Citations

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell‐type‐specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP‐associated genes and co‐expression networks that are enriched with cell‐type marker genes. We extended our work to identify cell‐type‐specific expression perturbations in PSP using a systems approach and in vivo validations in a model system.MethodSingle‐nucleus RNAseq (snRNAseq) was performed using 33 frozen brain temporal cortex (TCX) samples from PSP and control brains. After quality control (QC), integration, and clustering of nuclei, each cluster was annotated for its cell type. We identified differentially expressed genes (DEG) in PSP and further investigated them using an independent bulk RNAseq dataset comprising 408 PSP and control TCX samples for replication and assessing co‐expression patterns. Top DEGs were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau‐mediated cellular toxicity was evaluated in a tau transgenic Drosophila model.ResultAfter QC, 30 clusters comprised of 27,284 nuclei were obtained, encompassing two neuronal and six glial cell types. DEGs of each cluster revealed cell‐type‐specific PSP associations. Notably, many of the up‐regulated DEGs in the astroglial clusters were members of the bulk RNAseq co‐expression modules that were also up‐regulated in PSP and enriched with astrocytic markers. There were also consistent findings for the up‐regulated DEGs in the endothelial and microglial clusters, and for down‐regulated DEGs in the oligodendroglial clusters. Subsequently, we prioritized 240 DEGs with congruent cell‐type‐specific perturbations in snRNAseq and bulk RNAseq and validated 29 of those using transgenic mouse model data. Lastly, a significant number of the up‐regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau‐mediated cellular toxicity, suggesting novel potential therapeutic avenues.ConclusionPSP brains demonstrated robust cell‐type‐specific gene expression perturbations in the glial cells populations that were validated across different datasets. Importantly, inhibiting the up‐regulated expression perturbations rescued tau‐mediated toxicity in a Drosophila model. Our findings highlight the cell‐type‐specific transcriptome changes in PSP and provide potential therapeutic options for primary tauopathies.

Abstract Background Nearly 50% of post-insertion catheter-related infections are due to microbial ingress from needleless connectors (NC), widely used devices which connect to the end of catheters or infusion sets and enable access for injection of medications and attachment of infusions. Infections arising from NC could result in central line associated bloodstream infection (CLABSI). The clinical guideline for disinfecting NC is to wipe the hub of the NC with a 70% alcohol and to manually scrub the connector surface for at least 15 seconds. Unfortunately, multiple studies have found low compliance with the 15 second disinfection scrub. Methods In this study, we investigated the efficacy of 1 second of ultraviolet light-C exposure in the reduction of the 3 most common CLABSI associated organisms: Staphylococcus aureus, Candida albicans, Candida auris, and Methicillin-resistant Staphylococcus aureus (MRSA). We tested a total of 30 NC samples for each organism with 3 positive controls and 1 negative control. Results The log reductions were 5.68, 5.05, 4.41, and 6.38 for S. aureus, C. albicans, C. auris and MRSA, respectively. Growth of Candida albicans with and without UV-C exposure for 1 second. The figure shows the observed growth of Candida albicans from the surface of the connector with and without UV-C exposure for 1 second, displaying no growth on the agar plate for samples that were exposed to 1 second of UV-C disinfection. Log reduction of tested organisms after exposure of UV-C for 1 second. Table 1 displays the overall log reduction of tested organisms after 1 second of UV-C exposure. The results are shown for positive control concentration and log reduction for the test organisms Staphylococcus aureus, Candida albicans, Candida auras, and Methicillin-resistant Staphylococcus aureus. Conclusion Our findings demonstrate greater than 4 log reduction of common CLABSI-associated organisms with 1 second of UV-C exposure, which we believe would decrease CLABSI rates, increase aseptic technique compliance, and reduce disruption in hospital workflow. Disclosures Julia Rasooly, MS, Puracath Medical, Inc: Board Member|Puracath Medical, Inc: Stocks/Bonds Michael Fourkas, MS, Puracath Medical, Inc: Grant/Research Support Gregory Schears, MD, Puracath Medical, Inc: Advisor/Consultant|Puracath Medical, Inc: Stocks/Bonds.

