Factors Associated with Correction of Personal Protective Equipment Nonadherence in a Multidisciplinary Emergency Department Setting: A Retrospective Video Review.

BACKGROUND: Despite local and national recommendations, healthcare provider adherence to personal protective equipment (PPE) varied during the COVID-19 pandemic. Previous studies have identified factors influencing initial PPE adherence but did not address factors influencing behaviors leading to correction after initial nonadherence. METHODS: We conducted a retrospective video review of 18 pediatric resuscitations involving aerosol-generating procedures (AGPs) from March 2020 to December 2022 to identify factors associated with nonadherence correction. We quantified adherent and nonadherent providers, instances of PPE nonadherence, and time to correction. We also analyzed correction behaviors, including provider actions and correction locations. RESULTS: Among 434 providers, 362 (83%) were nonadherent with at least one PPE. Only 186 of 1,832 instances of nonadherence were corrected, primarily upon room entry and during patient care. Correction time varied by PPE type and nonadherence level (incomplete versus absent). Most corrections were self-initiated, with few reminders from other providers. DISCUSSION: Potential barriers to correction include a lack of social pressure and external reminders. Solutions include optimizing PPE availability, providing real-time feedback, and educating on double-gloving. CONCLUSIONS: Most providers were nonadherent to PPE requirements during high-risk infection transmission events. The low correction rate suggests challenges in promoting collective responsibility and maintaining protective behaviors during medical emergencies.

Assessment of Thrombectomy versus Combined Thrombolysis and Thrombectomy in Patients with Acute Ischemic Stroke and Medium Vessel Occlusion.

Background The combination of intravenous thrombolysis (IVT) with mechanical thrombectomy (MT) may have clinical benefits for patients with medium vessel occlusion. Purpose To examine whether MT combined with IVT is associated with different outcomes than MT alone in patients with acute ischemic stroke (AIS) and medium vessel occlusion. Materials and Methods This retrospective study included consecutive adult patients with AIS and medium vessel occlusion treated with MT or MT with IVT at 37 academic centers in North America, Asia, and Europe. Data were collected from September 2017 to July 2021. Propensity score matching was performed to reduce confounding. Univariable and multivariable logistic regression analyses were performed to test the association between the addition of IVT treatment and different functional and safety outcomes. Results After propensity score matching, 670 patients (median age, 75 years [IQR, 64-82 years]; 356 female) were included in the analysis; 335 underwent MT alone and 335 underwent MT with IVT. Median onset to puncture (350 vs 210 minutes, P < .001) and onset to recanalization (397 vs 273 minutes, P < .001) times were higher in the MT group than the MT with IVT group, respectively. In the univariable regression analysis, the addition of IVT was associated with higher odds of a modified Rankin Scale (mRS) score 0-2 (odds ratio [OR], 1.44; 95% CI: 1.06, 1.96; P = .019); however, this association was not observed in the multivariable analysis (OR, 1.37; 95% CI: 0.99, 1.89; P = .054). In the multivariable analysis, the addition of IVT also showed no evidence of an association with the odds of first-pass effect (OR, 1.27; 95% CI: 0.9, 1.79; P = .17), Thrombolysis in Cerebral Infarction grades 2b-3 (OR, 1.64; 95% CI: 0.99, 2.73; P = .055), mRS scores 0-1 (OR, 1.27; 95% CI: 0.91, 1.76; P = .16), mortality (OR, 0.78; 95% CI: 0.49, 1.24; P = .29), or intracranial hemorrhage (OR, 1.25; 95% CI: 0.88, 1.76; P = .21). Conclusion Adjunctive IVT may not provide benefit to MT in patients with AIS caused by distal and medium vessel occlusion. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Wojak in this issue.

Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology.

Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease (AD) progression, but details of microglia's disease-driving influence are poorly understood. Microglial cells can be parsed into subtypes based on their histologic appearance. One microglia subtype, termed dystrophic microglia, is characterised structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-ß might induce dystrophic changes in microglia, potentially linking amyloid-ß and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in AD progression. We speculated that if their presence is unique to AD neuropathologic change (ADNC), they would be substantially more common in ADNC than in neurodegenerative diseases characterised by other proteinopathies, e.g., α-synuclein or TDP-43 pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced AD stages, including comparative conditions such as Lewy Body Disease (LBD) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Using stereological sampling and digital pathology, we assessed ramified, hypertrophic, and dystrophic microglia populations. We found a significant increase in dystrophic microglia in areas early affected by ADNC, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest dystrophic microglia may impact the regional spread of ADNC. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which then was associated with the spread of amyloid-ß and tau. These results suggest that a loss of microglia's protective role could contribute to the spread of ADNC and indicate that further research into preserving microglial function may be warranted.

Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial.

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Electric buses as an air pollution and meteorological observation network: Methodology and preliminary results.

Many local agencies in the United States and other countries are tasked to install air pollution monitoring systems of highly accurate sensors that have high acquisition, operating, and maintenance costs. The need for expanded coverage of air quality measurements across Salt Lake County (SLCO), Utah is being met by mounting air quality and temperature sensors on an expanding fleet of battery electric buses (BEBs). Monitoring air quality from a mobile sensor network provides real-time insights into air pollution patterns at high temporal and spatial resolution. Mobile measurements contribute to assessing residents' exposure to air pollution, facilitating the implementation of cost-effective public health policies and highlighting disparities. The Electric Bus Air Quality Observation Project was launched in SLCO during July 2021 and has collected millions of observations to date. A BEB traveling at typical traffic speeds (~10 m s-1) can provide multiple measurements along city block lengths of up to ~200 m. With careful analysis that factors in the time response of the differing sensors, variability from block-to-block may be attributed to fine-scale factors (e.g., pollution and heat sources, tree shading and urban vegetation, etc.). Preliminary findings showcase the value of increased coverage and resolution. During an extreme heat event in July 2023, both the morning and afternoon temperature readings showed differences of over 6.5 °C (12 °F), primarily as an east-west gradient with similar gradients in ozone. We conclude that temperature and pollutant concentration readings, at fine spatial and temporal resolutions, will facilitate future health studies and equitable policy and mitigation strategies. Our study demonstrates that our partnerships established with governmental, non-profit, and transit agencies facilitate the successful transfer of research and development to operational real-time mobile air quality monitoring.

Laborie Optilume® Drug-coated balloon may lower the re-treatment rate post-intervention for challenging urethral stricture disease in long-term follow-up: A prospective cohort study.

BACKGROUND: Urethral stricture disease is a common and at times unsatisfying condition that can lead to complications severely impacting a patient's quality of life. Open urethroplasty remains the gold standard treatment; however, it is an invasive and highly specialized procedure. Strictures between 2 to 4 cm in length have been shown to recur at a rate of 50% within 12 months, a rate that typically decreases with each subsequent treatment. The Laborie Optilume drug-coated balloon (DCB) is the first of its kind developed for adjunct treatment of urethral strictures in men. The DCB initially treats the stricture through balloon dilatation and subsequently aims to prevent recurrence via the localized application of Paclitaxel. Our study assesses the safety and efficacy of the DCB in an Australian population with strictures exceeding 2 cm who have undergone at least two prior procedures for urethral stricture disease. METHODS: Patients were prospectively recruited from November 2019 to September 2021. International prostate symptom score (IPSS), IPSS quality of life (QOL) and voiding parameters were collected at baseline, and again at 1, 6, 12 and 18 months. The drug coated balloon was applied by a single consultant urologist under rigid cystoscope with shallow direct vision internal urethrotomy with a cold knife prior to application of the DCB. RESULTS: 17 patients were recruited with an average of 7.7 prior urethral procedures for recurrent stricture disease. 76% were stricture free at 30 months follow-up. There were improvements in almost all parameters including max flow, average flow, IPSS and IPSS QOL scores at 12 and 24 months. There were no complications. CONCLUSION: The DCB is a safe and effective method at reducing the rates of recurrence for high-risk stricture disease and can delay or prevent the need for urethroplasty in what remains a very challenging cohort of patients.

Experimental Evaluation of Higher Order Stability Zones Using a Digitally Operated Quadrupole Mass Filter.

