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Presents an abstract of 'Cytokine Dysregulation Associated with Exam Stress in Healthy Medical Students,' by G.D. Marshall, S.K. Agarwal, C. Lloyd, L. Cohen, E.M. Henninger and G.J. Morris, published in the 1998 issue of 'Brain Behavioral Immunity.'

Background: Although coronavirus disease 2019 (COVID-19) patients who develop in-hospital acute kidney injury (AKI) have worse short-term outcomes, their long-term outcomes have not been fully characterized. We investigated 90-day and 1-year outcomes after hospital AKI grouped by time to recovery from AKI., Methods: This study consisted of 3296 COVID-19 patients with hospital AKI stratified by early recovery (<48 hours), delayed recovery (2-7 days) and prolonged recovery (>7-90 days). Demographics, comorbidities and laboratory values were obtained at admission and up to the 1-year follow-up. The incidence of major adverse cardiovascular events (MACE) and major adverse kidney events (MAKE), rehospitalization, recurrent AKI and new-onset chronic kidney disease (CKD) were obtained 90-days after COVID-19 discharge., Results: The incidence of hospital AKI was 28.6%. Of the COVID-19 patients with AKI, 58.0% experienced early recovery, 14.8% delayed recovery and 27.1% prolonged recovery. Patients with a longer AKI recovery time had a higher prevalence of CKD (P < .05) and were more likely to need invasive mechanical ventilation (P < .001) and to die (P < .001). Many COVID-19 patients developed MAKE, recurrent AKI and new-onset CKD within 90 days, and these incidences were higher in the prolonged recovery group (P < .05). The incidence of MACE peaked 20-40 days postdischarge, whereas MAKE peaked 80-90 days postdischarge. Logistic regression models predicted 90-day MACE and MAKE with 82.4 ± 1.6% and 79.6 ± 2.3% accuracy, respectively., Conclusion: COVID-19 survivors who developed hospital AKI are at high risk for adverse cardiovascular and kidney outcomes, especially those with longer AKI recovery times and those with a history of CKD. These patients may require long-term follow-up for cardiac and kidney complications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Aims: This study characterized incidence, patient profiles, risk factors and outcomes of in-hospital diabetic ketoacidosis (DKA) in patients with COVID-19 compared with influenza and pre-pandemic data., Methods: This study consisted of 13 383 hospitalized patients with COVID-19 (March 2020-July 2022), 19 165 hospitalized patients with influenza (January 2018-July 2022) and 35 000 randomly sampled hospitalized pre-pandemic patients (January 2017-December 2019) in Montefiore Health System, Bronx, NY, USA. Primary outcomes were incidence of in-hospital DKA, in-hospital mortality, and insulin use at 3 and 6 months post-infection. Risk factors for developing DKA were identified., Results: The overall incidence of DKA in patients with COVID-19 and influenza, and pre-pandemic were 2.1%, 1.4% and 0.5%, respectively (p < .05 pairwise). Patients with COVID-19 with DKA had worse acute outcomes (p < .05) and higher incidence of new insulin treatment 3 and 6 months post-infection compared with patients with influenza with DKA (p < .05). The incidence of DKA in patients with COVID-19 was highest among patients with type 1 diabetes (12.8%), followed by patients with insulin-dependent type 2 diabetes (T2D; 5.2%), non-insulin dependent T2D (2.3%) and, lastly, patients without T2D (1.3%). Patients with COVID-19 with DKA had worse disease severity and higher mortality [odds ratio = 6.178 (4.428-8.590), p < .0001] compared with those without DKA. Type 1 diabetes, steroid therapy for COVID-19, COVID-19 status, black race and male gender were associated with increased risk of DKA., Conclusions: The incidence of DKA was higher in COVID-19 cohort compared to the influenza and pre-pandemic cohort. Patients with COVID-19 with DKA had worse outcomes compared with those without. Many COVID-19 survivors who developed DKA during hospitalization became insulin dependent. Identification of risk factors for DKA and new insulin-dependency could enable careful monitoring and timely intervention., (© 2023 John Wiley & Sons Ltd.)