Abstract Purpose Medical school tuition has increased at alarming rates ahead of inflation over the past 20 years. The authors investigated whether state-funded medical schools have had an increased number of out-of-state matriculants, which may create a diaspora of displaced in-state medical students matriculating to out-of-state programs and incurring substantial debt. Method Publicly available data from the Association of American Medical Colleges (AAMC) were accessed from 2004 through 2019 for applicants and matriculants at U.S. state-funded schools. Schools listed as public that reported tuition charges in the AAMC Tuition and Student Fees reports were included in this study. The numbers and trends of medical school applications and trends in tuition costs and average indebtedness were summarized for in-state and out-of-state matriculants. Values were analyzed by group as median and interquartile range (IQR). Group differences were assessed via t tests. P values less than .05 were considered statistically significant. Results From 2004 through 2019, the annual number of out-of-state matriculants in state-funded schools increased 7% (16%–23% [7,195–11,144]). Among 74 schools with data in 2004, the median percentage of out-of-state applications increased from 60% (IQR, 31%–74%) to 80% (IQR, 57%–85%; P < .001), and the median percentage of out-of-state matriculants increased from 13% (IQR, 5%–23%) to 17% (IQR, 11%–33%; P < .001). In 2004, the mean (standard error) debt upon completion of medical school (inflation adjusted to 2018 dollars) was $144,100 ($10,950); by 2016, the mean debt had increased to $251,600 ($32,040), a 75% increase over 12 years. Conclusions Since 2004, substantial increases have occurred in out-of-state matriculants at state-funded medical schools. This may displace residents from attending their in-state schools, causing them to attend out-of-state or private medical schools, where tuition is typically much higher.

AbstractBackground and PurposeDuring the coronavirus disease 2019 (COVID‐19) pandemic many countries reported a decline in stroke volumes. The aim of this study was to analyze if the decline was related to the intensity of the COVID‐19 pandemic.MethodsThe first pandemic year (1 March 2020 to 28 February 2021) overall and during the three COVID‐19 waves were compared with the preceding year. Volumes of acute ischaemic stroke (AIS), subarachnoid hemorrhage, intracerebral hemorrhage and recanalization treatments (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) were obtained from the National Register of Reimbursed Health Services. Door‐to‐needle time, onset‐to‐door time and National Institutes of Health Stroke Scale at admission were obtained from the Registry of Stroke Care Quality.ResultsDuring the pandemic year compared to the preceding year there were 26,453 versus 28,771 stroke admissions, representing an 8.8% decline (p < 0.001). The declines (−10%, −11%, −19%) appeared in COVID‐19 waves (spring 2020, autumn 2020, winter 2021) except for an increase (2%) during summer 2020. Admissions for AIS declined by 10.2% (p < 0.001), whilst hemorrhagic stroke volumes were minimally decreased. The absolute volumes of IVT and MT decreased by 9.4% (p < 0.001) and 5.7% (p = 0.16), respectively. However, the proportions of ischaemic stroke patients receiving IVT (18% vs. 18%; p = 0.72) and MT (6% vs. 6%; p = 0.28) remained unchanged.ConclusionsThere was a decline in stroke admissions, but such decline was not related to COVID‐19 incidence. The frequency of use of recanalization procedures (IVT, MT) and times (onset‐to‐door time, door‐to‐needle time) in AIS were preserved in the Czech Republic during the first year of the pandemic.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P &amp;lt; .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P &amp;lt; .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P &amp;lt; .001) and among those with culture-confirmed LOS (23%-79%, P &amp;lt; .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

ObjectiveThis study assessed patient‐reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life.MethodsPatients completed Patient‐Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1‐10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression.ResultsOf 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43‐0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF.ConclusionIndividuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs.