Recent improvements to the comparison-based method of digital waveform generation increased the reproducibility of the waveforms so that the higher-order Mathieu stability zones can be accessed reliably. Digitally driven quadrupole mass filters access these zones using a fixed AC voltage and rectangular waveforms that are defined by a duty cycle. In this context, the duty cycle is the fraction of the waveform period where the waveform remains in the high state. Because digitally driven quadrupoles navigate stability using a duty cycle, there is no need to apply a resolving DC offset between electrode pairs. Accessing the higher stability zones using a conventional resonantly tuned RF requires the use of thousands of AC and DC voltages making the mode of operation less accessible with these devices. Stability zones higher than (1,1) and (2,1) have theoretical resolving powers that are on the order 1,140 and 3,447 at fwhm which drives efforts to practically access these operational conditions. Accessing these zones digitally requires the use of extremely precise waveforms. In a previous effort, waveform generation produced waveforms to reliably access the (1,1) and (2,1) zones without impacting performance. However, recent work found more improvement was needed to reliably access neighboring higher stability zones. Derived from that work, it was determined that a waveform resolution of ∼10 ppm or less was needed to reliably access the (3,1) and (3,2) zones. The present work utilized digital waveforms that achieve this level of precision to experimentally access and characterize attributes of the (3,1) and (3,2) zones. This work dives into the investigation of different beam energies to overcome the destabilizing fringing fields, improve transmission, and their overall effect on the experimental resolving power and signal-to-noise. In addition, the AC voltage of the driving RF was varied to understand the effects on the initial ion beam energy that is needed to achieve balanced separation and how the overall signal-to-noise is affected. Lastly, an assessment was made on the effects of the temporal parameters of a digital mass scan on peak sensitivity, peak fidelity, and overall duration for a scan.

Indazole to 2-cyanoindole scaffold progression for mycobacterial lipoamide dehydrogenase inhibitors achieves extended target residence time and improved antibacterial activity.

Tuberculosis remains a leading cause of death from a single infection worldwide. Drug resistance to existing and even new antimycobacterials calls for research into novel targets and unexplored mechanisms of action. Recently we reported on the development of tight-binding inhibitors of Mycobacterium tuberculosis (Mtb) lipoamide dehydrogenase (Lpd), which selectively inhibit the bacterial but not the human enzyme based on a differential modality of inhibitor interaction with these targets. Here we report on the striking improvement in inhibitor residence time on the Mtb enzyme associated with scaffold progression from an indazole to 2-cyanoindole. Cryo-EM of Lpd with the bound 2-cyanoindole inhibitor 19 confirmed displacement of the buried water molecule deep in the binding channel with a cyano group. The ensuing hours-long  improvement in on-target residence time is associated with enhanced antibacterial activity in axenic culture and in primary mouse macrophages. Resistance to 2-cyanoindole inhibitors involves mutations within the inhibitor binding site that have little effect on inhibitor affinity but change the modality of inhibitor-target interaction, resulting in fast dissociation from Lpd. These findings underscore that on-target residence time is a major determinant of antibacterial activity and in vivo efficacy.

A Scoping Review of the Intersectionality of Autism and Intellectual and Developmental Disability with Social Inequity on Diagnosis and Treatment of Youth.

Objective: To describe how the intersectionality of race, ethnicity, and language with autism and intellectual and developmental disability (IDD) impacts mental health inequities in psychopharmacological management of youth. Method: This was a scoping review in which a series of searches were conducted in PubMed, Web of Science, Google Scholar, and manual review of the articles collected. Results: Although autism and/or IDD increases the risk for poor physical and mental health, social determinants of health such as race, ethnicity, and language account for approximately a third of poor outcomes. Minoritized children with autism/IDD experience significantly greater delays to diagnosis and misdiagnosis and are less likely to receive appropriate services. Access to psychological testing and psychosocial services is often limited by availability, skilled practitioners, a shortage of non-English-language providers or interpreters, and poor reimbursement. Conclusion: The intersectionality of autism and/or IDD with race, ethnicity, and language compounds the health inequities associated with either of these challenges independently.

Label-free morpho-molecular phenotyping of living cancer cells by combined Raman spectroscopy and phase tomography.

