressive behavior, skewness and kurtosis values were within an acceptable range of ±2 , with higher parental education determining lower aggressive behavior. Inhibitory control, added at the last step of the model, proved to be a significant determinant of aggressive behavior (ΔR2 = 0.06) over and above the effects of parental education.The results of the regression model are shown in Previous analyses of regression showed that when simultaneously including parental education and inhibitory control in the model, these variables accounted for 18% of the variance in aggressive behavior when age and gender were controlled. This result — which suggests that both constructs are relevant in determining the aggressive behavior of children — led us to construct a mediation model and moderate mediation model to test the relation among these variables. To do so, we first investigated the hypothesis that inhibitory control can be an important mechanism in the relation between parental education and aggressive behavior in children.c in Figure 2, the mediation analysis showed that aggressive behavior was lower in children whose parents had a higher educational level. Moreover, path a in Figure 2 shows that parental education was positively associated with inhibitory control, suggesting that those children whose parents have a higher parental educational level reported higher inhibitory control. Finally, as can be seen in path b in Figure 2, inhibitory control was negatively related to aggressive behavior. Using an indirect procedure, the bootstrapped 95% CI confirmed that parental education exerted a significant negative indirect effect on aggressive behavior through inhibitory control . This result points to the possibility that inhibitory control partially mediates the association between parental education and aggressive behavior.In particular, we tested whether inhibitory control mediates the relation between parental education and aggressive behavior. As can be seen in path Table 3 presents coefficients, standard errors, and a summary of the moderated mediation model.Given that previous research indicates that inhibitory control could be influenced by gender, with higher scores of inhibitory control being reported for girls , a moderTable 3 for coefficients and confidence intervals). Parental education was in turn related to aggressive behavior. When controlling for inhibitory control, the relation between parental education and aggressive behavior was less significant. The 95% bias-corrected bootstrap-CI indicated conditional indirect effects of parental education on aggressive behavior through inhibitory control, although the magnitude of these effects was only significant for boys (Table 4). The moderated mediation model accounted for 23% of the variance in aggressive behavior scores.Inhibitory control was associated with aggressive behavior, and a gender by group interaction was found for this association  or the ability to perceive, use, understand and regulate emotions  may alsoWe also found that the mediation effect was moderated by gender. Thus, in our study gender emerged as a moderator of the link between inhibitory control and aggressive behavior, which is consistent with our third hypothesis. Specifically, for the girls in our study, lower parental education was a determinant of aggressive behavior independently of inhibitory control, whilst for the boys inhibitory control played a mediatory role in this relation. Our results are consistent with those previously reported in the literature , along wIn addition to all of the the results reported here, it is important to note that our sample was composed of children, on which there are considerably fewer studies and where prevention is easier than in older individuals. Indeed, childhood represents an ideal period for training and modifying undesirable behaviors. Moreover, in our study we avoided relying on the subjective perceptions of the children by using external reports for assessing aggressive behavior. Finally, inhibitory control was also measured through an objective laboratory task. Taken together, these aspects of our methodology strengthen the validity of our findings.These findings demonstrate that both parental education and inhibitory control are determinants of aggressive behavior in children aged between 7 and 10 years, supporting the idea that both factors are critical for understanding these behavior problems. Furthermore, inhibitory control played a role in mediating the relation between parental education and aggression, but only for the boys in our sample. Future studies are needed to replicate these findings and to further explore the effects of gender on the links between parental education, inhibitory control, and aggression.RC conceived of the study, participated in the data collection, analyzed the data, led preparation and wrote the first draft of the manuscript. MG-C wrote the first draft of the manuscript. PF-B conceived of the study, analyzed the data and contributed to writing the manuscript. All authors contributed to the interpretation of data, helped to draft and revise the manuscript and have read and approved the final manuscript.