Validation of a zebrafish developmental defects assay as a qualified alternative test for its regulatory use following the ICH S5(R3) guideline.

Zebrafish is a popular toxicology model and provides an ethically acceptable small-scale analysis system with the complexity of a complete organism. Our goal is to further validate this model for its regulatory use for reproductive and developmental defects by testing the compounds indicated in the "Guideline on detection of reproductive and developmental toxicity for human pharmaceuticals" (ICH S5(R3) guideline.) To determine the embryotoxic and developmental risk of the 32 reference compounds listed in the ICH S5(R3) guideline, the presence of morphological alterations in zebrafish embryos was analyzed at two different stages to calculateLC50 and EC50 values for each stage. Teratogenic Indexes were established as the ratio between LC50 and EC50 critical for the proper compound classification as teratogenic when it is ≥ 2. A total of three biological replicates have been conducted to study the reproducibility of the assay. The chemicals' concentration in the medium and internally in the zebrafish embryos was evaluated. In this study, the 3 negative compounds were properly categorized while 23 compounds out of the 29 reference ones (sensitivity of 79.31%) were classified as teratogenic in zebrafish. The 6 that had false-negative results were classified 4 as inconclusive, 1 as not toxic, and 1 compound resulted toxic for zebrafish embryos under testing conditions. After the bioavailability experiments, some of the obtained inconclusive results were refined. The developmental defects assay in zebrafish gives an accuracy of 89.66%, sensitivity of 88.46%, specificity and repeatability of 100% compared to mammals; therefore, this is a well-integrated strategy using New Alternative Methods, to minimize the use of animals in developmental toxicity studies.

Pilot testing of the Becoming Breastfeeding Friendly toolbox in Ghana.

BACKGROUND: Ghana has achieved significant progress in breastfeeding practices in the past two decades. Further progress is, however, limited by insufficient government funding and declining donor support for breastfeeding programs. The current study pretested feasibility of the Becoming Breastfeeding Friendly (BBF) toolbox in Ghana, to assess the existing enabling environment and gaps for scaling-up effective actions. METHODS: Between June 2016 and April 2017, a 15-person expert country committee drawn from government and non-government agencies was established to implement the BBF toolbox. The committee used the BBF index (BBFI), comprising of 54 benchmarks and eight gears of the Breastfeeding Gear Model (advocacy; political will; legislation and policy; funding and resources; training and program delivery; promotion; research and evaluation; and coordination, goals and monitoring). Available evidence (document reviews, and key informant interviews) was used to arrive at consensus-scoring of benchmarks. Benchmark scores ranged between 0 (no progress) and 3 (major progress). Scores for each gear were averaged to estimate the Gear Total Score (GTS), ranging from 0 (least) to 3.0 (strong). GTS's were aggregated as a weighted average to estimate the BBFI which ranged from 0 (weak) to 3.0 (outstanding). Gaps in policy and program implementation and recommendations were proposed for decision-making. RESULTS: The BBFI score was 2.0, indicating a moderate scaling-up environment for breastfeeding in Ghana. Four gears recorded strong gear strength: advocacy (2.3); political will (2.3); legislation and policy (2.3); and coordination, goals and monitoring (2.7). The remaining four gears had moderate gear strength: funding and resources (1.3); training and program delivery (1.9); promotion (2.0); and research and evaluation (1.3). Key policy and program gaps identified by the committee included sub-optimal coordination across partners, inadequate coverage and quality of services, insufficient government funding, sub-optimal enforcement of policies, and inadequate monitoring of existing initiatives. Prioritized recommendations from the process were: 1) strengthen advocacy and empower breastfeeding champions, 2) strengthen breastfeeding regulations, including maternity protection, 3) strengthen capacity for providing breastfeeding services, and 4) expand and sustain breastfeeding awareness initiatives. CONCLUSIONS: The moderate environment for scaling-up breastfeeding in Ghana can be further strengthened by addressing identified gaps in policy and programs.

Exercise-based cardiac rehabilitation in twelve European countries results of the European cardiac rehabilitation registry.

AIM: Results from EuroCaReD study should serve as a benchmark to improve guideline adherence and treatment quality of cardiac rehabilitation (CR) in Europe. METHODS AND RESULTS: Data from 2.054 CR patients in 12 European countries were derived from 69 centres. 76% were male. Indication for CR differed between countries being predominantly ACS in Switzerland (79%), Portugal (62%) and Germany (61%), elective PCI in Greece (37%), Austria (36%) and Spain (32%), and CABG in Croatia and Russia (36%). A minority of patients presented with chronic heart failure (4%). At CR start, most patients already were under medication according to current guidelines for the treatment of CV risk factors. A wide range of CR programme designs was found (duration 3 to 24weeks; total number of sessions 30 to 196). Patient programme adherence after admission was high (85%). With reservations that eCRF follow-up data exchange remained incomplete, patient CV risk profiles experienced only small improvements. CR success as defined by an increase of exercise capacity >25W was significantly higher in young patients and those who were employed. Results differed by countries. After CR only 9% of patients were admitted to a structured post-CR programme. CONCLUSIONS: Clinical characteristics of CR patients, indications and programmes in Europe are different. Guideline adherence is poor. Thus, patient selection and CR programme designs should become more evidence-based. Routine eCRF documentation of CR results throughout European countries was not sufficient in its first application because of incomplete data exchange. Therefore better adherence of CR centres to minimal routine clinical standards is requested.

Benchmarking Outpatient Rehabilitation Clinics Using Functional Status Outcomes.

OBJECTIVE: To utilize functional status (FS) outcomes to benchmark outpatient therapy clinics. DATA SOURCES: Outpatient therapy data from clinics using Focus on Therapeutic Outcomes (FOTO) assessments. STUDY DESIGN: Retrospective analysis of 538 clinics, involving 2,040 therapists and 90,392 patients admitted July 2006-June 2008. FS at discharge was modeled using hierarchical regression methods with patients nested within therapists within clinics. Separate models were estimated for all patients, for those with lumbar, and for those with shoulder impairments. All models risk-adjusted for intake FS, age, gender, onset, surgery count, functional comorbidity index, fear-avoidance level, and payer type. Inverse probability weighting adjusted for censoring. DATA COLLECTION METHODS: Functional status was captured using computer adaptive testing at intake and at discharge. PRINCIPAL FINDINGS: Clinic and therapist effects explained 11.6 percent of variation in FS. Clinics ranked in the lowest quartile had significantly different outcomes than those in the highest quartile (p < .01). Clinics ranked similarly in lumbar and shoulder impairments (correlation = 0.54), but some clinics ranked in the highest quintile for one condition and in the lowest for the other. CONCLUSIONS: Benchmarking models based on validated FS measures clearly separated high-quality from low-quality clinics, and they could be used to inform value-based-payment policies.