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Infection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis. In latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions. These results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post-transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection.

UN AIDS has set ambitious 95-95-95 HIV care continuum targets for global HIV elimination by 2030. The U.S. HIV Care Continuum in 2018 showed that 65% of persons with HIV(PWH) are virally suppressed and 58% retained in care. Incomplete care-engagement not only affects individual health but drives ongoing HIV transmission. Data to Care (D2C) is a strategy using public health surveillance data to identify and re-engage out-of-care (OOC) PWH. Optimization of this strategy is needed. Statewide partnership with Connecticut Department of Public Health (CT DPH), 23 HIV clinics and Yale University School of Medicine (YSM). Our site was one of 3 participants in the CDC-sponsored RCT evaluating the efficacy of DPH-employed Disease Intervention Specialists (DIS) for re-engagement in care. From 11/2016-7/2018, a data reconciliation process using public health surveillance and clinic visit data was used to identify patients eligible for randomization (defined as in-Care for 12 months and OOC for subsequent 6-months) to receive DIS intervention. Clinic staff further reviewed this list and designated those who would not be randomized based on established criteria. 2958 patients were eligible for randomization; 655 (22.1%) were randomized. Reasons for non-randomizing included: well patient [499 (16.9%)]; recent visit [946 (32.0%)]; upcoming visit [398 (13.5%)]. Compared to non-randomized patients, those who were randomized were likely to be younger (mean age 46.1 vs. 51.6, p < .001), Black (40% vs 35%)/Hispanic (37% vs 32.8%) [(p < .001)], have CD4<200 cells/ul (15.9% vs 8.5%, p < .001) and viral load >20 copies/ml (43.8% vs. 24.1%, 0<0.001). Extrapolating these estimates to a statewide HIV care continuum suggests that only 8.3% of prevalent PWH are truly OOC. A D2C process that integrated DPH surveillance and clinic data successfully refined the selection of newly OOC PWH eligible for DIS intervention. This approach more accurately reflects real world care engagement and can help prioritize DPH resources.

Biphasic environments can enable successful chemical reactions where any single solvent results in poor substrate solubility or poor catalyst reactivity. For screening biphasic reactions at high throughput, a platform based on microfluidic double emulsions can use widely available FACS (Fluorescence Activated Cell Sorting) machines to screen millions of picoliter reactors in a few hours. However, encapsulating biphasic reactions within double emulsions to form FACS‐sortable droplet picoreactors requires optimized solvent phases and surfactants to produce triple emulsion droplets that are stable over multi‐hour assays and compatible with desired reaction conditions. This work demonstrates such FACS‐sortable triple emulsion picoreactors with a fluorocarbon shell and biphasic octanol‐in‐water core. First, surfactants are screened to stabilize octanol‐in‐water emulsions for the picoreactor core. With these optimized conditions, stable triple emulsion picoreactors (>70% of droplets survived to 24 hr), produced protein in the biphasic core via cell‐free protein synthesis are generated, and sorted these triple emulsions based on fluorescence using a commercial FACS sorter at >100 Hz with 75–80% of droplets recovered. Finally, an in‐droplet lipase assay with a fluorogenic resorufin substrate that partitions into octanol is demonstrated. These triple emulsion picoreactors have the potential for future screening bead‐encoded catalyst libraries, including enzymes such as lipases for biofuel production. Biphasic reactions can enhance reactions where the catalyst and substrate have different solvent preferences. This study optimizes triple emulsion picoreactors that encapsulate a biphasic solvent environment. These triple emulsion picoreactors can be sorted in commercially available cell sorters for future high‐throughput screens with biphasic reaction conditions for enzymes such as lipases.

Multiple sclerosis (MS) is a chronic neurodegenerative disease driven by infiltration of activated innate immune cells into the central nervous system (CNS). Current imaging approaches for diagnosing and monitoring disease progression rely on structural lesions and cannot directly assess innate immune activity. Here, we describe a dendrimer positron emission tomography (PET) tracer, 18 F-flurimedrimer ( 18 F-FMD), for non-invasive, longitudinal tracking of activated myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) murine model, 18 F-FMD specifically detects myeloid activation at presymptomatic and symptomatic stages, with PET signal correlating with disease severity. Moreover, 18 F-FMD sensitively captures therapeutic response to fingolimod (FTY720) and a CSF1R dendranib (H74DS3M8), both of which suppress immune cell activation and attenuate disease severity. These findings highlight the potential of 18 F-FMD PET for specific, real-time monitoring of innate immune responses, and the applicability of the dendrimer in clinical settings for monitoring therapeutic efficacy, advancing the development of personalized, myeloid-targeted strategies for MS. Non-invasive strategies to detect and track activated myeloid cells will facilitate disease diagnosis and monitoring in patients affected by neuroinflammatory disorders. Here, the authors present 18F-FMD, a dendrimer-based PET tracer that detects and monitors activated myeloid cells at different stages (presymptomatic and symptomatic) of Experimental Autoimmune Encephalomyelitis (EAE) in mice and in response to disease-modifying therapies.

