Antibody-mediated autoimmunity in symptom-based disorders: position statement and proceedings from an international workshop.

A 2-day closed workshop was held in Liverpool, United Kingdom, to discuss the results of research concerning symptom-based disorders (SBDs) caused by autoantibodies, share technical knowledge, and consider future plans. Twenty-two speakers and 14 additional participants attended. This workshop set out to consolidate knowledge about the contribution of autoantibodies to SBDs. Persuasive evidence for a causative role of autoantibodies in disease often derives from experimental "passive transfer" approaches, as first established in neurological research. Here, serum immunoglobulin (IgM or IgG) is purified from donated blood and transferred to rodents, either systemically or intrathecally. Rodents are then assessed for the expression of phenotypes resembling the human condition; successful phenotype transfer is considered supportive of or proof for autoimmune pathology. Workshop participants discussed passive transfer models and wider evidence for autoantibody contribution to a range of SBDs. Clinical trials testing autoantibody reduction were presented. Cornerstones of both experimental approaches and clinical trial parameters in this field were distilled and presented in this article. Mounting evidence suggests that immunoglobulin transfer from patient donors often induces the respective SBD phenotype in rodents. Understanding antibody binding epitopes and downstream mechanisms will require substantial research efforts, but treatments to reduce antibody titres can already now be evaluated.

Effects of NF-κB Inhibitor on Sepsis Depend on the Severity and Phase of the Animal Sepsis Model.

Hyperinflammation occurs in sepsis, especially in the early phase, and it could have both positive and negative effects on sepsis. Previously, we showed that a new concept of NF-κB inhibitor, exosome-based super-repressor IκBα (Exo-srIκB) delivery, has a beneficial effect on sepsis. Here, we further investigate the therapeutic effects of Exo-srIκB at different severities and phases of sepsis using an animal polymicrobial intra-abdominal infection model. We used a rat model of fecal slurry polymicrobial sepsis. First, we determined the survival effects of Exo-srIκB on sepsis according to the severity. We used two different severities of the animal sepsis model. The severe model had a mortality rate of over 50%. The mild/moderate model had a less than 30% mortality rate. Second, we administered the Exo-srIκB at various time points (1 h, 6 h, and 24 h after fecal slurry administration) to determine the therapeutic effect of Exo-srIκB at different phases of sepsis. Lastly, we determined the effects of the Exo-srIκB on cytokine production, arterial blood gas, electrolyte, and lactate. The survival gain was statistically significant in the severe sepsis model when Exo-srIκB was administered 6 h after sepsis. Interleukin 6 and interleukin-10 were significantly decreased in the kidney when administered with Exo-srIκB. The laboratory data showed that lactate, glucose, and potassium levels were significantly lowered in the NF-κB inhibitor group. In conclusion, Exo-srIκB exhibited a beneficial therapeutic effect when administered 6 h post fecal slurry administration in a severe sepsis model.

Clinical Outcomes after Bilateral Implantation of a Wavefront-Shaping Extended Depth of Focus (EDOF) IOL with Mini-Monovision.

Background: To compare the visual outcomes and optical quality of patients who underwent bilateral implantation of EDOF (AcrySof® IQ Vivity IOL, DFT015) for mini-monovision, trifocal (AcrySof® IQ PanOptix, TNFT00), or monofocal (AcrySof® IQ IOL, SN60WF) IOL. Methods: The monocular-corrected and uncorrected distance visual acuities (CDVA and UDVA, respectively) were evaluated postoperatively at 1 and 3 months. The binocular visual acuity by distance, the binocular defocus curve, contrast sensitivity, and patient satisfaction were examined 3 months postoperatively. All patients were asked to complete questionnaires regarding their satisfaction, visual symptoms, and spectacle dependency. Results: This study included 178 eyes from 89 patients. The postoperative binocular UDVA did not differ significantly among the three groups. In the defocus curve, the Vivity group showed better visual acuity over a range of far and intermediate (60 cm) than the other two IOLs groups. In near-vision, the PanOptix group showed the best near-vision, and the Vivity group showed significantly better vision than the IQ group. The Vivity group showed contrast sensitivity and optical quality comparable to the IQ group. Conclusions: The bilateral implantation of AcrySof® IQ Vivity IOL with the mini-monovision approach provided excellent distance and intermediate visual acuity with good near-vision, resulting in high satisfaction.

