A national analysis of systemic adverse events of beta-blockers used for glaucoma therapy.

PURPOSE: To evaluate systemic complications for timolol, carteolol, levobunolol, and/or betaxalol by using an FDA Federal Adverse Event Reporting System (FAERS). METHODS: We evaluated FAERS for adverse events associated with ß-blocker use for glaucoma. All reported symptoms were reviewed to identify systemic adverse events and to detect safety signals, defined as information on a new or known side effect that may be caused by a medicine. We used the proportional reporting ratio (PRR), reporting odds ratio (ROR), empirical Bayes geometric mean (EBGM), and information component (IC) as a part of a disproportionality analysis comparing the frequency of ß-blocker symptoms with all other adverse event reports. We considered a signal to be detected when all four disproportionality analysis metrics were positive. RESULTS: We found 10,500,309 total adverse event reports from the FAERS database 2004-2022Q3, which included 8,793 case reports with a primary suspect of a ß-blocker use for glaucoma. 1,838 unique adverse symptoms were reported were associated with ß-blocker. Regarding outcomes, there were 165 (1.88%) reports of disability, 671 (7.63%) reports of hospitalisation, and 1,934 (21.99%) reports of some other unspecified complication. Regarding adverse events, the most reported general, cardiac, and respiratory symptoms were respectively dizziness (n = 281), bradycardia (n = 145), and dyspnoea (n = 195). 256 (2.91%) cases of death were reported. We found significant signals on bradycardia (n = 145), complete atrioventricular block (n = 38), and bronchospasm (n = 23). No allergic, endocrine, constitutional, or gastrointestinal symptoms generated positive signals. CONCLUSION: ß-blocker use in glaucoma therapy can be rarely associated with serious systemic and life-threatening complications.

Recent trends and disparities in 24-hour movement behaviors among US youth with mental, behavioral and neurodevelopmental conditions.

BACKGROUND: Meeting 24-h movement behaviors (24-HMB: physical activity [PA], screen time [ST], and sleep [SL]) recommendations may be associated with positive health outcomes among youth with specific mental, behavioral, and neurodevelopmental (MBD) conditions. However, temporal trends and disparities in meeting 24-HMB guidelines in these higher-risk groups have not been investigated, hampering the development of evidence-based clinical and public health interventions. METHODS: Serial, cross-sectional analyses of nationally National Survey of Children's Health (NSCH) data (including U.S. youth aged 6-17 years with MBD conditions) were conducted. The time-trends survey data was conducted between 2016 and 2021. The prevalence of 24-HMB adherence estimates were reported for the overall sample and for various sociodemographic subgroups. The subgroups analyzed included: age group (children[aged 6 to 13 years], adolescents[aged 14 to 17 years]), sex, socioeconomic status, and ethnicity. RESULTS: Data on 52,634 individuals (mean age, 12.0 years [SD,3.5]; 28,829 [58.0 %] boys) were analyzed. From 2016 to 2021 the estimated trend in meeting PA + ST + SL guidelines declined (-0.8 % [95%CI, -1.0 % to -0.5 %], P for trend <0.001), whereas meeting none of 24-HMB guidelines increased (2.2 % [1.8 % to 2.6 %], P for trend <0.001). White participants, children, and boys reported higher estimated prevalence of meeting full integrated (PA + ST + SL) guidelines. DISCUSSION: The temporal trends observed in this study highlight the importance of consistently monitoring movement behavior among MBD youth and identifying variations by sociodemographic groups in meeting 24-HMB guidelines for health promotion within these vulnerable groups.

Innovating Flexor Tendon Repair Training with a Three-dimensional Printed Model.

