Metastatic cells are preferentially vulnerable to lysosomal inhibition.

Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A1, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A1 were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts. Genetic inactivation of macroautophagy regulators and lysosomal proteins indicated that this was due to greater reliance on the lysosome but not upon macroautophagy. To identify the mechanism underlying these effects, we generated cells resistant to CQ in vitro. Surprisingly, selection for in vitro CQ resistance was sufficient to alter gene expression patterns such that unsupervised cluster analysis of whole-transcriptome data indicated that selection for CQ resistance alone created tumor cells that were more similar to the poorly metastatic parental cells from which the metastatic cells were derived; importantly, these tumor cells also had diminished metastatic ability in vivo. These effects were mediated in part by differential expression of the transcriptional regulator ID4 (inhibitor of DNA binding 4); depletion of ID4 both promoted in vitro CQ sensitivity and restored lung colonization and metastasis of CQ-resistant cells. These data demonstrate that selection for metastasis ability confers selective vulnerability to lysosomal inhibitors and identify ID4 as a potential biomarker for the use of lysosomal inhibitors to reduce metastasis in patients.

The impact of interpersonal support, supervisory support, and employee engagement on employee turnover intentions: Differences between financially distressed and highly financially distressed hospitals.

BACKGROUND: Critical access hospitals (CAHs) are small hospitals in rural communities in the United States. Because of changes in rural population demographics, legacy financial obligations, and/or structural issues in the U.S. health care system, many of these institutions are financially distressed. Indeed, many have closed due to their inability to maintain financial viability, resulting in a health care and economic crisis for their communities. Employee recruitment, retention, and turnover are critical to the performance of these hospitals. There is limited empirical study of the factors that influence turnover in such institutions. PURPOSE: The primary purpose of the study was to study relationships between interpersonal support, supervisory support, employee engagement, and employee turnover intentions in CAHs. A secondary purpose was to study how financial distress affects these relationships. METHODOLOGY: Based on a survey of CAH employees (n = 218), the article utilizes mediated moderation analysis of a structural equation model. RESULTS: Interpersonal support and supervisory support are positively associated with employee engagement, whereas employee engagement mediates the relationships between both interpersonal support and supervisory support and employee turnover intentions. Statistically significant differences are found between these relationships in financially distressed and highly financially distressed institutions. CONCLUSIONS: Our results are consistent with the social exchange theory upon which our hypotheses and model are built and demonstrate the value of using the degree of organizational financial distress as a contextual variable when studying motivational factors influencing employee turnover intentions. PRACTICAL IMPLICATIONS: In addition to advancing management theory as applied in the CAH context, our study presents the practical insight that employee perceptions of their employer's financial condition should be considered when organizations develop employee retention strategies. Specifically, employee engagement strategies appear to be of greater value in the case of highly financially distressed organizations, whereas supervisory support seems more effective in financially distressed organizations.

Discovery and characterization of small molecules that target the GTPase Ral.

The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and (1)H-(15)N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.

Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice.

Amylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl-/-) mouse that recapitulates biochemical and histological features of GSDIII. Agl-/- mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl-/- mice had 19 differentially expressed genes compared with control mice. An 'Agl Loss' gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers.

Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series.

BACKGROUND: Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. METHODS: We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline. Complete remission was defined as a UPCR < 0.3 g/g. Secondary outcomes were serious adverse events and the change in proteinuria, serum creatinine, serum albumin, cholesterol, triglycerides, and immunoglobulin G levels after 1 year of treatment. RESULTS: Over a median follow-up time of 37 (IQR, 34-44) months, 100% of patients achieved partial remission and 93% of patients achieved complete remission at a median time of 2 and 13 months, respectively. After 1 year of treatment, median (IQR) UPCR declined from 8.2 (6.6-11.1) to 0.3 (0.2-0.7) g/g (P < 0.001). Three serious adverse events occurred over 51 patient years. No patients died or progressed to ESKD. CONCLUSIONS: Treatment of idiopathic membranous nephropathy with RCP resulted in high rates of complete remission. Larger studies evaluating this regimen are warranted.

A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors.