Re-Esterified Triglyceride ω-3 Fatty Acids in Dry Eye Disease With Meibomian Gland Dysfunction: A Randomized Clinical Trial.

Importance: Taking ω-3 supplements has been associated with a reduction in symptoms of dry eye disease (DED) associated with meibomian gland dysfunction (MGD). However, a recent relatively large clinical trial concluded that treating DED with ω-3 consumption was ineffective, potentially warranting additional investigations. Objectives: To investigate the effect of re-esterified triglyceride (rTG) ω-3 fatty acid supplementation on DED associated with MGD. Design, Setting, and Participants: This double-masked, parallel-group, randomized clinical trial was conducted at 7 institutions from September 2020 to January 2023. Patients with DED associated with MGD were included and randomly assigned to the ω-3 group (received 1680 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid), whereas those in the grape-seed group received 3000 mg of grape-seed oil daily. Interventions: rTG ω-3 Fatty acid supplementation vs grape-seed oil. Main Outcome Measures: The primary end point was the Ocular Surface Disease Index (OSDI) from baseline to 6 and 12 weeks. The safety parameters were visual acuity and intraocular pressure change. Results: A total of 132 patients (mean [SD] age, 50.6 [13.8] years; 103 female [78.0%]) were included in this study. The mean (SD) baseline OSDI scores of the ω-3 and grape-seed groups were 43.5 (16.5) and 44.1 (16.6), respectively. A total of 58 patients (87.9%) and 57 patients (86.4%) in the ω-3 and grape-seed groups, respectively, completed 12 weeks of follow-up. There were no differences in compliance with the dietary supplement intake between groups (ω-3, 95.8% and grape-seed, 95.4%). The OSDI (SD) change from baseline to 6 and 12 weeks was -20.5 (16.0) and -22.7 (15.7), respectively, in the ω-3 group and -15.1 (20.2) and -18.8 (21.7), respectively, in the grape-seed control group (difference at 6 weeks = -5.4; 95% CI, -12.15 to 1.33; P = .12 and at 12 weeks = -3.9; 95% CI, -10.90 to 3.13; P = .28). There were no changes in safety parameters or adverse events related to taking the dietary supplement in either group. Conclusions and Relevance: This randomized clinical trial did not show a benefit of the rTG form of ω-3 for ameliorating symptoms of DED associated with MGD, although fewer than 60 participants were evaluated in each group. Any secondary outcomes from this study should be considered for hypothesis generation of future evaluations of the effect of the rTG form of ω-3 on DED associated with MGD. Trial Registration: CRIS Identifier: KCT0004927.

Trends of emergency department visits for cannabinoid hyperemesis syndrome in Nevada: An interrupted time series analysis.

Cannabis-related emergency department visits have increased after legalization of cannabis for medical and recreational use. Accordingly, the incidence of emergency department visits due to cannabinoid hyperemesis syndrome in patients with chronic cannabis use has also increased. The aim of this study was to examine trends of emergency department visit due to cannabinoid hyperemesis syndrome in Nevada and evaluate factors associated with the increased risk for emergency department visit. The State Emergency Department Databases of Nevada between 2013 and 2021 were used for investigating trends of emergency department visits for cannabinoid hyperemesis syndrome. We compared patients visiting the emergency department due to cannabinoid hyperemesis syndrome with those visiting the emergency department due to other causes except cannabinoid hyperemesis and estimated the impact of cannabis commercialization for recreational use. Emergency department visits due to cannabinoid hyperemesis syndrome have continuously increased during the study period. The number of emergency department visits per 100,000 was 1.07 before commercialization for recreational use. It increased to 2.22 per 100,000 (by approximately 1.1 per 100,000) after commercialization in the third quarter of 2017. Those with cannabinoid hyperemesis syndrome were younger with fewer male patients than those without cannabinoid hyperemesis syndrome. A substantial increase in emergency department visits due to cannabinoid hyperemesis syndrome occurred in Nevada, especially after the commercialization of recreational cannabis. Further study is needed to explore factors associated with emergency department visits.