Background: Flexor tendon repair is a technically demanding procedure, with functional outcome directly proportional to skillful execution. A repair must be strong to manage early mobilization and precise to allow for gliding through the tendon sheath. As a result, junior residents face a steep learning curve that may be mitigated by exposure to surgical simulators. Methods: To facilitate flexor tendon repair training, a surgical training device and accompanying instructional video were developed. Simulation workshops were held for junior orthopedic and plastic surgery residents (n = 11). To objectively assess validity of the curriculum, study participants performed cadaveric flexor tendon repairs before and after the workshop. Anonymous recordings of these repairs were graded by two certified hand surgeons. Additionally, a tensometer was used to measure strength of repair. Results: Model realism, educational utility, and overall usefulness rated high: 4.6 ±â€…0.52 95% confidence interval (CI) for realism, 4.9 ±â€…0.42 95% CI for device, 4.7 ±â€…0.96 95% CI for video, and 4.9 ±â€…0.66 95% CI overall. Subjective confidence increased after the training session (73% ranked "moderately" or "extremely"). Likewise, scores given by the surgeons grading the repairs improved for overall quality and time of repair (pre: 2.77 ±â€…0.61, post: 4.22 ±â€…0.56, P= 0.0002). Strength of repair did not change (P = 0.87). Conclusions: The proposed three-dimensional surgical simulator for flexor tendon repair is realistic and useful, with improved surgical technique and improved confidence demonstrated after use. This design can be three-dimensionally printed en masse and provide value to hand surgery training curriculum.

Are Alpha-2 Adrenergic Agonists Being Used in Infants?

Purpose: To identify and quantify adverse events (AEs) associated with alpha-2 adrenergic agonists prescribed for the treatment of glaucoma in infants. Methods: We queried the Federal Adverse Event Reporting System (FAERS) from 2004-2023Q1 for AE reports related to brimonidine use in patients aged 12 months or younger. We then conducted a disproportionality analysis using data mining algorithms, including the reporting odds ratio, proportional reporting ratio, empirical bayes geometric mean, and information component to identify significant symptoms. Results: We identified 35 unique AE reports associated with brimonidine. Of these, 27 cases involved hospitalization, 13 cases involved life-threatening complications, 18 cases reported other complications, and 1 case involved a congenital anomaly. The most commonly reported AE was hypotonia, occurring in 20 cases. This was followed by other systemic symptoms, including hypothermia, depressed level of consciousness, lethargy, general toxicity, and pallor, among others. All symptoms were found to be significant in the disproportionality analysis. Notably, most cases were not known to involve an ophthalmic route of exposure. Conclusions: The use of alpha-2 adrenergic agonists in infants aged 1 year or younger has been associated with various systemic AEs, including hypotension, respiratory depression, and central nervous system depression. Ophthalmologists should be aware of these potential risks. Further, more rigorous warnings should be in place to prevent unintentional exposure of infants to brimonidine.

Evaluating Research Activity and NIH-Funding Among Academic Ophthalmologists Using Relative Citation Ratio.

PURPOSE: The objective of this study was to evaluate the relationship between research activity and National Institutes of Health (NIH) funding status of the United States (US) academic ophthalmologists. METHODS: A retrospective cross-sectional analysis of bibliometric data was conducted. The NIH Research Portfolio Online Reporting Tools Expenditures and Reports (rePORTER) website was utilized to identify ophthalmology departments in the US that received NIH funding. Affiliated faculty from these institutions were then identified using NIH rePORTER and institutional websites. H-index was calculated using the Scopus database, and the NIH iCite tool was used to determine the Relative Citation Ratio (RCR). The h-index and w-RCR quantified research productivity, while m-RCR measured research impact. RESULTS: Data on 2688 faculty members from 66 departments we re identified, of which 21% were NIH-funded. Faculty members who received NIH-funding had significantly greater research productivity and impact as measured by h-index (32.5 vs 16.6; p < .001), m-RCR (2.2 vs 1.6; p < .001), and w-RCR (147.2 vs 70.1; p < .001) than their non-funded peers. When stratified by academic rank, NIH-funded faculty still had significantly higher h-index (16.1 vs 7.9; p < .001), m-RCR (2.2 vs 1.4; p < .001), and w-RCR (63.2 vs 61.8; p < .001) than non-funded peers. A similar trend was observed among non-tenured faculty members. CONCLUSION: NIH funding is associated with higher research productivity and impact among US academic ophthalmologists as measured by h-index and RCR, which suggests that NIH funding may be a critical factor in enhancing scholarly contributions of ophthalmologists.  These findings underscore the importance of continued investment in NIH funding to foster high-impact research within the field of ophthalmology.

