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HIV status may influence survival from non-small cell lung cancer (NSCLC). Among NSCLC patients in the Bronx, NY, we assessed (1) associations of CD4 count, CD4/CD8 ratio and HIV viral load (VL) with survival and (2) prognostic factors among persons living with HIV (PLWH). We compared survival from NSCLC diagnosis (2004–2017) between HIV-negative persons (HIV-, n=2,881) and PLWH (n=88) accounting for clinical and sociodemographic factors. HIV-survival was also compared with PLWH, dichotomized by CD4 (<200 vs. ≥200cells/µL), CD4/CD8 (median, <0.43 vs. ≥0.43) and VL (<75 vs. ≥75copies/mL) at NSCLC diagnosis. Among PLWH, we assessed the relationships of CD4, CD4/CD8, and VL with survival, adjusting for age, sex, and cancer stage. PLWH with CD4< 200cells/µL had lower survival than HIV- [hazard ratio, 95% confidence interval [HR(95%CI)]=1.86(0.98–3.55)]. Survival was similar between PLWH with CD4≥ 200cells/µL and HIV- [HR(95%CI) = 0.90(0.61–1.33)]. Results were similar when categorizing PLWH by CD4/CD8 [vs. HIV-: low CD4/CD8: HR(95%CI) = 1.74(1.07–3.89); high CD4/CD8: HR(95%CI) = 0.63(0.37–1.07)] and VL [vs. HIV-: <75copies/mL: HR(95%CI) = 0.74(0.46–1.21), ≥75copies/mL: HR(95%CI) = 1.41(0.88–2.27)]. Among PLWH, CD4< 200cells/µL was associated with worse survival [vs. CD4≥ 200cells/µL: HR(95%CI) = 2.37(1.14–4.92)]. CD4, CD4/CD8, and VL may be prognostic markers for PLWH with NSCLC, suggesting immune status may be important in NSCLC survival among PLWH. [ABSTRACT FROM AUTHOR]

Importance: "Awake" cannulation for venovenous extracorporeal membrane oxygenation (ECMO), where patients remain spontaneously breathing without invasive mechanical ventilation during the cannulation procedure, may reduce lung injury from positive pressure ventilation and promote patient mobility., Objectives: To examine the association between "awake" cannulation for venovenous ECMO and patient outcomes., Design, Setting, and Participants: Analysis of the prospectively collected by the multicenter Extracorporeal Life Support Organization registry. Patients 18 years old or older who were cannulated for venovenous ECMO between 2016 and 2022 were included., Main Outcomes and Measures: Propensity score matching techniques were used to examine the association between the primary exposure of "awake" cannulation and the primary outcome of hospital mortality., Results: This study analyzed data from 28,627 patients who received venovenous ECMO, including 797 (2.8%) who underwent awake cannulation. Patients undergoing awake cannulation were older (52.2 vs. 47.8 yr), had greater prevalence of chronic lung diseases (50.6% vs. 48.9%), and ischemic heart disease (4.3% vs. 2.7%) compared with those cannulated while receiving mechanical ventilation. Hospital survival to discharge was did not differ significantly between awake and nonawake cannulation groups after propensity score matching (2.4% increased rate of survival for patients cannulated awake; 95% CI, -1.7% to 6.4%; p = 0.26)., Conclusions and Relevance: In this large, multicenter study, awake cannulation for venovenous ECMO was uncommon but increasingly used over time. Survival to hospital discharge was similar to patients cannulated while on mechanical ventilation. Future research should focus on identification of patient cohorts most likely to benefit from ""awake" cannulation., Competing Interests: Dr. Gong received grant funding from the National Institutes of Health (NIH), the Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention; she received fees for serving on Data and Safety Monitoring Boards for NIH-funded Behavioral Economic and Staffing Strategies to Increase Adoption of the ABCDEF Bundle in the ICU (BEST ICU) trial, Replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) trial, and Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock (ANDROMEDA) trial; and she received fees for serving on the scientific advisory panel for Philips Healthcare, Radiometer. Dr. Mohamed received consulting fees from Baxter Healthcare unrelated to this work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 ( MECP2 ) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2 -null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2 -knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron's plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment.

