Simplified J774A.1 macrophage assay for fungal pathogenicity demonstrates non-clinical Nakaseomyces glabratus strains survive better than lab strains.

Nakaseomyces glabratus (formerly known as Candida glabrata ) is the second most common cause of candidiasis, whereas the closely related yeast, Saccharomyces cerevisiae, causes few infections. Macrophages can control N. glabratus infections through phagocytosis, but in cell culture, N. glabratus is able to persist in macrophages better than non-pathogenic yeast. Using J774A.1 macrophages, we simplified a standard persistence/survival assay by counting yeast cells with flow cytometry and incorporating an antifungal treatment. These improvements minimized wash steps and variation so fewer replicates were needed. Here, we demonstrate that loss of NgTUP11 does not lower pathogenicity, and that three non-clinical N. glabratus strains survive in macrophages better than a laboratory strain.

Mesh exposure after ventral hernia repair with onlay biosynthetic mesh: a retrospective review of associated risk factors and management strategies.

BACKGROUND: Although intraperitoneal and retromuscular mesh placement in ventral hernia repair (VHR) are associated with lower recurrence rates, the onlay plane remains a well-established option for certain clinical scenarios. A knowledge gap remains regarding resorbable biosynthetic onlay mesh and mesh exposure. We aim to determine exposure rate, risk factors, and treatment options. STUDY DESIGN: A single-center, two-surgeon retrospective review was performed examining patients who underwent VHR with onlay, Poly-4-hydroxybutyrate (P4HB) mesh from 2015 to 2021. Demographics, operative characteristics, outcomes, and mesh exposure management were analyzed. RESULTS: Of 346 patients, 15 (4.3%) experienced mesh exposure. The mean age was 53 years and BMI of 33.6 kg/m2. Patients were majority ASA class 3 (65%), female (64.2%), and averaged a defect size of 307.9 ± 235.2 cm2. Independent risk factors included diabetes (AOR = 4.3,CI 1.5-12.5;p < 0.005) and COPD (AOR = 5.2,CI 1.3-21.8;p = 0.02). Mesh exposures were identified as outpatient (20%) or intraoperative (80%). All underwent operative debridement, in which nine were managed with skin reclosure, two with partial closure, and four healed by secondary intention. Five patients required excision of unincorporated mesh. Four patients required further debridement from chronic surgical site occurrences; however, all mesh exposure patents healed after a mean of 260.8 ± 313.2 days and retained original mesh. The recurrence rate was 6.7% for mesh exposure patients. CONCLUSION: When faced with mesh exposure, resorbable biosynthetic mesh placed in onlay fashion was retained in all patients. Patients with a history of diabetes or COPD have increased risk of mesh exposure and should be counseled.

Myeloperoxidase-ANCA IgG induces different forms of small vessel vasculitis based on type of synergistic immune stimuli.

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has diverse patterns of injury including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Necrotizing and crescentic glomerulonephritis (NCGN) occurs in all syndromes and as renal limited vasculitis (RLV). Single-dose intravenous ANCA IgG-specific for mouse myeloperoxidase (MPO) causes RLV in mice. Although multiple mouse models have elucidated ANCA-IgG induced necrotizing and crescentic glomerulonephritis (NCGN), pathogenesis of ANCA-induced granulomatosis and vasculitis outside the kidney has not been clarified. To investigate this, we used intravenous MPO-ANCA IgG in the same strain of mice to induce different patterns of lung disease mirroring patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Repeated intravenous MPO-ANCA IgG induced GPA with NCGN, lung capillaritis, arteritis and granulomatosis. Lung leukocyte phenotypes were evaluated by immunohistochemical image analysis and by flow cytometry. ANCA lung capillaritis and microabscesses began within one day and evolved into granulomas in under seven days. Influenza plus single-dose MPO-ANCA IgG induced MPA with NCGN, lung capillaritis and arteritis, but no granulomatosis. Allergic airway disease caused by house dust mites or ovalbumin plus single-dose intravenous MPO-ANCA IgG induced EGPA with eosinophilic bronchiolitis, NCGN, capillaritis, arteritis, and granulomatosis. Thus, our study shows that the occurrence and pattern of lung lesions are determined by the same ANCA IgG accompanied by different synergistic immune factors.

Small molecular weight epigenetic inhibitors modulate the extracellular matrix during pancreatic acinar ductal metaplasia.