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. The reviewer EC and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Addressing language and cultural nuance is required to improve the quality of care among all patients. The tenth version of the National Standards for Culturally and Linguistically Appropriate Services in Health Care (CLAS) recommends implementing ongoing assessments to integrate specific actions into measurement and continuous quality improvement activities. To this end, we have created the Interventional Cultural and Language Assistance Program (ICLAP). As part of ICLAP, we conducted a cross-sectional needs assessment survey with 564 consecutive patients receiving outpatient Positron emission tomography-computed tomography (PET/CT) imaging at a comprehensive cancer center in the five most prevalent languages of New York City: English, Spanish, Russian, Chinese, and Arabic. The purpose of this study is to describe the language assistance characteristics and needs of a sample of patients receiving care in the cancer center. We examined the relationship between race, ethnicity, birthplace, communication and language assistance characteristics and the satisfaction with the care received. Our results show that race and ethnicity, birthplace, cultural beliefs, language assistance, and communication characteristics were all factors associated with patients’ satisfaction with care, illustrating that there is an unmet need among cancer patients to have cultural and linguistic sensitive services. The ability to provide patient-centered cancer care to all patients is intimately tied to linguistically and culturally competent communication ,2. The NU.S. Census bureau statistics also make this an updated NM approach a necessity. Approximately 24 million 8.6%) of the U.S. population and 1.8 million people in New York City have limited English proficiency (LEP) , a growt% of the It is uncertain if awareness of interpreter services, need for these services, and use of interpretation services has an impact on patients’ satisfaction with care in the context of this study centered in an NM outpatient practice. Therefore, we first performed an initial cross-sectional survey-based needs assessment so that a follow-up intervention could have a more data-centric design. As a first step toward measuring cultural and communication factors in an outpatient imaging setting, we surveyed over a 3 month period patients scheduled to have a PET/CT at our outpatient imaging setting at a comprehensive cancer center to determine the impact of demographic characteristics, communication and language assistance needs and utilization, and satisfaction with care.A cross-sectional tablet-based needs assessment survey was conducted with 564 cancer patients waiting for an outpatient imaging procedure between January 2016 to May 2016, as part of the Interventional Cultural and Language Assistance Program (ICLAP) at our comprehensive cancer center. The recruitment period for the study was between January 2016 to May 2016. In order to be eligible for the study, patients had to be scheduled for an outpatient clinical F-Fluorodeoxyglucose (FDG) PET/CT scan. Potential participants were informed that the study was voluntary, anonymous and confidential. After obtaining informed consent, Session Assistants provided a tablet to patients to self-administer the survey, which was available in five of the most widely spoken languages in New York City: English, Spanish, Russian, Chinese, and Arabic. Session Assistants invited 575 consecutive patients to participate, eleven could not complete the survey because they speak other languages not available in the survey . Surveys for 564 outpatients were considered evaluable.All measures were assessed by self-report. The tablet-based assessment survey included four sections: sociodemographic, cultural, migration, linguistic and cultural beliefs questions, need and use of interpretation services, and satisfaction with care. The sociodemographic section included age, gender, marital status, employment status, education, income level. The cultural and migration-related sections included questions assessing participants’ preferred and dominant language, race, ethnicity, country of origin and a question assessing if their cultural background influences their medical decisions. The interpretation needs section assessed need for interpretation in medical settings, preferred language for healthcare, use of interpretation services in the clinic and frequency of use of such services. Satisfaction with the outpatient imaging clinic, satisfaction with the cancer center, and satisfaction with the interpretation services were assessed using a 1–10 rating scale.Statistical analyses were conducted using the SPSS19 software package. First, the demographic characteristics of the 564 participants were described using descriptive statistics. Then, the need for and use of interpretation services questions were described. Bivariate logistic regression models were used to identify linguistic and cultural factors significantly associated with satisfaction with clinical care at the service level and at the institution level. Satisfaction with care  was assessed with a question with a response format of a scale from 1–10; given that the scale was severely skewed, the scales were reduced to binomial outcomes for the purpose of analysis .Potential explanatory variables included sociodemographics , linguistic and migration-related factors , interpretation-related , and beliefs influencing medical decisions . Unadjusted odds ratios (ORs) and 95% confidence intervals were calculated to assess the relationship of these factors with satisfaction with nuclear medicine clinical care and with clinical care provided by the cancer center.Logistic regression models were adjusted for relevant variables  to determine the contribution of linguistic, migration-related, interpretation-related factors and beliefs influencing medical decisions to satisfaction with care. A two-sided p significant level of less than 0.05 was considered statistically significant.Five hundred seventy participants were approached; eleven could not complete the survey because the survey was unavailable in their preferred languages . Surveys for 564 outpatients were considered evaluable. The mean age of the sample was 52 years (SD=18.1) and nearly 57% of the respondents were male. With regards to race and ethnicity, 14% of the sample was Hispanic or Latino and 8% was Black or African-American. Three quarters of the sample were born in United States, almost 6% were born in Europe, 4% in Eastern Asia and the Philippines, and 4% in Latin America