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The Argentinian flag sign (AFS) is a feared complication during cataract extraction. Intralenticular pressures, especially excessive posterior pressure, have been identified as potential mechanisms for capsular stress and tearing associated with AFS. Capsular tension is created by positive intralenticular pressures, which cause the irido-lens diaphragm to move anteriorly once the manual capsulorhexis has been initiated. This tension can cause inadvertent tears that self-propagate to the lens equator, causing an AFS, among other intraoperative complications. Thus, this review highlights the importance of identifying intumescent cataracts as well as a combination of techniques to relieve intracapsular pressures needed to prevent AFS. However, some instances of anterior capsular tears are unavoidable. Therefore, focus will also be placed on techniques during cataract extraction used to manage anterior capsular tears, mitigating extension to the posterior capsule.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout ([Tet2.sup.-/-]) and floxed control mice ([Tet2.sup.fl/fl]) with Streptococcus pneumoniae. As with human CHIP carriers, [Tet2.sup.-/-] mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in [Tet2.sup.-/-] mice. We delineated the transcriptional landscape of [Tet2.sup.-/-] neutrophils and found that, while inflammation-related pathways were upregulated in [Tet2.sup.-/-] neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by [Tet2.sup.-/-] neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments., Introduction Human aging is accompanied by dysregulation of hematopoiesis in the bone marrow (BM), which may have adverse clinical consequences (1). Hematopoiesis is a tightly regulated process by which hematopoietic [...]

Abnormal involuntary movements, or dyskinesias, are seen in many neurologic diseases, including disorders where the brain appears grossly normal. This observation suggests that alterations in neural activity or connectivity may underlie dyskinesias. One influential model proposes that involuntary movements are driven by an imbalance in the activity of striatal direct and indirect pathway neurons (dMSNs and iMSNs, respectively). Indeed, in some animal models, there is evidence that dMSN hyperactivity contributes to dyskinesia. Given the many diseases associated with dyskinesia, it is unclear whether these findings generalize to all forms. Here, we used male and female mice in a mouse model of paroxysmal nonkinesigenic dyskinesia (PNKD) to assess whether involuntary movements are related to aberrant activity in the striatal direct and indirect pathways. In this model, as in the human disorder PNKD, animals experience dyskinetic attacks in response to caffeine or alcohol. Using optically identified striatal single-unit recordings in freely moving PNKD mice, we found a loss of iMSN firing during dyskinesia bouts. Further, chemogenetic inhibition of iMSNs triggered dyskinetic episodes in PNKD mice. Finally, we found that these decreases in iMSN firing are likely because of aberrant endocannabinoid-mediated suppression of glutamatergic inputs. These data show that striatal iMSN dysfunction contributes to the etiology of dyskinesia in PNKD, and suggest that indirect pathway hypoactivity may be a key mechanism for the generation of involuntary movements in other disorders.SIGNIFICANCE STATEMENT Involuntary movements, or dyskinesias, are part of many inherited and acquired neurologic syndromes. There are few effective treatments, most of which have significant side effects. Better understanding of which cells and patterns of activity cause dyskinetic movements might inform the development of new neuromodulatory treatments. In this study, we used a mouse model of an inherited human form of paroxysmal dyskinesia in combination with cell type-specific tools to monitor and manipulate striatal activity. We were able to narrow in on a specific group of neurons that causes dyskinesia in this model, and found alterations in a well-known form of plasticity in this cell type, endocannabinoid-dependent synaptic LTD. These findings point to new areas for therapeutic development.