Background/Objective Describe vitreomacular interface abnormalities (VMIA) using spectral-domain optical coherence tomography (SD-OCT), and correlations with age-related macular degeneration (AMD) grade in Ghanaian Africans. Subjects/Methods Prospective, cross-sectional study of adults aged ≥50 years recruited in Ghana AMD Study. Participant demographics, medical histories, ophthalmic examination, digital colour fundus photography (CFP) were obtained. High-resolution five-line raster OCT, Macular Cube 512 × 128 scans, and additional line scans in areas of clinical abnormality, were acquired. SD-OCT VMI features classified by International Vitreomacular Traction Study Group system and relationships to AMD grade were evaluated. Outcomes: VMIA prevalence, posterior vitreous detachment (PVD), vitreomacular adhesions (VMA), vitreomacular traction (VMT), epiretinal membranes (ERM), correlations with AMD grade. Results The full Ghana AMD cohort included 718 participants; 624 participants (1248 eyes) aged ≥50 years (range = 50–101, mean = 68.8), 68.9% female were included in this analysis. CFP with OCT scans were available for 776 eyes (397 participants); 707 (91.1%) had gradable CFP and OCT scans for both AMD and VMI grading forming the dataset for this report. PVD was absent in 504 (71.3%); partial and complete PVD occurred in 16.7% and 12.0% respectively. PVD did not increase with age ( p  = 0.720). VMIA without traction and macular holes were observed in 12.2% of eyes; 87.8% had no abnormalities. VMIA was not significantly correlated with AMD grade ( p  = 0.819). Conclusions This provides the first assessment of VMIA in Ghanaian Africans. VMIA are common in Africans; PVD may be less common than in Caucasians. There was no significant association of AMD grade with VMIA.

The World Health Organization and the Centers for Disease Control and Prevention have set ambitious hepatitis C virus (HCV) elimination targets for 2030. Current estimates show that the United States is not on pace to meet elimination targets due to multiple patient, clinic, institutional, and societal level barriers that contribute to HCV testing and treatment gaps. Among these barriers are unawareness of testing and treatment needs, misinformation concerning adverse treatment reactions, need for substance use sobriety, and treatment efficacy. Strategies to improve viral hepatitis education are needed. We aim to provide a high-quality HCV educational app for patients and health care workers, particularly nonprescriber staff. The app was vetted by health care providers and designed to guide users through the HCV testing and treatment stages in a self-exploratory way to promote engagement and knowledge retention. The app is comprised of five learning modules: (1) Testing for Hep C (hepatitis C), (2) Tests for Hep C Positive Patients, (3) Treatments Available to You, (4) What to Expect During Treatment, and (5) What to Expect After Treatment. An HCV knowledge assessment survey was administered to providers and patients at the Yale School of Medicine and 11 Connecticut HIV clinics as part of a grant-funded activity. The survey findings and pilot testing feedback guided the app's design and content development. Data on app usage from November 2019 to November 2022 were analyzed, focusing on user demographics, engagement metrics, and module usage patterns. There were 561 app users; 216 (38.5%) accessed the training modules of which 151 (69.9%) used the app for up to 60 minutes. Of them, 65 (30.1%) users used it for >60 minutes with a median time spent of 5 (IQR 2-8) minutes; the median time between initial accession and last use was 39 (IQR 18-60) days. Users accessed one or more modules and followed a nonsequential pattern of use: module 1: 163 (75.4%) users; module 4: 82 (38%); module 5: 67 (31%); module 3: 49 (22.7%); module 2: 41 (19%). This app, created in an academic setting, is one of a few available in English and Spanish that provides content-vetted HCV education for patients and health care supportive staff. It offers the convenience of on-demand education, allowing users to access crucial information about HCV management and treatment in a self-directed fashion that acknowledges and promotes variable preferences in learning approaches. While app uptake was relatively limited, we propose that future efforts should focus on combined promotion efforts with marketing strategies experts aligned with academic experts. Incorporating ongoing user feedback and integrating personalized reminders and quizzes, will further enhance engagement, supporting the broader public health HCV elimination goals.

