Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents.

During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

An analysis of the physicochemical properties of oral drugs from 2000 to 2022.

Calculable physicochemical descriptors are a useful guide to assist compound design in medicinal chemistry. It is well established that controlling size, lipophilicity, hydrogen bonding, flexibility and shape, guided by descriptors that approximate to these properties, can greatly increase the chances of successful drug discovery. Many therapeutic targets and new modalities are incompatible with the optimal ranges of these properties and thus there is much interest in approaches to find oral drug candidates outside of this space. These considerations have been a focus for a while and hence we analysed the physicochemical properties of oral drugs approved by the FDA from 2000 to 2022 to assess if such concepts had influenced the output of the drug-discovery community. Our findings show that it is possible to find drug molecules that lie outside of the optimal descriptor ranges and that large molecules in particular (molecular weight >500 Da) can be oral drugs. The analysis suggests that this is more likely if lipophilicity, hydrogen bonding and flexibility are controlled. Crude physicochemical descriptors are useful in that regard but more accurate and robust means of understanding substructural classes, shape and conformation are likely to be required to improve the chances of success in this space.

On the lasting impact of mild traumatic brain injury on working memory: Behavioural and electrophysiological evidence.

Despite increasing recognition of the significance of mild traumatic brain injury (mTBI), the long-term cognitive consequences of the injury remain unclear. More sensitive measures that can detect subtle cognitive changes and consideration of individual variability are needed to properly characterise cognitive outcomes following mTBI. Here, we used complex behavioural tasks, individual differences approaches, and electrophysiology to investigate the long-term cognitive effects of a history of mTBI. In Experiment 1, participants with self-reported mTBI history (n=82) showed poorer verbal working memory performance on the operation span task compared to control participants (n=88), but there were no group differences in visual working memory, multitasking, cognitive flexibility, attentional control, visuospatial ability, or information processing speed. Individual differences analyses revealed that time since injury and presence of memory loss predicted visual working memory capacity and visuospatial ability, respectively, in those with mTBI history. In Experiment 2, participants with mTBI history (n=20) again demonstrated poorer verbal working memory on the operation span task compared to control participants (n=38), but no group differences were revealed on a visuospatial complex span task or simpler visual working memory measures. We also explored the electrophysiological indices of visual working memory using EEG during a change detection task. No differences were observed in early sensory event-related potentials (P1, N1) or the later negative slow wave associated with visual working memory capacity. Together, these findings suggest that mTBI history may be associated with a lasting, isolated disruption in the subsystem underlying verbal working memory storage. The results emphasize the importance of sensitive cognitive measures and accounting for individual variability in injury characteristics when assessing mTBI outcomes.

Incident Epilepsy Among US Medicare Beneficiaries, 2019: Differences by Age, Sex, and Race/Ethnicity.

BACKGROUND AND OBJECTIVES: Epilepsy is common among older adults, but previous incident studies have had limited ability to make comparisons across key subgroups. We aimed to provide updated epilepsy incidence estimates among older adults, comparing across age, sex, and race/ethnicity. METHODS: Using a random sample of 4,999,999 US Medicare beneficiaries older than 65 years, we conducted a retrospective cohort study of epilepsy incidence using administrative claims for 2016-2019. Sampled beneficiaries were enrolled in the Fee-for-Service (FFS) program in each of 2016-2018 and had no epilepsy claims in those years. Non-Hispanic Black and Hispanic beneficiaries were oversampled to ensure adequate cases for detailed comparisons. Incidence in 2019 was identified in the Master Beneficiary Summary File as ≥1 inpatient claim or ≥2 outpatient nondrug claims occurring at least 1 day apart (ICD-10 G40.x). Incidence models were estimated by age, sex, race/ethnicity, and combinations thereof, with adjustment for the racial/ethnic oversampling. RESULTS: We identified 20,545 incident epilepsy cases. The overall epilepsy incidence rate (IR) was 393 per 100,000 (99% CI 385-400). Incidence peaked at ages 85-89 (504 [481-529]) and was higher for men (396 [385-407]) than women (376 [366-385]). The sex difference in IRs was constant with age. Incidence was higher for non-Hispanic Black (678 [653-702]) and Hispanic (405 [384-426]), and lower for non-Hispanic Asian/Pacific Islander (272 [239-305]) beneficiaries, compared with non-Hispanic White beneficiaries (354 [299-408]). The age-specific IRs significantly differed by race/ethnicity and sex, but only among non-Hispanic Black beneficiaries-where men had higher rates at younger ages and women at older ages. DISCUSSION: We found higher epilepsy IRs among those enrolled in the Medicare FFS system 2016-2019 than previous studies using Medicare claims data from at least a decade ago. The risk of epilepsy onset is higher for those in their late 80s, men, and non-Hispanic Black and Hispanic older adults. There is also evidence that these age-graded risks operate differently for Black men and Black women. Efforts to provide care and services that improve quality of life for older adults living with epilepsy should consider differences by multiple social characteristics simultaneously: age, sex, and race/ethnicity.

