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.

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.

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.

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.

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.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

Stepping up infection control measures in ophthalmology during the novel coronavirus outbreak: an experience from Hong Kong.

PURPOSE: Coronavirus disease (COVID-19) has rapidly emerged as a global health threat. The purpose of this article is to share our local experience of stepping up infection control measures in ophthalmology to minimise COVID-19 infection of both healthcare workers and patients. METHODS: Infection control measures implemented in our ophthalmology clinic are discussed. The measures are based on detailed risk assessment by both local ophthalmologists and infection control experts. RESULTS: A three-level hierarchy of control measures was adopted. First, for administrative control, in order to lower patient attendance, text messages with an enquiry phone number were sent to patients to reschedule appointments or arrange drug refill. In order to minimise cross-infection of COVID-19, a triage system was set up to identify patients with fever, respiratory symptoms, acute conjunctivitis or recent travel to outbreak areas and to encourage these individuals to postpone their appointments for at least 14 days. Micro-aerosol generating procedures, such as non-contact tonometry and operations under general anaesthesia were avoided. Nasal endoscopy was avoided as it may provoke sneezing and cause generation of droplets. All elective clinical services were suspended. Infection control training was provided to all clinical staff. Second, for environmental control, to reduce droplet transmission of COVID-19, installation of protective shields on slit lamps, frequent disinfection of equipment, and provision of eye protection to staff were implemented. All staff were advised to measure their own body temperatures before work and promptly report any symptoms of upper respiratory tract infection, vomiting or diarrhoea. Third, universal masking, hand hygiene, and appropriate use of personal protective equipment (PPE) were promoted. CONCLUSION: We hope our initial experience in stepping up infection control measures for COVID-19 infection in ophthalmology can help ophthalmologists globally to prepare for the potential community outbreak or pandemic. In order to minimise transmission of COVID-19, ophthalmologists should work closely with local infection control teams to implement infection control measures that are appropriate for their own clinical settings.

Occlusion therapy in amblyopia: an experience from Hong Kong.

OBJECTIVES. To review the results of patching for amblyopia management in Hong Kong. DESIGN. Retrospective case series. SETTING. Regional hospital, Hong Kong. PATIENTS. Records of all patients attending Paediatric Ophthalmology Clinic at United Christian Hospital, Hong Kong from 1 January 2009 to 31 March 2009 were retrospectively reviewed. Records of all children who underwent patching for amblyopia in the study period were evaluated. RESULTS. The mean age of 50 children (50 eyes) was 4 (standard deviation, 1; range, 2-7) years and mean pretreatment visual acuity was 0.35 (0.15; 0.02-0.63) [~20/60]. The values for mean, standard deviation, and range of treatment duration were 27, 16, 4-67 months respectively, and corresponding values for prescribed patching per day were 4, 1, 2-8 hours. The mean, standard deviation, and range of visual acuity at final post-treatment assessment were 0.66, 0.16, 0.1-1.0 (~20/30), respectively. The overall success rate (ie final visual acuity >0.7 or 20/30) was 62%. Children with moderate amblyopia (20/40-20/80) and severe amblyopia (20/100-20/400) had success rates of 74% and 55%, respectively. The mean visual acuity improvements for moderate and severely amblyopic children were 2.3 lines and 5.8 lines, respectively. The mean, standard deviation, and range of patching prescriptions for moderate and severely amblyopic children were 5, 1, 2-7 hours and 5, 1, 3-6 hours, respectively. Recurrence ensued in 7% of the children with moderate amblyopia and 46% of those with severe amblyopia. Reported compliance was good (>75% of the time) in 68% of the children. CONCLUSION. Occlusion therapy is the mainstay of treatment in Hong Kong. The overall success rate was comparable to that achieved in the Amblyopia Treatment Study. Recurrence was more common in patients with severe amblyopia, for whom maintenance therapy may reduce the risk of recurrence. The duration of treatment was much longer in our locality than in western countries. Reported compliance was suspicious possibly due to traditional cultural contexts. It is important to emphasise compliance to all parents.

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.

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.

Dynamic composite hydrogels of gelatin methacryloyl (GelMA) with supramolecular fibers for tissue engineering applications.

In the field of tissue engineering, there is a growing need for biomaterials with structural properties that replicate the native characteristics of the extracellular matrix (ECM). It is important to include fibrous structures into ECM mimics, especially when constructing scar models. Additionally, including a dynamic aspect to cell-laden biomaterials is particularly interesting, since native ECM is constantly reshaped by cells. Composite hydrogels are developed to bring different combinations of structures and properties to a scaffold by using different types and sources of materials. In this work, we aimed to combine gelatin methacryloyl (GelMA) with biocompatible supramolecular fibers made of a small self-assembling sugar-derived molecule (N-heptyl-D-galactonamide, GalC7). The GalC7 fibers were directly grown in the GelMA through a thermal process, and it was shown that the presence of the fibrous network increased the Young's modulus of GelMA. Due to the non-covalent interactions that govern the self-assembly, these fibers were observed to dissolve over time, leading to a dynamic softening of the composite gels. Cardiac fibroblast cells were successfully encapsulated into composite gels for 7 days, showing excellent biocompatibility and fibroblasts extending in an elongated morphology, most likely in the channels left by the fibers after their degradation. These novel composite hydrogels present unique properties and could be used as tools to study biological processes such as fibrosis, vascularization and invasion.

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.

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.

Elevated water temperature and carbon dioxide concentration increase the growth of a keystone echinoderm.

Anthropogenic climate change poses a serious threat to biodiversity. In marine environments, multiple climate variables, including temperature and CO(2) concentration ([CO(2)]), are changing simultaneously. Although temperature has well-documented ecological effects, and many heavily calcified marine organisms experience reduced growth with increased [CO(2)], little is known about the combined effects of temperature and [CO(2)], particularly on species that are less dependent on calcified shells or skeletons. We manipulated water temperature and [CO(2)] to determine the effects on the sea star Pisaster ochraceus, a keystone predator. We found that sea star growth and feeding rates increased with water temperature from 5 degrees C to 21 degrees C. A doubling of current [CO(2)] also increased growth rates both with and without a concurrent temperature increase from 12 degrees C to 15 degrees C. Increased [CO(2)] also had a positive but nonsignificant effect on sea star feeding rates, suggesting [CO(2)] may be acting directly at the physiological level to increase growth rates. As in past studies of other marine invertebrates, increased [CO(2)] reduced the relative calcified mass in sea stars, although this effect was observed only at the lower experimental temperature. The positive relationship between growth and [CO(2)] found here contrasts with previous studies, most of which have shown negative effects of [CO(2)] on marine species, particularly those that are more heavily calcified than P. ochraceus. Our findings demonstrate that increased [CO(2)] will not have direct negative effects on all marine invertebrates, suggesting that predictions of biotic responses to climate change should consider how different types of organisms will respond to changing climatic variables.

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.