The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment is distinguished by a high degree of fibrosis and inflammation, known as desmoplasia. Desmoplasia increases the stromal deposition and extracellular matrix (ECM) stiffness observed in the tumor microenvironment, contributing to the dampened penetration of pharmacological agents. The molecular and biophysical composition of the ECM during the earliest cellular changes in the development of PDAC, i.e. acinar ductal metaplasia (ADM), has not been extensively explored. We report that the mRNA expression of key protein components of the ECM increases during ADM in p48Cre/+;LSL-KrasG12D (KC) mouse acinar organoids cultured in Matrigel. Treatment of the organoids with small molecular weight epigenetic modulating compounds that inhibit or reverse ADM (largazole, FK228 and chaetocin) dramatically reduced the tissue mRNA expression of collagens, hyaluronan synthase, laminin and fibronectin. The storage moduli, determined by video tracking of fluorescent nanoparticles embedded into the Matrigel, increased during ADM and was reduced following treatment with the epigenetic modulating compounds. We report that the ECM of mouse organoids stiffens during ADM and is further enhanced by the presence of mutant Kras. Moreover, select HDAC and HMT inhibitors reduced the mRNA expression of ECM components and ECM stiffness during inhibition and reversal of ADM, suggesting that these compounds may be useful as adjuvants to enhance the tumor penetration of agents used to treat PDAC.

Long-term impact of Hurricane Maria on point-of-use drinking water quality in Puerto Rico and associated potential adverse health effects.

Drinking water security in Puerto Rico (PR) is increasingly challenged by both regulated and emerging anthropogenic contaminants, which was exacerbated by the Hurricane Maria (HM) due to impaired regional water cycle and damaged water infrastructure. Leveraging the NIEHS PROTECT (Puerto Rico Testsite for Exploring Contamination Threats) cohort, this study assessed the long-term tap water (TW) quality changes from March 2018 to November 2018 after HM in PR, by innovatively integrating two different effect-based quantitative toxicity assays with a targeted analysis of 200 organic and 22 inorganic pollutants. Post-hurricane PR TW quality showed recovery after >6-month period as indicated by the decreased number of contaminants showing elevated average concentrations relative to pre-hurricane samples, with significant difference of both chemical and toxicity levels between northern and southern PR. Molecular toxicity profiling and correlation revealed that the HM-accelerated releases of certain pesticides and PPCPs could exert increased cellular oxidative and/or AhR (aryl hydrocarbon receptor)-mediated activities that may persist for more than six months after HM. Maximum cumulative ratio and adverse outcome pathway (AOP) assessment identified the top ranked detected TW contaminants (Cu, Sr, V, perfluorooctanoic acid) that potentially associated with different adverse health effects such as inflammation, impaired reproductive systems, cancers/tumors, and/or organ toxicity. These insights can be incorporated into the regulatory framework for post-disaster risk assessment, guiding water quality control and management for public health protection.

Neuronal and Behavioral Responses to Naturalistic Texture Images in Macaque Monkeys.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anesthetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, suggesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stimuli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Further, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and therefore unlikely to directly reflect the formation of perceptual decisions.

Youth Pitcher Fatigue: Medial Elbow Laxity, Ultrasonographic Assessment of Flexor-Pronator Mass Energy Depletion, and Association With Pitch Count.

Background: Ulnar collateral ligament (UCL) injuries in youth pitchers continue to be concerning despite the institution of pitch count limits. Flexor-pronator mass fatigue can lead to diminished dynamic stability, resulting in greater stress on the UCL. Purpose/Hypothesis: To evaluate fatigue of the flexor-pronator mass by assessing changes in medial elbow laxity; noninvasively characterizing alterations in muscle glycogen; and identifying changes in subjective fatigue, strength, range of motion (ROM), pitching velocity, and accuracy with increasing pitches thrown by youth pitchers to their recommended 75-pitch count limit. It was hypothesized that, with increased pitches, medial elbow laxity would increase and that the glycogen content of the flexor-pronator mass would decrease. Study Design: Descriptive laboratory study. Methods: Healthy male pitchers aged 10 years (n = 22) threw 3 sets of 25 pitches with 12 minutes between sets (3 timepoints). Bilateral ulnohumeral joint gapping was measured by applying a standardized valgus force and utilizing ultrasound imaging. Relative changes in muscle glycogen in the bilateral flexor carpi radialis (FCR), and the flexor digitorum superficialis/flexor carpi ulnaris (FDS/FCU) muscles were measured with ultrasound software and recorded as fuel percentiles. Additional measures obtained included subjective fatigue, strength, ROM, velocity, and accuracy. Results: There were no differences in medial elbow joint-line gapping between the throwing and nonthrowing arms or between timepoints. The throwing arm demonstrated a significant decline in fuel percentile of the FCR from baseline to after 75 pitches (P = .05). There were no differences across timepoints for FDS/FCU fuel percentile values. Fatigue measurements for both arms were significantly higher at all timepoints compared with baseline (P≤ .03). Grip strength of the dominant arm after 75 pitches was decreased significantly compared with after 25 pitches (P = .02). Conclusion: Although an increase in medial elbow joint gapping was not demonstrated within the recommended 75 pitch count limit in 10-year-olds, a relative decrease in glycogen stores of the flexor-pronator mass did occur, as well as a decrease in grip strength, with increasing subjective fatigue. Clinical Relevance: This study provides a foundation for further objective testing of physiologic changes that occur with pitching to better guide pitch count limits and improve the safety of young athletes.