and the Hispanic Caribbean. The most common diagnosis was lymphatic cancer (18%), followed by lung cancer (12%) .The majority of the sample reported that they prefer English for their healthcare services (94%). Almost two thirds of the sample (62%) were aware of interpretation services, 6% reported that they needed an interpreter and 5% that they received interpretation in the clinic. However, 11% reported that their dominant language was a non-English language. Patients more frequently reported using ad-hoc interpretation, family members and/or friends interpreted for them when needed.One out of six patients (17%) responded that they did not understand their doctor because of language; 12% of patients responded that they would prefer to speak about their medical condition in a language other than English; 12% of the respondents that they did not fully understand what the doctor said; and 18% of the respondents thought that their doctor did not understand them .In analyses adjusting for demographic characteristics  several cultural, language assistance, and communication factors were significant predictors of less satisfaction with imaging clinic and institutional care . EthniciPatients who reported preferring a non-English language for their healthcare were three times more likely  to be less satisfied with the care at the service and eight times more likely to be dissatisfied with the care received at the cancer center . Patients who needed interpretation were three times more likely to be dissatisfied with the care of the service  and five times less likely to be satisfied with the care of the center . Patients who used interpretation in the clinic were three times less likely to be satisfied with the care of the center .Patients who reported that they do not understand their doctor because of language were almost two times more likely to be dissatisfied with the care of the service  and three times less likely to be satisfied with the care of the center . Patients who reported feeling more comfortable discussing their medical condition in a language other than English were two times more likely to be less satisfied with the service  and three times less likely to be satisfied with the care of the center . Further, patients who reported that they did not fully understand what the doctor said were four times more likely to be less satisfied with the care of the service  and nine times less likely to be satisfied with the care of the center .This study was designed to explore patient perception of quality of care received during an outpatient imaging encounter. While the overall satisfaction with care at our comprehensive cancer center is high, we still perceived the need to explore care delivery in the context of race, ethnicity, birthplace, language preference and the presence of interpreter. In this first study we found that these factors  are associated with patients’ satisfaction metrics. This is the first study to measure cultural and linguistically competent delivery of care in a Radiology/Nuclear Medicine setting. The diagnostic and therapeutic branch of Nuclear Medicine has grown considerably, and now involves having critical interactions with many cancer patients being diagnosed and followed with PET/CT. Our findings demonstrate a clear unmet need to have services provided in these encounters with greater cultural and linguistic competence.Our findings show that Asian patients were less satisfied with care, but Latino patients reported being more satisfied with the care received. This finding is consistent with the study of Palmer and colleagues  who founStudies have revealed that access to linguistic assistance and culturally competent care are critical for optimal care of cancer patients . PatientHealth care facilities in the United States resort to multiple strategies to address language barriers, and while matching patients with providers who speak their language is the ideal scenario, the use of health care interpreters is by far the most common strategy. Looking nationally at the practice of Nuclear Medicine/Molecular Imaging, the application of linguistic and culturally responsive practices cannot be elicited from a search of the published literature. The current practice of nuclear medicine involves not only the interpretation of diagnostic imaging but also the administration of therapy. This evolution is evident in the name change at many institutions from Nuclear Medicine to Molecular Imaging and Therapy. The imaging acquisition and clinical read component is essentially “colorblind” , but the administration of therapy is decidedly not colorblind. In these broadening therapeutic applications, the clinicians in this field and the supporting staff find themselves at a crossroads where meaningful care cannot be delivered without probing how it interfaces with the community of patients. After several decades of treating patients for thyroid cancer with radioiodine, the therapeutic branch of nuclear medicine has grown to other cancers such as lung, neuroendocrine, and breast. Patient provider communication must improve and optimal training must be developed and implemented. Additionally, since most of these treatments require radiation safety precautions, meaningful communication is needed to address safety concerns. At our center all of radionuclide therapy patients receive oral and written radiation safety precautions. Lack of understanding or partial compliance might result in unnecessary exposure to patient, immediate relatives, healthcare personnel or the general public. Often times, detailed information about patients’ living conditions is necessary to provide them with individual precautions. This can only be obtained with optimal communication with the patient. It requires detailed questions and exchanges about sleeping, accommodation or transportation arrangements, to name a few. Therefore, creating a framework for improving