Increases in drug abuse, injection, and opioid overdoses in suburban communities led us to study injectors residing in suburban communities in southwestern Connecticut, US. We sought to understand the influence of residence on risk and injection-associated diseases. Injectors were recruited by respondent-driven sampling and interviewed about sociodemographics, somatic and mental health, injection risk, and interactions with healthcare, harm reduction, substance abuse treatment, and criminal justice systems. HIV, hepatitis B and C (HBV and HCV) serological testing was also conducted. Our sample was consistent in geographic distribution and age to the general population and to the patterns of heroin-associated overdose deaths in the suburban towns. High rates of interaction with drug abuse treatment and criminal justice systems contrasted with scant use of harm reduction services. The only factors associated with both dependent variables—residence in less disadvantaged census tracts and more injection risk—were younger age and injecting in one’s own residence. This contrasts with the common association among urban injectors of injection-associated risk behaviors and residence in disadvantaged communities. Poor social support and moderate/severe depression were associated with risky injection practices (but not residence in specific classes of census tracts), suggesting that a region-wide dual diagnosis approach to the expansion of harm reduction services could be effective at reducing the negative consequences of injection drug use.

Introduction Data‐to‐care programmes utilize surveillance data to identify persons who are out of HIV care, re‐engage them in care and improve HIV care outcomes. We assess the costs and cost‐effectiveness of re‐engagement in an HIV care intervention in the United States. Methods The Cooperative Re‐engagement Control Trial (CoRECT) employed a data‐to‐care collaborative model between health departments and HIV care providers, August 2016–July 2018. The health departments in Connecticut (CT), Massachusetts (MA) and Philadelphia (PHL) collaborated with HIV clinics to identify newly out‐of‐care patients and randomize them to receive usual linkage and engagement in care services (standard‐of‐care control arm) or health department‐initiated active re‐engagement services (intervention arm). We used a microcosting approach to identify the activities and resources involved in the CoRECT intervention, separate from the standard‐of‐care, and quantified the costs. The cost data were collected at the start‐up and recurrent phases of the trial to incorporate potential variation in the intervention costs. The costs were estimated from the healthcare provider perspective. Results The CoRECT trial in CT, MA and PHL randomly assigned on average 327, 316 and 305 participants per year either to the intervention arm (n = 166, 159 and 155) or the standard‐of‐care arm (n = 161, 157 and 150), respectively. Of those randomized, the number of participants re‐engaged in care within 90 days in the intervention and standard‐of‐care arms was 85 and 70 in CT, 84 and 70 in MA, and 98 and 67 in PHL. The additional number of participants re‐engaged in care in the intervention arm compared with those in the standard‐of‐care arm was 15 (CT), 14 (MA) and 31 (PHL). We estimated the annual total cost of the CoRECT intervention at$490,040 in CT, $ 473,297 in MA and$439,237 in PHL. The average cost per participant enrolled was $ 2952,$2977 and $ 2834 and the average cost per participant re‐engaged in care was$5765, $ 5634 and$4482. We estimated an incremental cost per participant re‐engaged in care at $ 32,669 (CT),$33,807 (MA) and $ 14,169 (PHL). Conclusions The costs of the CoRECT intervention that identified newly out‐of‐care patients and re‐engaged them in HIV care are comparable with other similar interventions, suggesting a potential for its cost‐effectiveness in the US context.

Agencies should consult researchers and administrators on how to cut bureaucratic red tape Concerns about the growth of research regulations and reporting requirements and their impact on scientific productivity and international competitiveness have prompted many reports and recommendations over the past two decades ( 1 – 6 ). In the United States, investigators spend a considerable portion of their time on federally funded research engaged in associated administrative tasks ( 7 ). This takes time and effort away from research and can serve as a disincentive to seek grants or enter the field. Congress aimed to increase the efficiency of the federal investment in research and development and to reduce administrative burden on federally funded scientists through provisions of the 21st Century Cures Act (Cures Act, 13 December 2016) and the American Innovation and Competitiveness Act (AICA, 7 January 2017) ( 8 , 9 ). Addressing research regulatory burden in law and associated oversight may provide the relief that reports and recommendations alone have not generated. But more than a year and a half after enactment of these laws, under an administration that has eagerly expressed intent to reduce regulations and associated costs, we see limited progress, transparency, and engagement with the research institutions that accept federal awards. Here, we focus on U.S. efforts to address research regulatory reform and allow for more direct engagement by the stakeholder community in the regulatory process, similar to the efforts of other nations and the European Union (EU).