Origins of fine structure in DNA melting curves.

With the help of the one-dimensional random Potts-like model, we study the origins of fine structures observed on differential melting profiles of double-stranded DNA. We theoretically assess the effects of sequence arrangement on DNA melting curves through the comparison of results for random, correlated, and block sequences. Our results re-confirm the smearing out of the fine structure with the increase in chain length for all types of sequence arrangements and suggest that the fine structure is a finite-size effect. We have found that the fine structures on melting curves of chains comprised of blocks with correlations in sequence are more persistent, probably because of increased sequence disorder the blocks introduce. Many natural DNAs show a well-expressed fine structure of melting profiles. Our results for block sequences may suggest the existence of such sequence motifs in natural DNA sequences.

Sociodemographic Trends and Perinatal Outcomes in Fathers 50 Years and Older.

Importance: The age of fathers at childbirth is rising, with an increasing number of births attributed to older fathers. While the impact of advanced paternal age has been documented, sociodemographic data about fathers aged 50 years and older remain scarce. Objectives: To explore sociodemographic and temporal trends among the oldest US fathers (age ≥50 years) and their associations with perinatal outcomes. Design, Setting, and Participants: This retrospective cross-sectional study included data from all US births from 2011 to 2022 using the National Vital Statistics System. Data were analyzed from August 2023 and May 2024. Exposures: Reported paternal age at childbirth. Main Outcomes and Measures: Outcomes of interest were sociodemographic factors, temporal trends in older fatherhood, and perinatal outcomes, including preterm birth, low birth weight, gestational diabetes, gestational hypertension, assisted reproductive technology (ART), rates of maternal primiparity, and the infant sex ratio. Results: From 2011 to 2022, the US recorded 46 195 453 births, with an overall mean (SD) paternal age of 31.5 (6.8) years and 484 507 (1.1%) involving fathers aged 50 years or older, 47 785 (0.1%) aged 60 years or older, and 3777 (0.008%) aged 70 years or older. Births to fathers aged 50 years or older increased from 1.1% in 2011 to 1.3% in 2022 (P for trend < .001). Fathers aged 50 years or older were more diverse, with variations in educational achievement and race and ethnicity. Marital status and maternal racial and ethnic and educational backgrounds also varied by paternal age and race. Despite controlling for maternal age and other sociodemographic and perinatal factors, every 10-year increase in paternal age was consistently associated with greater use of ART (eg, age 50-59 years: adjusted odds ratio [aOR], 2.23; 95% CI, 2.19-2.27), higher likelihood of first maternal birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.17), and increased risks of preterm birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.18) and low birth weight (eg, age 50-59 years: aOR, 1.14; 95% CI, 1.13-1.15) compared with fathers aged 30 to 39 years. No significant changes in the infant sex ratio were observed, except among fathers aged 70 years or older (aOR, 0.92; 95% CI, 0.86-0.99) and 75 years or older (aOR, 0.84; 95% CI, 0.73-0.97), who showed a decreased likelihood of having male offspring. Conclusions and Relevance: In this cross-sectional study of all US births from 2011 to 2022, the percentage attributed to older fathers, while small, increased. Notable variations in paternal and maternal race and education were identified. Older fatherhood was associated with increased ART use, first-time maternal births, adverse perinatal outcomes, and altered sex ratio. Further research of this population is crucial for improving patient counseling and family planning.

Micronuclear collapse from oxidative damage.

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.

Adjunctive use of netarsudil 0.02% in the treatment of refractory glaucoma: a one year analysis.