Purpose: To investigate the evolution of COVID-19 patient characteristics and multiorgan injury across the pandemic., Methods: This retrospective cohort study consisted of 40,387 individuals tested positive for SARS-CoV-2 in the Montefiore Health System in Bronx, NY, between March 2020 and February 2022, of which 11,306 were hospitalized. Creatinine, troponin, and alanine aminotransferase were used to define acute kidney injury (AKI), acute cardiac injury (ACI) and acute liver injury, respectively. Demographics, comorbidities, emergency department visits, hospitalization, intensive care utilization, and mortality were analyzed across the pandemic., Results: COVID-19 positive cases, emergency department visits, hospitalization and mortality rate showed four distinct waves with a large first wave in April 2020, two small (Alpha and Delta) waves, and a large Omicron wave in December 2021. Omicron was more infectious but less lethal (p = 0.05). Among hospitalized COVID-19 patients, age decreased (p = 0.014), female percentage increased (p = 0.023), Hispanic (p = 0.028) and non-Hispanic Black (p = 0.05) percentages decreased, and patients with pre-existing diabetes (p = 0.002) and hypertension (p = 0.04) decreased across the pandemic. More than half (53.1%) of hospitalized patients had major organ injury. Patients with AKI, ACI and its combinations were older, more likely males, had more comorbidities, and consisted more of non-Hispanic Black and Hispanic patients (p = 0.005). Patients with AKI and its combinations had 4-9 times higher adjusted risk of mortality than those without., Conclusions: There were shifts in demographics toward younger age and proportionally more females with COVID-19 across the pandemic. While the overall trend showed improved clinical outcomes, a substantial number of COVID-19 patients developed multi-organ injuries over time. These findings could bring awareness to at-risk patients for long-term organ injuries and help to better inform public policy and outreach initiatives., Competing Interests: The authors declare the following conflict of interests: Wouter S. Hoogenboom, co-author, is employed by Elsevier and functions as an external editor for Heliyon. Wouter S. Hoogenboom had no part in the peer-review process or the editorial decision-making and the work carried out in this manuscript was completed before WSH was employed by Elsevier., (© 2023 The Authors. Published by Elsevier Ltd.)

Objective: To investigate perinatal complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy in the four major waves of the coronavirus disease 2019 (COVID-19) pandemic in the Bronx, New York., Methods: This retrospective cohort study included all patients who delivered at a single academic medical center between March 1, 2020, and February 13, 2022. SARS-CoV-2 positivity was defined as a positive SARS-CoV-2 test result during pregnancy. Primary outcomes were preterm birth, low birth weight, stillbirth, cesarean delivery, and preeclampsia associated with SARS-CoV-2 infection. Secondary analyses examined outcomes by predominant variant at the time of infection. Group differences in categorical variables were tested using χ 2 tests., Results: Of the 8,983 patients who delivered, 638 (7.1%) tested positive for SARS-CoV-2 infection during pregnancy. Age, race, ethnicity, and major comorbidities did not differ significantly between the SARS-CoV-2-positive and SARS-CoV-2-negative cohorts ( P >.05). Primary outcomes did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative cohorts ( P >.05). There was a marked increase in positive SARS-CoV-2 test results in individuals who gave birth during the Omicron wave (140/449, 31.2%). However, among patients who tested positive for SARS-CoV-2 infection, the preterm birth rate during the Omicron wave (9.9%) was significantly lower than during the original wave (20.3%) and the Alpha (18.4%) wave ( P <.05). Vaccination rates were low before the Omicron wave and rose to 47.2% during the Omicron wave among individuals hospitalized with SARS-CoV-2 infection. Finally, second-trimester infection was significantly associated with worse perinatal outcomes compared with third-trimester infection ( P <.05)., Conclusion: There was a general trend toward improvement in preterm birth rates across the pandemic among pregnant patients with SARS-CoV-2 infection. The Omicron variant was more infectious, but the preterm birth rate during the Omicron wave was low compared with that during the original wave and the Alpha wave., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

This study examined the relationship between sensory processing difficulties, parental stress, and behavioral problems in a clinical sample of young children with developmental and behavioral difficulties. We hypothesized that a high rate of sensory processing difficulties would be found, that there would be a high rate of comorbidity between sensory processing difficulties and behavioral problems, and that children's sensory processing difficulties and parental stress would be highly correlated. Parents of 59 children ages two to five who attended an out-patient clinic in a low income, urban community completed the Child Behavior Checklist, Parental Stress Inventory-Short Form and the Short Sensory Profile. Children in this clinical population showed a high prevalence (55.9%) of sensory processing difficulties, a significantly higher rate than previously reported. Sensory processing deficits were correlated with behavioral difficulties and parental stress levels-suggesting that as sensory processing difficulties increase, so do behavioral difficulties and parental stress. Parents of children with sensory processing deficits had significantly higher levels of parental stress than parents of children without sensory deficits. Parenting stress levels were also clinically elevated for the cohort of children in which sensory processing difficulties and behavioral concerns co-existed. These findings suggest that treatment outcomes might improve and parental stress could be reduced if mental health clinicians were trained to identify and address sensory problems. This could result in more children being screened and treated for sensory processing difficulties and an eventual reduction in the rates of parental stress.