Geographic information systems (GIS) have been used to understand relationships between trauma mechanisms, locations and social determinants for injury prevention. We hypothesized that GIS analysis of trauma center registry data for assault patients ages 14-29 with census tract data would identify geospatial and structural determinants of youth violence. Admissions to a Level 1 trauma center from 2010 to 2019 were retrospectively reviewed to identify assaults in those 14-29 years. Prisoners were excluded. Home and injury scene addresses were geocoded. Cluster analysis was performed with the Moran I test for spatial autocorrelation. Census tract comparisons were done using American Communities Survey (ACS) data by t-test and linear regression. There were 1608 admissions, 1517 (92.4%) had complete addresses and were included in the analysis. Mean age was 23 yrs ± 3.8, mean ISS was 7.5 ± 6.2, there were 11 (0.7%) in-hospital deaths. Clusters in six areas of the trauma catchment were identified with a Moran I value of 0.24 (Fig 1, Z score = 17.4, p < 0.001). Linear regression of ACS demographics showed predictors of assault were unemployment (OR 4.5, 95% CI: 2.7- 6.4, p < 0.001), Spanish spoken at home (OR 6.6, 95% CI: 3.4-9.8, p < 0.001) and poverty level (OR 1.9, 95% CI: 1.1-2.7, p < 0.001). Education level of less than high school diploma, single parent households and race were not significant predictors. GIS analysis of registry data can identify high risk areas for youth violence and correlated social and structural determinants. Violence prevention efforts can be better targeted geographically and socioeconomically with better understanding of these risk factors. Epidemiological, level III.

Ras homolog family member A (RhoA) acts as a signaling hub in many cellular processes, including cytoskeletal dynamics, division, migration, and adhesion. RhoA activity is tightly spatiotemporally controlled, but whether downstream effectors share these activation dynamics is unknown. We developed a novel single-color FRET biosensor to measure Rho-associated kinase (ROCK) activity with high spatiotemporal resolution in live cells. We report the validation of the Rho-Kinase Activity Reporter (RhoKAR) biosensor. RhoKAR activation was specific to ROCK activity and was insensitive to PKA activity. We then assessed the mechanisms of ROCK activation in mouse fibroblasts. Increasing intracellular calcium with ionomycin increased RhoKAR activity and depleting intracellular calcium with EGTA decreased RhoKAR activity. We also investigated the signaling intermediates in this process. Blocking calmodulin or CaMKII prevented calcium-dependent activation of ROCK. These results indicate that ROCK activity is increased by calcium in fibroblasts and that this activation occurs downstream of CaM/CaMKII.

PurposeUnited States (US) Latinos have the lowest educational attainment of any US racial/ethnic group, which may contribute to their disparate burden of Type 2 Diabetes. Herein, we aimed to examine the association between intergenerational educational mobility and Type 2 Diabetes among US Latino adults.MethodsWe used data from the Niños Lifestyle and Diabetes Study (2013-2014) and the Sacramento Area Latino Study on Aging (1998-1999) to link 616 adult Latino children to their parents. Model-based standardization and robust Poisson regression were used to estimate the prevalence of prediabetes, Type 2 Diabetes, treatment and glycemic control, and describe their associations with intergenerational educational mobility.ResultsAdult children with stable high intergenerational educational attainment had a higher prevalence of prediabetes (Prevalence Ratio, PR=1.58; 95% Confidence Interval, CI=1.08, 2.34) and lower prevalence of Type 2 Diabetes (PR=0.64, CI=0.41, 0.99), as compared to those who experienced low educational attainment across generations. Downward mobility was associated with a higher prevalence of prediabetes (PR=1.54, CI=1.06, 2.23) and worse glycemic control (PR=2.20, CI=1.13, 4.30), and upward mobility was associated with a lower prevalence of Type 2 Diabetes (PR=0.39, CI=0.22, 0.70).ConclusionsOur findings from a predominantly Mexican-heritage community suggest that higher education across generations may buffer individuals from glycemic dysregulation. As such, higher education may be a promising public health target to address the rising burden of Type 2 Diabetes in the US.