Oxidative stress has long been implicated in Parkinson's disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants reportedly mitigate LRRK2 toxicity. Here, using CRISPR-Cas9 gene-edited HEK293 cells, RAW264.7 macrophages, rat primary ventral midbrain cultures, and PD patient-derived lymphoblastoid cells, we found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation and that this was blocked by inhibitors of either LRRK2 kinase or NADPH oxidase 2 (NOX2). Oxidative stress induced by the pesticide rotenone was ameliorated by LRRK2 kinase inhibition and was absent in cells devoid of LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation normally seen in nigral dopaminergic neurons in this model. Mechanistically, LRRK2 kinase activity was shown to regulate phosphorylation of serine-345 in the p47 phox subunit of NOX2. This, in turn, led to translocation of p47 phox from the cytosol to the membrane-associated gp91 phox (NOX2) subunit, activation of the NOX2 enzyme complex, and production of ROS. Thus, LRRK2 kinase activity may drive cellular ROS production in PD through the regulation of NOX2 activity.

Objective: To evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on first transfer live birth rate (LBR) and cumulative LBR (CLBR) in donor oocyte in vitro fertilization (IVF) cycles., Design: Retrospective cohort study of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database., Setting: Fertility centers reporting to Society for Assisted Reproductive Technology., Patient(s): A total of 11,348 fresh and 7,214 frozen-thawed donor oocyte IVF cycles were analyzed., Intervention(s): The first reported donor stimulation cycle per patient between January 1, 2014, and December 31, 2015, and all linked embryo transfer cycles between January 1, 2014, and December 31, 2016, were included in the study., Main Outcome Measure(s): Live birth rate was compared for patients using fresh and frozen-thawed donor oocytes, with or without PGT-A. Logistic regression models were adjusted for age, body mass index, gravidity, infertility etiology, and prior IVF cycles., Result(s): Among patients who had blastocysts available for transfer or PGT-A, the use of PGT-A was associated with a decreased first transfer LBR (46.9 vs. 53.2%) and CLBR (58.4 vs. 66.6%) in fresh oocyte donor cycles compared with no PGT-A. Live birth rate in frozen-thawed oocyte donor cycles with PGT-A were nominally higher than those without PGT-A (48.3% vs. 40.5%) but were not statistically significant in multivariable logistic regression models. Early pregnancy loss was not significantly different with and without PGT-A. Multiple gestation, preterm birth, and low birth weight infants were all reduced with the addition of PGT-A in fresh donor oocyte cycles, although these outcomes were not significantly different when comparing single embryo transfers in fresh oocyte cycles and also not significantly different among frozen-thawed donor oocyte cycles., Conclusion(s): Preimplantation genetic testing for aneuploidy in fresh oocyte donor cycles was associated with decreased LBR and CLBR, whereas effects on frozen-thawed oocyte donor cycles were clinically negligible. Obstetric benefits associated with PGT-A in fresh donor cycles appear linked to increased single embryo transfer., Competing Interests: Declaration of Interests J.A.G. has nothing to disclose. A.K. has nothing to disclose. H.W. has nothing to disclose. M.F. has nothing to disclose. H.L. has nothing to disclose. G.D.B. has nothing to disclose. K.D. has nothing to disclose. S.J. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood. We found that the production of 4-hydroxynonenal (4-HNE), a lipid hydroperoxidation end-product, is a common biochemical response to these diverse stimuli. 4-HNE forms post-translational adducts with Cys2024 and Cys2025 in the kinase activation loop of WT LRRK2, significantly increasing its kinase activity. Additionally, we discovered that the 4-HNE responsible for regulating LRRK2 is generated by the action of 15-lipoxygenase (15-LO), making 15-LO an upstream regulator of the pathogenic hyperactivation of LRRK2 kinase activity. Pharmacological inhibition or genetic ablation of 15-LO prevents 4-HNE post-translational modification of LRRK2 kinase and its subsequent pathogenic hyperactivation. Therefore, 15-LO inhibitors, or methods to lower 4-HNE levels, or the targeting of Cys2024/2025 could provide new therapeutic strategies to modulate LRRK2 kinase activity and treat PD.