The mechanisms of stress-related immune alterations have not been fully elucidated. Cell-mediated immune responses as well as antibody and certain cytokines are reported as being suppressed during times of high stress. However, the role of suppression vs dysregulation has not been established in human stress models. The effect of exam stress on regulatory cytokines in 16 healthy medical students was assessed by measuring type-1 (IFN-gamma) and type-2 (IL-10) cytokines from 72-h PHA/PMA-stimulated PBMC 4 weeks before and 48 h after exams. Results demonstrated decreased IFN-gamma accompanied by increased IL-10 during exam stress that resulted in a decreased IFN-gamma:IL-10 ratio. There was a significant correlation between the cytokine response to PHA/PMA and number and subjective adjustment to daily hassles. Additionally, students who reported greater levels of loneliness also reported greater numbers of and poorer subjective adjustment to hassles. The differences were consistent in both males and females but did not correlate with AM cortisol levels. Additionally, when individuals were grouped into high vs low preexam hassle levels, the type-1/type-2 shift in the IFN-gamma:IL-10 ratio occurred in the low hassles group only. These data suggest that psychologically stressful situations shift type-1/type-2 cytokine balance toward type-2 and result in an immune dysregulation rather than overall immunosuppression. This may partially explain the increased incidence of type-2-mediated conditions such as increased viral infections, latent viral expression, allergic/asthmatic reactions, and autoimmunity reported during periods of high stress., (Copyright 1998 Academic Press.)

Parenterally administered human recombinant type I interferons (hrIFN) in relapsing-remitting multiple sclerosis (RRMS) decrease relapses and spontaneous in vitro IFN-gamma production, reduce clinical progression, and decrease magnetic resonance imaging (MRI)-defined disease activity and lesions. Parenterally administered type I IFN use is limited by clinical and chemical toxicities, and the induction of antibodies that abrogate their activity in vivo correlated with the loss of clinical benefit. Therefore, we determined whether ingested IFN-alpha was non-toxic and had biological effects in humans. Ingested hrIFN-alpha showed no toxicity in normal volunteers or patients with RRMS at doses ranging from 300 to 100,000 units. In subjects with RRMS, a significant decrease in Con A-mediated proliferation and serum soluble intercellular adhesion molecule-1 (sICAM-1), a surrogate measure for disease activity in MS, was found after ingesting 10,000 and 30,000 units IFN-alpha The RRMS subjects also showed decreased IL-2 secretion after ingesting 10,000 units IFN-alpha and decreased IFN-gamma, TGF-beta and IL-10 production after ingesting 30,000 units IFN-alpha. The decreased secretion of IFN-gamma and IL-2 by ingested IFN-alpha suggests that oral IFN-alpha may cause a functional inhibition of Th J-like T helper cells in RRMS, a potential site of intervention at the level of effector T cells in MS. Our studies support the oral use of human IFN-alpha as a biological response modifier in humans.

MS is presumed to be a T-cell-mediated chronic inflammatory disease of the CNS. We examined proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 [anti-CD3] monoclonal antibody (MAb) or concanavalin A (Con A) in subjects with stable relapsing-remitting MS (RR MS) before and after initiating interferon (IFN)-beta 1b treatment. There was no significant difference in pretreatment to on-treatment anti-CD3 mAb or Con A-induced proliferation in RR MS patients. There was significantly increased Con A-induced secretion of tumor necrosis factor (TNF)-alpha, IFN-gamma, interleukin (IL)-2, IL-6, and IL-10 and decreased IL-4 secretion in on-treatment compared with pretreatment peripheral blood mononuclear cell samples. However, on-treatment CD3-mediated secretion of TNF-alpha was significantly decreased, and IL-6 secretion was significantly increased compared with pretreatment values. IFN-gamma was also decreased in on-treatment cultures stimulated with anti-CD3 MAb, but these values did not reach statistical significance. Systemic side effects from IFN-beta 1b were associated with increased IL-6 secretion. There were no significant changes in CD3-mediated IL-4, IL-10, transforming growth factor (TGF)-beta, or IL-2 secretion or Con A-induced TGF-beta secretion. IFN-beta 1b (Betaseron) decreases CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL-6, that could potentially counteract its beneficial immunomodulatory effects.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that has been postulated to be T-cell mediated. We examined the proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 (anti-CD3) monoclonal antibody concanavalin A, or ionomycin plus myristic acid palmityl ester in subjects with stable relapsing-remitting MS. Control subjects demonstrated good proliferation to anti-CD3 monoclonal antibody whereas subjects with relapsing-remitting MS showed a significantly decreased anti-CD3 monoclonal antibody-mediated response. There was no difference in concanavalin or ionomycin plus myristic acid palmityl ester stimulation between control subjects and MS subjects. Secretion of interferon-gamma was significantly decreased and transforming growth factor-beta was significantly increased from cultures stimulated with anti-CD3 monoclonal antibody, but not ionomycin plus myristic acid palmityl ester or concanavalin A, in MS patients compared to control subjects. Secretion of interleukin-10 and tumor necrosis factor-alpha was not different between control subjects and MS patients following stimulation with anti-CD3 monoclonal antibody, concanavalin A, or ionomycin plus myristic acid palmityl ester, or of interleukin-2 and interleukin-4 following stimulation with anti-CD3 monoclonal antibody or concanavalin A. An abnormality of signal transduction and secretion of the immunomodulatory molecule interferon-gamma may exist in MS via the CD3 T-cell receptor complex.