TSWIFT, a novel method for iterative staining of embedded and mounted human brain sections.

Comprehensive characterization of protein networks in mounted brain tissue represents a major challenge in brain and neurodegenerative disease research. In this study, we develop a simple staining method, called TSWIFT, to iteratively stain pre-mounted formalin fixed, paraffin embedded (FFPE) brain sections, thus enabling high-dimensional sample phenotyping. We show that TSWIFT conserves tissue architecture and allows for relabeling a single mounted FFPE sample more than 10 times, even after prolonged storage at 4 °C. Our results establish TSWIFT as an efficient method to obtain integrated high-dimensional knowledge of cellular proteomes by analyzing mounted FFPE human brain tissue.

How does V1 population activity inform perceptual certainty?

Neural population activity in sensory cortex informs our perceptual interpretation of the environment. Oftentimes, this population activity will support multiple alternative interpretations. The larger the spread of probability over different alternatives, the more uncertain the selected perceptual interpretation. We test the hypothesis that the reliability of perceptual interpretations can be revealed through simple transformations of sensory population activity. We recorded V1 population activity in fixating macaques while presenting oriented stimuli under different levels of nuisance variability and signal strength. We developed a decoding procedure to infer from V1 activity the most likely stimulus orientation as well as the certainty of this estimate. Our analysis shows that response magnitude, response dispersion, and variability in response gain all offer useful proxies for orientation certainty. Of these three metrics, the last one has the strongest association with the decoder's uncertainty estimates. These results clarify that the nature of neural population activity in sensory cortex provides downstream circuits with multiple options to assess the reliability of perceptual interpretations.

G2 arrest primes hematopoietic stem cells for megakaryopoiesis.

In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is unclear, however. Here, we show that DNA damage induces MK markers in HSCs and that G2 arrest, an integral part of the DNA damage response, suffices for MK priming followed by irreversible MK differentiation in HSCs, but not in progenitors. We also show that replication stress causes DNA damage in HSCs and is at least in part due to uracil misincorporation in vitro and in vivo. Consistent with this notion, thymidine attenuated DNA damage, improved HSC maintenance, and reduced the generation of CD41+ MK-committed HSCs. Replication stress and concomitant MK differentiation is therefore one of the barriers to HSC maintenance. DNA damage-induced MK priming may allow rapid generation of a lineage essential to immediate organismal survival, while also removing damaged cells from the HSC pool.

Impact of removing ESBL status labelling from culture reports on the use of carbapenems for non-bacteraemic patients diagnosed with ESBL-positive urinary tract infections.

OBJECTIVES: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports. METHODS: This was a retrospective cohort study of adult patients treated for at least 48 h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA. The primary endpoint was the rate of carbapenem prescribing for initial definitive treatment of urinary tract infections. Secondary endpoints included total days of therapy for initial definitive treatment with carbapenems, clinical cure rates, time to transition to oral antibiotic therapy for initial definitive treatment, rate of guideline-compliant therapy, rate of relapsed infection within 30 days, 30 day readmission rate, and 30 day all-cause in-hospital mortality. RESULTS: Of 3055 patients screened, 199 were included in the pre group and 153 were included in the post group. The rate of carbapenem prescribing for initial definitive treatment was 156 patients (78%) in the pre group, compared with 93 patients (61%) in the post group (P = <0.01). Days of therapy for initial definitive therapy with carbapenem was 620 in the pre group compared with 372 in the post group (P < 0.01). There was no difference between other secondary outcomes. CONCLUSIONS: Removing ESBL status labels from laboratory reports reduced carbapenem use for initial definitive treatment of urinary tract infections from 78% to 61% (P < 0.01) without impacting clinical outcomes.