Ultrasound biomicroscopy in dogs suggests postoperative ocular hypertension may be associated with ciliary cleft changes related to cataract surgery.

OBJECTIVE: To determine whether novel pre- and postsurgical ultrasound biomicroscopy (UBM) measurements of the canine ciliary cleft (CC) are associated with postoperative ocular hypertension (POH) following cataract surgery and to explore the relationship between intraocular pressure and CC UBM measurements. METHODS: Following pharmacologic mydriasis, UBM images were obtained from 31 client-owned dogs before elective cataract surgery, immediately postsurgery, and 4 to 6 hours following surgery or while experiencing POH ≥ 25 mm Hg. Presurgery and the pre- to postsurgery change in CC measurements were assessed for association with POH using individual mixed-effects logistic regression models and forward variable selection models. Linear mixed-effects models were used to evaluate the relationship of intraocular pressure to UBM measurements within the same eye across multiple time points. RESULTS: Presurgical measurements were not predictive of POH development. An increase in pectinate ligament distance and CC area from presurgical baseline to immediate postsurgical measurement was associated with reduced odds of developing POH, while increasing CC length (from apex to mid point on the pectinate ligament) from pre- to postsurgery and immature cataracts was associated with increased odds of POH. CONCLUSIONs: The change in CC morphology following cataract surgery appears more impactful in the development of POH than individual variations in presurgery CC measurements. Several changes in the CC dimensions following surgery appear associated with POH risk. CLINICAL RELEVANCE: This understanding of a potential mechanism of POH development opens new avenues for researching preventative measures associated with modifying surgical techniques to influence CC morphology following cataract surgery.

Therapeutic errors involving diabetes medications reported to United States poison centers.

BACKGROUND: To investigate the characteristics and trends of therapeutic errors that occur outside of healthcare facilities involving diabetes medications reported to US poison centers. METHODS: National Poison Data System data from 2000 to 2021 were retrospectively analyzed. RESULTS: There were 157,623 exposure cases of non-healthcare facility-related therapeutic errors associated with diabetes medications as the primary substance reported to US poison centers from 2000 to 2021. The rate of all therapeutic errors involving diabetes medications increased by 279.8% from 2000 to 2011, followed by a slower 15.0% increase to 2021. Half (50.1%) of the exposure cases were treated/evaluated and released and 44.1% did not receive treatment in a healthcare facility; however, 9.9% experienced a serious medical outcome, including 17 fatalities, and 1.0% were admitted to a critical care unit and 2.2% to a non-critical care unit. Insulin had the highest rates of therapeutic errors and serious medical outcomes, while sulfonylureas and insulin had the highest medical hospital admission rates. Metformin accounted for 59% (n = 10) of fatalities. CONCLUSIONS: Although most cases of therapeutic errors involving diabetes medications had no or minimal clinical consequences, an important minority were associated with a serious medical outcome or medical hospital admission. Increased efforts to prevent therapeutic errors involving diabetes medications are warranted.

Duration of Morning Hyperinsulinemia Determines Hepatic Glucose Uptake and Glycogen Storage Later in the Day.

The second meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 hours of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, we administered the same total amount of insulin either over 2h in the first (Ins2h-A) or second (Ins2h-B) half of the morning, or over the entire 4h (Ins4h) of the morning. In the 4h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared to the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.

Paternal undernutrition and overnutrition modify semen composition and preimplantation embryo developmental kinetics in mice.