Background: Mycoplasma genitalium (MG) is an emerging sexually transmitted infection. Treatment of MG is complicated by increasing resistance to primary treatment regimens, including macrolides and fluoroquinolones. Understanding the various clinical presentations and relative effectiveness of treatments for MG is crucial to optimizing care., Methods: Patients with a positive MG nucleic acid amplification test between July 1, 2019, and June 30, 2021, at a large health system in New York City were included in a retrospective cohort. Demographics, clinical presentations, coinfections, treatment, and follow-up microbiologic tests were obtained from the electronic medical record. Associations with microbiologic cure were evaluated in bivariate and multivariable logistic regression models., Results: Five hundred two unique patients had a positive MG nucleic acid amplification test result during the study period. Male individuals presented predominantly with urethritis (117 of 187 [63%]) and female individuals with vaginal symptoms (142 of 315 [45%]). Among patients with follow-up testing who received a single antibiotic at the time of treatment, 43% (90 of 210) had persistent infection and 57% (120 of 210) had microbiologic cure. Eighty-two percent of patients treated with moxifloxacin had microbiologic cure compared with 41% of patients receiving azithromycin regimens ( P < 0.001). In multivariable analysis, treatment with moxifloxacin was associated with 4 times the odds of microbiologic cure relative to low-dose azithromycin (adjusted odds ratio [aOR], 4.18; 95% confidence interval, 1.73-10.13; P < 0.01)., Conclusions: Clinical presentations of MG vary, with urethritis or vaginal symptoms in most cases. Among patients who received a single antibiotic, only treatment with moxifloxacin was significantly associated with microbiologic cure relative to low-dose azithromycin., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Objectives: Electronic health records (EHRs) have transformed the way modern medicine is practiced, but they remain a major source of documentation burden among physicians. This study aims to use data from Signal, a tool provided by the Epic EHR, to analyze physician metadata in the Montefiore Health System via cluster analysis to assess EHR burden and efficiency. Methods: Data were obtained for a one-month period (July 2020) representing a return to normal operation post-telemedicine implementation. Six metrics from Signal were used to phenotype physicians: time on unscheduled days, pajama time, time outside of 7 AM to 7 PM, turnaround time, proficiency score, and visits closed the same day. k-Means clustering was employed to group physicians, and the clusters were assessed overall and by sex and specialty. Results: Our results demonstrate the partitioning of physicians into a higher-efficiency, lower-time outside of scheduled hours (TOSH) cluster and a lower-efficiency, higher-TOSH cluster even when stratified by sex and specialty. Intra-cluster comparisons showed general homogeneity of physician metrics with the exception of the higher-efficiency, lower-TOSH cluster when stratified by sex. Conclusions: Taken together, the clusters uniquely reflect the EHR efficiency-burden of the Montefiore Health System. Applying k-means clustering to readily available EHR data allows for a scalable, efficient, and adaptable approach of assessing physician EHR burden and efficiency, allowing health systems to examine documentation trends and target wellness interventions.

