Molecular classification of amyotrophic lateral sclerosis by unsupervised clustering of gene expression in motor cortex

AbstractAmyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. Although 10% of ALS cases are familial (FALS), the majority are sporadic (SALS) and probably associated to a multifactorial etiology. Currently there is no cure or prevention for ALS. A prerequisite to formulating therapeutic strategies is gaining understanding of its etio-pathogenic mechanisms. In this study we analyzed whole-genome expression profiles of 41 motor cortex samples of control (10) and sporadic ALS (31) patients. Unsupervised hierarchical clustering was able to separate control from SALS patients. In addition, SALS patients were subdivided in two different groups that were associated to different deregulated pathways and genes, some of which were previously associated to familiar ALS. These experiments are the first to highlight the genomic heterogeneity of sporadic ALS and reveal new clues to its pathogenesis and potential therapeutic targets

An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development

Genetically complex ocular neuropathies, such as glaucoma, are a major cause of visual impairment worldwide. There is a growing need to generate suitable human representative in vitro and in vivo models, as there is no effective treatment available once damage has occured. Retinal organoids are increasingly being used for experimental gene therapy, stem cell replacement therapy and small molecule therapy. There are multiple protocols for the development of retinal organoids available, however, one potential drawback of the current methods is that the organoids can take between 6 weeks and 12 months on average to develop and mature, depending on the specific cell type wanted. Here, we describe and characterise a protocol focused on the generation of retinal ganglion cells within an accelerated four week timeframe without any external small molecules or growth factors. Subsequent long term cultures yield fully differentiated organoids displaying all major retinal cell types. RPE, Horizontal, Amacrine and Photoreceptors cells were generated using external factors to maintain lamination.</p

Effect of the Newhints home-visits intervention on neonatal mortality rate and care practices in Ghana: a cluster randomised controlled trial.

BACKGROUND: In 2009, on the basis of promising evidence from trials in south Asia, WHO and UNICEF issued a joint statement about home visits as a strategy to improve newborn survival. In the Newhints trial, we aimed to test this home-visits strategy in sub-Saharan Africa by assessing the effect on all-cause neonatal mortality rate (NMR) and essential newborn-care practices. METHODS: The Newhints cluster randomised trial was undertaken in 98 zones in seven districts in the Brong Ahafo Region, Ghana. 49 zones were randomly assigned to the Newhints intervention and 49 to the control intervention by use of restricted randomisation with stratification to ensure comparability between interventions. Community-based surveillance volunteers (CBSVs) in Newhints zones were trained to identify pregnant women in their community and to make two home visits during pregnancy and three in the first week of life to promote essential newborn-care practices, weigh and assess babies for danger signs, and refer as necessary. Primary outcomes were NMR and coverage of key essential newborn-care practices. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00623337. FINDINGS: 16,168 (99%) of 16,329 deliveries between November, 2008, and December, 2009, were livebirths; the status at 1 month was known for 15,619 (97%) livebirths. 482 neonatal deaths were recorded. Coverage data were available from 6029 women in Newhints zones; of these 4358 (72%) reported having CBSV visits during pregnancy and 3815 (63%) reported having postnatal visits. This coverage increased substantially from June, 2009, after the introduction of new implementation strategies and reached almost 90% for pregnancy visits by the end of the trial and 75% for postnatal visits. The Newhints intervention significantly increased coverage of key essential newborn-care behaviours, except for four or more antenatal-care visits (5975 [76%] of 7859 vs 5988 [74%] of 8121, respectively; relative risk 1·02, 95% CI 0·96-1·09; p=0·52) and baby delivered in a facility (5373 [68%] vs 5539 [68%], respectively; 0·97, 0·81-1·14; p=0·69). The largest increase was for care-seeking, with 102 (77%) of 132 sick babies in Newhints zones taken to a hospital or clinic compared with 77 (55%) of 139 in control zones (1·43, 1·17-1·76; p=0·001). Increases were also noted in bednet use during pregnancy (5398 [69%] of 7859 vs 5135 [63%] of 8121, respectively; 1·12, 1·03-1·21; p=0·005), money saved for delivery or emergency (5730 [86%] of 6681 vs 5525 [80%] of 6941, respectively; 1·09, 1·05-1·12; p<0·0001), transport arranged in advance for facility (2496 [37%] vs 2061 [30%], respectively; 1·30, 1·12-1·49; p=0·0004), birth assistant for home delivery washed hands with soap (1853 [93%] of 1992 vs 1817 [87%] of 2091, respectively; 1·05, 1·02-1·09; p=0·001), initiation of breastfeeding in less than 1 h of birth (3743 [49%] of 7673 vs 3280 [41%] of 7921, respectively; 1·22, 1·07-1·40; p=0·004), skin to skin contact (3355 [44%] vs 1931 [24%], respectively; 2·30, 1·85-2·87; p=0·0002), first bath delayed for longer than 6 h (3131 [41%] vs 2269 [29%], respectively; 1·65, 1·27-2·13; p<0·0001), exclusive breastfeeding for 26-32 days (1217 [86%] of 1414 vs 1091 [80%] of 1371; 1·10, 1·04-1·16; p=0·001), and baby sleeping under bednet for 8-56 days (4548 [79%] of 5756 vs 4291 [73%] of 5846; 1·09, 1·03-1·15; p=0·002). There were 230 neonatal deaths in the Newhints zones compared with 252 in the control zones. The overall NMRs per 1000 livebirths were 29·8 and 31·9, respectively (0·92, 0·75-1·12; p=0·405). INTERPRETATION: The reduction in NMR with Newhints is consistent with the reductions achieved in three trials undertaken in programme settings in south Asia. Because there is no suggestion of any heterogeneity (p=0·850) between these trials and Newhints, the meta-analysis summary estimate of a reduction of 12% (95% CI 5-18) provides the best evidence for the likely effect of the home-visits strategy delivered within programmes in sub-Saharan Africa and in south Asia. Improvements in the quality of delivery and neonatal care in health facilities and development of innovative, effective strategies to increase coverage of home visits on the day of birth could lead to the achievement of more substantial reductions. FUNDING: WHO, Bill & Melinda Gates Foundation, and UK Department for International Development

Supervising community health workers in low-income countries--a review of impact and implementation issues.

BACKGROUND: Community health workers (CHWs) are an increasingly important component of health systems and programs. Despite the recognized role of supervision in ensuring CHWs are effective, supervision is often weak and under-supported. Little is known about what constitutes adequate supervision and how different supervision strategies influence performance, motivation, and retention. OBJECTIVE: To determine the impact of supervision strategies used in low- and middle-income countries and discuss implementation and feasibility issues with a focus on CHWs. DESIGN: A search of peer-reviewed, English language articles evaluating health provider supervision strategies was conducted through November 2013. Included articles evaluated the impact of supervision in low- or middle-income countries using a controlled, pre-/post- or observational design. Implementation and feasibility literature included both peer-reviewed and gray literature. RESULTS: A total of 22 impact papers were identified. Papers were from a range of low- and middle-income countries addressing the supervision of a variety of health care providers. We classified interventions as testing supervision frequency, the supportive/facilitative supervision package, supervision mode (peer, group, and community), tools (self-assessment and checklists), focus (quality assurance/problem solving), and training. Outcomes included coverage, performance, and perception of quality but were not uniform across studies. Evidence suggests that improving supervision quality has a greater impact than increasing frequency of supervision alone. Supportive supervision packages, community monitoring, and quality improvement/problem-solving approaches show the most promise; however, evaluation of all strategies was weak. CONCLUSION: Few supervision strategies have been rigorously tested and data on CHW supervision is particularly sparse. This review highlights the diversity of supervision approaches that policy makers have to choose from and, while choices should be context specific, our findings suggest that high-quality supervision that focuses on supportive approaches, community monitoring, and/or quality assurance/problem solving may be most effective

Влияние условий синтеза на размер наночастиц железа

Показана возможность получения наночастиц железа разного размера путем варьирования условий синтеза. Методами электронной микроскопии, ИК спектроскопии и электронной дифракции изучена их морфология и структура. Установлено, что при нанесении наночастиц железа на угольный носитель размер, распределение и строение частиц не меняется.Показана можливість отримання наночастинок заліза різного розміру шляхом варіювання умов синтезу. Методами електронної мікроскопії, ІЧ спектроскопії та електронної дифракції вивчено їх морфологію та структуру. Знайдено, що при нанесенні наночастинок заліза на носії розмір, розподіл та будова не змінюється.The preparation of monodisperse Fe nanoparticles of various sizes by varying synthesis conditions is reported. Nanoparticles have been studied by transmission electron microscopy, IR spectroscopy, and electron diffraction. It was shown that Fe nanoparticles do not change its size, distribution, and structure after impregnation of support

Implementing global knowledge in local practice: a WHO lung health initiative in Nepal