BACKGROUND: The importance of parental diet in relation to eventual offspring health is increasing in prominence due to the increased frequency of parents of reproductive age consuming poor diets. Whilst maternal health and offspring outcome have been studied in some detail, the paternal impacts are not as well understood. A father's poor nutritional status has been shown to have negative consequences on foetal growth and development and ultimately impact the long-term adult health of the offspring. In this study, we examined sperm- and seminal vesicle fluid-mediated mechanisms of preimplantation embryo development alterations in response to sub-optimal paternal diets. RESULTS: Male mice were fed a diet to model either under (low-protein diet (LPD)) or over (high-fat/sugar 'Western' diet (WD)) nutrition, LPD or WD supplemented with methyl donors or a control diet (CD) before mating with age-matched females. Male metabolic health was influenced by WD and MD-WD, with significant changes in multiple serum lipid classes and hepatic 1-carbon metabolites. Sperm RNA sequencing revealed significant changes to mRNA profiles in all groups when compared to CD (LPD: 32, MD-LPD: 17, WD: 53, MD-WD: 35 transcripts). Separate analysis of the seminal vesicle fluid proteome revealed a significant number of differentially expressed proteins in all groups (LPD: 13, MD-LPD: 27, WD: 24, MD-WD: 19) when compared to control. Following mating, in vitro time-lapse imaging of preimplantation embryos revealed a significant increase in the timing of development in all experimental groups when compared to CD embryos. Finally, qPCR analysis of uterine tissue at the time of implantation identified perturbed expression of Cd14 and Ptgs1 following mating with WD-fed males. CONCLUSIONS: Our current study shows that paternal nutritional status has the potential to influence male metabolic and reproductive health, impacting on embryonic development and the maternal reproductive tract. This study highlights potential direct (sperm-mediated) and indirect (seminal vesicle fluid-mediated) pathways in which a father's poor diet could shape the long-term health of his offspring.

How Might we Build an Equitable Future? Design Justice, a Counternarrative to Dominant Approaches in Medical Education.

PHENOMENON: Marginalized individuals in medicine face many structural inequities which can have enduring consequences on their progress. Therefore, inequity must be addressed by dismantling underlying unjust policies, environments, and curricula. However, once these injustices have been taken apart, how do we build more just systems from the rubble? Many current strategies to address this question have foundational values of urgency, solutionism, and top-down leadership. APPROACH: This paper explores a counternarrative: Design Justice. As a set of guiding principles, Design Justice centers the experiences and perspectives of marginalized individuals and communities. These principles include mutual accountability and transparency, co-ownership, and community-led outcomes, and honoring local, traditional, Indigenous knowledge. FINDINGS: Rooted in critical scholarship and critical design, Design Justice recognizes the interconnectedness of various forms of marginalization and works to critically examine power dynamics that exist in every design process. These co-created principles act as practical guardrails, directing progress toward justice. INSIGHTS: This paper begins with an overview of Design Justice's history in critical scholarship and critical design, providing foundational background knowledge for medical educators, scholars, and leaders in key concepts of justice and design. We explore how the Design Justice principles were developed and have been applied across sectors, highlighting its applications, including education applications. Finally, we raise critical questions about medical education prompted by Design Justice.

Improving rigor and reproducibility in western blot experiments with the blotRig analysis.

Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.

The War on Drugs, Racialized Capitalism, and Health Care Utilization Among White People Who Use Drugs in 22 Rural Appalachian Counties.

Objectives. To analyze War on Drugs encounters and their relationships to health care utilization among White people who use drugs (PWUD) in 22 Appalachian rural counties in Kentucky, West Virginia, Ohio, and North Carolina. Methods. We recruited White PWUD using chain referral sampling in 2018 to 2020. Surveys asked about criminal-legal encounters, unmet health care needs, and other covariates. We used generalized estimating equations to regress unmet need on criminal-legal encounters in multivariable models. Results. In this sample (n = 957), rates of stop and search, arrest, incarceration, and community supervision were high (44.0%, 26.8%, 36.3%, and 31.1%, respectively), as was unmet need (68.5%). Criminal-legal encounters were unrelated to unmet need (stops: adjusted prevalence ratio [APR] = 1.13; 95% confidence interval [CI] = 0.97, 1.32; arrest: APR = 0.95; 95% CI = 0.78, 1.15; incarceration: APR = 1.01; 95% CI = 0.89, 1.14; community supervision: APR = 0.99; 95% CI = 0.90, 1.09). Conclusions. Contrasting with findings from predominantly Black urban areas, criminal-legal encounters and unmet need were unrelated among White Appalachian PWUD. Research should explore whether and under what conditions White supremacy's benefits might buffer adverse impacts of the War on Drugs in Appalachia. (Am J Public Health. 2024;114(10):1086-1096. https://doi.org/10.2105/AJPH.2024.307744).

Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.

Partnership to Increase Care Access Through Mobile Outreach to Migrant Farm Communities: A Feasibility Study.

