Territorial and Trans-Territorial Community-Institutional Partnerships to Build Healthier Communities in Developing Countries: Lessons Learned from a Dominican Republic Low-Resource Community

This descriptive case study examines the value of multi-level partnerships to foster a Building a Healthier Community (BHC) process in a low-resource community in the Dominican Republic. Partnerships developed for this BHC project were categorized under the Global Health Education Framework. Partners included a U.S-based university (trans-territorial partnership), a Dominican university, and various governmental, non-governmental, and community organizations in the Dominican Republic (territorial partnerships). Las Malvinas BHC project is an interdisciplinary and holistic approach to community health and well-being improvement that supports community members’ efforts and at the same time promotes participating students’ global health competence. Strategies, methods, the value of community-institutional partnerships, lessons learned, challenges and opportunities are discussed. Partnerships facilitated identification of public health priorities and strategies to improve community’s health and well-being. Lessons learned included the importance of engaging community member’s voices and talents, the value of building relationships based on trust, the relevance of community capacity building, the role of the government in achieving outcomes in a low-resource context, and the importance of incorporating community assets in the process. Important challenges included a continuous availability of governmental funds and resources, community members’ time constraints and changes in community structure. Opportunities included the value of partnerships in promoting the exchange of assets, theories, and innovation in order to identify and begin remedying social determinants of health affecting Las Malvinas. Process outcomes resulting from this project demonstrate the value of mutually beneficial community-based participatory research and intervention alliances at the territorial and trans-territorial dimensions

Factors affecting continuation of clean intermittent catheterisation in people with multiple sclerosis: results of the COSMOS mixed-methods study

Background:  Clean intermittent catheterisation (CIC) is often recommended for people with multiple sclerosis (MS).  Objective:  To determine the variables that affect continuation or discontinuation of the use of CIC.  Methods:  A three-part mixed-method study (prospective longitudinal cohort (n = 56), longitudinal qualitative interviews (n = 20) and retrospective survey (n = 456)) was undertaken, which identified the variables that influenced CIC continuation/discontinuation. The potential explanatory variables investigated in each study were the individual’s age, gender, social circumstances, number of urinary tract infections, bladder symptoms, presence of co-morbidity, stage of multiple sclerosis and years since diagnosis, as well as CIC teaching method and intensity.  Results:  For some people with MS the prospect of undertaking CIC is difficult and may take a period of time to accept before beginning the process of using CIC. Ongoing support from clinicians, support at home and a perceived improvement in symptoms such as nocturia were positive predictors of continuation. In many cases, the development of a urinary tract infection during the early stages of CIC use had a significant detrimental impact on continuation.  Conclusion:  Procedures for reducing the incidence of urinary tract infection during the learning period (i.e. when being taught and becoming competent) should be considered, as well as the development of a tool to aid identification of a person’s readiness to try CIC

A lytic bacteriophage isolate reduced Clostridium perfringens induced lesions in necrotic enteritis challenged broilers

Background Bacteriophages are viral predators of bacteria and are common in nature. Their host-specific infections against specific bacteria make them an attractive natural agent to control bacterial pathogens. Interest in the potential of bacteriophages as antibacterial agents in the production animal industries has increased. Methods A total of 18 bacteriophages were isolated from Australian commercial poultry environments, from which three highly active phages were chosen for enrichment. Sequencing libraries were prepared using a Nextera XT kit (Illumina) and sequenced on an Illumina MiSeq instrument using 2 × 300 bp paired-end chemistry. The sequence data were then assembled and aligned with a2 bacteriophage as the reference. An animal trial was performed by oral gavaging Clostridium perfringens netB containing strain EHE-NE18 to the Ross 308 broiler chickens prior inoculation with Eimeria species. The chickens were raised following the management guide for Ross 308 from d 0 to d 21 and fed with starter and grower diets met the specific breed nutrient requirements. Body weight gain and feed intake were measured on d 9 and d 21 and FCR adjusted with mortality was calculated. Results The isolated bacteriophages only had only 96.7% similarity to the most closely related, previously characterized, Clostridium bacteriophage indicated that they might represent a novel strain of bacteriophage. A “cocktail” containing the three bacteriophages was capable of lysing four known disease-inducing C. perfringens strains in vitro. Oral administration of the bacteriophages cocktail to broilers challenged with necrotic enteritis markedly alleviated intestinal necrotic lesions in the duodenum and jejunum on day 16 post-hatch. The phage treatment significantly reduced the lesion scores of birds challenged with NE (P 0.05). However, no effect on the growth performance was observed during the recorded period of days 9-21. Conclusion These findings suggest that bacteriophage treatment is a promising approach to protect intestinal health from C. perfringens induced necrotic enteritis. Further research will be required on the dosing, route of administration, and large scale validation studies to further advance this approach to pathogen control