Since the 1980s, it has been known that the administration of ganglioside GM1 to cultured cells induced or enhanced neuronal differentiation. GM1 mechanism of action relies on its direct interaction and subsequent activation of the membrane tyrosine kinase receptor, TrkA, which naturally serves as NGF receptor. This process is mediated by the sole oligosaccharide portion of GM1, the pentasaccharide β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal-(1-4)-β-Glc. Here we detailed the minimum structural requirements of the oligosaccharide portion of GM1 for mediating the TrkA dependent neuritogenic processing. By in vitro and in silico biochemical approaches, we demonstrated that the minimal portion of GM1 required for the TrkA activation is the inner core of the ganglioside's oligosaccharide β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal. The addition of a sialic acid residue at position 3 of the outer galactose of the GM1 oligosaccharide, which forms the oligosaccharide of GD1a, prevented the interaction with TrkA and the resulting neuritogenesis. On the contrary, the addition of a fucose residue at position 2 of the outer galactose, forming the Fucosyl-GM1 oligosaccharide, did not prevent the TrkA-mediated neuritogenesis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1 G93A motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A series of biologically unexplored substituted 1,3,4-subtituted-pyrrolo[3,2-c]quinoline derivatives (PQs) was evaluated against a panel of about 60 tumor cells (NCI). Based on the preliminary antiproliferative data, the optimizations efforts permitted us to design and synthesize a new series of derivatives allowing us to individuate a promising hit (4g). The insertion of a 4-benzo[d] [1,3]dioxol-5-yl moiety on increased and extended the activity towards five panel tumor cell lines such as leukemia, CNS, melanoma, renal and breast cancer, reaching IG 50 in the low μM range. Replacement of this latter with a 4-(OH-di-Cl-Ph) group (4i) or introduction a Cl-propyl chain in position 1 (5), selectively addressed the activity against the entire leukemia sub-panel (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). Preliminary biological assays on MCF-7 such as cell cycle, clonogenic assay, ROS content test alongside a comparison of viability between MCF-7 and non-tumorigenic MCF-10 were investigated. Among the main anticancer targets involved in breast cancer, HSP90 and ER receptors were selected for in silico studies. Docking analysis revealed a valuable affinity for HSP90 providing structural insights on the binding mode, and useful features for optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Hospitalizations among people living with HIV (PLWH) are frequent and costly. This study examined the association between psychiatric, HIV-related, and demographic factors and hospitalization rates among PLWH using data from the Einstein-Rockefeller-City University of New York Center for AIDS Research Clinical Cohort Database. Of the 10,215 PLWH included in the sample, 45% had at least one non-psychiatric hospitalization between 2009 and 2018, with significant risk factors including prior psychiatric outpatient visits, depression, or alcohol-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. Additionally, 14% had an HIV-related hospitalization, with significant risk factors including prior psychiatric outpatient visits, alcohol- and substance-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. The study emphasizes the need for tailored interventions, including integrated treatment and comprehensive case management, for PLWH with comorbid psychiatric disorders, women, and older adults., (© 2023. The Author(s).)

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABA A Rs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABA A R synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABA A R subunit composition, there was a redistribution of extrasynaptic GABA A Rs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABA A Rs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca 2+ /calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance., Competing Interests: Declaration of Competing Interest The authors have no disclosures and declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ethnic and racial disparities have recently been observed both in treatment-related toxicities and rates of long-lasting cure in acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (ALLy), the most common pediatric malignancy. Despite significant improvements in overall survival in the recent past, a large number of children die from aggressive disease., Methods: We performed a retrospective cohort analysis of 274 pediatric ALL/ALLy patients within Montefiore Health System from 2004 to 2021 to determine differences in all-cause mortality within the Pediatric Hematologic Malignancies Cohort using Cox Proportional Hazard regression modeling, adjusted for age at diagnosis, race/ethnicity, administration of intensive chemotherapy, preferred language, maximum glucose, and hypertension., Results: Among our 274 patients, 132 were Hispanic, 54 Non-Hispanic Black, and 25 Non-Hispanic White, with 25 identified as "Non-Hispanic Other," including Asian, Arabic, and Other. Hispanic patients were 78% less likely to die (HR 0.22; 95% CI 0.07, 0.73) when compared with Non-Hispanic Black individuals. Spanish speakers were 2.91 times more likely to die compared with those who spoke English (HR 2.91; 95% CI 1.08, 7.82). Among those English speakers, the diagnosis of hypertension and Hispanic ethnicity significantly impacted the risk of death, while these factors did not impact survival in Spanish speakers. High-risk cytogenetics did not impact survival., Conclusions: Hispanic children with ALL/ALLy have improved survival outcomes compared with Non-Hispanic Blacks. Additionally, Spanish language preference was strongly associated with poorer survival, a novel finding that should be validated in future studies., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies., Methods: Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤-1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use., Results: A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD., Conclusion: AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson's disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood-brain barrier is denied. Recently, we demonstrated that the GM1 oligosaccharide head group (GM1-OS) is the GM1 bioactive portion that, interacting with the TrkA-NGF complex at the membrane surface, promotes the activation of a multivariate network of intracellular events regulating neuronal differentiation, protection, and reparation. Here, we evaluated the GM1-OS neuroprotective potential against the Parkinson's disease-linked neurotoxin MPTP, which destroys dopaminergic neurons by affecting mitochondrial bioenergetics and causing ROS overproduction. In dopaminergic and glutamatergic primary cultures, GM1-OS administration significantly increased neuronal survival, preserved neurite network, and reduced mitochondrial ROS production enhancing the mTOR/Akt/GSK3β pathway. These data highlight the neuroprotective efficacy of GM1-OS in parkinsonian models through the implementation of mitochondrial function and reduction in oxidative stress.