Volume loss during muscle reinnervation surgery is correlated with reduced CMAP amplitude but not reduced force output in a rat hindlimb model.

Introduction: Muscle reinnervation (MR) surgery offers rehabilitative benefits to amputees by taking severely damaged nerves and providing them with new denervated muscle targets (DMTs). However, the influence of physical changes to muscle tissue during MR surgery on long-term functional outcomes remains understudied. Methods: Our rat hindlimb model of MR surgery utilizes vascularized, directly neurotized DMTs made from the lateral gastrocnemius (LG), which we employed to assess the impact of muscle tissue size on reinnervation outcomes, specifically pairing the DMT with the transected peroneal nerve. We conducted MR surgery with both DMTs at full volume and DMTs with partial volume loss of 500 mg at the time of surgery (n = 6 per group) and measured functional outcomes after 100 days of reinnervation. Compound motor action potentials (CMAPs) and isometric tetanic force production was recorded from reinnervated DMTs and compared to contralateral naïve LG muscles as positive controls. Results: Reinnervated DMTs consistently exhibited lower mass than positive controls, while DMTs with partial volume loss showed no significant mass reduction compared to full volume DMTs (p = 0.872). CMAP amplitudes were lower on average in reinnervated DMTs, but a broad linear correlation also exists between muscle mass and maximum CMAP amplitude irrespective of surgical group (R2 = 0.495). Surprisingly, neither MR group, with or without volume loss, demonstrated decreased force compared to positive controls. The average force output of reinnervated DMTs, as a fraction of the contralateral LG's force output, approached 100% for both MR groups, a notable deviation from the 9.6% (±6.3%) force output observed in our negative control group at 7 days post-surgery. Tissue histology analysis revealed few significant differences except for a marked decrease in average muscle fiber area of reinnervated DMTs with volume loss compared to positive controls (p = 0.001). Discussion: The results from our rat model of MR suggests that tissue electrophysiology (CMAPs) and kinesiology (force production) may recover on different time scales, with volumetric muscle loss at the time of MR surgery not significantly reducing functional outcome measurements for the DMTs after 100 days of reinnervation.

The associations of herpes simplex virus and varicella zoster virus infection with dementia: a nationwide retrospective cohort study.

BACKGROUND: In this study, the risk of dementia in patients with a history of herpes simplex virus (HSV) or varicella zoster virus (VZV) infection was evaluated. METHODS: This nationwide cohort study used data from the Korean National Health Insurance Service collected between 2006 and 2017. A total of 752,205 subjects ≥ 45 years of age not diagnosed with dementia until 2006 were included. A multivariate Cox regression model, adjusted for age, sex, and other comorbidities, was used to assess the hazard ratio (HR) for dementia based on VZV or HSV infection. The interaction effects of both viral infections were analysed. Viral infections are classified into four categories: eye, central nervous system (CNS), simple, and complicated. The hazard ratio (HR) of viral infection was analysed based on the type of dementia. RESULTS: In multivariable analysis, both HSV and VZV infection were associated with an increased risk of dementia (HR = 1.38, 95% confidence interval, CI:1.33-1.43) and (HR = 1.41, 95% CI:1.37-1.46), respectively. Patients who experienced both HSV and VZV infections were also at an increased risk of dementia (HR = 1.57, 95% CI:1.50-1.63). The co-infection group showed the shortest time from viral infection to dementia diagnosis (4.09 ± 3.02 years). In the subgroup analysis, all types of HSV and VZV infections were associated with an increased risk of dementia compared to the non-infection group. The eye, CNS, and complicated VZV infections were associated with a significantly higher risk than simple VZV infections. There were no significant differences between the subtypes of HSV infection. Furthermore, HSV, VSV, and co-infection were associated with an increased risk of all dementia types, including Alzheimer's disease (AD) and vascular dementia (VD). CONCLUSIONS: Individual HSV and VZV infections were associated with an increased risk of all types of dementia, including AD and VD. Patients co-infected with HSV and VZV, VZV infection in the eye, CNS, or complicated type were more vulnerable to the development of dementia.

AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. METHODS: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. RESULTS: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. CONCLUSIONS: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that leads to abnormal heartbeats and a higher risk of sudden cardiac death. ARVC is often caused by changes in a gene called PKP2, that then makes less PKP2 protein. PKP2 protein is important for the normal structure and function of the heart. Human ARVC characteristics can be mimicked in a mouse model missing this gene. Given no therapeutic option, our goal was to test if adding a working copy of PKP2 gene in the heart of this mouse model, using a technique called gene therapy that can deliver genes to cells, could improve heart function. Here, we show that a single dose of PKP2 gene therapy can improve heart function and heartbeats as well as extend lifespan in mice. PKP2 gene therapy may be a promising approach to treat ARVC patients with PKP2 mutations.

Predictive cut-off values for the triglyceride-to-high-density lipoprotein cholesterol ratio to predict metabolic syndrome in the middle-aged Korean population.

BACKGROUND AND AIMS: The triglyceride-to-high density lipoprotein cholesterol (TG/HDL) ratio is associated with insulin resistance related diseases, including metabolic syndrome (MetS). However, specific TG/HDL values that can predict MetS have not been well identified. In this study, we analyzed both cross-sectional and longitudinal data from two national Korean datasets to obtain TG/HDL cut-off values that can identify MetS and predict its occurrence. METHODS AND RESULTS: To distinguish the presence and occurrence of MetS, the cut-off values were determined using the maximum F-score calculated through a logistic regression analysis. To predict new-onset MetS within 10 years, Cox proportional hazard models were used to consider the time of occurrence. The TG/HDL cut-off values of 3.97, 3.24, and 3.24 were optimal for identifying current MetS and predicting new-onset MetS within 10 years and five years, respectively, in Korean men. In Korean women, the optimal values for each task were 3.18, 2.38, and 2.26, respectively. CONCLUSIONS: We suggest the TG/HDL ratio as a potential candidate predictor for MetS. Therefore, we anticipate that future studies will apply individual lipid levels as well as their combinatory values to establish models that predict the prevalence and occurrence of MetS, diabetes, and cardiovascular disease.

Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?

Dysautonomia, or dysfunction of the autonomic nervous system (ANS), may occur following an infectious insult and can result in a variety of debilitating, widespread, and often poorly recognized symptoms. Dysautonomia is now widely accepted as a complication of COVID-19 and is an important component of Post-Acute Sequelae of COVID-19 (PASC or long COVID). PASC shares many overlapping clinical features with other infection-associated chronic illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS), suggesting that they may share common underlying mechanisms including autonomic dysfunction. Despite the recognition of this complication of Lyme disease in the care of patients with PTLD, there has been a scarcity of research in this field and dysautonomia has not yet been established as a complication of Lyme disease in the medical literature. In this review, we discuss the evidence implicating Borrelia burgdorferi as a cause of dysautonomia and the related symptoms, propose potential pathogenic mechanisms given our knowledge of Lyme disease and mechanisms of PASC and ME/CFS, and discuss the diagnostic evaluation and treatments of dysautonomia. We also outline gaps in the literature and priorities for future research.

Plasma-Activated Media Produced by a Microwave-Excited Atmospheric Pressure Plasma Jet Is Effective against Cisplatin-Resistant Human Bladder Cancer Cells In Vitro.