There are two distinct forms of urothelial (bladder) cancer: muscle-invasive (MI) and nonmuscle invasive (NMI) disease. Since it is currently believed that bladder cancer arises by transformation of urothelial cells of the basal layer, bladder cancer stem cells (CSCs) have been isolated based on expression markers found in such cells. However, these CSCs have only been identified in MI tumors raising the intriguing hypothesis that NMI tumor progenitors do not arise from the basal compartment. To test this hypothesis, we carried out genome-wide expression profiling of laser capture microdissected basal and umbrella cells, the two most histologically distinct cell types in normal urothelium and developed a cell of origin (COO) gene signature that distinguishes these. The COO signature was a better predictor of stage and survival than other bladder, generic, or breast CSC signatures and bladder cell differentiation markers in multiple patient cohorts. To assess whether NMI and MI tumors arise from a distinct progenitor cell (DPC) or common progenitor cell, we developed a novel statistical framework that predicts COO score as a function of known genetic alterations (TP53, HRAS, KDM6A, and FGFR3) that drive either MI or NMI bladder cancer and compared this to the observed COO score of the tumor. Analysis of 874 patients in five cohorts established the DPC model as the best fit to the available data. This observation supports distinct progenitor cells in NMI and MI tumors and provides a paradigm shift in our understanding of bladder cancer biology that has significant diagnostic and therapeutic implications.

Efficacy and safety of flow-directed pulmonary artery catheter thrombolysis for treatment of submassive pulmonary embolism.

OBJECTIVE: The purpose of this study was to assess the efficacy and safety of flow-directed catheter thrombolysis for treatment of submassive pulmonary embolism (PE). MATERIALS AND METHODS: In this single-institution retrospective study, 19 patients (nine men and 10 women; mean age [± SD], 54 ± 13 years) with submassive PE underwent catheter-directed thrombolysis between 2009 and 2013. Presenting symptoms included dyspnea in 18 of 19 (95%) cases. Submassive PE was diagnosed by pulmonary CT arteriography and right ventricular strain. PE was bilateral in 17 of 19 (89%) and unilateral in two of 19 (11%) cases. Thrombolysis was performed via a pulmonary artery (PA) catheter infusing 0.5- 1.0 mg alteplase per hour and was continued to complete or near complete clot dissolution with reduction in PA pressure. IV systemic heparin was administered. Measured outcomes included procedural success, PA pressure reduction, clinical success, survival, and adverse events. RESULTS: Procedural success, defined as successful PA catheter placement, fibrinolytic agent delivery, PA pressure reduction, and achievement of complete or near complete clot dissolution, was achieved in 18 of 19 (95%) cases. Thrombolysis required 57 ± 31 mg of alteplase administered over 89 ± 32 hours. Initial and final PA pressures were 30 ± 10 mm Hg and 20 ± 8 mm Hg (p < 0.001). All 18 (100%) technically successful cases achieved clinical success because all patients experienced symptomatic improvement. Eighteen of 19 (95%) patients survived to hospital discharge; 18 of 19 (95%) and 15 of 16 (94%) patients had documented 1-month and 3-month survival. One fatal case of intracranial hemorrhage was attributed to supratherapeutic anticoagulation because normal fibrinogen levels did not suggest remote fibrinolysis; procedural success was not achieved in this case because of early thrombolysis termination. No other complications were encountered. CONCLUSION: Among a small patient cohort, flow-directed catheter thrombolysis with alteplase effectively dissolved submassive PE and reduced PA pressure. Postprocedure short-term survival was high, and patients undergoing thrombolysis required close observation for bleeding events.

Examining the relationship between rural residents' satisfaction with local hospital's COVID-19 response and intention to use the hospital.

PURPOSE: The COVID-19 pandemic highlighted the importance of having emergency and acute care services close to home and emerged as an opportunity for hospital-community engagement. This study examined whether rural residents' satisfaction with their local hospital's pandemic response was associated with improved community perception of the hospital and an intention to use it in the future. METHODS: Data for the study were obtained from a survey of rural residents of 6 Georgia rural communities and analyzed using multivariable logistic regression and mediation analyses. RESULTS: Rural residents' satisfaction with their local hospital's pandemic response was associated with an improved perception of the hospital. Improvement in the perception of rural hospitals following the pandemic was found to partially mediate a positive association between community residents' satisfaction with hospital pandemic response and the intention to use the hospital when needed. CONCLUSION: The COVID-response efforts may have given rural hospitals an opportunity to influence public perception.

