Arbidol attenuates liver fibrosis and activation of hepatic stellate cells by blocking TGF-ß1 signaling.

Chronic liver diseases (CLD) impact over 800 million people globally, causing about 2 million deaths annually. Arbidol (ARB), an indole-derivative used to treat influenza virus infection, was extensively used during COVID-19 pandemic in China. In recent years, studies have shown that ARB, compared to other antiviral drugs, exhibits greater liver-protective efficacy, indicating a potential hepatoprotective effect beyond its antiviral activity. However, the mechanism remains unclear. In this study, we investigated the impact of ARB on liver injury/fibrosis in bile duct ligated (BDL) mice and its effect on spontaneous and transforming growth factor ß1 (TGF-ß1)-induced activation of primary cultured hepatic stellate cells (HSCs). Oral administration of ARB significantly ameliorated BDL-induced liver injury/fibrosis as reflected by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), reduced collagen deposition, and diminished mRNA expression of fibrosis markers. ARB notably inhibited spontaneous and TGF-ß1-induced activation of primary cultured HSCs. Moreover, ARB also drastically attenuated mRNA expression levels of platelet-derived growth factor receptor (Pdgfr), transforming growth factor-beta receptor (Tgfbr) 1, Tgfbr2, matrix metalloproteinase (Mmp)-2, and Mmp-9 in activated HSCs. We further demonstrate that ARB mitigated Smad2/3 phosphorylation in both TGF-ß1 treated HSCs and BDL mice. These data together demonstrate that the therapeutic efficacy of ARB on liver fibrosis is independent of its antiviral activity and likely is achieved by blocking TGF-ß1 signaling-mediated HSC activation.

Immunosuppressive Medications and COVID-19 Outcomes in Patients with Noninfectious Uveitis in the Era of COVID-19 Vaccinations.

Purpose: To determine the risk of coronavirus disease 2019 (COVID-19) infection, hospitalization, and death in the era of COVID-19 vaccination among patients with noninfectious uveitis (NIU) taking immunosuppressive therapies. Design: Retrospective cohort study from July 1, 2021, to June 30, 2022, using data from the Optum Labs Data Warehouse (OLDW) de-identified claims database. Participants: Patients with a diagnosis of NIU from January 1, 2017, and who had ≥ 1 year of continuous enrollment in the OLDW. Methods: Incidence rates (IRs) were calculated for each COVID-19 outcome. Unadjusted and adjusted hazard ratios (HRs) were estimated for each variable and COVID-19 outcome using Cox proportional hazards models with time-updated dichotomous indicators for outpatient immunosuppressive medication exposure. To assess the dose-dependent effect of systemic corticosteroid (SC) exposure, the average daily dose of prednisone over the exposed interval was included in the adjusted models. Main Outcome Measures: Hazard ratios and IRs for COVID-19 infection, hospitalization, and death. Results: This study included 62 209 patients with NIU. A total of 12 895 (20.7%) were exposed to SCs during the risk period. Incidence rates were increased when exposed to SCs versus unexposed for all COVID-19 outcomes. Incidence rates were also increased for all COVID-19 outcomes when exposed to SCs without COVID-19 vaccination versus exposed to SCs with ≥ 1 vaccination. In adjusted models, SCs were associated with increased risk of COVID-19 infection (HR, 3.57; 95% confidence interval [CI], 3.24-3.93; P < 0.0001), hospitalization (HR, 2.75; 95% CI, 2.07-3.65; P < 0.0001), and death (HR, 2.49; 95% CI 1.29-4.82; P = 0.007). Incremental increases in SC dose were associated with a greater risk for all outcomes. Disease-modifying anti-rheumatic drugs were associated with a decreased risk of infection (HR, 0.84; 95% CI, 0.74-0.96; P = 0.01), and tumor necrosis factor-α inhibitors were associated with an increased risk of infection (HR, 1.18; 95% CI, 1.01-1.39; P = 0.04). Conclusions: Systemic corticosteroid exposure continues to be associated with greater risk of COVID-19 infection, hospitalization, and death among patients with NIU in an era of widespread COVID-19 vaccination. Unvaccinated individuals who are exposed to immunosuppressive treatments have a greater risk of severe outcomes. Coronavirus disease 2019 vaccination should be strongly encouraged in these patients. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

An Instrument for High-throughput Testing of Heart Tissue In Vitro.