IntroductionPatient outcome prediction models are underused in clinical practice because of lack of integration with real-time patient data. The electronic health record (EHR) has the ability to use machine learning (ML) to develop predictive models. While an EHR ML model has been developed to predict clinical deterioration, it has yet to be validated for use in trauma. We hypothesized that the Epic Deterioration Index (EDI) would predict mortality and unplanned intensive care unit (ICU) admission in trauma patients.MethodsA retrospective analysis of a trauma registry was used to identify patients admitted to a level 1 trauma center for >24 hours from October 2019 to July 2020. We evaluated the performance of the EDI, which is constructed from 125 objective patient measures within the EHR, in predicting mortality and unplanned ICU admissions. We performed a 5 to 1 match on age because it is a major component of EDI, then examined the area under the receiver operating characteristic curve (AUROC), and benchmarked it against Injury Severity Score (ISS) and new injury severity score (NISS).ResultsThe study cohort consisted of 1,325 patients admitted with a mean age of 52.5 years and 91% following blunt injury. The in-hospital mortality rate was 2%, and unplanned ICU admission rate was 2.6%. In predicting mortality, the maximum EDI within 24 hours of admission had an AUROC of 0.98 compared with 0.89 of ISS and 0.91 of NISS. For unplanned ICU admission, the EDI slope within 24 hours of ICU admission had a modest performance with an AUROC of 0.66.ConclusionEpic Deterioration Index appears to perform strongly in predicting in-patient mortality similarly to ISS and NISS. In addition, it can be used to predict unplanned ICU admissions. This study helps validate the use of this real-time EHR ML-based tool, suggesting that EDI should be incorporated into the daily care of trauma patients.Level of evidencePrognostic, level III.

BackgroundThe etiology of dementias and cognitive decline remain largely unknown. It is widely accepted that inflammation in the central nervous system plays a critical role in the pathogenesis of dementia. However, less is known about the role of the peripheral immune system and interactions with cortisol, though evidence suggests that these, too, may play a role.MethodsUsing data from 1337 participants aged 60+ years from the Sacramento Area Latino Study of Aging (observational cohort) we investigated variation in trajectories of cognitive decline by pathogen IgG and cytokine levels. Linear mixed effects models were used to examine the association between baseline Interleukin (IL)-6, C-reactive protein, tumor necrosis factor (TNF)-α, and five persistent pathogens' IgG response and trajectories of cognition over 10 years, and to examine interactions between immune biomarkers and cortisol. Stratified cumulative incidence functions were used to assess the relation between biomarkers and incident dementia. Inverse probability weights accounted for loss-to-follow-up and confounding.ResultsIL-6, TNF-α, and CMV IgG were statistically significantly associated with a higher log of Modified Mini-Mental State Examination errors (IL-6, β=0.0935 (95%CI: 0.055, 0.13), TNF-alpha β= 0.0944 (95%CI: 0.032, 0.157), and CMV, β= 0.0409 (95%CI: 0.013, 0.069)). Furthermore, cortisol interacted with HSV-1 and IL-6, and CRP for both cross-sectional cognitive function and rate of decline. No statistically significant relationship was detected between biomarkers and incidence of dementia.ConclusionsThese findings support the theory that the peripheral immune system may play a role in cognitive decline but not incident dementia. Furthermore, they identify specific markers amenable for intervention for slowing decline.

Detrimental effects of early life stress on cardiovascular health are evident in adolescence. Cardiovascular reactivity and recovery in response to interpersonal stress may be a mechanism. This study aimed to evaluate if adolescent girls with higher early life stress demonstrated greater cardiovascular reactivity and slower recovery to peer rejection. A sample of 92 adolescent girls (age: M = 13.24) self-reported early life stressors. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were continuously measured before, during, and after a laboratory peer rejection paradigm. Counter to hypotheses, adolescent girls with higher early life stress had lower, not higher, HR during the recovery period. Early life stress was not associated with SBP or DBP recovery. Additionally, early life stress was not associated with SBP, DBP, or HR reactivity. Future research is needed to assess if blunted cardiovascular reactivity to interpersonal rejection during adolescence is a mechanism linking early life stress and later cardiovascular disease risk in women., Author(s): Sharon Y. Lee [sup.1] [sup.2] , Chrystal Vergara-Lopez [sup.1] [sup.2] , Margaret H. Bublitz [sup.1] [sup.3] [sup.4] , Allison E. Gaffey [sup.5] [sup.6] , Christina D'Angelo [sup.1] [sup.7] , [...]