Media exposed to atmospheric pressure plasma (APP) produce reactive oxygen and nitrogen species (RONS), with hydrogen peroxide (H2O2), nitrite (NO2-), and nitrate (NO3-) being among the most detected species due to their relatively long lifetime. In this study, a standardized microwave-excited (ME) APP jet (APPJ) source was employed to produce gaseous RONS to treat liquid samples. The source was a commercially available plasma jet, which generated argon plasma utilizing a coaxial transmission line resonator at the operating frequency of 2.45 GHz. An ultraviolet-visible spectrophotometer was used to measure the concentrations of H2O2 and NO3- in plasma-activated media (PAM). Three different types of media (deionized water, Hank's balanced salt solution, and cell culture solution Dulbecco's modified eagles medium [DMEM]) were utilized as liquid samples. Among these media, the plasma-treated DMEM was observed to have the highest levels of H2O2 and NO3-. Subsequently, the feasibility of using argon ME-APPJ-activated DMEM (PAM) as an adjuvant to enhance the therapeutic effects of cisplatin on human bladder cancer cells (T-24) was investigated. Various cancer cell lines, including T-24 cells, treated with PAM were observed in vitro for changes in cell viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. A viability reduction was detected in the various cancer cells after incubation in PAM. Furthermore, the study's results revealed that PAM was effective against cisplatin-resistant T-24 cells in vitro. In addition, a possible connection between HER expression and cell viability was sketched.

Antidromic snare technique for re-implantation of a coronary sinus lead into the same cardiac vein after transvenous lead extraction: a case report.

Background: After coronary sinus (CS) lead extraction in patients with cardiac resynchronization therapy (CRT), occlusion of the branch vessel from which CS lead was extracted is a major obstacle to re-implantation, particularly if that vessel is the only optimal vessel for resynchronization. Case summary: A 75-year-old female who underwent CRT implantation 11 years prior presented with worsening dyspnoea, right ventricle-only pacing rhythm, and increased CS lead pacing threshold. Because she was a CRT responder, we decided to replace the malfunctioning CS lead. After successful extraction, the vessel from which CS lead was extracted was not visualized, and guidewire re-insertion attempts failed. No other branch vessels suitable for re-implantation were observed. Fortunately, distal portion of the target vessel was viewed by a retrograde flow of contrast. A guidewire was advanced retrograde into the target vein via a connecting vessel, and the distal end of the guidewire was snared around CS ostium and then pulled out of the sheath. A new CS lead was inserted through the distal end of the guidewire and successfully implanted antegrade into the same target vein using a veno-venous loop of the guidewire ('anti-dromic snare technique'). The patient was discharged 2 days after the procedure without complications. Discussion: Antegrade re-implantation of CS lead may not be possible after extracting CS leads with long dwell times, possibly due to extraction-induced vessel occlusion. If the occluded vessel is the only proper vessel for CS lead re-implantation, the anti-dromic snare technique could be a safe and effective bail-out strategy.

Effectiveness and Safety of Sodium-Glucose Cotransporter 2 Inhibitors Added to Dual or Triple Treatment in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: We evaluated the effectiveness and safety of sodium-glucose cotransporter 2 inhibitor (SGLT2i) add-on treatment in patients with type 2 diabetes mellitus (T2DM) in the real-world setting. METHODS: This single-center retrospective study used the clinical database of Seoul National University Hospital in South Korea. Patients who received metformin monotherapy or combination therapy with ≥ 1 other oral hypoglycemic medication and had a baseline glycosylated hemoglobin (HbA1c) between 7.0% and 10.5% were included. Propensity score matching was applied between patients treated with and without SGLT2 inhibitors (SGLT2i and non-SGLT2i groups, respectively). Changes in HbA1c from baseline to week 26 were compared between the SGLT2i and non-SGLT2i groups, and risk of adverse events (AE) were also assessed. RESULTS: A total of 1106 patients were included. At week 26, HbA1c was significantly more reduced by 0.35 percentage points in the SGLT2i group than in the non-SGLT2i group (95% CI 0.30-0.41, P < 0.001). Likewise, the proportion of patients achieving HbA1c < 7% was also significantly higher (51.9% vs. 37.6%, P < 0.05) in the SGLT2i group than in the non-SGLT2i group. The risk of adverse events in the SGLT2i group was mostly comparable with those in the non-SGLT2i group except for diseases of the liver, pain, hypertensive diseases, and metabolic disorders, which showed significantly higher odds in the SGLT2i group. CONCLUSIONS: SGLT2i add-on treatment is an effective and safe therapeutic option for patients with T2DM in the real-world practice setting.