Cardiac trabeculae are small samples of heart muscle tissue that can be dissected and studied in vitro to better understand the underlying physiology of cardiac muscle. However, instruments for such experimentation often (1) involve delicate mounting of the muscle, (2) constrain investigations to one muscle at a time and, thus, (3) cannot retain the muscle in the same experimental configuration for post-experimental assessment including imaging analysis. Here, we present a novel device that allows trabeculae to be secured by a visible-light photo-initiated hydrogel, manipulated via a force sensor, and stimulated while being imaged. We use our robust, accurate image registration techniques to measure cantilever and gel deformation during trabecula contraction and thereby provide a measure of trabecula force production during twitches. A variety of experiments can then be conducted, with the potential for the trabecula to be fixed in place using hydrogel for further post-experiment analysis, as well as longitudinal evaluation. The device has multiple wells making it amenable to high-throughput testing.Clinical Relevance- These methods may allow longitudinal and high-throughput studies of cardiac tissue samples in health and disease.

ART-related medication errors in hospitalized people with HIV in the INSTI-era: analysis from 2 health systems in South Georgia, U.S.

ABSTRACTART-related medication errors occur at high rates in hospitalized people with HIV (PWH), but few studies included modern regimens. As such, we evaluated ART-related medication errors in hospitalized PWH in an era where use of INSTI-based regimens dominate. This multi-center, retrospective cohort included PWH at least 18 years hospitalized in South Georgia, U.S. between March 2016 and March 2018. Of those eligible for inclusion, 400 were randomly selected and included. Three hundred sixty-three inpatient ART-related medication errors occurred in 203 patients during the study period due to incorrect scheduling (44%), an incorrect or incomplete regimen (27%), and drug-drug interactions (27%). Approximately 25% of errors persisted to discharge. Medication errors were more likely to occur in patients receiving NNRTI- or PI-containing multi-tablet regimens, whereas those receiving INSTI-containing multi-tablet regimens were less likely to experience a medication error. ART-related medication errors are less likely in patients receiving INSTI-containing multi-tablet regimens. Ensuring appropriate transition of ART throughout hospitalization remains an area in need of significant improvement.

A prospective study on neonatal ophthalmic injuries associated with forceps delivery.

BACKGROUND: Assisted delivery by forceps is needed to expedite vaginal delivery in certain maternal and fetal conditions. The aim of this study was to evaluate the incidence and the extent of ophthalmological injuries in neonates after forceps delivery. METHODS: Women with cephalic fetuses delivered vaginally by forceps from July 2020 to June 2022 were recruited prospectively. Ophthalmologists would be consulted when there were signs of external ophthalmic injuries, such as periorbital forceps marks or facial bruising. Demographic data, pregnancy characteristics, delivery details, and perinatal outcomes were evaluated to identify any associated risk factors for neonatal ophthalmological injuries. RESULTS: A total of 77 forceps deliveries were performed in the study period, in which 20 cases (26%) required ophthalmological consultations. There were more right or left occipital fetal head positions in the group requiring ophthalmological assessment than those that did not require assessment (35% vs 12.3% [P = 0.023]). The degree of moulding of the fetal head was more marked in the former group (65% vs 28% [P = 0.001]). The overall incidence of detectable ophthalmological lesions was 16.9% (13/77). All ophthalmic injuries were mild, and most resolved with conservative management. CONCLUSIONS: In our study cohort, external ophthalmic injuries were common after forceps delivery. We recommended ophthalmological consultation in newborns delivered by forceps with evidence of compressive trauma to rule out serious ophthalmological trauma.

Non-contact quantification of aortic stenosis and mitral regurgitation using carotid waveforms from skin displacements.

Objective. Early diagnosis of heart problems is essential for improving patient prognosis.Approach. We created a non-contact imaging system that calculates the vessel-induced deformation of the skin to estimate the carotid artery pressure displacement waveforms. We present a clinical study of the system in patients (n= 27) with no underlying condition, aortic stenosis (AS), or mitral regurgitation (MR).Main results. Displacement waveforms were compared to aortic catheter pressures in the same patients. The morphologies of the pressure and displacement waveforms were found to be similar, and pulse wave analysis metrics, such as our modified reflection indices (RI) and waveform duration proportions, showed no significant differences. Compared with the control group, AS patients displayed a greater proportion of time to peak (p= 0.026 andp= 0.047 for catheter and displacement, respectively), whereas augmentation index (AIx)was greater for the displacement waveform only (p= 0.030). The modified RI for MR (p= 0.047 andp= 0.004 for catheter and displacement, respectively) was lower than in the controls. AS and MR were also significantly different for the proportion of time to peak (p= 0.018 for the catheter measurements), RI (p= 0.045 andp= 0.002 for the catheter and displacement, respectively), and AIx (p= 0.005 for the displacement waveform).Significance. These findings demonstrate the ability of our system to provide insights into cardiac conditions and support further development as a diagnostic/telehealth-based screening tool.

