Lessening the Impact of Opioid Misuse at a Federally Qualified Health Center in New York: Outcomes of an Integrated Workforce Training Program.

The COVID-19 pandemic has placed an unprecedented burden on patients, health care providers, and communities and has been particularly challenging for medically underserved populations impacted by the social determinants of health, as well as people with co-occurring mental health and substance use risks. This case study examines outcomes and lessons learned from a multisite low-threshold medication-assisted treatment (MAT) program at a federally qualified health center in partnership with a large suburban public university in New York to integrate and train Health Resources & Services Administration Behavioral Health Workforce Education and Training-funded graduate student trainees in social work and nursing in screening, brief intervention, and referral to treatment and patient care coordination, including social determinants of health and medical and behavioral comorbidities. The MAT program for the treatment of opioid use disorder has a low threshold for entry that is accessible and affordable, reduces barriers to care, and uses a harm reduction approach. Outcome data showed an average 70% retention rate in the MAT program and reductions in substance use. And, while more than 73% of patients reported being somewhat or definitely impacted by the pandemic, most patients endorsed the effectiveness of telemedicine and telebehavioral health, such that 86% indicated the pandemic did not affect the quality of their health care. The main implementation lessons learned were the importance of increasing the capacity of primary care and health care centers to deliver integrated care, using cross-disciplinary practicum experiences to enhance trainee competencies, and addressing the social determinants of health among populations with social vulnerabilities and chronic medical conditions.

Value-based payment, the safety net, and rethinking risk.

Safety-net providers can benefit from demonstrations of condition-specific and defined-scope-of-practice alternative payment models that account for the nonfinancial as well as financial risks that providers face.

Regulation of ADSC Osteoinductive Potential Using Notch Pathway Inhibition and Gene Rescue: A Potential On/Off Switch for Clinical Applications in Bone Formation and Reconstructive Efforts.

BACKGROUND: Although there has been tremendous research in the ability of mesenchymal-derived adipose derived stem cells (ADSCs) to form bone, less is known regarding the molecular mechanisms that regulate the osteogenic potential of ADSCs. Notch, which consists of a key family of regulatory ligands involved in bone formation, is expressed in the bone marrow-derived mesenchymal stem cell niche and is critical for proliferation, migration, and ultimately osseous differentiation. The authors investigate how Notch impacts ADSC proliferation and osteogenic differentiation to determine a translatable application of these cells in bone regeneration. METHODS: Enriched ADSC populations were isolated from tissue and examined for their ability to respond to Notch pathway signaling events. Proliferation, viability, extracellular matrix deposition, and osteoinduction were assessed following Notch activation and inhibition. Notch pathway rescue was conducted using a lentiviral vector encoding a downstream Notch-1 intracellular domain (NICD). RESULTS: Proliferation, osteogenic induction, and the ability to form bone elements were reduced following Notch inhibition (p < 0.05). However, ADSCs, while in the presence of the Notch inhibition, were able to be rescued following lentiviral transduction with NICD, restoring osteogenic potential at both the molecular and cellular functional levels (p < 0.05). CONCLUSIONS: These data suggest a potential translatable "on/off switch," using endogenous Notch signaling to regulate the proliferation, differentiation, and osteogenic potential of ADSCs. Although Notch inhibition reduced ADSC proliferation and down-regulated osteoinduction, targeted gene therapy and the delivery of the downstream NICD peptide restored bone formation, suggesting pragmatic clinical utility of ADSCs for bone regeneration.

Implementing value-based physician compensation: advice from early adopters.

Provider organizations that have experience in implementing value-based physician compensation can recommend the following best practices, among others: Clearly link changes in physician compensation to the broader strategic and financial objectives of the organization. Focus financial incentives on evidence-based measures that physicians find credible and achievable. Make sure everyone understands the incentive measures and compensation formulas before implementing changes. Provide complete data transparency for all aspects of performance.

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.

Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.

OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS: Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.

We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85ß), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.

Beyond bankable dollars: establishing a business case for improving health care.

To address widespread deficiencies in the quality of health care, the authors argue that health care organizations need to be able to make a "business case" for improving quality--a compelling rationale for financial investment in quality improvement programs. The authors' framework for such a business case is organized around three broad areas: direct financial considerations, strategic considerations, and internal organizational considerations. Within these categories, they offer a total of 10 specific business case arguments, with examples, for investing in quality improvement.