Abstract Background The genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. Methods Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). Results Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. Conclusions To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis–trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

Abstract Background Traditionally, weight loss (WL) trials utilize dual energy X‐ray absorptiometry (DXA) to measure lean mass. This method assumes lean mass, as the sum of all non‐bone and non‐fat tissue, is a reasonable proxy for muscle mass. In contrast, the D3‐creatine (D3Cr) dilution method directly measures whole body skeletal muscle mass, although this method has yet to be applied in the context of a geriatric WL trial. The purpose of this project was to (1) describe estimates of change and variability in D3Cr muscle mass in older adults participating in an intentional WL intervention and (2) relate its change to other measures of body composition as well as muscle function and strength. Methods The INVEST in Bone Health trial (NCT04076618), used as a scaffold for this ancillary pilot project, is a three‐armed, 12‐month randomized, controlled trial designed to determine the effects of resistance training or weighted vest use during intentional WL on a battery of musculoskeletal health outcomes among 150 older adults living with obesity. A convenience sample of 24 participants (n = 8/arm) are included in this analysis. At baseline and 6 months, participants were weighed, ingested a 30 mg D3Cr tracer dose, provided a fasted urine sample 3–6 days post‐dosage, underwent DXA (total body fat and lean masses, appendicular lean mass) and computed tomography (mid‐thigh and trunk muscle/intermuscular fat areas) scans, and performed 400‐m walk, stair climb, knee extensor strength, and grip strength tests. Results Participants were older (68.0 ± 4.4 years), mostly White (75.0%), predominantly female (66.7%), and living with obesity (body mass index: 33.8 ± 2.7 kg/m2). Six month total body WL was −10.3 (95% confidence interval, CI: −12.7, −7.9) kg. All DXA and computed tomography‐derived body composition measures were significantly decreased from baseline, yet D3Cr muscle mass did not change [+0.5 (95% CI: −2.0, 3.0) kg]. Of muscle function and strength measures, only grip strength significantly changed [+2.5 (95% CI: 1.0, 4.0) kg] from baseline. Conclusions Among 24 older adults, significant WL with or without weighted vest use or resistance training over a 6‐month period was associated with significant declines in all bioimaging metrics, while D3Cr muscle mass and muscle function and strength were preserved. Treatment assignment for the trial remains blinded; therefore, full interpretation of these findings is limited. Future work in this area will assess change in D3Cr muscle mass by parent trial treatment group assignment in all study participants.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

ABSTRACTArginine catabolism by the bacterial arginine deiminase system (ADS) has anticariogenic properties through the production of ammonia, which modulates the pH of the oral environment. Given the potential protective capacity of the ADS pathway, the exploitation of ADS-competent oral microbes through pre- or probiotic applications is a promising therapeutic target to prevent tooth decay. To date, most investigations of the ADS in the oral cavity and its relation to caries have focused on indirect measures of activity or on specific bacterial groups, yet the pervasiveness and rate of expression of the ADS operon in diverse mixed microbial communities in oral health and disease remain an open question. Here, we use a multivariate approach, combining ultra-deep metatranscriptomic sequencing with paired metataxonomic and in vitro citrulline quantification to characterize the microbial community and ADS operon expression in healthy and late-stage cavitated teeth. While ADS activity is higher in healthy teeth, we identify multiple bacterial lineages with upregulated ADS activity on cavitated teeth that are distinct from those found on healthy teeth using both reference-based mapping and de novo assembly methods. Our dual metataxonomic and metatranscriptomic approach demonstrates the importance of species abundance for gene expression data interpretation and that patterns of differential expression can be skewed by low-abundance groups. Finally, we identify several potential candidate probiotic bacterial lineages within species that may be useful therapeutic targets for the prevention of tooth decay and propose that the development of a strain-specific, mixed-microbial probiotic may be a beneficial approach given the heterogeneity of taxa identified here across health groups.IMPORTANCETooth decay is the most common preventable chronic disease, affecting more than two billion people globally. The development of caries on teeth is primarily a consequence of acid production by cariogenic bacteria that inhabit the plaque microbiome. Other bacterial strains in the oral cavity may suppress or prevent tooth decay by producing ammonia as a byproduct of the arginine deiminase metabolic pathway, increasing the pH of the plaque biofilm. While the benefits of arginine metabolism on oral health have been extensively documented in specific bacterial groups, the prevalence and consistency of arginine deiminase system (ADS) activity among oral bacteria in a community context remain an open question. In the current study, we use a multi-omics approach to document the pervasiveness of the expression of the ADS operon in both health and disease to better understand the conditions in which ADS activity may prevent tooth decay.