Transcatheter embolotherapy for gastrointestinal bleeding: a single center review of safety, efficacy, and clinical outcomes.

PURPOSE: The purpose of this study was to assess safety, efficacy, and clinical outcomes following transcatheter arterial embolization (TAE) of acute gastrointestinal (GI) bleeding. MATERIALS AND METHODS: Ninety-five patients (male:female ratio = 53:42, mean age 62 years) that underwent 95 TAEs for GI hemorrhage between 2002 and 2010 were retrospectively studied. Seventy-six of 95 (80 %) patients had upper GI bleeds and 19/95 (20 %) patients had lower GI bleeds. A mean of 7 (range 0-27) packed red blood cell units were transfused pre-procedure, and 90/95 (95 %) procedures were urgent or emergent. Twenty-seven of 95 (28 %) patients were hemodynamically unstable. Measured outcomes included procedure technical success, adverse events, and 30-day rebleeding and mortality rates. RESULTS: Bleeding etiology included peptic ulcer disease (45/95, 47 %), cancer (14/95, 15 %), diverticulosis (13/95, 14 %), and other (23/95, 24 %). Vessels embolized (n = 109) included gastroduodenal (42/109, 39 %), pancreaticoduodenal (22/109, 20 %), gastric (21/109, 19 %), superior mesenteric (12/109, 11 %), inferior mesenteric (8/109, 7 %), and splenic (4/109, 4 %) artery branches. Technical success with immediate hemostasis was achieved in 93/95 (98 %) cases. Most common embolic agents included coils (66/109, 61 %) and/or gelatin sponge (19/109, 17 %). Targeted versus empiric embolization were performed in 57/95 (60 %) and 38/95 (40 %) cases, respectively. Complications included bowel ischemia (4/95, 4 %) and coil migration in 3/95 (3 %). 30-day rebleeding rate was 23 % (22/95). Overall 30-day mortality rate was 18 % (16/89). Empiric embolization resulted in similar rebleeding (23 vs 24 %) but higher mortality (31 vs 9 %) rates compared to embolization for active extravasation. CONCLUSIONS: TAE controlled GI bleeding with high technical success, safety, and efficacy, and should be considered when endoscopic therapy is not feasible or unsuccessful.

TIPS for treatment of variceal hemorrhage: clinical outcomes in 128 patients at a single institution over a 12-year period.

PURPOSE: To assess clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) treatment of variceal hemorrhage. MATERIALS AND METHODS: A total of 128 patients (82 men and 46 women; mean age, 52 y) with liver cirrhosis and refractory variceal hemorrhage underwent TIPS creation from 1998 to 2010. Mean Child-Pugh and Model for End-stage Liver Disease (MELD) scores were 9 and 18, respectively. From 1998 to 2004, 12-mm Wallstents (n = 58) were used, whereas from 2004 to 2010, 10-mm VIATORR covered stent-grafts (n = 70) were used. Technical success, hemodynamic success, complications, shunt dysfunction, recurrent bleeding, and overall survival were assessed. RESULTS: Technical and hemodynamic success rates were 100% and 94%, respectively. Mean portosystemic gradient reduction was 13 mm Hg. Complications at 30 days included encephalopathy (14%), renal failure (5.5%), infection (1.6%), and liver failure (0.8%). Shunt patency rates were 93%, 82%, and 60% at 30 days, 1 year, and 2 years, respectively. Dysfunction, or loss of TIPS primary patency, occurred more with Wallstent versus VIATORR TIPSs (29% vs 11%; P = .009). Recurrent bleeding incidences were 9%, 22%, and 29% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (19% vs 19%; P = .924). Variceal embolization significantly reduced recurrent bleeding rates (5% vs 25%; P = .013). Overall survival rates were 80%, 69%, and 65% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (35% vs 26% mortality rate; P = .312). Advanced MELD score was associated with increased mortality on multivariate analysis. CONCLUSIONS: Wallstent and VIATORR TIPSs effectively treat variceal hemorrhage, particularly when accompanied by variceal embolization. Although TIPS with a VIATORR device showed improved shunt patency, patient survival is similar to that with Wallstent TIPS. These results further validate TIPS creation for refractory variceal bleeding.

State Expectations and Medicaid Managed Care Organizations' Efforts to Address the Social Needs of Medicaid Enrollees.

Existing work on states' efforts to address the social needs of Medicaid enrollees indicate the implementation of several state-level strategies to move Medicaid Managed Care Organizations (MMCOs) toward the provision of whole-person care. However, less is known about how these expectations drive MMCOs' SDOH efforts. To address this gap, we interviewed representatives of eight MMCOs (N=28) and 12 state Medicaid offices (N=17). Participants described varying state-implemented instruments for encouraging an SDOH-focus among MMCOs, including both coercive (e.g., contractual mandates) and subtle approaches (e.g., request for proposal process and performance measurement expectations). However, regardless of states' expectations, MMCOs, driven by organizational and industry-related factors, recognized the importance of addressing SDOH as part of a holistic approach to health care. Collectively, regulatory pressures, organizational strategy, and market forces influenced MMCOs' efforts to address SDOH leading to a normalization of their role in addressing members' social needs within a medical paradigm.

COVID-19 and social determinants of health: Medicaid managed care organizations' experiences with addressing member social needs.

BACKGROUND: The significant adverse social and economic impact of the COVID-19 pandemic has cast broader light on the importance of addressing social determinants of health (SDOH). Medicaid Managed Care Organizations (MMCOs) have increasingly taken on a leadership role in integrating medical and social services for Medicaid members. However, the experiences of MMCOs in addressing member social needs during the pandemic has not yet been examined. AIM: The purpose of this study was to describe MMCOs' experiences with addressing the social needs of Medicaid members during the COVID-19 pandemic. METHODS: The study was a qualitative study using data from 28 semi-structured interviews with representatives from 14 MMCOs, including state-specific markets of eight national and regional managed care organizations. Data were analyzed using thematic analysis. RESULTS: Four themes emerged: the impact of the pandemic, SDOH response efforts, an expanding definition of SDOH, and managed care beyond COVID-19. Specifically, participants discussed the impact of the pandemic on enrollees, communities, and healthcare delivery, and detailed their evolving efforts to address member nonmedical needs during the pandemic. They reported an increased demand for social services coupled with a significant retraction of community social service resources. To address these emerging social service gaps, participants described mounting a prompt and adaptable response that was facilitated by strong existing relationships with community partners. CONCLUSION: Among MMCOs, the COVID-19 pandemic has emphasized the importance of addressing member social needs, and the need for broader consideration of what constitutes SDOH from a healthcare delivery standpoint.

Addressing the Social Needs of Medicaid Enrollees Through Managed Care: Lessons and Promising Practices from the Field.

With growing recognition of the adverse health impacts of unmet social needs, Medicaid managed care organizations (MMCOs) are increasingly focusing on addressing the social needs of Medicaid enrollees as part of a holistic approach to care. Information and knowledge sharing among MMCOs pertaining to lessons learned and promising practices from their social determinants of health (SDOH) targeted efforts can help identify successful practical approaches for navigating common challenges, developing robust SDOH programming, and effectively delivering whole-person care. Using data from interviews with 28 representatives of 8 national and regional MMCOs, this qualitative study describes the perspectives of MMCO representatives on the lessons learned and emerging promising practices from addressing SDOH among their Medicaid enrollees. Participants discussed the importance of member and community-centeredness, structured programming, and delivery system realignment in the effective delivery of whole person care. Ten lessons learned and emerging promising practices are discussed. Findings from this study suggest that success in addressing the social needs of Medicaid beneficiaries may be achieved through adaptive, data-driven, member- and community-centric efforts by MMCOs, facilitated by system-level changes that formally integrate social services within health care. Lessons learned and promising practices can serve as a foundation for identifying and evaluating best practices and guidelines for effective MMCOs' SDOH-related programming.

Targeted Long-Read Bisulfite Sequencing Identifies Differences in the TERT Promoter Methylation Profiles between TERT Wild-Type and TERT Mutant Cancer Cells.