To date there are no therapeutic strategies that limit the progression of Parkinson's disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO 2 -OA). In N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO 2 -OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification, and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO 2 -OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates., (© 2023. The Author(s).)

Introduction: Electrical isolation of pulmonary veins (PVI) is a cornerstone for atrial fibrillation (AF) ablation. The overall effect of AF ablation, and especially lesions beyond PVI, on left atrial (LA) function is currently poorly understood. Our aim was to determine if LA function is different in patients after extensive LA ablation compared to PVI only. We performed non-inferiority analysis of LA function after PVI with additional nonpulmonary vein ablation lesions in LA (PVI+) and PVI alone., Methods: We studied 68 patients consecutive patients who underwent AF ablation and who had complete transthoracic echocardiogram (TTE) within 12 months before AF ablation and 1-12 months after the procedure. Patients were stratified into two groups: PVI only and PVI+. Primary outcome was change in LA reservoir strain (LASr). Noninferiority margin was defined at 6%., Results: The PVI only group had a higher proportion of patients with paroxysmal AF (70% vs. 30%). The PVI+ group was observed to have a slightly higher increase in LASr compared to PVI alone (5.0% vs. 4.3%, p < .01 for noninferiority). LASr noninferiority was confirmed when adjusted for age, sex, coronary artery disease, hyperlipidemia, and AF type, rhythm at preprocedure TTE in a multivariable linear regression model, 90% CI (-5.46 to 2.04), p < .01., Conclusion: LA functional improvement evaluated by LASr was noninferior after PVI with additional LA ablation lesions compared to PVI alone. These findings were confirmed when adjusted for confounding clinical variables, suggesting that more extensive ablation does not negatively affect LA function., (© 2022 Wiley Periodicals LLC.)

Purpose: To evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on cumulative live birth rate (CLBR) in IVF cycles., Methods: Retrospective cohort study of the SART CORS database, comparing CLBR for patients using autologous oocytes, with or without PGT-A. The first reported autologous ovarian stimulation cycle per patient between January 1, 2014, and December 31, 2015, and all linked embryo transfer cycles between January 1, 2014, and December 31, 2016, were included in the study. Exclusion criteria were donor oocyte cycles, donor embryo cycles, gestational carrier cycles, cycles which included both a fresh embryo transfer (ET) combined with a thawed embryo previously frozen (ET plus FET), or cycles with a fresh ET after PGT-A., Results: A total of 133,494 autologous IVF cycles were analyzed. Amongst patients who had blastocysts available for either ET or PGT-A, including those without transferrable embryos, decreased CLBR was noted in the PGT-A group at all ages, except ages > 40 (p < 0.01). A subgroup analysis of only those patients who had PGT-A and a subsequent FET, excluding those without transferrable embryos, demonstrated a very high CLBR, ranging from 71.2% at age < 35 to 50.2% at age > 42. Rates of multiple gestations, preterm birth, early pregnancy loss, and low birth weight were all greater in the non-PGT-A group., Conclusions: PGT-A was associated with decreased CLBR amongst all patients who had blastocysts available for ET or PGT-A, except those aged > 40. The negative association of PGT-A use and CLBR per cycle start was especially pronounced at age < 35., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The interactions between gangliosides and proteins belonging to the same or different lipid domains and their influence on physiological and pathological states have been analysed in detail. A well-known factor impacting on lipid-protein interactions and their biological outcomes is the dynamic composition of plasma membrane. This review focuses on GM1 and GM3 gangliosides because they are an integral part of protein-receptor complexes and dysregulation of their concentration shows a direct correlation with the onset of pathological conditions. We first discuss the interaction between GM3 and insulin receptor in relation to insulin responses, with an increase in GM3 correlating with the onset of metabolic dysfunction. Next, we describe the case of the GM1-TrkA interaction, relevant to nerve-cell differentiation and homeostasis as deficiency in plasma-membrane GM1 is known to promote neurodegeneration. These two examples highlight the fact that interactions between gangliosides and receptor proteins within the plasma membrane are crucial in controlling cell signalling and pathophysiological cellular states., (© 2022 Federation of European Biochemical Societies.)

Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (~2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study., Competing Interests: Declaration of Competing Interest We have no conflict of interest.

Background: COVID-19-associated mucormycosis (CAM) is associated with high morbidity and mortality. MUNCO is an international database used to collect clinical data on cases of CAM in real time. Preliminary data from the Mycotic Infections in COVID-19 (MUNCO) online registry yielded 728 cases from May to September 2021 in four South Asian countries and the United States. A majority of the cases (694; 97.6%) consisted of a mucormycosis infection. The dataset allowed for the analysis of the risk factors for adverse outcomes from CAM and this analysis is presented in this paper., Methods: The submission of cases was aided by a direct solicitation and social media online. The primary endpoints were full recovery or death measured on day 42 of the diagnosis. All patients had histopathologically confirmed CAM. The groups were compared to determine the contribution of each patient characteristic to the outcome. Multivariable logistic regression models were used to model the probability of death after a CAM diagnosis., Results: The registry captured 694 cases of CAM. Within this, 341 could be analyzed as the study excluded patients with an unknown CAM recovery status due to either an interruption or a lack of follow up. The 341 viable cases consisted of 258 patients who survived after the completion of treatment and 83 patients who died during the period of observation. In a multivariable logistic regression model, the factors associated with an increased risk of mortality include old age (OR = 1.04, 95% CI 1.02-1.07, p = 0.001), history of diabetes mellitus (OR 3.5, 95% CI 1.01-11.9, p = 0.02) and a lower BMI (OR 0.9, 95% CI 0.82-0.98, p = 0.03). Mucor localized to sinus disease was associated with 77% reduced odds of death (OR = 0.23, 95% CI 0.09-0.57, p = 0.001), while cerebral mucor was associated with an increased odds of death (OR = 10.96, 95% CI 4.93-24.36, p = ≤0.0001)., Conclusion: In patients with CAM, older age, a history of diabetes and a lower body mass index is associated with increased mortality. Disease limited to the sinuses without a cerebral extension is associated with a lower risk of mortality. Interestingly, the use of zinc and azithromycin were not associated with increased mortality in our study.

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.

Objective: The aim of this study was to examine the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and preterm birth, cesarean birth, and composite severe maternal morbidity by studying women with and without SARS-CoV-2 infection at the time of delivery hospitalization from similar residential catchment areas in New York City., Study Design: This was a retrospective cohort study of pregnant women with laboratory-confirmed or laboratory-denied SARS-CoV-2 on nasopharyngeal swab under universal testing policies at the time of admission who gave birth between March 13 and May 15, 2020, at two New York City medical centers. Demographic and clinical data were collected and follow-up was completed on May 30, 2020. Groups were compared for the primary outcome and preterm birth, in adjusted (for age, race/ethnicity, nulliparity, body mass index) and unadjusted analyses., Results: Among this age-matched cohort, 164 women were positive and 247 were negative for SARS-CoV-2. Of the positive group, 52.4% were asymptomatic and 1.2% had critical coronavirus disease 2019 (COVID-19). The groups did not differ by race and ethnicity, body mass index, or acute or chronic comorbidities. Women with SARS-CoV-2 were more likely to be publicly insured. Preterm birth, cesarean birth, and severe maternal morbidity did not differ between groups. Babies born to women with SARS-CoV-2 were more likely to have complications of prematurity or low birth weight (7.7 vs. 2%, p  = 0.01)., Conclusion: Preterm and cesarean birth did not differ between women with and without SARS-CoV-2 across disease severity in adjusted and unadjusted analysis among this cohort during the pandemic peak in New York City., Competing Interests: None declared., (Thieme. All rights reserved.)