cultural and linguistic competency would respond to an unmet need in Molecular Imaging.Studies providing information about the potential impact of language barriers on quality of care in Nuclear Medicine are warranted. Such studies are needed to develop an evidence base to inform health services delivery and policy. Evidence suggests that cancer disparities in ethnic minorities are related to receipt of lower quality care –13. ThusThis study is limited by its cross-sectional, descriptive design and causality cannot be determined. It is also limited by the fact that patients with low literacy or lack of ease with tablets could not participate, likely underestimating needs and dissatisfaction with care. As such, ICLAP was designed for hypothesis generation for future studies with longitudinal designs, and interventions designed to elicit changes on satisfaction with care and potential alterations to the existing standard for how we are delivering care in this setting. Further, a small number of patients (11 patients) could not participate because the survey was not available in their languages . It might be more critical to understand the levels of satisfaction of patients that speak less common languages or languages of less diffusion. Providing care for these patients might be more challenging; as such it is critically important to conduct research with patients that speak languages of lower diffusion to understand their communication needs. Additionally, while ICLAP was conducted in an urban metropolitan cancer center the patient population receiving imaging services does not always reflect the diverse urban environment of its catchment area. Finally, the results are limited to the self-report of patients and questions that our group considered to be the most appropriate to our outpatients. In our next iteration with CHIP, we will use questions  that have been vetted in the cancer control community setting to better understand how our Center can be an active participant in cancer control and survivorship in New York City.The tenth regulation of the National Standards for Culturally and Linguistically Appropriate Services in Health Care is to conduct ongoing assessments of the organization’s CLAS-related activities and integrate CLAS-related measures into measurement and continuous quality improvement activities . This as


Most neglected tropical diseases (NTDs) occur in remote areas of low- and middle-income countries, where health systems are often poorly developed. Therefore, these neglected patients generally lack access to quality preventive, diagnostic, and therapeutic care . The difwww.nidiag.org). The study design was that of a descriptive, prospective clinical study to reach a final, confirmed diagnosis in the largest possible number of febrile patients (fever ≥7 days) with the support of national and international reference laboratories. Hence, the study required the shipment of a large number of samples within-country and abroad (The introduction of rapid diagnostic tests (RDTs) for malaria in clinical practice in the tropics has been a game changer in the management of febrile illness, revealing the frequency of nonmalarial fevers and the long list of differential diagnosis ,3. Unford abroad . The knoProtocol development took much longer than expected because of the intrinsic complexity of harmonising the study protocol for field sites situated in four countries . More than a year elapsed between the circulation of the first draft protocol (November 2011) and the approval of version 1.0 (January 2013) .PLOS Neglected Tropical Diseases issue [For each procedure in the study, be it patient recruitment, physical examination, or diagnostic test, a standard operating procedure (SOP) was drafted . In totaes issue . The prees issue , includiSeven months passed between the first submission of the study protocol to an ethical committee in Europe and the clearance in all participating countries. We submitted the study protocol first to the Ethical Committee of the sponsor  on 23 May 2012 and got approval on 25 June 2012. The National Ethics Committee for Health Research, Cambodia , the Nepal Health Research Council , the Ethical Committee of the University of Khartoum, Sudan , the National Research Ethics Review Committee, Sudan , and the Comité d’Ethique de l’ Ecole de Santé Publique de l’Université de Kinshasa, DRC  followed. The minor changes requested by the national committees were country-specific and did not require resubmission of the common protocol.In brief, this study, which had looked relatively simple at the outset, took us almost two years of preparation. Protocol preparation and ethical clearance was a lengthy process, and the time required to develop the case report form (CRF) and SOPs was much longer than expected. Over to Sudan now to examine the challenges encountered during study implementation.We established several criteria for the selection of the study site: (1) location in the most endemic area for visceral leishmaniasis and close to the referral hospital in Gedaref; (2) logistical capacity ; and (3) reliable supply of medicines and food. With these criteria in mind, we selected Tabarak Allah (TBK) Rural Hospital in Gedaref State as the study site . This hoWe faced major logistical constraints. Tabarak Allah is located 200 km away from Gedaref town, and a large part of the road is black-cotton soil that gets impassable—even for 4x4 vehicles—during the rainy season. Gedaref town is located at about 600 km from Khartoum . Blood sPatient enrolment started in Tabarak Allah Rural Hospital on 21 March 2013, and within about two weeks, 28 patients were recruited. However, on 8 April 2013 the recruitment had to be interrupted because a laboratory monitoring visit pointed to the poor quality of locally purchased materials and the lack of equipment and consumables that could not be purchased from the local market. This interruption was