Evaluation of a transitions clinic to bridge emergency department and primary care.

BACKGROUND: Suboptimal transitions from the emergency department (ED) to ambulatory settings contribute to poor clinical outcomes and unnecessary nonurgent ED utilization. Care transition clinics (CTCs) are a potential solution by providing ED follow-up and facilitating the bridge to longer-term primary care. OBJECTIVE: The objective was to evaluate the implementation of an ED transitions clinic on 30-day ED revisits and hospital readmissions. DESIGNS: Retrospective cross-sectional study. SETTINGS AND PARTICIPANTS: This study included adults 18 years and older discharged from the ED and reeferred to the CTC. MAIN OUTCOME AND MEASURES: Appointment attendance, follow-up time, and frequencies of care type provided were computed to assess clinic utilization. Rates of 30-day ED revisit and hospital admission were compared between completed and missed appointments using logistic regression. RESULTS: Between March 2021 and March 2022, 373 patients were referred to the CTC totaling 405 appointments. Half (53%) of appointments were completed with a median follow-up time of 4 days (IQR = [2, 7]). The most common care types provided were wound care (44%) and clinical problem management (33%), with wound care appointments more likely to be completed compared with clinical appointments (OR = 1.7, CI = [1.1, 2.8], p = .03). Patients who completed their CTC appointment were 50% less likely to return to the ED in 30 days compared with those who did not complete their appointment (OR = 0.51, CI = [0.27, 0.98], p < .05). No effect was seen for CTC appointment completion on hospital readmission. Transition clinics are a viable method to provide timely access to follow-up for patients discharged from the ED and may help reduce excess ED use for ambulatory care needs.

Can Digital Communication Protect Against Depression for Older Adults With Hearing and Vision Impairment During COVID-19?

OBJECTIVES: During social isolation imposed by the coronavirus disease 2019 (COVID-19) pandemic, older adults with impaired hearing and vision potentially experienced more communication challenges, increasing their risk for poor mental health. Digital communication (e.g., video calls, e-mail/text/social media) may alleviate in-person isolation and protect against depression. We addressed this question using data from the National Social Life, Health, and Aging Project, a nationally representative panel study of community-dwelling older adults. METHOD: Two thousand five hundred fifty-eight adults aged 55 and older comprised the analytic sample. Interviewer rating at baseline (2015-2016) classified those with vision impairment (VI) or hearing impairment (HI). Olfactory impairment (OI) was measured by objective testing. During COVID-19 (2020-2021), respondents reported how often they contacted nonhousehold family or friends and whether this was by phone, e-mail/text/social media, video, or in-person. They also quantified the frequency of depressive feelings. RESULTS: Older adults with VI or HI but not OI at baseline were significantly less likely to report regular use of video calling and e-mail/text/social media during the pandemic compared to those without impairment. Sensory impairments did not affect the frequency of phone or in-person communication. Adults with VI or HI were more likely to experience frequent depressive feelings during COVID-19. Video calls mitigated this negative effect of VI- and HI-associated depressive feelings in a dose-dependent manner. DISCUSSION: Among communication modalities, video calling had a protective effect against depressive feelings for people with sensory impairment during social isolation. Improving access to and usability of video communication for older adults with sensory impairment could be a strategy to improve their mental health.

Androgen and oestrogen receptor co-expression determines the efficacy of hormone receptor-mediated radiosensitisation in breast cancer.

PURPOSE: Radiation therapy (RT) and hormone receptor (HR) inhibition are used for the treatment of HR-positive breast cancers; however, little is known about the interaction of the androgen receptor (AR) and estrogen receptor (ER) in response to RT in AR-positive, ER-positive (AR+/ER+) breast cancers. Here we assessed radiosensitisation of AR+/ER+ cell lines using pharmacologic or genetic inhibition/degradation of AR and/or ER. METHODS: Radiosensitisation was assessed with AR antagonists (enzalutamide, apalutamide, darolutamide, seviteronel, ARD-61), ER antagonists (tamoxifen, fulvestrant) or using knockout of AR. RESULTS: Treatment with AR antagonists or ER antagonists in combination with RT did not result in radiosensitisation changes (radiation enhancement ratios [rER]: 0.76-1.21). Fulvestrant treatment provided significant radiosensitisation of CAMA-1 and BT-474 cells (rER: 1.06-2.0) but not ZR-75-1 cells (rER: 0.9-1.11). Combining tamoxifen with enzalutamide did not alter radiosensitivity using a 1 h or 1-week pretreatment (rER: 0.95-1.14). Radiosensitivity was unchanged in AR knockout compared to Cas9 cells (rER: 1.07 ± 0.11), and no additional radiosensitisation was achieved with tamoxifen or fulvestrant compared to Cas9 cells (rER: 0.84-1.19). CONCLUSION: While radiosensitising in AR + TNBC, AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast cancer. The efficacy of ER antagonists in combination with RT may also be dependent on AR expression.

Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models.

Endocrine therapy (ET) is an effective first-line therapy for women with estrogen receptor-positive (ER + ) breast cancers. While both ionizing radiation (RT) and ET are used for the treatment of women with ER+ breast cancer, the most effective sequencing of therapy and the effect of ET on tumor radiosensitization remains unclear. Here we sought to understand the effects of inhibiting estrogen receptor (ER) signaling in combination with RT in multiple preclinical ER+ breast cancer models. Clonogenic survival assays were performed using variable pre- and post-treatment conditions to assess radiosensitization with estradiol, estrogen deprivation, tamoxifen, fulvestrant, or AZD9496 in ER+ breast cancer cell lines. Estrogen stimulation was radioprotective (radiation enhancement ratios [rER]: 0.51-0.82). Conversely, when given one hour prior to RT, ER inhibition or estrogen depletion radiosensitized ER+ MCF-7 and T47D cells (tamoxifen rER: 1.50-1.60, fulvestrant rER: 1.76-2.81, AZD9496 rER: 1.33-1.48, estrogen depletion rER: 1.47-1.51). Combination treatment resulted in an increase in double-strand DNA (dsDNA) breaks as a result of inhibition of non-homologous end joining-mediated dsDNA break repair with no effect on homologous recombination. Treatment with tamoxifen or fulvestrant in combination with RT also increased the number of senescent cells but did not affect apoptosis or cell cycle distribution. Using an MCF-7 xenograft model, concurrent treatment with tamoxifen and RT was synergistic and resulted in a significant decrease in tumor volume and a delay in time to tumor doubling without significant toxicity. These findings provide preclinical evidence that concurrent treatment with ET and RT may be an effective radiosensitization strategy.

Estimating the incidence of cocaine use and mortality with music lyrics about cocaine.

In the United States, cocaine use and mortality have surged in the past 5 years. Considering cocaine's reputation as a fashionable social drug, the rise of cocaine mentions in popular music may provide a signal of epidemiological trends of cocaine use. We characterized the relationship between mentions of cocaine in song lyrics and incidence of cocaine use and mortality in the US. Incidence of cocaine use from 2002 to 2017 was obtained from the National Survey on Drug Use and Health and cocaine overdose mortality rate from 2000 to 2017 was obtained from the Centers for Disease Control. Distributed lag models were fit using ordinary least squares on the first difference to identify associations between changes in cocaine lyric mentions and changes in incidence of cocaine use and mortality. A total of 5955 song lyrics with cocaine mentions were obtained from Lyrics.com. Cocaine mentions in song lyrics were stable from 2000 to 2010 then increased by 190% from 2010 to 2017. The first-order distributed lag model estimated that a 0.01 increase in mentions of cocaine in song lyrics is associated with an 11% increase in incidence of cocaine use within the same year and a 14% increase in cocaine mortality with a 2-year lag. Lag-times were confirmed with cross-correlation analyses and the association remained after accounting for street pricing of cocaine. Mentions of cocaine in song lyrics are associated with the rise of incidence of cocaine use and cocaine overdose mortality. Popular music trends are a potentially valuable tool for understanding cocaine epidemiology trends.

Estimation of Asthma Symptom Onset Using Internet Search Queries: Lag-Time Series Analysis.

BACKGROUND: Asthma affects over 330 million people worldwide. Timing of an asthma event is extremely important and lack of identification of asthma increases the risk of death. A major challenge for health systems is the length of time between symptom onset and care seeking, which could result in delayed treatment initiation and worsening of symptoms. OBJECTIVE: This study evaluates the utility of the internet search query data for the identification of the onset of asthma symptoms. METHODS: Pearson correlation coefficients between the time series of hospital admissions and Google searches were computed at lag times from 4 weeks before hospital admission to 4 weeks after hospital admission. An autoregressive integrated moving average (ARIMAX) model with an autoregressive process at lags of 1 and 2 and Google searches at weeks -1 and -2 as exogenous variables were conducted to validate our correlation results. RESULTS: Google search volume for asthma had the highest correlation at 2 weeks before hospital admission. The ARIMAX model using an autoregressive process showed that the relative searches from Google about asthma were significant at lags 1 (P<.001) and 2 (P=.04). CONCLUSIONS: Our findings demonstrate that internet search queries may provide a real-time signal for asthma events and may be useful to measure the timing of symptom onset.