Background: TERT promoter methylation, located several hundred base pairs upstream of the transcriptional start site, is cancer specific and correlates with increased TERT mRNA expression and poorer patient outcome. Promoter methylation, however, is not mutually exclusive to TERT activating genetic alterations, as predicted for functionally redundant mechanisms. To annotate the altered patterns of TERT promoter methylation and their relationship with gene expression, we applied a Pacific Biosciences-based, long-read, bisulfite-sequencing technology and compared the differences in the methylation marks between wild-type and mutant cancers in an allele-specific manner. Results: We cataloged TERT genetic alterations (i.e., promoter point mutations or structural variations), allele-specific promoter methylation patterns, and allele-specific expression levels in a cohort of 54 cancer cell lines. In heterozygous mutant cell lines, the mutant alleles were significantly less methylated than their silent, mutation-free alleles (p < 0.05). In wild-type cell lines, by contrast, both epialleles were equally methylated to high levels at the TERT distal promoter, but differentially methylated in the proximal regions. ChIP analysis showed that epialleles with the hypomethylated proximal and core promoter were enriched in the active histone mark H3K4me2/3, whereas epialleles that were methylated in those regions were enriched in the repressive histone mark H3K27me3. Decitabine therapy induced biallelic expression in the wild-type cancer cells, whereas the mutant cell lines were unaffected. Conclusions: Long-read bisulfite sequencing analysis revealed differences in the methylation profiles and responses to demethylating agents between TERT wild-type and genetically altered cancer cell lines. The causal relation between TERT promoter methylation and gene expression remains to be established.

Comprehensive review of TIPS technical complications and how to avoid them.

OBJECTIVE: The goal of this article is to describe potential technical complications related to transjugular intrahepatic portosystemic shunts (TIPS) placement and to discuss strategies to avoid and manage complications if they arise. CONCLUSION: TIPS is an established interventional therapy for complications of portal hypertension. Although TIPS remains a relatively safe procedure, direct procedure-related morbidity rates are as high as 20%. The technical complexity of this intervention increases the risk for methodologic mishaps during all phases of TIPS placement, including venous access and imaging, transhepatic needle puncture, shunt insertion, and variceal embolization. Thus, interventional radiologists require a thorough stepwise understanding of TIPS insertion, possible adverse sequela, and technical tips and tricks to maximize the safety of this procedure.

Microwave lung ablation complicated by bronchocutaneous fistula: case report and literature review.

Microwave ablation is a developing treatment option for unresectable lung cancer. Early experience suggests that it may have advantages over radiofrequency (RF) ablation with larger ablation zones, shorter heating times, less susceptibility to heat sink, effectiveness in charred lung, synergism with multiple applicators, no need for grounding pads, and similar survival benefit. Newer microwave ablation devices are being developed and as their use becomes more prevalent, a greater understanding of device limitations and complications are important. Herein we describe a microwave lung ablation complicated by bronchocutaneous fistula (BCF) and its treatment. BCF treatment options include close monitoring, surgical closure, percutaneous sealant injection, and endoscopic plug or sealant in those who are not surgical candidates.

Tract seeding following radiofrequency ablation for hepatocellular carcinoma: prevention, detection, and management.

Radiofrequency ablation (RFA) has become an important tool in the armamentarium of interventional oncology, particularly in the treatment of primary hepatocellular carcinoma and metastatic tumors. This procedure has proven to be an effective adjunct in treating hepatic tumors as a bridge to liver transplantation, and has a low complication profile. Although adverse events are rare and usually minor, a notable negative outcome is dissemination and implantation of viable tumor cells into the route of applicator entry, or tract seeding. Counter to the goal of treating a patient's cancer, this results in metastatic disease. In this report, the authors present 2 cases of tract seeding after RFA, methods of detection, and means of reducing the incidence of this relatively rare, but significant, complication.

Assessment of the Financial Health of Rural Hospitals After Implementation of the Georgia Rural Hospital Tax Credit Program.

