Laying the Groundwork for a National Impact Investing Marketplace

The practice of impact investing is rapidly gaining momentum, but the level of activity among individual and institutional investors, including philanthropists and foundations, has barely penetrated projections of market potential. The marketplace that should connect impact investors with investees or social ventures does not function effectively. Developing cost-effective ways to engage new investors and break down barriers to investment is an essential part of growing the industry. Developing cost-effective ways to “prime the pump” for social ventures to become investor-ready — through a capacity-building process that includes outreach, education, and technical assistance — is an essential part of growing the industry. The Impact Finance Center partnered with foundations and other investors in Colorado to create “CO Impact Days and Initiative” to demonstrate how to address this need for a more efficient and effective marketplace. CO Impact Days and Initiative was designed to expand regionally and be replicated

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

Lessons learnedTKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.BackgroundPolo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.MethodsA 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.ResultsThe study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.ConclusionTKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted

Barriers and facilitators to implementing dementia care mapping in care homes: results from the DCM™ EPIC trial process evaluation

Background Psychosocial person-centred interventions are considered best practice for addressing complex behaviours and care needs such as agitation and anxiety, and for improving the quality of life of people with dementia in care homes. Dementia Care Mapping (DCM™) is an established practice development tool and process aimed to help care home staff deliver more person-centred care. To date, few studies have evaluated the efficacy of DCM™ and have found mixed results. These results are suggested to be the outcome of intervention implementation, which may be impacted by a range of factors. This study reports the barriers and facilitators to DCM™ implementation in care homes found during the process evaluation conducted as part of a randomized controlled trial. Methods Eighteen of the 31 DCM™ intervention care homes were recruited to participate in the embedded process evaluation. Semi-structured interviews were conducted with 83 participants, comprising care home managers, trained DCM™ users (mappers), expert external mappers, staff members, relatives, and residents. Results Barriers and facilitators to DCM™ implementation were found at the mapper level (e.g. motivation and confidence), the DCM™ intervention level (e.g. understanding of DCM™) and the care home level (e.g. staffing issues, manager support). Further barriers caused by the burden of trial participation were also identified (e.g. additional paperwork). Conclusions Implementing DCM™ is complex and a greater consideration of potential barriers and facilitators in planning future studies and in practice could help improve implementation

Impact of Bordetella pertussis exposures on a Massachusetts tertiary care medical system

OBJECTIVE: To assess the impact of outbreaks of Bordetella pertussis infection on a tertiary care medical system. DESIGN: Retrospective study. SETTING: Academic tertiary care medical center and affiliated ambulatory care settings. SUBJECTS: All patients and healthcare workers (HCWs) who were in close contact with patients with laboratory-confirmed cases of B. pertussis infection from October 1, 2003, through September 30, 2004. INTERVENTION: Direct and indirect medical center costs were determined, including low and high estimates of time expended in the evaluation and management of exposed patients and HCWs during outbreak investigations of laboratory-confirmed cases of B. pertussis infection. RESULTS: During this period, 20 primary and 3 secondary laboratory-confirmed cases of B. pertussis infection occurred, with 2 primary pertussis cases and 1 secondary case occurring in HCWs. Outbreak investigations prompted screening of 353 medical center employees. Probable or definitive exposure was identified for 296 HCWs, and 287 subsequently received treatment or prophylaxis for B. pertussis infection. Direct medical center costs for treatment and prophylaxis were $13,416 and costs for personnel time were$19,500-$31,190. Indirect medical center costs for time lost from work were$51,300-$52,300. The total cost of these investigations was estimated to be$85,066-$98,456. CONCLUSIONS: Frequent B. pertussis exposures had a major impact on our facility. Given the impact of exposures on healthcare institutions, routine vaccination for HCWs may be beneficial

Effects of Dabigatran in Mouse Models of Aging and Cerebral Amyloid Angiopathy

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) (Tg N = 7; WT N = 10) or vehicle (Tg N = 9; WT N = 7) by gavage for 4 weeks. Anticoagulation effects of DE were confirmed using thrombin time assay. No mice experienced intracerebral hemorrhage. Cerebral microhemorrhage analysis, performed using Prussian-blue and H&E staining, showed no significant change in either number or size of cerebral microhemorrhage in DE-treated animals. Analysis of biochemical parameters for endothelial activation (ICAM-1), blood-brain barrier disruption (IgG, claudin-5, fibrinogen), microglial activation (Iba-1), or astrocyte activation (GFAP) showed neither exacerbation nor protective effects of DE in either Tg2576 or WT mice. Our study provides histological and biochemical evidence that aged mice, with or without predisposing factors for brain hemorrhage, tolerate anticoagulation with dabigatran. The absence of dabigatran-induced intracerebral hemorrhage or increased frequency of acute microhemorrhage may provide some reassurance for its use in high-risk patient populations