Clinical practice guidelines are used widely to improve the quality of primary health care in different health systems, including those of low-income countries. Often developed at international level and adapted to national contexts to increase the feasibility of effective uptake, guideline initiatives aim to transfer global scientific knowledge into local practice. The WHO's Practical Approach to Lung Health (PAL) is an example of such an initiative and is currently being developed to improve the quality of care for youths and adults with respiratory diseases. We assessed ex-ante the feasibility of successful implementation of PAL in a pilot programme in rural Nepal, studying three components: the quality of the innovation (i.e. the guidelines), the effectiveness of the implementation strategy (i.e. training) and the receptiveness of the social system of health staff at all levels (i.e. social and organizational characteristics). We assessed the guideline innovation with the AGREE instrument for guidelines, the intended implementation strategy by critical comparison with literature on effective strategies, and the social system with both a stakeholder analysis and a descriptive analysis of the health care system at district level. This ex-ante assessment of an adaptive local implementation of international WHO guidelines showed that in July 2002 the ‘implementability' of the package was challenged on the three components studied. To increase the chances of successful implementation, the national guideline development process should be improved and the implementation strategy needs to be upgraded. In order to successfully transfer global knowledge into local practice, we need to develop additional multifactorial sustained interventions that tackle other culture-specific and health system-specific barriers as well. The primary health workers are key informants for these barrier

The role of small molecules and their effect on the molecular mechanisms of early retinal organoid development

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.Ophthalmic researc

Association between probable postnatal depression and increased infant mortality and morbidity: findings from the DON population-based cohort study in rural Ghana.

OBJECTIVES: To assess the impact of probable depression in the immediate postnatal period on subsequent infant mortality and morbidity. DESIGN: Cohort study nested within 4 weekly surveillance of all women of reproductive age to identify pregnancies and collect data on births and deaths. SETTING: Rural/periurban communities within the Kintampo Health Research Centre study area of the Brong-Ahafo Region of Ghana. PARTICIPANTS: 16,560 mothers who had a live singleton birth reported between 24 March 2008 and 11 July 2009, who were screened for probable postnatal depression (pPND) between 4 and 12 weeks post partum (some of whom had also had depression assessed at pregnancy), and whose infants survived to this point. PRIMARY/SECONDARY OUTCOME MEASURES: All-cause early infant mortality expressed per 1000 infant-months of follow-up from the time of postnatal assessment to 6 months of age. The secondary outcomes were (1) all-cause infant mortality from the time of postnatal assessment to 12 months of age and (2) reported infant morbidity from the time of the postnatal assessment to 12 months of age. RESULTS: 130 infant deaths were recorded and singletons were followed for 67,457.4 infant-months from the time of their mothers' postnatal depression assessment. pPND was associated with an almost threefold increased risk of mortality up to 6 months (adjusted rate ratio (RR), 2.86 (1.58 to 5.19); p=0.001). The RR up to 12 months was 1.88 (1.09 to 3.24; p=0.023). pPND was also associated with increased risk of infant morbidity. CONCLUSIONS: There is new evidence for the association between maternal pPND and infant mortality in low-income and middle-income countries. Implementation of the WHO's Mental Health Gap Action Programme (mhGAP) to scale up packages of care integrated with maternal health is encouraged as an important adjunct to child survival efforts

Association between probable postnatal depression and increased infant mortality and morbidity: findings from the DON population-based cohort study in rural Ghana.

OBJECTIVES: To assess the impact of probable depression in the immediate postnatal period on subsequent infant mortality and morbidity. DESIGN: Cohort study nested within 4 weekly surveillance of all women of reproductive age to identify pregnancies and collect data on births and deaths. SETTING: Rural/periurban communities within the Kintampo Health Research Centre study area of the Brong-Ahafo Region of Ghana. PARTICIPANTS: 16,560 mothers who had a live singleton birth reported between 24 March 2008 and 11 July 2009, who were screened for probable postnatal depression (pPND) between 4 and 12 weeks post partum (some of whom had also had depression assessed at pregnancy), and whose infants survived to this point. PRIMARY/SECONDARY OUTCOME MEASURES: All-cause early infant mortality expressed per 1000 infant-months of follow-up from the time of postnatal assessment to 6 months of age. The secondary outcomes were (1) all-cause infant mortality from the time of postnatal assessment to 12 months of age and (2) reported infant morbidity from the time of the postnatal assessment to 12 months of age. RESULTS: 130 infant deaths were recorded and singletons were followed for 67,457.4 infant-months from the time of their mothers' postnatal depression assessment. pPND was associated with an almost threefold increased risk of mortality up to 6 months (adjusted rate ratio (RR), 2.86 (1.58 to 5.19); p=0.001). The RR up to 12 months was 1.88 (1.09 to 3.24; p=0.023). pPND was also associated with increased risk of infant morbidity. CONCLUSIONS: There is new evidence for the association between maternal pPND and infant mortality in low-income and middle-income countries. Implementation of the WHO's Mental Health Gap Action Programme (mhGAP) to scale up packages of care integrated with maternal health is encouraged as an important adjunct to child survival efforts