Science Communication Demands a Critical Approach That Centers Inclusion, Equity, and Intersectionality

We live in an era of abundant scientific information, yet access to information and to opportunities for substantive public engagement with the processes and outcomes of science are still inequitably distributed. Even with increasing interest in science communication and public engagement with science, historically marginalized and minoritized individuals and communities are largely overlooked and undervalued in these efforts. To address this gap, this paper aims to define inclusive science communication and clarify and amplify the field. We present inclusive science communication as one path forward to redress the systemic problems of inequitable access to and engagement with STEMM (science, technology, engineering, mathematics, and medicine). We describe the first national Inclusive Science Communication (InclusiveSciComm) Symposium held in the U.S. Based on the experience of organizing the symposium, we discuss recommendations for other convenings to help build a community of practice for inclusive science communication. In both research and practice, we advocate for more experimentation to help make inclusive science communication the future of science communication writ large, in order to engage diverse publics in their multiple ways of knowing and expand a sense of belonging in STEMM

LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle

Mutations in the human LMNA gene, encoding A-type lamins, give rise to laminopathies, which include several types of muscular dystrophy. Here, heterozygous sequence variants in LMNA, which result in single amino-acid substitutions, were identified in patients exhibiting muscle weakness. To assess whether the substitutions altered lamin function, we performed in vivo analyses using a Drosophila model. Stocks were generated that expressed mutant forms of the Drosophila A-type lamin modeled after each variant. Larvae were used for motility assays and histochemical staining of the body-wall muscle. In parallel, immunohistochemical analyses were performed on human muscle biopsy samples from the patients. In control flies, muscle-specific expression of the wild-type A-type lamin had no apparent affect. In contrast, expression of the mutant A-type lamins caused dominant larval muscle defects and semi-lethality at the pupal stage. Histochemical staining of larval body wall muscle revealed that the mutant A-type lamin, B-type lamins, the Sad1p, UNC-84 domain protein Klaroid and nuclear pore complex proteins were mislocalized to the cytoplasm. In addition, cytoplasmic actin filaments were disorganized, suggesting links between the nuclear lamina and the cytoskeleton were disrupted. Muscle biopsies from the patients showed dystrophic histopathology and architectural abnormalities similar to the Drosophila larvae, including cytoplasmic distribution of nuclear envelope proteins. These data provide evidence that the Drosophila model can be used to assess the function of novel LMNA mutations and support the idea that loss of cellular compartmentalization of nuclear proteins contributes to muscle disease pathogenesis

The effect of early versus late treatment initiation after diagnosis on the outcomes of patients treated for multidrug-resistant tuberculosis: a systematic review.

BACKGROUND: Globally it is estimated that 480 000 people developed multidrug-resistant tuberculosis (MDR-TB) in 2014 and 190 000 people died from the disease. Successful treatment outcomes are achieved in only 50 % of patients with MDR-TB, compared to 86 % for drug susceptible disease. It is widely held that delay in time to initiation of treatment for MDR-TB is an important predictor of treatment outcome. The objective of this review was to assess the existing evidence on the outcomes of multidrug- and extensively drug-resistant tuberculosis patients treated early (≤4 weeks) versus late (>4 weeks) after diagnosis of drug resistance. METHODS: Eight sources providing access to 17 globally representative electronic health care databases, indexes, sources of evidence-based reviews and grey literature were searched using terms incorporating time to treatment and MDR-TB. Two-stage sifting in duplicate was employed to assess studies against pre-specified inclusion and exclusion criteria. Only those articles reporting WHO-defined treatment outcomes were considered for inclusion. Articles reporting on fewer than 10 patients, published before 1990, or without a comparison of outcomes in patient groups experiencing different delays to treatment initiation were excluded. RESULTS: The initial search yielded 1978 references, of which 1475 unique references remained after removal of duplicates and 28 articles published pre-1990. After title and abstract sifting, 64 papers underwent full text review. None of these articles fulfilled the criteria for inclusion in the review. CONCLUSIONS: Whilst there is an inherent logic in the theory that treatment delay will lead to poorer treatment outcomes, no published evidence was identified in this systematic review to support this hypothesis. Reports of programmatic changes leading to reductions in treatment delay exist in the literature, but attribution of differences in outcomes specifically to treatment delay is confounded by other contemporaneous changes. Further primary research on this question is not considered a high priority use of limited resources, though where data are available, improved reporting of outcomes by time to treatment should be encouraged