Mechanical load stimulates expression of novel genesin vivoandin vitroin avian flexor tendon cells

OBJECTIVE: Our experiments were designed to test the hypothesis that tendon cells might respond differently to applied strain in vitro than in vivo. DESIGN: We tested cells in whole tendons from exercised chickens and from isolated surface (TSC) and internal tendon (TIF) in vitro that were subjected to mechanical strain. We hypothesized that tendon cells differentially express genes in response to mechanical loading in vivo and in vitro. METHODS: We utilized an in-vivo exercise model in which chickens were run on a treadmill in an acute loading regime for 1 h 45 min with the balance of time at rest to 6 h total time. Gene expression was analyzed by a differential display technique. In addition, isolated avian flexor digitorum profundus TSC and TIF cells were subjected to cyclic stretching at 1 Hz, 5% average elongation for 6 h, +/- PDGF-BB, IGF-I, TGF-beta 1, PTH, estrogen, PGE2, or no drug and/or no load. mRNA was then collected and samples were subjected to differential display analysis. CONCLUSIONS: Load with or without growth factor and hormone treatments induced expression of novel genes as well as some known genes that were novel to tendon cells. We conclude that the study of gene expression in mechanically loaded cells in vivo and in vitro will lead to the discovery of novel and important marker proteins that may yield clues to positive and negative cell strain responses that are protective under one set of conditions and destructive under another

Height, adiposity and body fat distribution and breast density in young women

INTRODUCTION: Breast density is one of the strongest risk factors for breast cancer, but determinants of breast density in young women remain largely unknown. METHOD: Associations of height, adiposity and body fat distribution with percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) were evaluated in a cross-sectional study of 174 healthy women, 25-29 years old. Adiposity and body fat distribution were measured by anthropometry and dual-energy x-ray absorptiometry (DXA), while %DBV and ADBV were measured by magnetic resonance imaging (MRI). Associations were evaluated using linear mixed effects models. All tests of statistical significance are 2-sided. RESULTS: Height was significantly positively associated with %DBV but not ADBV; for each standard deviation (SD) increase in height, %DBV increased by 18.7% in adjusted models. In contrast, all measures of adiposity and body fat distribution were significantly inversely associated with %DBV; a SD increase in body mass index (BMI), percent fat mass, waist circumference and the android:gynoid fat mass ratio (A:G ratio) each was associated significantly with a 44.4% - 47.0% decrease in %DBV after adjustment for childhood BMI and other covariates. Although associations were weaker than for %DBV, all measures of adiposity and body fat distribution also were significantly inversely associated with ADBV before adjustment for childhood BMI. However, after adjustment for childhood BMI only the DXA measures percent fat mass and A:G ratio remained significant; a SD increase in each was associated with a 13.8% - 19.6% decrease in ADBV . In mutually adjusted analysis, percent fat mass and the A:G ratio remained significantly inversely associated with %DBV, but only the A:G ratio was significantly associated with ADBV; a SD increase in A:G ratio was associated with a 18.5% decrease in ADBV. CONCLUSIONS: Total adiposity and body fat distribution are independently inversely associated with %DBV, whereas in mutually adjusted analysis only body fat distribution (A:G ratio) remained significantly inversely associated with ADBV in young women. Research is needed to identify biological mechanisms underlying these associations

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

The implementation of Dementia Care MappingTM in a randomised controlled trial in long-term care: results of a process evaluation

This study explored intervention implementation within a pragmatic, cluster randomised controlled trial of Dementia Care MappingTM (DCM) in UK care homes. DCM is a practice development tool comprised of a five component cycle (staff briefing, mapping observations, data analysis and reporting, staff feedback, action planning) that supports delivery of person-centred care. Two staff from the 31 intervention care homes were trained in DCM and asked to deliver three cycles over a 15-month period, supported by a DCM expert during cycle 1. Implementation data were collected after each mapping cycle. There was considerable variability in DCM implementation fidelity, dose and reach. Not all homes trained two mappers on schedule and some found it difficult to retain mappers. Only 26% of homes completed more than one cycle. Future DCM trials in care home settings should consider additional methods to support intervention completion including intervention delivery being conducted with ongoing external support