Empiric Transcatheter Embolization for Acute Arterial Upper Gastrointestinal Bleeding: A Meta-Analysis.

OBJECTIVE. The purpose of this study was to conduct a meta-analysis to assess the safety and efficacy of empiric embolization compared with targeted embolization in the treatment of acute upper gastrointestinal bleeding (UGIB). MATERIALS AND METHODS. We searched the PubMed and Cochrane Library databases for studies performed without language restrictions from January 2000 to November 2019. Only clinical studies with a sample size of five or more were included. Clinical success, rebleeding and complication rates, survival rates, bleeding cause, embolic materials, and vessels embolized were recorded. Empiric embolization and targeted embolization (i.e., embolization performed based on angiographic evidence of ongoing bleeding) were compared when possible. Meta-analysis was performed. RESULTS. Among 13 included studies (12 retrospective and 1 prospective), a total of 357 of 725 patients (49.2%) underwent empiric embolization for UGIB. The clinical success rate of empiric embolization was 74.7% (95% CI, 63.1-86.3%) among the 13 studies, and the survival rate was 80.9% (95% CI, 73.8-88.0%) for 10 studies. On the basis of comparative studies, no statistically significant difference was observed between empiric and targeted embolization in terms of rebleeding rate in 111 studies (36.5% vs 29.6%; odds ratio [OR], 1.13; 95% CI, 0.77-1.65; p = .53), mortality in eight studies (23.3% vs 18.0%; OR, 1.44; 95% CI, 0.89-2.33; p = .14), and need for surgery to control rebleeding in four studies (17.8% vs 13.4%; OR, 1.34; 95% CI, 0.58-3.07; p = .49). The pooled embolization-specific complications were 1.9% (empiric) and 2.4% (targeted). CONCLUSION. According to all available published evidence, empiric embolization assessed with endoscopic or preprocedural imaging findings (or both) appears to be as effective as targeted embolization in preventing rebleeding and mortality in patients with angiographically negative acute UGIB. Because of its favorable safety profile, empiric embolization should be considered for patients in this clinical scenario.

Investigation of Geographic and Macrolevel Variations in LGBTQ Patient Experiences: Longitudinal Social Media Analysis.

BACKGROUND: Discrimination in the health care system contributes to worse health outcomes among lesbian, gay, bisexual, transgender, and queer (LGBTQ) patients. OBJECTIVE: The aim of this study is to examine disparities in patient experience among LGBTQ persons using social media data. METHODS: We collected patient experience data from Twitter from February 2013 to February 2017 in the United States. We compared the sentiment of patient experience tweets between Twitter users who self-identified as LGBTQ and non-LGBTQ. The effect of state-level partisan identity on patient experience sentiment and differences between LGBTQ users and non-LGBTQ users were analyzed. RESULTS: We observed lower (more negative) patient experience sentiment among 13,689 LGBTQ users compared to 1,362,395 non-LGBTQ users. Increasing state-level liberal political identification was associated with higher patient experience sentiment among all users but had stronger effects for LGBTQ users. CONCLUSIONS: Our findings highlight that social media data can yield insights about patient experience for LGBTQ persons and suggest that a state-level sociopolitical environment influences patient experience for this group. Efforts are needed to reduce disparities in patient care for LGBTQ persons while taking into context the effect of the political climate on these inequities.

Evaluation of Volume of News Reporting and Opioid-Related Deaths in the United States: Comparative Analysis Study of Geographic and Socioeconomic Differences.

BACKGROUND: News media coverage is a powerful influence on public attitude and government action. The digitization of news media covering the current opioid epidemic has changed the landscape of coverage and may have implications for how to effectively respond to the opioid crisis. OBJECTIVE: This study aims to characterize the relationship between volume of online opioid news reporting and opioid-related deaths in the United States and how these measures differ across geographic and socioeconomic county-level factors. METHODS: Online news reports from February 2018 to April 2019 on opioid-related events in the United States were extracted from Google News. News data were aggregated at the county level and compared against opioid-related death counts. Ordinary least squares regression was used to model opioid-related death rate and opioid news coverage with the inclusion of socioeconomic and geographic explanatory variables. RESULTS: A total of 35,758 relevant news reports were collected representing 1789 counties. Regression analysis revealed that opioid-related death rate was positively associated with news reporting. However, opioid-related death rate and news reporting volume showed opposite correlations with educational attainment and rurality. When controlling for variation in death rate, counties in the Northeast were overrepresented by news coverage. CONCLUSIONS: Our results suggest that regional variation in the volume of opioid-related news reporting does not reflect regional variation in opioid-related death rate. Differences in the amount of media attention may influence perceptions of the severity of opioid epidemic. Future studies should investigate the influence of media reporting on public support and action on opioid issues.