PURPOSE: This study evaluates the long-term adjunctive use of netarsudil ophthalmic solution 0.02% in lowering IOP in patients with refractory glaucoma. METHODS: This retrospective chart review study was conducted at a tertiary care center. Patients who were prescribed add-on netarsudil therapy and on ≥ 3 topical glaucoma medications from 01/01/2018 to 08/31/2020 were reviewed. 47 patients (69 eyes) met the inclusion criteria. Baseline IOPs prior to the addition of netarsudil were compared to IOPs measured at 3-, 6-, and 12-month intervals. Any patients with inadequate follow-up or who had glaucoma surgery after netarsudil initiation were excluded. RESULTS: Median baseline IOP (± SD) was 21 ± 5.8 mmHg (median of 2 visits prior to initiation of netarsudil). At 3-month follow-up, 64 eyes had a median IOP of 16 ± 6.7 mmHg (p < 0.01). At 6-month follow-up, 56 eyes had a median IOP of 18 ± 4.6 mmHg (p < 0.01). At 12-month follow-up, 44 eyes had a median IOP of 15 ± 6.8 mmHg (p < 0.01). At the conclusion of the study, 64% of eyes reached 1 year follow-up due to several reasons. CONCLUSIONS: Patients with refractory glaucoma showed statistically and clinically significant IOP reductions on netarsudil. IOP reduction was stable long-term with the largest decrease in IOP seen at 12 months. Although some patients will still go on to require further laser or incisional surgery, for most patients netarsudil is an effective treatment for adjunctive use in refractory glaucoma.

Discovery of Novel Peptide Antagonists Targeting GPR55 for Liver Inflammation and Fibrosis.

Liver fibrosis is a condition characterized by aberrant proliferation of connective tissue in the liver resulting from diverse etiological factors. G protein-coupled receptor GPR55 has recently been identified as a regulator of liver diseases. Herein, we report the discovery of a cyclic peptide P1-1 that antagonizes GPR55 and suppresses collagen secretion in hepatic stellate cells. The alanine scanning and docking study was carried out to predict the binding mode and allowed for further structural optimization of peptide antagonists for GPR55. The subsequent in vivo study demonstrated that P1-1 ameliorates CCl4-induce and MCD-diet-induce acute liver inflammation and fibrosis. Further study indicates that P1-1 reduces reactive oxygen species (ROS) production, attenuates ER stress, and inhibits mitochondria-associated hepatocyte apoptosis. In this work, we provided the first successful example of antagonizing GPR55 for liver inflammation and fibrosis, which validates GPR55 as a promising target for the treatment of liver fibrosis and affords a high-potent GPR55 antagonist P1-1 as a potential therapeutic candidate.

Chromosomal instability as a driver of cancer progression.

Chromosomal instability (CIN) refers to an increased propensity of cells to acquire structural and numerical chromosomal abnormalities during cell division, which contributes to tumour genetic heterogeneity. CIN has long been recognized as a hallmark of cancer, and evidence over the past decade has strongly linked CIN to tumour evolution, metastasis, immune evasion and treatment resistance. Until recently, the mechanisms by which CIN propels cancer progression have remained elusive. Beyond the generation of genomic copy number heterogeneity, recent work has unveiled additional tumour-promoting consequences of abnormal chromosome segregation. These mechanisms include complex chromosomal rearrangements, epigenetic reprogramming and the induction of cancer cell-intrinsic inflammation, emphasizing the multifaceted role of CIN in cancer.

Auditory hair cells and spiral ganglion neurons regenerate synapses with refined release properties in vitro.

Ribbon synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) in the inner ear are damaged by noise trauma and with aging, causing "synaptopathy" and hearing loss. Cocultures of neonatal denervated organs of Corti and newly introduced SGNs have been developed to find strategies for improving IHC synapse regeneration, but evidence of the physiological normality of regenerated synapses is missing. This study utilizes IHC optogenetic stimulation and SGN recordings, showing that, when P3-5 denervated organs of Corti are cocultured with SGNs, newly formed IHC/SGN synapses are indeed functional, exhibiting glutamatergic excitatory postsynaptic currents. When using older organs of Corti at P10-11, synaptic activity probed by deconvolution showed more mature release properties, closer to the specialized mode of IHC synaptic transmission crucial for coding the sound signal. This functional assessment of newly formed IHC synapses developed here, provides a powerful tool for testing approaches to improve synapse regeneration.

Uveal Effusion Syndrome Temporally Associated with Primary COVID-19 Infection.