Mitochondrial dysfunction and oxidative stress are strongly implicated in Parkinson's disease (PD) pathogenesis and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2). Although NOX2 has been examined in the context of PD, most attention has focused on glial NOX2, and the role of neuronal NOX2 in PD remains to be defined. Additionally, pharmacological NOX2 inhibitors have typically lacked specificity. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and two animal models thereof, both neuronal and microglial NOX2 are highly active in substantia nigra under chronic conditions. However, in acute and sub-acute PD models, we observed neuronal, but not microglial NOX2 activation, suggesting that neuronal NOX2 may play a primary role in the early stages of the disease. Aberrant NOX2 activity is responsible for the formation of oxidative stress-related post-translational modifications of α-synuclein, and impaired mitochondrial protein import in vitro in primary ventral midbrain neuronal cultures and in vivo in nigrostriatal neurons in rats. In a rat model, administration of a brain-penetrant, highly specific NOX2 inhibitor prevented NOX2 activation in nigrostriatal neurons and its downstream effects in vivo, such as activation of leucine-rich repeat kinase 2 (LRRK2). We conclude that NOX2 is an important enzyme that contributes to progressive oxidative damage which in turn can lead to α-synuclein accumulation, mitochondrial protein import impairment, and LRRK2 activation. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Understanding the distribution of organ failure before and during the COVID-19 pandemic surge can provide a deeper understanding of how the pandemic strained health care systems and affected outcomes., Objective: To assess the distribution of organ failure in 3 New York City hospitals during the COVID-19 pandemic., Methods: A retrospective cohort study of adult admissions across hospitals from February 1, 2020, through May 31, 2020, was conducted. The cohort was stratified into those admitted before March 17, 2020 (prepandemic) and those admitted on or after that date (SARS-CoV-2-positive and non-SARS-CoV-2). Sequential Organ Failure Assessment scores were computed every 2 hours for each admission., Results: A total of 1 794 975 scores were computed for 20 704 admissions. Before and during the pandemic, renal failure was the most common type of organ failure at admission and respiratory failure was the most common type of hospital-onset organ failure. The SARS-CoV-2-positive group showed a 231% increase in respiratory failure compared with the prepandemic group. More than 65% of hospital-onset organ failure in the prepandemic group and 83% of hospital-onset respiratory failure in the SARS-CoV-2-positive group occurred outside intensive care units. The SARS-CoV-2-positive group showed a 341% increase in multiorgan failure compared with the prepandemic group. Compared with the prepandemic and non-SARS-CoV-2 patients, SARS-CoV-2-positive patients had significantly higher mortality for the same admission and maximum organ failure score., Conclusion: Most hospital-onset organ failure began outside intensive care units, with a marked increase in multiorgan failure during pandemic surge conditions and greater hospital mortality for the severity of organ failure., (©2022 American Association of Critical-Care Nurses.)