RNA cytosine methyltransferase NSUN5 promotes protein synthesis and tumorigenic phenotypes in glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine-C(5))-methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.

Real-World Outcomes of Proprotein Convertase Subtilisin Kexin-9 Inhibitor Use.

ABSTRACT: Although the proprotein convertase subtilisin kexin-9 inhibitors (PCSK9i) were shown to significantly lower low-density lipoprotein and reduce atherosclerotic cardiovascular disease events in clinical trials, there is a dearth of use data on these agents in real-world settings. This study compares PCSK9i use in a population of real-world patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia. This was a matched cohort study of adult patients who were dispensed a PCSK9i along with adult patients who did not receive a PCSK9i. PCSK9i patients were matched on a propensity to have received a PCSK9i score up to 1:10 to non-PCSK9i patients. The primary outcomes were changes in cholesterol levels. Secondary outcomes included a composite outcome of all-cause mortality, major cardiovascular events, and ischemic strokes along with health care utilization during follow-up. Adjusted conditional, multivariate Cox proportional hazards, and negative binomial modeling were performed. Ninety-one PCSK9i patients were matched to 840 non-PCSK9i patients. Seventy-one percent of PCSK9i patients either discontinued or switched PCSK9i therapy. PCSK9i patients had greater median reductions in low-density lipoprotein (-73.0 mg/dL vs. -30.0 mg/dL) and total (-77.0 vs. -31.0) cholesterol (both P < 0.001). No adjusted between-group differences in the composite outcome or individual components of the composite outcome were identified (all P > 0.05). PCSK9i patients had a lower rate of medical office visits during follow-up (adjusted incidence rate ratio = 0.61, P = 0.019). These findings support the effectiveness of PCSK9i therapy in real-world settings but suggest that use may be limited by PCSK9i adverse reactions and patient cost barriers.

Evaluation of cross-platform compatibility of a DNA methylation-based glucocorticoid response biomarker.

BACKGROUND: Identifying blood-based DNA methylation patterns is a minimally invasive way to detect biomarkers in predicting age, characteristics of certain diseases and conditions, as well as responses to immunotherapies. As microarray platforms continue to evolve and increase the scope of CpGs measured, new discoveries based on the most recent platform version and how they compare to available data from the previous versions of the platform are unknown. The neutrophil dexamethasone methylation index (NDMI 850) is a blood-based DNA methylation biomarker built on the Illumina MethylationEPIC (850K) array that measures epigenetic responses to dexamethasone (DEX), a synthetic glucocorticoid often administered for inflammation. Here, we compare the NDMI 850 to one we built using data from the Illumina Methylation 450K (NDMI 450). RESULTS: The NDMI 450 consisted of 22 loci, 15 of which were present on the NDMI 850. In adult whole blood samples, the linear composite scores from NDMI 450 and NDMI 850 were highly correlated and had equivalent predictive accuracy for detecting DEX exposure among adult glioma patients and non-glioma adult controls. However, the NDMI 450 scores of newborn cord blood were significantly lower than NDMI 850 in samples measured with both assays. CONCLUSIONS: We developed an algorithm that reproduces the DNA methylation glucocorticoid response score using 450K data, increasing the accessibility for researchers to assess this biomarker in archived or publicly available datasets that use the 450K version of the Illumina BeadChip array. However, the NDMI850 and NDMI450 do not give similar results in cord blood, and due to data availability limitations, results from sample types of newborn cord blood should be interpreted with care.

DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival.

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.

Ocular Features and Autism Spectrum Disorder: A 10-Year Retrospective Review.

We reviewed the medical records of our pediatric ophthalmology and strabismus clinic of our hospitals for the period 1 January, 2009 to 31 December, 2018, to identify children with autism spectrum disorder (ASD). We found that refractive errors (62%) and strabismus (63%) were the most common ocular manifestations in children with ASD. With timely management, amblyopia and strabismus could have favorable outcome. As amblyopia was significantly associated with intellectual disability (P=0.02), early ophthalmic monitoring via multidisciplinary approach is warranted.

Challenges to dietary hypertension self-management as described by a sample of African American older adults.