meant to last only two weeks—the time needed to import better quality laboratory products—after which recruitment would be resumed. Unfortunately, on the following day (9 April 2013), the study team had a severe car accident on their way from Gedaref to Khartoum, causing almost total damage to the car but fortunately only minor injuries to the team and the driver. The biological samples from six patients were lost in the accident. The study had to be interrupted for about five months instead of only two weeks. The study was restarted on 8 September 2013. From that day onwards, MSF kindly provided transport with hired tractors for the study team during the rainy season.One of the biggest challenges we had to overcome was totally unexpected. The EU grant had to be transferred to the Sudanese principal investigator (PI) in several instalments. The first and second bank transfer went smoothly, but in July 2014, probably as a result of a recent court case in the US related to the embargo , severalOne month after the restart of the study, the NIDIAG study physician in Tabarak Allah developed severe malaria and had to be brought back to Khartoum for treatment; after that episode he refused to return to Tabarak Allah. The site investigator worked single-handedly for about three months, as it was so difficult to recruit a second doctor because of the tough field conditions and mass emigration of young doctors—particularly to Saudi Arabia—for better job opportunities. In December 2013, the site investigator and one of the two NIDIAG site technicians developed an acute febrile illness and the study had to be interrupted again for two weeks.On average, 12 eligible patients with persistent fever were seen per day at Tabarak Allah Hospital, but only four participants could be enrolled per day because of the limited laboratory capacity. The NIDIAG study became popular in the area, as the news spread that investigations and other costs were taken care of by the project. Hence, more and more patients with fever syndrome came from further away. This led to a significantly increased workload: higher numbers of noneligible febrile patients and a higher rate of patients with noninfectious diseases  in the hospital. In addition, a lot of patients came back for scheduled as well as unscheduled follow-up visits (up to 15 patients per day).Access to the clinic facilities was maintained throughout the study period, so patient safety and well-being was not compromised at any point during the study. Patients were given follow-up cards and the doctor kept all the essential information  so as to be able to reach the patient easily in case a patient did not come for a scheduled follow-up visit. Active follow-up was not feasible because of limited human and logistic  resources on site. Only 64% (431) patients completed their one-month follow-up visit. In light of all the constraints, this seems a reasonable follow-up rate.A large amount of time and energy went into the selection, purchase, and supply of the required diagnostic tests. HIV kits were supplied by the Sudanese National AIDS Programme. First, we used SD Bioline HIV 1/2 as a screening test, in line with the Sudanese HIV testing algorithm, and we developed study SOPs and CRF accordingly. However, when the Sudanese AIDS Programme changed its algorithm, the study also switched to Determine HIV 1–2 and the study documents had to be changed. In addition, we were out of stock of Determine HIV 1–2 tests for about three weeks and had to store the samples for delayed testing. We faced several issues with the supply of the required RDTs. Because of delays with the start of patient recruitment, some lots of rK39 and rK28 RDT for visceral leishmaniasis were already expired when the study started on 21 March 2013 or would expire shortly thereafter. These problems were solved by ordering new tests (rK28) and thanks to donation of test kits (rK39) by the MoH and MSF. Moreover, there were several issues with the quality of imported RDTs that will be discussed elsewhere  [There was no suitable equipment for biochemistry assays available on site in Tabarak Allah. The original plan was for the NIDIAG technician at Suba University Hospital in Khartoum to perform biochemistry assays under the supervision of a specialist. Accordingly, the clinical samples had to be transferred weekly to the Leishmania Research Laboratory . Optimising the available biochemistry equipment  for the biochemistry procedures at this laboratory was problematic, so the actual testing was done retrospectively on frozen samples by technologists at the Chemical Pathology Department of Suba University Hospital.Leishmania cultures at field level was frequent and required retraining of laboratory technicians and changes in the preparation of culture media. In addition, direct agglutination testing for visceral leishmaniasis was at times delayed for some patients because of unavailability of the MSF laboratory technician.Contamination of a.m. In Khartoum, the samples had then to be dispatched to four different laboratories. Needless to say, the transport had to be run with the rigor of a military operation . The NIDIAG driver sometimes had to travel further to Doka or even to Tabarak Allah and often arrived in Khartoum around 3 tion see .Every Friday: Lab team in Tabarak Allah (TBK) prepares the shipments of samples.Every Saturday: Transport from Khartoum to TBK of original result forms and transport from TBK to Khartoum of samples.Every Saturday night: Reception of samples from TBK at Suba University Hospital (SUH).Brucella work, Faculty of Medicine (FOM) for Salmonella work, Leishmaniasis Research Laboratory (LRL) for Leishmania culture, and the National Health Laboratory (NHL) for tuberculosis culture.Every Sunday morning: Laboratory manager picks up samples at SUH and dispatches samples to four central laboratories: Veterinary Research Institute (VRI) for Brucella