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma.

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3'UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

Clinical Evaluation of a Hydrophobic Intraocular Lens Using a Preloaded Automated Injector in a Korean Population.

Purpose: This study assessed post-market clinical outcomes of the Clareon monofocal intraocular lens (IOL) preloaded in the AutonoMe Delivery System in a real-world setting of Korean patients. Methods: This prospective, multicenter, single-arm study in Korea was conducted from July 2020 to December 2021. Patients were ≥20 years old with unilateral or bilateral cataracts who received Clareon IOLs (CNA0T0) preloaded in an automated injector system. Best corrected distance visual acuity (BCDVA) and uncorrected distance visual acuity (UCDVA) were evaluated under photopic conditions. Surgeon delivery system preference was assessed using a survey questionnaire. Glistenings, surface haze, adverse events, posterior capsule opacification (PCO), and Nd:YAG capsulotomy rates were also assessed during the 12-month postoperative follow-up. Results: Mean ± SD monocular BCDVA was 0.02 ± 0.11 and 0.00 ± 0.10 logMAR at 1 month and 12 months, respectively. BCDVA of 0.2 logMAR or better was achieved by 94.4% and 99.1% of eyes at 1 month and 12 months after implantation, respectively. Mean monocular UCDVA was 0.11 ± 0.14 and 0.07 ± 0.13 logMAR at 1 month and 12 months, respectively. UCDVA of 0.3 logMAR or better was achieved by 97.4% of eyes at 12 months after implantation. Preparation of the automated injector system was rated as "very easy" or "easy" and CNA0T0 IOL delivery was rated as "very controllable" or "controllable" by all surgeons. Only grade 0 glistenings and no surface haze were observed during the 12-month follow-up. No clinically significant PCO or Nd:YAG capsulotomy were reported throughout the study; clinically nonsignificant PCO was reported in 23% of eyes. Conclusion: This 12-month real-world study of the CNA0T0 IOL and the automated injector system demonstrated excellent visual outcomes and high surgeon satisfaction.

Exercise capacity and risk of incident atrial fibrillation in healthy adults.

BACKGROUND/AIMS: Atrial fibrillation (AF) is a common arrhythmia and is associated with cardiovascular morbidity and mortality. It is important to identify and control the modifiable risk factors of AF. We aimed to examine the association of exercise capacity with the risk of incident AF within 3 years in healthy subjects. METHODS: We evaluated asymptomatic adults who had undergone more than two consecutive health checkups. We included subjects who exhibited normal sinus rhythm on the first health examination and who developed AF on the second or subsequent health examinations. Subjects who underwent cardiopulmonary exercise testing within 3 years before the diagnosis of AF were examined. RESULTS: The study population in the analyses included 428 cases (mean age 58.4 ± 7.6 yr, male 95.6%). There were significant differences in maximal systolic blood pressure (SBP; case 169.4 ± 24.2 vs. control 173.9 ± 22.3 mmHg), peak VO2 (29.5 ± 5.4 vs. 30.4 ± 4.8 mL/kg per minute), and maximal metabolic equivalents (METs; 8.5 ± 1.6 vs. 8.7 ± 1.4) between the two groups. In the multivariable logistic models, adjusted odds ratios were 0.99 for maximal SBP (95% confidence interval [CI] 0.98-0.99), 0.97 for peak VO2 (95% CI 0.95-0.99), and 0.91 for maximal METs (95% CI 0.83-0.98). CONCLUSION: We demonstrated that poorer exercise capacity was associated with the development of AF in a healthy population. A prospective, systematic trial is necessary to confirm that appropriate exercise training will be beneficial in preventing the development of AF in such patients.