BACKGROUND: Hypertension rates are disproportionately higher among Black or African Americans (Black/African American) compared to other racial and ethnic groups in the United States. However, research on self-management strategies to control hypertension through healthy eating such as the Dietary Approaches to Stop Hypertension (DASH), and ketogenic diets has underexplored the use of dietary strategies among older Black/African American adults. In reporting contemporary challenges with implementing dietary strategies targeting blood pressure control among Black/African American older adults living with hypertension, this study addresses a clear need. AIMS: Prior research has only partially addressed the challenges older Black/African Americans face in implementing and maintaining dietary strategies to control hypertension, therefore the current study aimed to address this gap by reporting contemporary challenges, as reported by a sample of Black/African American older adults living with hypertension. METHODS: Nineteen Black/African American older adults living with hypertension participated in a focus group. An interview guide with open-ended questions on dietary approaches to self-management hypertension was used to guide data collection. Responses were audio-recorded, transcribed verbatim, and interpreted using qualitative thematic analysis. RESULTS: Study participants were 71.6 years (SD = 8.3), 87.1% were women, and all were self-identified as Black/African American. Overall, participants shared that they were interested in improving their hypertension self-management skills. They expressed uncertainty about dietary strategies related in part to a lack of knowledge about incorporating or excluding certain foods and adhering to complex dietary recommendations. Participants also related financial concerns about accessing the recommended foods to control hypertension and expressed confusion about how to manage hypertension alongside other comorbidities. LINKING EVIDENCE TO ACTION: This study highlights several barriers that Black/African American older adults face (lack of dietary knowledge, lack of financial resources, and unique barriers to managing multiple comorbid health conditions), which often pose simultaneous and intersecting barriers to managing hypertension using existing evidence-based dietary strategies.

Roadblocks and successes in preparing COVID-19 vaccination clinics: Perspectives from pharmacy residents.

PURPOSE: To outline logistics challenges, barriers, and successes in the development of separate programs for mass COVID-19 vaccine distribution and administration to healthcare employees and community members. SUMMARY: In the face of the global coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccine development and distribution became a worldwide priority. AdventHealth Orlando was selected as the central hub for vaccination efforts for central Florida. There was a need to quickly evaluate literature, patient safety, and institutional resources and logistics to coordinate the development of employee and community vaccination clinics. These efforts were driven by postgraduate year 2 residents in health-system pharmacy administration and leadership, medication-use safety and policy, and informatics. Clinic development focused on 4 key areas: vaccine quality control, secure inventory movement, safe preparation and administration, and consolidation of inventory. Healthcare worker vaccinations were administered on the health system's main campus, and community vaccination events were carried out at temporary clinic facilities set up in the parking lot of Orlando International Airport. CONCLUSION: In a mass COVID-19 vaccination initiative directed by the pharmacy enterprise leadership of a large Florida health system, postgraduate year 2 pharmacy residents played a key role in developing and implementing vaccination clinics targeting healthcare worker and community populations. During multiple vaccination events, a total of more than 50,000 COVID-19 vaccine doses were administered, with minimal to no vaccine wastage.

Decreased Emotional Dysregulation Following Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation Therapy (3MDR): Identifying Possible Driving Factors in Remediation of Treatment-Resistant PTSD.

Multi-modal motion-assisted memory desensitization and reconsolidation therapy (3MDR), an interactive, virtual reality-assisted, exposure-based intervention for PTSD, has shown promising results for treatment-resistant posttraumatic stress disorder (TR-PTSD) among military members (MMs) and veterans in randomized controlled trials (RCT). Previous research has suggested that emotional regulation (ER) and emotional dysregulation (ED) may be factors which are correlated with symptom severity and maintenance of TR-PTSD. This embedded mixed-methods pilot study (n = 9) sought to explore the impact of 3MDR on ER and ED of MMs and veterans. Difficulties in Emotional Regulation Scale (DERS-18) data were collected at baseline, prior to each session, and at one week, one month, and three months postintervention and analyzed. Qualitative data collected from sessions, debriefs, and follow-up interviews were transcribed and descriptively analyzed. Results demonstrated statistically significant decreases in DERS-18 scores from preintervention to postintervention at each timepoint. Qualitatively, participants perceived improvements in ER within specified DERS-18 domains. We describe how 3MDR's unique and novel approach addresses ED through cognitive-motor stimulation, narration, divergent thinking, reappraisal of aversive stimuli, dual-task processing, and reconsolidation of traumatic memories. More studies are needed to better understand the underlying neurobiological mechanisms by which 3MDR addresses ER and PTSD.

The Implications of COVID-19 to Ophthalmology.

The coronavirus disease 2019 (COVID-19) pandemic has brought unprecedented challenges to ophthalmology. At least 16 ophthalmologists worldwide have succumbed to COVID-19. It reflects the susceptibility of ophthalmologists to COVID-19 infection as they are in close proximity to patients. This chapter provides an overview of the ocular manifestations of COVID-19, risks of COVID-19 to ophthalmologists and patients, clinical service adjustments due to COVID-19, and infection control measures to minimize the transmission of COVID-19 in ophthalmic practice.