BACKGROUND: Health care access for migrant farmworkers is limited given the nature of seasonal farm work, including migration patterns, capacity, and availability of local community health services. Consideration of these contextual elements when exploring a community-academic partnership to increase access to care for migrant farmworkers is essential. OBJECTIVE: Explore the partnerships and processes for integrating nursing faculty and students from a regional public university's school of nursing into a farmworker health outreach program's mobile clinic process. METHODS: A feasibility study was undertaken using Bowen et al.'s feasibility framework. RESULTS: Integrating faculty and students into the farmworker health outreach program's mobile clinic process was determined to be feasible. CONCLUSIONS: Integrating faculty providers and students into a farmworker outreach program's mobile health process has several nuances requiring consideration before operationalizing the partnership, including nursing faculty practice (e.g., credentialing, malpractice insurance), student clinical placement processes, the farmworker outreach program's processes, and farmworker availability.

Transient hypoxia drives soil microbial community dynamics and biogeochemistry during human decomposition.

Human decomposition in terrestrial ecosystems is a dynamic process creating localized hot spots of soil microbial activity. Longer-term (beyond a few months) impacts on decomposer microbial communities are poorly characterized and do not typically connect microbial communities to biogeochemistry, limiting our understanding of decomposer communities and their functions. We performed separate year-long human decomposition trials, one starting in spring, another in winter, integrating bacterial and fungal community structure and abundances with soil physicochemistry and biogeochemistry to identify key drivers of microbial community change. In both trials, soil acidification, elevated microbial respiration, and reduced soil oxygen concentrations occurred. Changes in soil oxygen concentrations were the primary driver of microbial succession and nitrogen transformation patterns, while fungal community diversity and abundance was related to soil pH. Relative abundance of facultative anaerobic taxa (Firmicutes and Saccharomycetes) increased during the period of reduced soil oxygen. The magnitude and timing of the decomposition responses were amplified during the spring trial relative to the winter, even when corrected for thermal inputs (accumulated degree days). Further, soil chemical parameters, microbial community structure, and fungal gene abundances remained altered at the end of 1 year, suggesting longer-term impacts on soil ecosystems beyond the initial pulse of decomposition products.

Are histomorphological patterns a predictor for survival in uveal melanoma patients with hepatic metastases undergoing hepatic artery infusion chemotherapy?

INTRODUCTION: In uveal melanoma (UM) patients with hepatic metastases, hepatic artery infusion chemotherapy (HAIC) is a viable, palliative treatment option. To evaluate the impact of two histomorphological patterns (spindle cell vs. epithelioid) of liver metastases on median overall survival (mOS) in UM patients undergoing HAIC. METHODS: A retrospective analysis with 60 UM patients (29 females, mean age: 61.6 ± 12.1 years) with hepatic metastases was performed. Histomorphological patterns in metastases were analysed and classified as either predominant spindle cell or epithelioid pattern. mOS between both patient groups was analysed using Kaplan-Meier curves and the log-rank test. RESULTS: In 73.3% (44/60) of the metastases, a predominant epithelioid pattern, in 21.7% (13/60) a predominant spindle cell pattern, and in 5% (3/60) other patterns were found. No significant differences between patients with an epithelioid (mOS: 14.2 months, 95% CI: 8.8-19.6) and a spindle cell pattern (mOS: 14.4 months, 95% CI: 4.3-24.5) were detected by the log-rank test, χ2(2) = 0.22, P = 0.881. CONCLUSION: Histomorphological patterns of UM metastases do not seem to be a predictor for mOS in UM patients undergoing HAIC.

Early-stage implementation of peer-led interventions for emergency department patients with substance use disorder: Findings from a formative qualitative evaluation.