Trends in medical care utilization in patients with cancer: An analysis of real-world data in a tertiary hospital in Korea, 2014-2019.

BACKGROUND: Rising costs of cancer treatments challenge even areas with universal health coverage. There's a need to assess current medical care utilization trends among patients with cancer to guide public health policy, resource allocation, and set informed healthcare goals. METHODS: We analyzed the latest trends in medical care utilization by cancer patients in four areas-drugs, radiation therapy (RT), surgery, and diagnostic procedures-using clinical databases extracted from electronic medical records of a tertiary hospital in Korea between 2014 and 2019. Compound adjusted growth rates (CAGR) were computed to capture the annual growth over the study period. RESULTS: A total of 74,285 cancer patients were identified, with 40.3% (29,962), 14.2% (10,577), 31.1% (23,066), and 92.6% (68,849) of patients having received at least one anticancer agent, RT, surgery, and diagnostic procedure, respectively, over the period. We observed a 1.7-fold increase in the use of targeted · immune-oncology agents (from 6.8% to 11.6%) and a 21-fold increase (from 3.0% in 2014 to 65.7%) in intensity-modulated RT (IMRT) use over the period. In contrast, we observed a continuous decrease in the proportion of patients who underwent surgical treatment from 12.2% in 2014 to 10.9% in 2019. This decrease was particularly noticeable in patients with colon cancer (from 28.5% to 24.2%) and liver cancer (from 4.1% to 2.9%). CONCLUSION: From 2014 to 2019, there was a significant rise in the use of targeted · immune-oncology agents and IMRT, alongside a decline in surgeries. While targeted · immune-oncology agents and IMRT may offer promising outcomes, their financial impact and potential for overuse necessitate careful oversight and long-term cost-effectiveness studies.

The Effect of Cataract Surgery on the Risk of Dementia: A Nationwide Cohort Study.

BACKGROUND: An advanced age and the female sex are widely recognized risk factors for both cataract and dementia. We investigated the effect of cataract surgery on the incidence of dementia in a Korean population aged ≥ 45 years with a previous diagnosis of cataract. METHODS: This nationwide cohort study was performed using Korean National Health Insurance Service data collected from 2006 to 2017. A total of 300,327 subjects aged ≥ 45 years with a history of cataract diagnosis but no previous diagnosis of dementia were analyzed. The relationship between cataract surgery and dementia was evaluated, applying a time-varying analysis to evaluate the hazard ratio (HR) and 95% confidence interval (CI) values according to dementia. It was calculated via a multivariable Cox regression model, with adjustments for age, sex, visual acuity (VA), ocular and systemic comorbidities, and social factors (including body mass index, income, smoking, and drinking). RESULTS: In the multivariate analysis, the cataract surgery group showed a marginal difference in dementia development (HR 1.10 [95% CI 1.02-1.19]) because both cataract and dementia share common risk factors. However, in the subgroup analysis, men (HR 0.49 [95% CI 0.26-0.90]) and patients under 65 years of age (HR 0.88 [95% CI 0.79-0.99]) in the group with cataract surgery and good VA showed a significantly lower incidence of dementia. CONCLUSION: Through visual improvement, together with timely surgical intervention, the procedure can alleviate the risk of dementia in visually impaired patients, especially in younger and male patients.

Efficacy and safety of 1% and 2% rebamipide clear solution in dry eye disease: a multicenter randomized trial.

BACKGROUND: To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED). METHODS: Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment. RESULTS: The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups. CONCLUSIONS: 1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED.

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

BACKGROUND: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSIONS: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.