work; collects results from FOM, VRI, and NHL laboratories; photocopies all the results forms; and gives the original copies to the driver to take them to TBK the next day.Every Thursday: Laboratory manager picks up blood cultures from FOM; takes them to VRI for Data entry could not be carried out on site in Tabarak Allah because of lack of facilities, space, and trained personnel, so we organised it in Khartoum. Data management was supervised by the GCP/GCLP unit of the Institute of Tropical Medicine Antwerp. We organised two training workshops on GCP-compliant data management, and continuous support was given to the data managers in Khartoum by email, telephone, and/or internet calls. Phone and internet connections were sometimes poor and did not allow any communication between the two teams. Our ambitious plan was to complete the first data entry within one month by training enough data entry clerks. This urgency was motivated by the fact that we wanted to retain the site investigator to respond to data queries, as he was about to migrate out to a Gulf country. A first workshop was rapidly organised to train data entry clerks. We had to organise later a second workshop, as the initial number of clerks was not sufficient to complete data entry on time. The main difficulty we encountered though was the transfer of the CRFs from Tabarak Allah to Khartoum. CRFs had to be transported weekly in batches from TBK to FOM. The road conditions were so bad during the rainy season that we could not get a single CRF out of Tabarak Allah for up to one month, even with a 4x4 vehicle.A formal three-day GCP/GCLP training was conducted in Khartoum prior to the study start for the study staff. As it was difficult to retain staff in tough field conditions, several field staff members—including a doctor, four internal quality managers, and two technologists—resigned during the study and had to be replaced. The newly appointed staff did not have access to an extensive three-day training workshop and were trained on site. The newly recruited collaborators were advised to access the GCP/GCLP documents on the NIDIAG website. The external monitors played an important role in training the newly appointed staff by running a few teaching sessions on GCP/GCLP during their monitoring visits in December 2013 and March 2014. Last but not least, the organization of the external monitoring was challenging. One visit planned in September 2013 had to be postponed for security reasons because of some instability in the country at that time. Additionally, it was difficult to obtain the required travel permits for the international monitors within 24 hours of their arrival in Khartoum, which they needed in order to spend the maximum possible time in the field.This paper relates the major hurdles one has to overcome when conducting clinical research on NTDs . It is lIn addition, the multicentre design of the study, taking place in four very different countries and settings, prolonged the preparation phase because of the longer-than-expected time needed to develop a common study protocol and to obtain ethical clearances from six ethical review committees, not to mention the writing of over 40 SOPs, the purchase of equipment and consumables, and the GCP/GCLP training of local investigators. In such studies, both researchers and funders should ensure that sufficient preparation time and budget is allocated prior to the start of patient recruitment. As described above, our study had to be interrupted after two weeks because some locally acquired laboratory consumables were missing or were of insufficient quality. This could have been avoided if the GCLP monitor had visited the site earlier, during the preparation phase. One of the most important lessons we learnt as a study team was that a substantial budget has to be earmarked for the GCP/GCLP package in clinical studies. This includes the staff time required for preparation of study documents and SOPs, the financing of GCP/GCLP monitoring, and the training of study personnel.The US embargo that is currently being imposed in Sudan added significantly to the complexity of our study, but with hindsight, the major bottleneck in this project was the lack of skilled human resources. In spite of the fact that the study doctors were generously paid in comparison to national standards, we experienced great difficulty in retaining our NIDIAG-trained doctors and in recruiting new ones. This may be partly related to the tough field conditions, including the risk of contracting severe infections or snake and/or scorpion bites . Sudan aIn spite of all the delays encountered, the study site in Sudan was able to recruit the targeted number of participants within the planned time frame. We attribute this first and foremost to the fact that we had a highly motivated and dedicated team, which we could strengthen by adding a study doctor and laboratory technician. This study team worked seven days on seven, without interruption. An additional factor explaining the high recruitment rate was that the study site became highly popular in the region and attracted patients from a much larger catchment area, even from other states.In conclusion, this study is considered by the Sudanese investigators as the toughest study they conducted since the start of their research career in 1986, though very rewarding. Against all odds, they achieved the required sample size within the planned time frame and obtained interesting results that will lead to better clinical care for patients at the primary health care level. The study gave them the stimulus to broaden their research scope and capacity to include other NTDs and to strengthen existing or establish new research collaborations. Most importantly, it brought European and Sudanese academic researchers together in the common quest to fulfil their mandate of social accountability.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.