AimThe rise of wearable sensing technology shows promise for addressing the challenges of measuring motor behavior in pediatric populations. The current pediatric wearable sensing literature is highly variable with respect to the number of sensors used, sensor placement, wearing time, and how data extracted from the sensors are analyzed. Many studies derive conceptually similar variables via different calculation methods, making it hard to compare across studies and clinical populations. In hopes of moving the field forward, this report provides referent upper limb wearable sensor data from accelerometers on 25 variables in typically-developing children, ages 3–17 years.MethodsThis is a secondary analysis of data from three pediatric cohorts of children 3–17 years of age. Participants (n = 222) in the cohorts wore bilateral wrist accelerometers for 2–4 days for a total of 622 recording days. Accelerometer data were reprocessed to compute 25 variables that quantified upper limb movement duration, intensity, symmetry, and complexity. Analyses examined the influence of hand dominance, age, gender, reliability, day-to-day stability, and the relationships between variables.ResultsThe majority of variables were similar on the dominant and non-dominant sides, declined slightly with age, and were not different between boys and girls. ICC values were moderate to excellent. Variation within individuals across days generally ranged from 3% to 32%. A web-based R shiny object is available for data viewing.InterpretationWith the use of wearable movement sensors increasing rapidly, these data provide key, referent information for researchers as they design studies, and analyze and interpret data from neurodevelopmental and other pediatric clinical populations. These data may be of particularly high value for pediatric rare diseases.

ObjectiveThis study aimed to estimate the association between cycles of poverty, measured by intergenerational educational attainment (IEA), and the burden of obesity and metabolic dysfunction among Hispanic/Latino individuals in the United States.MethodsThis is a cross-sectional study utilizing data from 392 adults linked to 286 biologic parents from the Niños Lifestyle and Diabetes Study and the Sacramento Area Latino Study on Aging. The educational attainment of parents and offspring was dichotomized in order to categorize IEA. Outcomes included obesity and metabolic syndrome (MetS). Model-based standardization with population weights was used to compare obesity and MetS across generations, and Poisson regression was used to estimate prevalence ratios by IEA.ResultsA higher prevalence of obesity and MetS was observed in offspring (54% and 69%, respectively) compared with their parents (48% and 42%, respectively). Compared with stable-low IEA, any category with high offspring education was associated with lower obesity and MetS prevalence. The upwardly mobile group saw the greatest benefit; they were 38% (95% CI: 10%-57%) and 46% (95% CI: 21%-63%) less likely to have obesity or MetS.ConclusionsIEA strongly patterns cardiometabolic health among Hispanic/Latino individuals living in the United States, suggesting that promotion of higher education is associated with reductions in obesity and MetS, potentially benefitting future generations of this population.

IntroductionSurgery plays a critical role in sustainable healthcare systems. Validated metrics exist to guide implementation of surgical services, but low-income countries (LIC) struggle to report recommended metrics and this poses a critical barrier to addressing unmet need. We present a comprehensive national sample of surgical encounters from a LIC by assessing the National Health Services of Mozambique.Material and methodsA prospective cohort of all surgical encounters from Mozambique's National Health Service was gathered for all provinces between July and December 2015. Primary outcomes were timely access, provider densities for surgery, anesthesiology, and obstetrics (SAO) per 100,000 population, annualized surgical procedure volume per 100,000, and postoperative mortality (POMR). Secondary outcomes include operating room density and efficiency.ResultsFifty-four hospitals had surgical capacity in 11 provinces with 47,189 surgeries. 44.9% of Mozambique's population lives in Districts without access to surgical services. National SAO density was 1.2/100,000, ranging from 0.4/100,000 in Manica Province to 9.8/100,000 in Maputo City. Annualized national surgical case volume was 367 procedures/100,000 population, ranging from 180/100,000 in Zambezia Province to 1,897/100,000 in Maputo City. National POMR was 0.74% and ranged from 0.23% in Maputo Province to 1.78% in Niassa Province.DiscussionSurgical delivery in Mozambique falls short of international targets. Subnational deficiencies and variations between provinces pose targets for quality improvement in advancing national surgical plans. This serves as a template for LICs to follow in gathering surgical metrics for the WHO and the World Bank and offers short- and long-term targets for surgery as a component of health systems strengthening.