Leveraging black-market street buprenorphine pricing to increase capacity to treat opioid addiction, 2010-2018.

Increasing capacity to provide buprenorphine, a treatment for opioid addiction, can help mitigate the opioid epidemic in the United States. This study models black-market pricing of buprenorphine to better understand supply and demand for opioid addiction treatment. A mixed effects linear model was used to quantify the effect of county-level racial composition, health insurance coverage, and drug characteristics on price variation. From November 2010 to June 2018, there were 2481 submissions for street buprenorphine transactions in the StreetRx dataset. The mean price was $3.95/mg (SD = $23.12/mg). Price decreased 3.05% each year and was highest in the summer and spring. Brand name buprenorphine was on average 11.18% more expensive than generic buprenorphine. Buprenorphine/naloxone combinations were on average 19.75% less expensive than pure buprenorphine. Purchases in bulk were on average 10.51% cheaper than purchases not in bulk. Street buprenorphine in film form was on average 14.34% more expensive than in pill/tablet form. Buprenorphine street price was 17.12% higher in spring and 22.26% higher in summer compared to fall. For every percentage point increase in percent white, buprenorphine sold for 0.88% higher price. For every percentage point increase in health insurance coverage, street buprenorphine sold for 0.02% lower price. Findings demonstrate that geographic, demographic, and socioeconomic factors shape the diversion of opioid addiction treatment to the black-market. Buprenorphine street pricing can help estimate public need, gaps in care and emerging public health priorities.

Engineered Human Cathelicidin Antimicrobial Peptides Inhibit Ebola Virus Infection.

The 2014-2016 West Africa Ebola virus (EBOV) outbreak coupled with the most recent outbreaks in Central Africa underscore the need to develop effective treatment strategies against EBOV. Although several therapeutic options have shown great potential, developing a wider breadth of countermeasures would increase our efforts to combat the highly lethal EBOV. Here we show that human cathelicidin antimicrobial peptide (AMP) LL-37 and engineered LL-37 AMPs inhibit the infection of recombinant virus pseudotyped with EBOV glycoprotein (GP) and the wild-type EBOV. These AMPs target EBOV infection at the endosomal cell-entry step by impairing cathepsin B-mediated processing of EBOV GP. Furthermore, two engineered AMPs containing D-amino acids are particularly potent in blocking EBOV infection in comparison with other AMPs, most likely owing to their resistance to intracellular enzymatic degradation. Our results identify AMPs as a novel class of anti-EBOV therapeutics and demonstrate the feasibility of engineering AMPs for improved therapeutic efficacy.

Use of social media to assess the impact of equitable state policies on LGBTQ patient experiences: An exploratory study.

Limited research has evaluated these equitable policies because of the difficulty of capturing LGBTQ patient experience. Previous studies have shown that LGBTQ persons report increased rates of discrimination across a wide variety of healthcare settings which may prevent them from disclosing their LGBTQ status. The goal of this research was to use a social media big dataset to evaluate the impact of equitable policies on patient experiences for LGBTQ persons.

Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells.

Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 µM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 µM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an in vivo AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation.

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC50 > 10 µmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo, the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257).

Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intraislet ghrelin-GHSR axis modulates insulin secretion and glucose metabolism using mouse models lacking ghrelin (Ghrl-/- ) or GHSR (Ghsr-/- ). Ghsr-/- and Ghsr+/+ mice had comparable islet ghrelin concentrations. Exogenous ghrelin decreased insulin secretion in perifused isolated islets in a GHSR-dependent manner. Islets isolated from Ghrl-/- or Ghsr-/- mice did not differ from controls in glucose-, alanine-, or GLP-1-stimulated insulin secretion during perifusion. Consistent with this finding, Ghrl-/- and Ghsr-/- male mice studied after either 6 or 16 h of fasting had blood glucose concentrations comparable with those of controls following intraperitoneal glucose, or insulin tolerance tests, or after mixed nutrient meals. Collectively, our data provide strong evidence against a paracrine ghrelin-GHSR axis mediating insulin secretion or glucose tolerance in lean, chow-fed adult mice.

Point source concentration of GDNF may explain failure of phase II clinical trial.

Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2-9%) of the human putamen in the clinical trial using this catheter and infusion protocol.