Moving Toward and Through Trauma: Participant Experiences of Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation (3MDR).

Introduction: Military members and Veterans are at risk of developing combat-related, treatment-resistant posttraumatic stress disorder (TR-PTSD) and moral injury (MI). Conventional trauma-focused therapies (TFTs) have shown limited success. Novel interventions including Multi-modal Motion-assisted Memory Desensitization and Reconsolidation therapy (3MDR) may prove successful in treating TR-PTSD. Objective: To qualitatively study the experiences of Canadian military members and Veterans with TR-PTSD who received the 3MDR intervention. Methods: This study explored qualitative data from a larger mixed-method waitlist control trial testing the efficacy of 3MDR in military members and veterans. Qualitative data were recorded and collected from 3MDR sessions, session debriefings and follow-up interviews up to 6 months post-intervention; the data were then thematically analyzed. Results: Three themes emerged from the data: (1) the participants' experiences with 3MDR; (2) perceived outcomes of 3MDR; and (3) keys to successful 3MDR treatment. Participants expressed that 3MDR provided an immersive environment, active engagement and empowerment. The role of the therapist as a coach and "fireteam partner" supports the participants' control over their therapy. The multi-modal nature of 3MDR, combining treadmill-walking toward self-selected trauma imagery with components of multiple conventional TFTs, was key to helping participants engage with and attribute new meaning to the memory of the traumatic experience. Discussion: Preliminary thematic analysis of participant experiences of 3MDR indicate that 3MDR has potential as an effective intervention for combat-related TR-PTSD, with significant functional, well-being and relational improvements reported post-intervention. Conclusion: Military members and Veterans are at risk of developing TR-PTSD, with worse outcomes than in civilians. Further research is needed into 3MDR and its use with other trauma-affected populations.

The use of short message service (SMS) to reduce outpatient attendance in ophthalmic clinics during the coronavirus pandemic.

PURPOSE: In order to minimize the risk of transmission of coronavirus disease 2019 (COVID-19), many clinic appointments were postponed to lower patient attendance. Actively calling patients to postpone appointments is a labour-intensive process. We were the first ophthalmic clinics in Hong Kong to use short message service (SMS) to dispatch messages simultaneously to a large number of patients to offer postponement of appointments. The aim of this study is to evaluate whether SMS is an effective method to reduce outpatient attendance during the COVID-19 pandemic. METHODS: This is an observational study reviewing data on SMS messages sent to all patients attending ophthalmology clinics of a tertiary eye centre in Hong Kong. All SMS were sent at least 5 days before the scheduled appointments. The text message included an enquiry hotline for postponement of appointments and offered drug refill. The study included data from February to April 2020. Two hundred patients were invited to take part in a questionnaire on satisfaction level and reason(s) for appointment rescheduling. RESULTS: During the study period, a total of 17,028 SMS were sent. The overall response rate was 23.6%. 14.3% postponed their appointments. This led to an overall 13.9% reduction of clinic attendance. The overall satisfaction was high (96%). The main reason for postponing appointment was worries about infection risk (93.1%). CONCLUSION: SMS was an efficient and cost-effective flow-control method which was well accepted by patients and can reduce outpatient attendance. The time saved can potentially allow healthcare workers to conduct other infection control measures during the COVID-19 pandemic.

A miniature mechanical testing device for testing hydrogel-based biomaterials in a confocal microscope.

Cardiac muscle cells are the fundamental building blocks of the heart, yet little is known about their mechanical properties in either healthy or diseased states. While many have explored unloaded myocyte behavior under a variety of interventions, methods for force measurements are limited due to cell fragility. Here, we present a custom device for manipulation and mechanical testing of hydrogels embedded with delicate cardiac muscle cells. Consisting of a custom disposable flexure, which is easily interchangeable, the device has the potential for high throughput testing of cell-gel constructs. Additionally, the mechanical testing device is the size of a microscope slide - appropriate for use in most microscopes, for simultaneous imaging of the sample. The mechanical properties of a gelatin-methacryloyl hydrogel sample were assessed, and 3D volumes of gel imaged using a confocal microscope. The Young's modulus of the gel was found to be 33kPa.Clinical Relevance- High-throughput testing provides the potential to gain insight into cardiac cell mechanics. Experimentation under the influence of a variety of pharmacological interventions could improve the rate at which treatments for cardiac disease are developed. Furthermore, methods may be extended to other embedded biological tissues.