Objective: To measure the consequences of nonadherence with the 2013 American Society for Reproductive Medicine elective single embryo transfer (eSET) guidelines for favorable-prognosis patients., Design: Retrospective cohort., Setting: In vitro fertilization clinics., Patient(s): A total of 28,311 fresh autologous, 2,500 frozen-thawed autologous, and 3,534 fresh oocyte-donor in vitro fertilization cycles in 2014-2016 at Society for Assisted Reproductive Technology-reporting centers., Intervention(s): Patients aged <35 years or using donors aged <35 years underwent first blastocyst transfer., Main Outcome Measure(s): Singleton birth rate, gestational age at delivery, and birth weight were compared between the eSET and non-eSET groups using the chi-square or Fisher's exact test or t-tests., Result(s): Among fresh transfers, 15,643 (55%) underwent eSET. Live births after non-eSETs were less likely singletons (38.0% vs. 96.5%; adjusted relative risk [aRR], 0.56) and more likely complicated by preterm delivery (55.0% vs. 20.1%; aRR, 2.39) and low birth weight (<2,500 g) (40.1% vs. 10.6%; aRR, 3.4) compared with those after eSET. Among frozen-thawed transfers, 1,439 (58%) underwent eSET. Live births after non-eSETs were less likely singletons (41.9% vs. 95.2%; aRR, 0.69; 95% confidence interval, 0.66-0.73) and more likely complicated by preterm delivery (56.4% vs. 19.5%; aRR, 2.6; 95% confidence interval, 2.2-3.1) and low birth weight (38.0% vs. 8.9%; aRR, 3.9) compared with those after eSET. Among fresh donor oocyte transfers, 1,946 (55%) underwent eSET. Live births after non-eSETs were less likely singletons (31.3% vs. 97.3%; aRR, 0.48) and more likely complicated by preterm delivery (61.1% vs. 25.7%; aRR, 2.09) and low birth weight (44.3% vs. 11.7%; aRR, 3.39) compared with those after eSET., Conclusion(s): Nonadherence with transfer guidelines was associated with dramatically increased multiple pregnancies, preterm births, and low birth weights., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: We explored a metabolic etiology of cerebral malaria (CM) coma., Methods: Plasma metabolites were compared between Malawian children with CM and mild Plasmodium falciparum malaria. A candidate molecule was further studied in animal models of malaria., Results: Clinically abnormal concentrations of pipecolic acid (PA) were present in CM plasma, and nearly normal in mild malaria samples. PA is renally cleared and the elevated PA blood levels were associated with renal insufficiency, which was present only in CM subjects. Prior studies demonstrate that PA has neuromodulatory effects and is generated by malaria parasites. PA brain levels in Plasmodium berghei ANKA-infected animals in the experimental cerebral malaria (ECM) model inversely correlated with normal behavior and correlated with blood-brain barrier (BBB) permeability. Mice infected with malaria species that do not induce neurological abnormalities or manifest BBB permeability had elevated plasma PA levels similar to ECM plasma at 7 days postinfection; however, they had low PA levels in the brain compared to ECM mice brains at 7 days postinfection., Conclusions: Our model suggests that malaria-generated PA induces coma in CM and in ECM. The role of BBB permeability and the mechanisms of PA neuromodulation in CM will require additional investigation., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Gangliosides are glycosphingolipids which are particularly abundant in the plasma membrane of mammalian neurons. The knowledge of their presence in the human brain dates back to the end of 19th century, but their structure was determined much later, in the middle of the 1950s. From this time, neurochemical studies suggested that gangliosides, and particularly GM1 ganglioside, display neurotrophic and neuroprotective properties. The involvement of GM1 in modulating neuronal processes has been studied in detail by in vitro experiments, and the results indicated its direct role in modulating the activity of neurotrophin-dependent receptor signaling, the flux of calcium through the plasma membrane, and stabilizing the correct conformation of proteins, such as α-synuclein. Following, in vivo experiments supported the use of ganglioside drugs for the therapy of peripheral neuropathies, obtaining very positive results. However, the clinical use of gangliosides for the treatment of central neurodegeneration has not been followed due to the poor penetrability of these lipids at the central level. This, together with an ambiguous association (later denied) between ganglioside administration and Guillain-Barrè syndrome, led to the suspension of ganglioside drugs. In this critical review, we report on the evolution of research on gangliosides, on the current knowledge on the role played by gangliosides in regulating the biology of neurons, on the past and present use of ganglioside-based drugs used for therapy of peripheral neuropathies or used in human trials for central neurodegenerations, and on the therapeutic potential represented by the oligosaccharide chain of GM1 ganglioside for the treatment of neurodegenerative diseases.

GM1 is a crucial component of neuronal membrane residing both in the soma and nerve terminals. As reported in Parkinson's disease patients, the reduction of GM1 determines the failure of fundamental functional processes leading to cumulative cell distress up to neuron death. This review reports on the role of GM1 in the pathogenesis of the disease, illustrating the current data available but also hypotheses on the additional mechanisms in which GM1 could be involved and which require further study. In the manuscript we discuss these points trying to explain the role of diminished content of brain GM1, particularly in the nigro-striatal system, in Parkinson's disease etiology and progression., (© 2021. The Author(s).)