INTRODUCTION: Emergency department (ED)-based peer recovery coach (PRC) programs can improve access to substance use disorder treatment (SUD) for ED patients. As literature on early stages of PRC implementation is limited, we conducted a qualitative assessment of ED PRC program implementation from several US-based PRC programs focusing on barriers and facilitators for implementation and providing recommendations based on the findings. METHODS: We collected qualitative data from 39 key informants (peer recovery coaches, PRC program managers, ED physicians and staff, representatives of community-based organizations) via 6 focus groups and 21 interviews in February-December 2023. We transcribed audio-recordings and analyzed data using codebook thematic analysis. RESULTS: We identified the following major themes related to specific barriers and recommendations to address them. To facilitate timely linkage to PRCs, programs would regularly inform ED staff about the program and its linkage procedures, establish trust between PRC and ED staff, streamline the linkage procedures, and choose an "opt-out" linkage approach. To address barriers related to external referrals, programs use "warm handoff" and "warm line" strategies, maintain and update a comprehensive catalog of resources, and familiarize peer coaches with local service providers. Telehealth services implementation requires addressing logistical barriers, ensuring patients' privacy, and training peer coaches on building trust and rapport online. Peer coaches' wellness and quality of services can be improved by limiting PRC's workload, prioritizing quality over quantity, facilitating self-, peer- and professional care to mitigate stress and burnout; and, importantly, by providing supportive supervision and training to peer coaches and advocating for PRC team as an equal partner in the ED settings. To facilitate PRC program adoption and sustainment program managers engage local communities and program champions, seek diverse sources of funding, and advocate for structural changes to accommodate recruitment and retention of peer recovery coaches. CONCLUSIONS: We compiled a wealth of best practices used by PRC programs to address numerous implementation barriers and challenges. These recommendations are intended for PRC program planners, managers and champions, hospital leadership, and state and local public health agencies leading SUD epidemic response.

A Majority Of Americans Have No Or Low Awareness Of Paxlovid, The At-Home COVID-19 Treatment.

Oral Paxlovid (nirmatrelvir-ritonavir) is highly effective at preventing hospitalization and death from COVID-19, yet it has been remarkably underused, even by patients at highest risk from COVID-19, since its December 2021 introduction in the US. The reasons behind this underuse are still unclear. To examine public awareness and perceptions of Paxlovid that might help explain its underuse, we conducted a nationally representative survey of 1,430 US adults in July 2023. A majority of respondents (85 percent) had no or low awareness of Paxlovid, including 31 percent who had never heard of it. Even among those who were aware of the drug, many held misperceptions about its effectiveness (39 percent), adverse effects (86 percent), and requisite timing (61 percent) that could lead to underuse. Lower awareness and misperceptions were more common among medically vulnerable and disadvantaged populations who might benefit most from Paxlovid access, including adults unvaccinated against COVID-19, those with lower levels of education, and Black and Hispanic or Latino adults. Results suggest that Paxlovid underuse may be partly driven by a lack of effective public communication to generate awareness and knowledge about the drug, leading to low demand. As Paxlovid loses full government subsidies, further public outreach is needed to ensure that the public accesses it when needed.

Geographic disparities and surgical trends of strabismus surgery among Medicare beneficiaries (2016-2021).

This study highlights the disparity between the prevalence of adult strabismus in the United States and the limited number of surgeons performing adult strabismus surgery on Medicare beneficiaries. Only 12.2% of pediatric ophthalmologists billed Medicare for adult strabismus procedures during the study period. Additionally, geographic disparities of surgeons performing adult strabismus surgery were evident, with drastically different surgeon-to-patient ratios by state. Overall, the study raises concerns about the adequacy of the surgeon supply to meet the demand for adult strabismus cases.

Isolation of a blaNDM-1-positive strain in Israel predating the earliest observations from India.

blaNDM, the most prevalent carbapenemase among carbapenem-resistant Enterobacteriaceae, is thought to have emerged in India, as its initial detection in 2008 was linked to this country, and subsequent retrospective surveys had so far established the earliest blaNDM-positive strains to be isolated in India in 2005. Molecular dating and analyses suggest blaNDM emerged within Acinetobacter species decades prior to 2005 on a Tn125 transposon. Despite early reports of elevated rates of carbapenem-resistant Acinetobacter species in Israel starting in the 1990s, limited molecular data are available from this location. We searched for blaNDM among Acinetobacter species isolated in Israel between 2001 and 2006. One A. junii strain, Ajun-H1-3, isolated in January 2004, carried blaNDM-1 within a Tn125-like transposon on a 49-kb plasmid, pNDM-Ajun-H1-3, making Ajun-H1-3 the earliest NDM-positive isolate observed to date. The pNDM-Ajun-H1-3 plasmid matched numerous BJ01-like NDM-positive plasmids identified from 2005 onward in Acinetobacter species as well as Enterobacterales. These results indicate the need for further retrospective work on global strain archives to shed light on the conditions favoring the emergence as well as subsequent evolution and spread of blaNDM. IMPORTANCE: This study presents the earliest observation of blaNDM-1, isolated in a geographical region distant from where it is believed to have originated. In doing so, this study provides novel insights into the emergence and spread of blaNDM, the most prevalent carbapenemase among carbapenem-resistant Enterobacteriaceae, and its associated mobile genetic elements. It also sheds light on the conditions that foster the evolution of antimicrobial resistance, one of the greatest public health challenges we face.