CDK-dependent nuclear localization of B-Cyclin Clb1 promotes FEAR activation during meiosis I in budding yeast

Cyclin-dependent kinases (CDK) are master regulators of the cell cycle in eukaryotes. CDK activity is regulated by the presence, post-translational modification and spatial localization of its regulatory subunit cyclin. In budding yeast, the B-cyclin Clb1 is phosphorylated and localizes to the nucleus during meiosis I. However the functional significance of Clb1's phosphorylation and nuclear localization and their mutual dependency is unknown. In this paper, we demonstrate that meiosis-specific phosphorylation of Clb1 requires its import to the nucleus but not vice versa. While Clb1 phosphorylation is dependent on activity of both CDK and polo-like kinase Cdc5, its nuclear localization requires CDK but not Cdc5 activity. Furthermore we show that increased nuclear localization of Clb1 during meiosis enhances activation of FEAR (Cdc Fourteen Early Anaphase Release) pathway. We discuss the significance of our results in relation to regulation of exit from meiosis I

Severe Sepsis: Variation in Resource and Therapeutic Modality use Among Academic Centers

Background: Treatment of severe sepsis is expensive, often encompassing a number of discretionary modalities. The objective of the present study was to assess intercenter variation in resource and therapeutic modality use in patients with severe sepsis. Methods: We conducted a prospective cohort study of 1028 adult admissions with severe sepsis from a stratified random sample of patients admitted to eight academic tertiary care centers. The main outcome measures were length of stay (LOS; total LOS and LOS after onset of severe sepsis) and total hospital charges. Results: The adjusted mean total hospital charges varied from $69 429 to US$237 898 across centers, whereas the adjusted LOS after onset varied from 15.9 days to 24.2 days per admission. Treatments used frequently after the first onset of sepsis among patients with severe sepsis were pulmonary artery catheters (19.4%), ventilator support (21.8%), pressor support (45.8%) and albumin infusion (14.4%). Pulmonary artery catheter use, ventilator support and albumin infusion had moderate variation profiles, varying 3.2-fold to 4.9-fold, whereas the rate of pressor support varied only 1.92-fold across centers. Even after adjusting for age, sex, Charlson comorbidity score, discharge diagnosis-relative group weight, organ dysfunction and service at onset, the odds for using these therapeutic modalities still varied significantly across centers. Failure to start antibiotics within 24 hours was strongly correlated with a higher probability of 28-day mortality (r2 = 0.72). Conclusion: These data demonstrate moderate but significant variation in resource use and use of technologies in treatment of severe sepsis among academic centers. Delay in antibiotic therapy was associated with worse outcome at the center level

CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation

Particulate ligands including cholesterol crystals and amyloid fibrils induce NLRP3-dependent production of interleukin-1β (IL-1β) in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands including oxidized-LDL, amyloid-β and amylin peptides accumulate in these diseases. Here we identify a CD36-mediated endocytic pathway that coordinates the intracellular conversion of these soluble ligands to crystals or fibrils, resulting in lysosomal disruption and NLRP3-inflammasome activation. Consequently, macrophages lacking CD36 failed to elicit IL-1β production in response to these ligands and targeting CD36 in atherosclerotic mice reduced serum IL-1β and plaque cholesterol crystal accumulation. Collectively, these findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation