[A local, population-based, multi-professional public health offering in primary care: Asalée]. / Une offre de santé publique de proximité, populationnelle, pluriprofessionnelle en soins primaires : Asalée.

Transforming healthcare provision to better meet healthcare needs and ensure continuity of care requires the development of coordinated practice. Whether it's a multi-professional health center (MSP), a primary care team (ESP), a territorial professional health community (CPTS) or a health center (CDS), whatever the way it's organized, this type of practice enables the coordination of the various professionals involved in primary care.

The use of formative research to inform the design of a seasonal malaria chemoprevention intervention in northern Nigeria.

BACKGROUND: Experience of seasonal malaria chemoprevention (SMC) is growing in the Sahel sub-region of Africa, though there remains insufficient evidence to recommend a standard deployment strategy. In 2012, a project was initiated in Katsina state, northern Nigeria, to design an appropriate and effective community-based delivery approach for SMC, in consultation with local stakeholders. Formative research (FR) was conducted locally to explore the potential feasibility and acceptability of SMC and to highlight information gaps and practical considerations to inform the intervention design. METHODS: The FR adopted qualitative methods; 36 in-depth interviews and 18 focus group discussions were conducted across 13 target groups active across the health system and within the community. Analysis followed the 'framework' approach. The process for incorporating the FR results into the project design was iterative which was initiated by a week-long 'intervention design' workshop with relevant stakeholders. RESULTS: The FR highlighted both supportive and hindering factors to be considered in the intervention design. Malaria control was identified as a community priority, the community health workers were a trusted resource and the local leadership exerted strong influence over household decisions. However, there were perceived challenges with quality of care at both community and health facility levels, referral linkage and supportive supervision were weak, literacy levels lower than anticipated and there was the potential for suspicion of 'outside' interventions. There was broad consensus across target groups that community-based SMC drug delivery would better enable a high coverage of beneficiaries and potentially garner wider community support. A mixed approach was recommended, including both community fixed-point and household-to-household SMC delivery. The FR findings were used to inform the overall distribution strategy, mechanisms for integration into the health system, capacity building and training approaches, supportive interventions to strengthen the health system, and the social mobilization strategy. CONCLUSIONS: Formative research played a valuable role in exploring local socio-cultural contexts and health system realities. Both opportunities and challenges for the introduction of SMC delivery were highlighted, which were appropriately considered in the design of the project.

Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma.

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

Nanobodies targeting mouse/human VCAM1 for the nuclear imaging of atherosclerotic lesions.

RATIONALE: A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions. OBJECTIVE: We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions. METHODS AND RESULTS: Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E-deficient (ApoE(-/-)) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE(-/-) mice were successfully identified by single-photon emission computed tomography imaging. (99m)Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions. CONCLUSIONS: The (99m)Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.

A safe bacterial microsyringe for in vivo antigen delivery and immunotherapy.

The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery.

From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151.

The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.

Pathological gambling in treatment-seeking alcoholics: a national survey in France.

AIMS: To estimate the prevalence of pathological gambling (pG) in people addicted to alcohol and drugs, particularly those with alcohol use disorders (AUDs), including new forms of gambling such as video and on-line games; and to update the socio-demographic profile of people suffering from both AUD and pG. METHOD: A cross-sectional survey was conducted in 1 week of 2009 in 55 French addiction treatment centres, including all consecutive patients attending that centre, using an anonymous questionnaire which included a tool specific for pG screening, the DEBA-jeu questionnaire (Détection et Besoin d'Aide en regard du Jeu Excessif). RESULTS: A total of 2790 patients entered the study. The most frequent reason for attending the Addiction Centres was AUD (77%). According to the DEBA test, 6.5% of the patients were pathological gamblers and 12% were subsyndromal gamblers. pG affected all age groups and did not decrease with abstinence from alcohol. pG was significantly associated with male sex [relative risk (RR) = 2.4; P < 0.001)] and, at a lower level of significance, with homelessness (RR = 1.52; P = 0.03) and unemployment (RR = 1.47; P = 0.04). CONCLUSIONS: pG appears to be a common feature of the French people with alcohol and drug disorders. Apart from male sex, no parameter had discriminatory power sufficient to target pG screening on a specific subgroup. Therefore, any patient attending a centre for drug or AUD should be asked about his gambling. Moreover, clinical teams should be trained to treat this addiction.

Not a "Get Out of Jail Free Card": Comparing the Legal Supervision of Persons Found Not Criminally Responsible on Account of Mental Disorder and Convicted Offenders.

BACKGROUND: The public often perceives the insanity defense as a "get out of jail free card". Conversely, several studies demonstrate the substantial control imposed upon these defendants. This study compares Review Boards decisions regarding people found not criminally responsible on account of mental disorder (NCRMD) to criminal courts decisions regarding convicted offenders for similar offenses in Canada. METHOD: Detention, using logistic regression, and duration under detention and supervision, using Cox regression, were compared between a cohort of 1794 individuals found NCRMD in three Canadian provinces (Quebec, Ontario, and British Columbia) between 2000 and 2005 followed until 2008 from the National Trajectory Project and a national sample of 3,20,919 Canadians convicted of criminal offense from Statistics Canada's Criminal Court Survey. RESULTS: Individuals found NCRMD are 3.8 times (95% CI 3.4-4.3) more likely to be detained than convicted offenders as well as 4.8 times (95% CI 4.5-5.3) and 2.9 times (95% CI 2.6-3.1) less likely to be released from detention and supervision, respectively. One year after the verdict, 73% of the NCRMD accused were still under legal supervision and 42% were still in detention, whereas these proportions were, respectively, 41 and 1% for their convicted counterparts. Interaction effects show that sex, age, jurisdiction, number of offenses, and severity of crimes committed have a differential impact on decisions applied to NCRMD accused compared to convicted persons. CONCLUSION: Contrary to popular perceptions, the insanity defense is not a loophole. Differences as to factors influencing the trajectories of the two samples confirm that Review Boards are able to distance their practices from the criminal courts and can set aside, at least in part, the principles of proportionality and punitiveness governing the traditional sentencing practices.

Evaluating the feasibility and acceptability of a community dialogue intervention in the prevention and control of schistosomiasis in Nampula province, Mozambique.

BACKGROUND: Schistosomiasis is a parasitic neglected tropical disease that ranks second only to malaria in terms of human suffering in the tropics and subtropics. Biomedical disease control interventions need to be complemented with effective prevention and health education strategies, that address the social and environmental determinants of disease. Malaria Consortium conducted an implementation research study between May 2014 and February 2016, in four districts of Nampula province, Mozambique, to test a Community Dialogue (CD) intervention to enhance schistosomiasis prevention and control. The study aimed to evaluate the acceptability and feasibility of using CD to improve communities' level of knowledge, attitudes and practices, and engagement in wider schistosomiasis prevention and control efforts. METHODS: The feasibility and acceptability of the CD intervention was evaluated using qualitative and process evaluation data collected throughout the development and implementation phases. Qualitative data sets included key informant interviews (N = 4) with health system personnel, focus group discussions (N = 22) with Community Dialogue facilitators and participants, field observation visits (N = 11), training reports (N = 7), feedback meeting reports (N = 5), CD monitoring sheets (N = 1,458) and CD planning sheets (N = 152). FINDINGS: The CD intervention was found highly acceptable and feasible, particularly well-suited to resource poor settings. Non-specialist community volunteers were able to deliver participatory CDs which resulted in increased knowledge among participants and triggered individual and communal actions for improved disease prevention and control. The visual flipchart was a key aid for learning; the use of participatory communication techniques allowed the correction of misconceptions and positioned correct prevention and control practices as the community recommendations, through consensus building. CONCLUSION: The Community Dialogue Approach should be embedded within neglected tropical disease control programmes and the health system to create long-lasting synergies between the community and health system for increased effectiveness. However, for behavioural change to be feasible, community engagement strategies need to be supported by improved access to treatment services, safer water and sanitation.

Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles.

PURPOSE: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies. PROCEDURES: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 µg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose). RESULTS: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 µg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 µg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 µGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 µSv/MBq, which is in the typical range for F-18 radiolabeled ligands. CONCLUSIONS: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.

Knowledge, attitudes and practices with regard to schistosomiasis prevention and control: Two cross-sectional household surveys before and after a Community Dialogue intervention in Nampula province, Mozambique.

BACKGROUND: The Community Dialogue Approach is a promising social and behaviour change intervention, which has shown potential for improving health seeking behaviour. To test if this approach can strengthen prevention and control of schistosomiasis at community level, Malaria Consortium implemented a Community Dialogue intervention in four districts of Nampula province, Mozambique, between August 2014 and September 2015. METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional household surveys were conducted before (N = 791) and after (N = 792) implementation of the intervention to assess its impact on knowledge, attitudes and practices at population level. At both baseline and endline, awareness of schistosomiasis was high at over 90%. After the intervention, respondents were almost twice as likely to correctly name a risk behaviour associated with schistosomiasis (baseline: 18.02%; endline: 30.11%; adjusted odds ratio: 1.91; 95% confidence interval: 1.14-2.58). Increases were also seen in the proportion of people who knew that schistosomiasis can be spread by infected persons and who could name at least one correct transmission route (baseline: 25.74%; endline: 32.20%; adjusted odds ratio: 1.36; 95% confidence interval: 1.01-1.84), those who knew that there is a drug that treats the disease (baseline: 29.20%, endline: 47.55%; adjusted odds ratio: 2.19; 95% confidence interval: 1.67-2.87) and those who stated that they actively protect themselves from the disease and cited an effective behaviour (baseline: 40.09%, endline: 59.30%; adjusted odds ratio: 2.14; 95% confidence interval: 1.40-3.28). The intervention did not appear to lead to a reduction in misconceptions. In particular, the belief that the disease is sexually transmitted continued to be widespread. CONCLUSIONS/SIGNIFICANCE: Given its overall positive impact on knowledge and behaviour at population level, Community Dialogue can play an important role in schistosomiasis prevention and control. The intervention could be further strengthened by better enabling communities to take suitable action and linking more closely with community governance structures and health system programmes.

Community dialogues for child health: results from a qualitative process evaluation in three countries.

BACKGROUND: Across the developing world, countries are increasingly adopting the integrated community case management of childhood illnesses (iCCM) strategy in efforts to reduce child mortality. This intervention's effectiveness is dependent on community adoption and changes in care-seeking practices. We assessed the implementation process of a theory-driven community dialogue (CD) intervention specifically designed to strengthen the support and uptake of the newly introduced iCCM services and related behaviours in three African countries. METHODS: A qualitative process evaluation methodology was chosen and used secondary project data and primary data collected in two districts of each of the three countries, in purposefully sampled communities. The final data set included 67 focus group discussions and 57 key informant interviews, totalling 642 respondents, including caregivers, CD facilitators community leaders, and trainers. Thematic analysis of the data followed the 'Framework Approach' utilising both a deduction and induction process. RESULTS: Results show that CDs contribute to triggering community uptake of and support for iCCM services through filling health information gaps and building cooperation within communities. We found it to be an effective approach for addressing social norms around child care practices. This approach was embraced by communities for its flexibility and value in planning individual and collective change. CONCLUSIONS: Regular CDs can contribute to the formation of new habits, particularly in relation to seeking timely care in case of child sickness. This study also confirms the value of process evaluation to unwrap the mechanisms of community mobilisation approaches in context and provides key insights for improving the CD approach.

How Do Patients and Health Workers Interact around Malaria Rapid Diagnostic Testing, and How Are the Tests Experienced by Patients in Practice? A Qualitative Study in Western Uganda.

BACKGROUND: Successful scale-up in the use of malaria rapid diagnostic tests (RDTs) requires that patients accept testing and treatment based on RDT results and that healthcare providers treat according to test results. Patient-provider communication is a key component of quality care, and leads to improved patient satisfaction, higher adherence to treatment and better health outcomes. Voiced or perceived patient expectations are also known to influence treatment decision-making among healthcare providers. While there has been a growth in literature on provider practices around rapid testing for malaria, there has been little analysis of inter-personal communication around the testing process. We investigated how healthcare providers and patients interact and engage throughout the diagnostic and treatment process, and how the testing service is experienced by patients in practice. METHODS: This research was conducted alongside a larger study which explored determinants of provider treatment decision-making following negative RDT results in a rural district (Kibaale) in mid-western Uganda, ten months after RDT introduction. Fifty-five patients presenting with fever were observed during routine outpatient visits at 12 low-level public health facilities. Observation captured communication practices relating to test purpose, results, diagnosis and treatment. All observed patients or caregivers were immediately followed up with in-depth interview. Analysis followed the 'framework' approach. A summative approach was also used to analyse observation data. RESULTS: Providers failed to consistently communicate the reasons for carrying out the test, and particularly to RDT-negative patients, a diagnostic outcome or the meaning of test results, also leading to confusion over what the test can detect. Patients appeared to value testing, but were frustrated by the lack of communication on outcomes. RDT-negative patients were dissatisfied by the absence of information on an alternative diagnosis and expressed uncertainty around adequacy of proposed treatment. CONCLUSIONS: Poor provider communication practices around the testing process, as well as limited inter-personal exchange between providers and patients, impacted on patients' perceptions of their proposed treatment. Patients have a right to health information and may be more likely to accept and adhere to treatment when they understand their diagnosis and treatment rationale in relation to their perceived health needs and visit expectations.

Have You Heard of Schistosomiasis? Knowledge, Attitudes and Practices in Nampula Province, Mozambique.

BACKGROUND: Schistosomiasis is a parasitic disease which affects almost 300 million people worldwide each year. It is highly endemic in Mozambique. Prevention and control of schistosomiasis relies mainly on mass drug administration (MDA), as well as adoption of basic sanitation practices. Individual and community perceptions of schistosomiasis are likely to have a significant effect on prevention and control efforts. In order to establish a baseline to evaluate a community engagement intervention with a focus on schistosomiasis, a survey to determine knowledge, attitudes and practices relating to the disease was conducted. METHODOLOGY/PRINCIPAL FINDINGS: A representative cross-sectional household survey was carried out in four districts of Nampula province, Mozambique. Interviews were conducted in a total of 791 households, using a structured questionnaire. While awareness of schistosomiasis was high (91%), correct knowledge of how it is acquired (18%), transmitted (26%) and prevented (13%) was low among those who had heard of the disease. Misconceptions, such as the belief that schistosomiasis is transmitted through sexual contact (27%), were common. Only about a third of those who were aware of the disease stated that they practiced a protective behaviour and only a minority of those (39%) reported an effective behaviour. Despite several rounds of MDA for schistosomiasis in the recent past, only a small minority of households with children reported that at least one of them had received a drug to treat the disease (9%). CONCLUSION/SIGNIFICANCE: Poor knowledge of the causes of schistosomiasis and how to prevent it, coupled with persisting misconceptions, continue to pose barriers to effective disease prevention and control. To achieve high levels of uptake of MDA and adoption of protective behaviours, it will be essential to engage individuals and communities, improving their understanding of the causes and symptoms of schistosomiasis, recommended prevention mechanisms and the rationale behind MDA.

Angular dependence of the luminance and contrast in medical monochrome liquid crystal displays.

Active-matrix liquid crystal displays (AMLCDs) are light-modulating devices that generate images by differentially transmitting a nearly uniform luminous field provided by a backlight. While emissive displays exhibit a quasi-Lambertian emission with almost constant contrast at off-normal viewing, the anisotropy of the electro-optic effect that controls light transmission in AMLCDs causes a pixel luminance that varies, sometimes strongly, with viewing angle. These variations are not identical for all gray levels and can eventually cause grayscale inversions. In this paper, we measured the luminance emission of a monochrome medical AMLCD, a medical cathode-ray tube monitor, and a color desktop AMLCD, using a collimated photopic probe positioned on a manual rotation arm, and a research radiometer with automatic readout. The probe measures luminance with a small acceptance angle and provides optical shielding from emissions at other viewing directions that contaminate the readings. We obtained luminance response curves versus angle in the vertical, horizontal and at 45 degrees diagonal directions. The display systems were calibrated to reflect the DICOM Part 3.14 standard grayscale display function (GDF) when measured using the manufacturer's probe and software tools. We analyzed the measurements at different viewing directions with respect to their departure from the GDF by computing the normalized contrast (deltaL/L) as a function of the DICOM just-noticeable difference index. Although cathode-ray tubes are known to be quasi-Lambertian emitters, the luminance at normal viewing is higher than the luminance observed at large angles. This decrease in luminance is however proportionally similar for all gray levels, resulting in a relatively flat contrast response for all angles. In addition to being more pronounced, the angular variation in AMLCDs does not follow the same profile at different intensities with the subsequent variation in the achieved display contrast. The changes due to off-normal viewing are substantial at large angles in the horizontal and vertical directions, and much worse in the diagonal viewing directions.