Accurate, rapid and non-invasive cancer cell phenotyping is a pressing concern across the life sciences, as standard immuno-chemical imaging and omics require extended sample manipulation. Here we combine Raman micro-spectroscopy and phase tomography to achieve label-free morpho-molecular profiling of human colon cancer cells, following the adenoma, carcinoma, and metastasis disease progression, in living and unperturbed conditions. We describe how to decode and interpret quantitative chemical and co-registered morphological cell traits from Raman fingerprint spectra and refractive index tomograms. Our multimodal imaging strategy rapidly distinguishes cancer phenotypes, limiting observations to a low number of pristine cells in culture. This synergistic dataset allows us to study independent or correlated information in spectral and tomographic maps, and how it benefits cell type inference. This method is a valuable asset in biomedical research, particularly when biological material is in short supply, and it holds the potential for non-invasive monitoring of cancer progression in living organisms.

Multicenter evaluation of mechanical thrombectomy for distal medium vessel occlusions with National Institute of Health Stroke Scale Scores ≥ 6 and ≤ 6.

BACKGROUND: While mechanical thrombectomy is considered standard of care for large vessel occlusions, scientific evidence to support treatment for distal and medium vessel occlusions remains scarce. PURPOSE: To evaluate feasibility, safety, and outcomes in patients with low National Institute of Health Stroke Scale scores undergoing mechanical thrombectomy for treatment of distal medium vessel occlusions. MATERIALS AND METHODS: Retrospective data review and analysis of prospectively maintained databases at 41 academic centers in North America, Asia, and Europe between January 2017 and January 2022. Characteristics and outcomes were compared between groups with low stroke scale score (≤ 6) versus and higher stroke scale scores (> 6). Propensity score matching using the optimal pair matching method and 1:1 ratio was performed. RESULTS: Data were collected on a total of 1068 patients. After propensity score matching, there were a total of 676 patients included in the final analysis, with 338 patients in each group. High successful reperfusion rates were seen in both groups, 90.2% in ≤ 6 and 88.7% in the > 6 stroke scale groups. The frequency of excellent and good functional outcome was seen more common in low versus higher stroke scale score patients (64.5% and 81.1% versus 39.3% and 58.6%, respectively). The 90-day mortality rate observed in the ≤ 6 stroke scale group was 5.3% versus 13.3% in the > 6 stroke scale group. CONCLUSION: Mechanical thrombectomy in distal and medium vessel occlusions, specifically in patients with low stroke scale scores is feasible, though it may not necessarily improve outcomes over IVT.

Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency.

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.

Gonococcal Mimitope Vaccine Candidate Forms a Beta-Hairpin Turn and Binds Hydrophobically to a Therapeutic Monoclonal Antibody.

The spread of multidrug-resistant strains of Neisseria gonorrhoeae, the etiologic agent of gonorrhea, represents a global health emergency. Therefore, the development of a safe and effective vaccine against gonorrhea is urgently needed. In previous studies, murine monoclonal antibody (mAb) 2C7 was raised against gonococcal lipooligosaccharide (LOS). mAb 2C7 elicits complement-dependent bactericidal activity against gonococci, and its glycan epitope is expressed by almost every clinical isolate. Furthermore, we identified a peptide, cyclic peptide 2 (CP2) that mimicked the 2C7 LOS epitope, elicited bactericidal antibodies in mice, and actively protected in a mouse vaginal colonization model. In this study, we performed structural analyses of mAb 2C7 and its complex with the CP2 peptide by X-ray crystallography, NMR spectroscopy, and molecular dynamics (MD) simulations. The crystal structure of Fab 2C7 bound to CP2 showed that the peptide adopted a beta-hairpin conformation and bound the Fab primarily through hydrophobic interactions. We employed NMR spectroscopy and MD simulations to map the 2C7 epitope and identify the bioactive conformation of CP2. We also used small-angle X-ray scattering (SAXS) and native mass spectrometry to obtain further information about the shape and assembly state of the complex. Collectively, our new structural information suggests strategies for humanizing mAb 2C7 as a therapeutic against gonococcal infection and for optimizing peptide CP2 as a vaccine antigen.

Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

The classification of hiatal shapes and their use as a marker for complexity, operative interventions, and recurrence.