Estimating Tiotropium Wasted Doses After Adding Revefenacin to an Inpatient Formulary: A Single-Center Cross-Sectional Study.

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

IL-1ß Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice.

BACKGROUND: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1ß or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1ß antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1ß antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS: Taken together, IL-1ß appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.

Reconstructing Nasal Defects With Acellular Dermal Matrix After Mohs Micrographic Surgery: A 12-year Experience.

BACKGROUND AND OBJECTIVE: Large defects of the nose after Mohs surgery pose a significant reconstructive challenge to both dermatologic and reconstructive surgeons. The authors present their 12-year experience utilizing acellular dermal matrices for nasal reconstruction. METHODS: A retrospective review of patients undergoing Mohs surgery and alloplastic nasal reconstruction with acellular dermal matrices between 2010 and 2022 was performed. Patients who underwent single-stage reconstruction and dual-stage reconstruction with skin graft with at least 90 days of follow-up were included. RESULTS: Fifty-one patients met criteria with a median age of 77 years. Fifty-three lesions were reconstructed with acellular dermal matrices. The most common lesion location was nasal sidewall (50%) with a mean defect size of 10.8 cm 2 . 30.8% underwent same-day acellular dermal matrix reconstruction, with 69.2% undergoing two-stage reconstruction. Acellular dermal matrices successfully reconstructed acquired defects in 94.2% of lesions. Average time to re-epithelialization was 27.6 + 6.2 days. Average time to repigmentation was 145.35 + 86 days. No recurrences were recorded. Total complication rate was 9.62%. Average size for successful healing was 10.8 cm 2 . Average defect size for complication or failure was 14.7 cm 2 . Seven sites (13.46%) underwent aesthetic improvement procedures. CONCLUSION: Acellular bilayer wound matrix is an adequate reconstructive option for single or dual-stage reconstruction of the nose with low complication and revision rates.

Early Experience With Artificial Intelligence Software to Detect Intracranial Occlusive Stroke in Trauma Patients.

Objective Identifying ischemic stroke is a diagnostic challenge in the trauma subpopulation. We describe our early experience with artificial intelligence-assisted image analysis software for automatically identifying acute ischemic stroke in trauma patients.  Methods Patients were retrospectively screened for (i) admission to the trauma service at a level one trauma center between 2020 and 2022, (ii) radiologist-confirmed intracranial occlusion, (iii) occlusion identified on computed tomography angiography performed within 24 hours of admission, (iv) no intracranial hemorrhage, and (v) contemporaneous analysis with the large vessel occlusion (LVO) detection program. Baseline characteristics, stroke detection, response-activation, and outcome data were summarized.  Results Of 9893 trauma patients admitted, 88 (0.89%) patients had a cerebral stroke diagnosis, of which 10 patients (10/88; 11.4%) met inclusion criteria. Most patients were admitted following a fall (8/10; 80%). Six (6/10; 60.0%) patients had LVOs. The program correctly detected 83.3% (5/6) of patients, and these patients were triaged in less than one hour from arrival on average. The program did not falsely identify non-LVOs as LVOs for any patients. Conclusions Identifying adjunct tools to aid timely identification and treatment of ischemic stroke in trauma patients is necessary to increase the chances for meaningful neurological recovery. Our early experience exhibited potential for using automated software to aid occlusion identification and subsequent stroke team mobilization. Future studies in larger cohorts will expand upon these preliminary findings to establish the accuracy and clinical benefit of automated stroke detection tool integration for the trauma population.

Improving appropriate use of intravenous albumin: results of a single-centre audit and multifaceted intervention.