[Attitudes and opinions of private practitioners towards alcoholism. A survey in the Languedoc-Roussillon region]. / Attitudes et opinions des médecins libéraux sur l'alcoolisme. Une enquête en région Languedoc-Roussillon.

OBJECTIVE: Information on the position of private practitioners faced with the problem of alcoholism mainly concerns the role of the general practitioner in the follow-up of these patients and there is little information from private specialists, hence the need for new data METHOD: All the general practitioners and specialists in the Languedoc-Roussillon area were interviewed through a mailed questionnaire regarding their opinion on alcohol consumption and public health; their definition of the risks; moderate consumption and health; how they approached the question of drinking during consultations and their involvement in training and prevention. RESULTS: Six hundred sixty-five practitioners (12.4% of those interviewed) returned the questionnaire. The profile of those who replied was identical to that of the whole population surveyed. The medical corps is clearly aware of the need to fight against alcohol abuse, but this is associated with a relative ignorance of the basics of alcoholism, a non-systematic approach of the question of drinking during consultations, little involvement in its management, limited use of the specialised structures and limited training on the question. The specialists are less involved than the general practitioners, but appear more at ease when approaching the question of drinking with their patients and resort more frequently to specialised structures than the general practitioners. Continued medical training on alcoholism only concerned a minority of practitioners and its practical impact was low. CONCLUSION: With regard to alcoholism, the practitioners fulfill their role in providing medical care, within the limits of available therapeutic resources, but their role with regard to the reduction of the risks, i.e., primary or early prevention is more or less disregarded.

Demand generation and social mobilisation for integrated community case management (iCCM) and child health: Lessons learned from successful programmes in Niger and Mozambique.

AIM: We present the approaches used in and outcomes resulting from integrated community case management (iCCM) programmes in Niger and Mozambique with a strong focus on demand generation and social mobilisation. METHODS: We use a case study approach to describe the programme and contextual elements of the Niger and Mozambique programmes. RESULTS: Awareness and utilisation of iCCM services and key family practices increased following the implementation of the Niger and Mozambique iCCM and child survival programmes, as did care-seeking within 24 hours and care-seeking from appropriate, trained providers in Mozambique. These approaches incorporated interpersonal communication activities and community empowerment/participation for collective change, partnerships and networks among key stakeholder groups within communities, media campaigns and advocacy efforts with local and national leaders. CONCLUSIONS: iCCM programmes that train and equip community health workers and successfully engage and empower community members to adopt new behaviours, have appropriate expectations and to trust community health workers' ability to assess and treat illnesses can lead to improved care-seeking and utilisation, and community ownership for iCCM.

Discovery and characterization of small molecule inhibitors of the BET family bromodomains.

Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.

Pharmacological inhibition of stearoyl-CoA desaturase 1 improves insulin sensitivity in insulin-resistant rat models.

Stearoyl-CoA Desaturase 1 (SCD1) is a central enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. SCD1 is an emerging target in obesity and insulin resistance due to the improved metabolic profile obtained when the enzyme is genetically inactivated. Here, we have investigated if the pharmacological inhibition of SCD1 could elicit the same profile. We have identified a small molecule, GSK993 and characterized it as a potent and orally available SCD1 inhibitor. In Zucker(fa/fa) rats, GSK993 exerted a marked reduction in hepatic lipids as well as a significant improvement of glucose tolerance. Furthermore, in a diet-induced insulin resistant rat model, GSK993 induced a very strong reduction in Triton-induced hepatic Very Low Density Lipoprotein-Triglyceride production. In addition, following a hyperinsulinemic-euglycemic clamp in GSK993-treated animals, we observed an improvement in the whole body insulin sensitivity as reflected by an increase in the glucose infusion rate. Taken together, these findings demonstrate that the pharmacological inhibition of SCD1 translates into improved lipid and glucose metabolic profiles and raises the interest of SCD1 inhibitors as potential new drugs for the treatment of insulin resistance.