BACKGROUND: Diaphragmatic reconstruction is a vital, but challenging component of hiatal hernia and antireflux surgery. Results are optimized by minimizing axial tension along the esophagus, assessed with intra-abdominal length, and radial tension across the hiatus, which has not been standardized. We categorized hiatal openings into 4 shapes, as a surrogate for radial tension, to correlate their association with operative interventions and recurrence. METHODS: We retrospectively reviewed all primary hiatal hernias (≥3 cm) repaired at a single center between 2010 and 2020. Patients with intraoperative hiatal photos with at least 1 year of follow-up were included. The hiatal openings were classified into 4 shapes: slit, inverted teardrop, "D," and oval, and ordered in this manner of hypothesized increased complexity and tension. RESULTS: A total of 239 patients were studied, with 113 (47%) having a recurrence. Age (P < .001), proportion of paraesophageal hernias (P < .001), hernia axial length (P < .001), and hiatal width (P < .001) all increased as shape progressed from slit to inverted teardrop to "D" to oval. Mesh (P = .003) and relaxing incisions (P < .001) were more commonly employed in more advanced shapes, "D" and ovals. However, recurrence (P = .88) did not correlate with hiatal shape. CONCLUSION: Four different hiatal shapes are commonly seen during hernia repair. These shapes represent a spectrum of hernia chronicity and complexity necessitating increased use of operative measures but not correlating with recurrence. Despite failing to be a direct marker for recurrence risk, hiatal shape may serve as an intraoperative tool to inform surgeons of the potential need for additional hiatal interventions.

Exploratory Mass Spectrometry of Cerebrospinal Fluid from Persons with Autopsy-Confirmed LATE-NC.

Common neuropathologies associated with dementia include Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. Participants (n = 29) had been autopsied and had antemortem CSF draws in a longitudinal cohort of older adults at the University of Kentucky AD Research Center. Cases were designated as LATE-NC + if they had LATE-NC stage > 1 (n = 9); the remaining 20 cases were designated LATE-NC-. This convenience sample of CSF specimens was analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry. Relative quantification was performed using Sciex software. Peptides referent to a total of 949 proteins were identified in the samples depleted of abundant proteins, and 820 different proteins were identified in the non-depleted samples. When the Bonferroni/false-discovery statistical correction was applied to account for having made multiple comparison tests, only 4 proteins showed differential expression (LATE-NC + vs LATE-NC-) in the non-depleted samples (RBP4, MIF, IGHG3, and ITM2B). Post hoc western blots confirmed that RBP4 expression was higher in the LATE-NC + cases at the group level. In summary, an exploratory assessment of proteomes of autopsy-confirmed LATE-NC and non-LATE-NC CSF did not demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was, however, an increase in RBP4 protein levels in CSF from LATE-NC cases.

Frailty and Clinical Outcomes of Ticagrelor Versus Clopidogrel in Older Adults With Acute Myocardial Infarction.

BACKGROUND: Ticagrelor is recommended over clopidogrel in acute coronary syndrome based on the results of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial. We aimed to emulate PLATO in older adults with and without frailty and with acute coronary syndrome treated with percutaneous coronary intervention. METHODS AND RESULTS: We created a new-user cohort of Medicare fee-for-service beneficiaries aged ≥65 years hospitalized for acute coronary syndrome from 2014 to 2018 and initiated ticagrelor or clopidogrel following percutaneous coronary intervention. Frailty was defined using a validated claims-based frailty index ≥0.25. Coprimary outcomes were major adverse cardiovascular events and major bleeding. Follow-up began on the date of first outpatient prescription for ticagrelor or clopidogrel and ended on the earliest date for an outcome event, death, discontinuation of the index drug, or disenrollment from Medicare. The study included 42 843 older adults; 23% were frail. After propensity score matching, the rates of major adverse cardiovascular events per 100 person-years comparing ticagrelor versus clopidogrel groups were 7.8 and 7.3 in the frail cohort (hazard ratio [HR], 1.07 [95% CI, 0.84-1.36]) and 3.7 and 4.2 in the nonfrail cohort (HR, 0.87 [95% CI, 0.75-1.02]). The corresponding rates of major bleeding were 4.3 and 3.8 in the frail cohort (HR, 1.12 95% CI, [0.80-1.56]) and 2.2 and 1.8 in the nonfrail cohort (HR, 1.22 [95% CI, 0.98-1.51]). CONCLUSIONS: There was a trend toward a modest reduction in risk of major adverse cardiovascular events and a trend toward a modest increase in risk of major bleeding with ticagrelor compared with clopidogrel in the nonfrail cohort. There was insufficient evidence for the benefit of ticagrelor in frail older adults.