Abstract Background: Young women with DCIS are at increased risk of recurrence and second BC compared to older women and may derive the greatest benefit from risk reduction strategies. Little is known about treatment decision-making, engagement in preventive behaviors, or fear of recurrence among young DCIS survivors. Thus, we sought to investigate treatment and prevention issues in this population. Methods: Using a multicenter prospective cohort that enrolled 1302 women with stage 0-IV BC at age ≤40, we identified participants with DCIS only who completed surveys in the year following diagnosis (dx). Surveys assessed treatment decisions, lifestyle factors (alcohol, smoking, physical activity [PA]), and fear of recurrence (Lasry Scale). Data was summarized with descriptive statistics and groups were compared with Fisher’s exact test. Results: Among 87 patients (median age 38, range 26-40), 75 had available treatment decision data, 19 (25%) of whom had breast-conserving surgery (BCS), 11 (15%) unilateral mastectomy (UM), and 45 (60%) bilateral mastectomy (BM). Most (77%) indicated their doctor said BCS was an option or recommended, including 34 (59%) who had BM. Of 40 patients who reported a patient-driven surgical decision, 73% had BM, 13% UM, and 15% BCS. Among 15 patients who reported the decision as doctor-driven, none had BM, 27% UM, and 73% BCS. Those who had BM were more likely to be extremely confident about the decision (80% vs. 73% UM vs. 53% BCS, p=0.022). Adjuvant tamoxifen was used by 10/27 (37%) patients with ER+ DCIS who had BCS/UM. Most who took tamoxifen reported this decision was shared with their doctor (90%); 1 reported the decision was made on her own. Of the 17 patients who did not take tamoxifen, 88% indicated their doctor said endocrine therapy was an option or recommended. Among all 87 patients, 31 (36%) were former and 3 (4%) were current smokers at baseline assessment (median 5 months post-dx); 51 (59%) never smoked. Overall, 4 quit within 1 year of dx. Most patients (83%) were current drinkers at baseline, though 79% consumed &lt;5 alcoholic beverages/week; 8% reported lower consumption at 1 year. Regarding PA at 1 year, 73% (58/80) reported ≥150 minutes of moderate-intensity PA/week. Overall, 41% of young survivors were at least moderately concerned about their BC coming back, with concern varying numerically by surgery (65% post-BCS, 50% post-UM, 29% post-BM, p=0.053). Conclusions: BC recurrence concerns were frequent among young DCIS patients, particularly among those with remaining breast tissue. BM decisions were largely patient-driven and made with high confidence, reflecting preferences towards surgical prevention. While adherence to survivorship lifestyle guidelines was high, including not smoking, consumption of ≤7 drinks/week, and engaging in PA, tamoxifen use was low, even when offered by a provider. Young DCIS survivors appear motivated to lower future BC risk through surgery and maintenance of healthy behaviors, and less so with tamoxifen; such values should be considered during treatment and survivorship counseling. Citation Format: Megan E. Tesch, Julia S. Wong, Laura Dominici, Kathryn J. Ruddy, Rulla Tamini, Lidia Schapira, Virginia F. Borges, Ellen Warner, Steven E. Come, Karen Sepucha, Laura C. Collins, Ann H. Partridge, Shoshana M. Rosenberg. Breast cancer (BC) risk reduction in young women with ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR009.

Background. Comorbid chronic pain and post-traumatic stress disorder (PTSD) complicate the treatment of both conditions. Previous research has identified pain catastrophizing as a potentially important variable contributing to the relationship between chronic pain and PTSD. However, little is known regarding how the different dimensions of pain catastrophizing—rumination, magnification, and helplessness—uniquely contribute to the relationship between PTSD symptomatology and measures of pain outcome. Methods. 491 treatment seeking participants were admitted to a three-week interdisciplinary pain rehabilitation program between July 2016 and March 2020. The patients completed measures of pain severity, pain interference, pain catastrophizing, depressive symptoms, quality of life (QOL), and PTSD symptoms at pretreatment. Results. Parallel mediation analyses were conducted to evaluate the mediating effect of the Pain Catastrophizing Scale subscales on the relationship between PTSD symptomatology and pain-relevant variables. The helplessness subscale accounted for significant unique variance in the relationship between PTSD symptomatology and pain severity (b = 0.010, SE = 0.002, 95% CI: 0.006, 0.014), pain interference (b = 0.004, SE = 0.002, 95% CI: 0.001, 0.008), and mental health QOL (b = −0.117, SE = 0.031, 95% CI: −0.179, −0.059), while the rumination and magnification subscales had no significant influence. Conclusions. Pain catastrophizing is a multifaceted construct. These results suggest that the helplessness dimension of pain catastrophizing may be the primary target when treating patients with comorbid chronic pain and PTSD symptoms. This study represents the first to evaluate the influence of the individual dimensions of pain catastrophizing on the relationship between PTSD symptomatology and chronic pain outcome.