BACKGROUND: Intravenous albumin has limited indications supported by randomised controlled trials, yet it is often prescribed for indications not supported by evidence. AIM: To reduce unnecessary transfusion of albumin. INTERVENTIONS: Under the leadership of a multidisciplinary quality improvement team, evidence-based recommendations were disseminated in tandem with a new electronic order set, an educational strategy, qualitative interviews with prescribers and a return policy change to reduce wastage. IMPLEMENTATION AND EVALUATION: Interventions were introduced in a staggered fashion. The primary outcome, appropriate use of albumin, was monitored and quantified using pre-intervention and post-intervention audits. Process measures included statistical process run charts of monthly usage of 5% and 25% albumin and wastage. Data on length of stay (hospital and intensive care), new inpatient starts on kidney replacement and mortality were collected as balancing measures. RESULTS: Appropriate albumin usage based on indication increased from 30% to 50% (p<0.0001). There was significantly less overall albumin usage in the post-intervention period compared with the pre-intervention period (negative coefficient, p<0.0001), driven by a major reduction in the utilisation of the 5% formulation (p<0.0001). Overall albumin usage was significantly lower in the post-intervention period, decreasing from 800 to 450 vials per month. The intervention resulted in significantly less wastage (negative coefficient, p=0.017). Mortality, length of stay and new starts on kidney replacement therapy remained constant throughout the study period. CONCLUSION: Improved prescribing of albumin was achieved with a multifaceted approach. Substantial and sustained reductions in usage were achieved without negatively impacting patient-important outcomes. The estimated annual savings for the purchase cost of albumin was CAN $300 000. We provide a structured process for other organisations to optimise their use of albumin.

Dopamine­iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Correlating Age and Hematoma Volume with Extent of Midline Shift in Acute Subdural Hematoma Patients: Validation of an Artificial Intelligence Tool for Volumetric Analysis.

OBJECTIVE: Decision for intervention in acute subdural hematoma patients is based on a combination of clinical and radiographic factors. Age has been suggested as a factor to be strongly considered when interpreting midline shift (MLS) and hematoma volume data for assessing critical clinical severity during operative intervention decisions for acute subdural hematoma patients. The objective of this study was to demonstrate the use of an automated volumetric analysis tool to measure hematoma volume and MLS and quantify their relationship with age. METHODS: A total of 1789 acute subdural hematoma patients were analyzed using qER-Quant software (Qure.ai, Mumbai, India) for MLS and hematoma volume measurements. Univariable and multivariable regressions analyzed association between MLS, hematoma volume, age, and MLS:hematoma volume ratio. RESULTS: In comparison to young patients (≤ 70 years), old patients (>70 years) had significantly higher average hematoma volume (old: 62.2 mL vs. young 46.8 mL, P < 0.0001), lower average MLS (old: 6.6 mm vs. young: 7.4 mm, P = 0.025), and lower average MLS:hematoma volume ratio (old: 0.11 mm/mL vs. young 0.15 mm/mL, P < 0.0001). Young patients had an average of 1.5 mm greater MLS for a given hematoma volume in comparison to old patients. With increasing age, the ratio between MLS and hematoma volume significantly decreases (P = 0.0002). CONCLUSIONS: Commercially available, automated, artificial intelligence (AI)-based tools may be used for obtaining quantitative radiographic measurement data in patients with acute subdural hematoma. Our quantitative results are consistent with the qualitative relationship previously established between age, hematoma volume, and MLS, which supports the validity of using AI-based tools for acute subdural hematoma volume estimation.

Discrimination, Drinking to Cope, Protective Behavioral Strategies, and Alcohol-Related Consequences Among University Students.

OBJECTIVE: University students who experience more discrimination typically report more negative consequences from alcohol use. The study aimed to assess whether drinking to cope and protective behavioral strategies for alcohol use would help explain the relationship between everyday discrimination and alcohol-related consequences among university student drinkers. METHOD: Data were collected in Fall 2020, and the sample included 707 undergraduate and graduate students from a large public institution in the Northeast who reported consuming alcohol in the past month. Participants identified predominantly as women (71.7%; 24.6% men) and White (65.1%; 7.9% Black/African American; 7.2% Asian/Asian American; 7.1% Hispanic/Latinx). A cross-sectional serial mediation analysis using structural equation modeling was conducted using Mplus. RESULTS: When we controlled for alcohol use, results supported a serial partial mediation model. More experiences of discrimination predicted a significant increase in alcohol-related consequences, above and beyond the increase attributed to drinking to cope. More frequent use of protective behavioral strategies significantly increased the odds of reporting no alcohol-related consequences. CONCLUSIONS: Drinking to cope and protective behavioral strategies for alcohol use may help explain why university students who report frequent discrimination are more likely to experience alcohol-related consequences, independent of how much alcohol they consume. Findings can inform clinical and prevention practice, advocacy, and training.