Importance: In 2016, Georgia implemented the Rural Hospital Tax Credit Program, which allows taxpayers to receive a tax credit for contributions to qualifying rural hospitals in the state. Empirical evidence of the program's association with the viability of the state's rural hospitals is needed. Objective: To examine the association of the tax credit program with the financial health of participating rural hospitals. Design, Setting, and Participants: This longitudinal cross-sectional study used hospital financial data from the Centers for Medicare & Medicaid Services for 2015 to 2019. A difference-in-differences analytic approach was used to examine the association of the tax credit program with rural hospital financial health. Study participants included Georgia rural hospitals eligible to participate in the program. Comparison hospitals were selected from the southern states of Alabama, Florida, Mississippi, North Carolina, South Carolina, and Tennessee. Exposures: Hospital participation in the Georgia Rural Hospital Tax Credit Program. Main Outcomes and Measures: The primary outcome of the study was financial health measured with total margin, days cash on hand, debt-asset ratio, and average age of plant as well as a Financial Strength Index (FSI), which combined the previous measures to assess overall financial strength. Results: The analytical sample included a balanced panel of 136 hospitals, with 47 Georgia Rural Hospital Tax Credit Program participants (18 [38%] critical access hospitals; 5 [11%] system affiliated; mean [SD] bed count, 60 [47]; mean [SD] Medicare inpatient mix, 52% [16]) and 89 comparison hospitals (43 [48%] critical access hospitals; 24 [27%] system affiliated; mean [SD] bed count, 52 [41]; mean [SD] Medicare inpatient mix, 67% [18]). Two years after implementation, program participation was associated with a 23% increased probability of good or excellent financial health (b = 0.23; 95% CI, 0.10-0.37; P < .001) and a 6.7-point increase in total margin (b = 6.67; 95% CI, 3.61-9.73; P < .001). Conclusions and Relevance: These early findings suggest that the Georgia Rural Hospital Tax Credit Program is associated with improvements in hospital financial health; however, additional studies are needed to assess the program's long-term impact on the financial sustainability of Georgia's rural hospitals.

Androgen Receptor Regulates CD44 Expression in Bladder Cancer.

The androgen receptor (AR) is important in the development of both experimental and human bladder cancer. However, the role of AR in bladder cancer growth and progression is less clear, with literature indicating that more advanced stage and grade disease are associated with reduced AR expression. To determine the mechanisms underlying these relationships, we profiled AR-expressing human bladder cancer cells by AR chromatin immunoprecipitation sequencing and complementary transcriptomic approaches in response to in vitro stimulation by the synthetic androgen R1881. In vivo functional genomics consisting of pooled shRNA or pooled open reading frame libraries was employed to evaluate 97 genes that recapitulate the direction of expression associated with androgen stimulation. Interestingly, we identified CD44, the receptor for hyaluronic acid, a potent biomarker and driver of progressive disease in multiple tumor types, as significantly associated with androgen stimulation. CRISPR-based mutagenesis of androgen response elements associated with CD44 identified a novel silencer element leading to the direct transcriptional repression of CD44 expression. In human patients with bladder cancer, tumor AR and CD44 mRNA and protein expression were inversely correlated, suggesting a clinically relevant AR-CD44 axis. Collectively, our work describes a novel mechanism partly explaining the inverse relationship between AR and bladder cancer tumor progression and suggests that AR and CD44 expression may be useful for prognostication and therapeutic selection in primary bladder cancer. SIGNIFICANCE: This study describes novel AREs that suppress CD44 and an expected inverse correlation of AR-CD44 expression observed in human bladder tumors.

Georgia Rural Hospital Tax Credit: Perspectives of Rural Health Executives.

PURPOSE: In 2016, Georgia implemented a rural hospital tax credit program through a legislative mandate that allows individuals and corporations to donate to qualifying rural hospitals in exchange for state income tax credit. The study examines the importance, success, and challenges of the program, and opportunities for improvement, from the perspective of Georgia rural hospital executives. METHODS: The study was a qualitative study using data from key informant telephone interviews with 21 hospital executives and administrators of eligible rural hospitals. FINDINGS: Hospital executives described the program as a valuable lifeline for struggling rural hospitals and an instrument for community engagement. They provided recommendations for legislative and programmatic modifications to ensure stability, transparency, and accountability. CONCLUSION: Results highlight the popularity of the program among rural hospital leaders, but they also identify potential areas for improvement. The findings of the study can inform policy-making efforts targeted at improving the nation's rural health infrastructure.