PURPOSE: To report a case of uveal effusion syndrome in association with primary COVID-19 infection to share our experience and insight in diagnosing and managing this unique case. CASE PRESENTATION: A 56-year-old woman presented with angle closure glaucoma of both eyes. Further examination and imaging revealed the etiology to be related to bilateral uveal effusions and choroidal thickening in the setting of recent COVID-19 infection. The patient's glaucoma was managed with bilateral iridotomies and medical therapy, while the precipitating uveal effusions resolved with treatment on oral steroids. CONCLUSION: While uveal effusion syndrome has been associated with COVID-19 vaccination, it has not yet been reported after primary infection. Recognition of this rare phenomenon will allow for better diagnosis and treatment in future cases.

Emerging alternatives to keratoplasty for corneal endothelial cell dysfunction.

PURPOSE OF REVIEW: While effective for treating endothelial dysfunction, keratoplasty has shortcomings including limited access to donor tissue for much of the world. Thus, alternative strategies are under development. This review explores the main advancements achieved in this field during 2022-2023. RECENT FINDINGS: Recent publications further support the validity of intracameral cultivated allogeneic endothelial cell injection and Descemet stripping only, while emphasizing the benefits of adjunctive Rho-associated kinase inhibitor (ROCKi) therapy. New donor-independent artificial implants, such as EndoArt, show favorable results. Multiple pharmacologic agents, especially ROCKi, show promise as monotherapies, yet none are currently approved for human treatment. Multiple regenerative and genetic therapies are being investigated but all are still in preclinical stages. SUMMARY: A plethora of innovative alternatives to keratoplasty for endothelial disease is in development. Among these, surgical methods are still the mainstay of treatment and closest to clinical application, though further studies to establish their benefits over keratoplasty are needed. Albeit promising, pharmacologic, regenerative, and genetic approaches require validation and are farther from clinical application.

A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis.

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. PURPOSE/INTRODUCTION: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. METHODS: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. RESULTS: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. CONCLUSIONS: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20.

CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.

Single-Lesion Skin Cancer Risk Stratification Triage Pathway.

Importance: Access to timely dermatologic care remains a challenge, especially for patients with new skin lesions. Assessing the efficiency of new triage pathways may assist in better resource allocation and shorter time to care. Objective: To evaluate whether a rule-based triage system was associated with better skin cancer risk stratification of patients and reduced wait times. Design, Setting, and Participants: This retrospective quality improvement cohort study of patients referred to Stanford University dermatology clinics was conducted between November 2017 and January 2023. A rules-based triage system based on a priori-determined high-risk lesion characteristics was implemented. Exposures: Referral reasons and risk factors of patients provided by their primary care physicians. Main Outcomes and Measures: Biopsy results of patients (diagnosis of any skin cancer and melanoma) at their visit or within 6 months after the visit. Regression models were used to assess the association between risk factors at referral and (1) biopsy outcomes and (2) time to first visit, adjusting for sociodemographic factors. Results: Among 37 478 patients (mean [SD] age, 54 (18) years; 21 292 women [57%]), the rates of aggregate biopsy, malignant biopsy specimens, and melanoma were comparable across patients seen after (n = 12 302) and before (n = 25 176) the implementation of the new triage pathway. Patients seen through the lesion pathway had a higher risk of having malignant biopsy results (adjusted risk ratio [aRR], 1.6; 95% CI, 1.4-1.9) and melanoma (aRR, 2.0; 95% CI, 1.2-3.2) than those not seen through the pathway. Lesions that were concerning to referring clinicians for skin cancer were associated with an increased risk of skin cancer (all skin cancer: aRR, 2.8; 95% CI, 2.2-3.5; melanoma: aRR, 2.02; 95% CI, 1.1-3.7). Patients in the 3 high-risk lesion groups were seen faster in the new triage pathway (mean reduction, 26 days; 95% CI, 18-34 days). Conclusions and Relevance: In this study, a new automated, rules-based referral pathway was implemented that expedited care for patients with high-risk skin cancer. This reform may have contributed to improving patient stratification, reducing the time from referral to first encounter, and maintaining accuracy in identifying malignant lesions. The findings highlight the potential to optimize clinical resource allocation by better risk stratification of referred patients.