Association of Frailty and Cardiopulmonary Resuscitation Outcomes in Older U.S. Veterans.

Objectives: Determine the association between frailty and immediate survival of cardiopulmonary resuscitation (CPR) in older Veterans. Secondary outcomes: compare in-hospital mortality, duration of resuscitation efforts, hospital and intensive care unit (ICU) length of stay, neurologic outcomes, and discharge disposition between frail and non-frail Veterans. Methods: Retrospective cohort study including Veterans 50 years and older, who were "Full Code" and had in-hospital cardiac arrest between 7/1/2017 and 6/30/2020, at the Miami VAMC. Frailty Index for the VA (VA-FI) was used to determine frailty status. Immediate Survival was determined by return of spontaneous circulation (ROSC) and in-hospital mortality was determined by all-cause mortality. We compared outcomes between frail and non-frail Veterans using chi-square test. After adjusting for age, gender, race, and previous hospitalizations, we used multivariate binomial logistic regression with 95% confidence intervals to analyze the relationship between immediate survival and frailty, and in-hospital mortality and frailty. Results: 91% Veterans were non-Hispanic, 49% Caucasian, 96% male, mean age 70.7 ± 8.5 years, 73% frail and 27% non-frail. Seventy-six (65.5%) Veterans had ROSC, without difference by frailty status (P = .891). There was no difference based on frailty status of in-hospital mortality, discharge disposition, or neurologic outcomes. Frail and non-frail Veterans had resuscitation efforts lasting the same amount of time. Conclusions and Implications: CPR outcomes were not different depending on frailty status in our Veteran population. With these results, we cannot use frailty - as measured by the VA-FI - as a prognosticator of CPR outcomes in Veterans.

Frailty as a risk factor for post-acute sequelae of COVID-19 among US veterans during the Delta and Omicron waves.

BACKGROUND: Older populations have suffered the highest rates of SARS-CoV-2 infection and associated complications, including Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Frailty is a geriatric syndrome that often coexists with COVID-19 infection. The vulnerability to stressors caused by multisystemic dysfunction that characterizes frailty may predispose older adults to develop PASC. METHODS: Retrospective cohort study using the VA COVID-19 Shared Data Resource to identify US veterans testing positive for SARS-CoV-2 between July 2021 and February 2022, without prior positive tests and who were alive 30 days after infection. Frailty was calculated using a 31-item VA Frailty Index generated from electronic health records. We categorized Veterans into robust (FI ≤ 0.10), prefrail (FI: >0.10- < 0.21), and frail (FI ≥ 0.21). We assessed the association between frailty and PASC and vaccination and PASC using Cox survival model, adjusting for covariates. RESULTS: We identified 245,857 COVID-19-positive veterans surviving 30 days after infection. The mean age was 57.5 ± 16.5 years; 87.2% were males, 68.1% were white, and 9.0% were Hispanic. Almost half of the sample (48.9%) were classified as robust, while 28.3% were pre-frail and 22.7% were frail; 99,886 (40.6%) were fully vaccinated, and 33,516 (13.6%) received booster doses. Over a median follow-up of 143 days (IQR = 101), 23,890 (9.7%) patients developed PASC. Within 6 months after infection, frailty and pre-frailty were associated with a 41% (adjusted HR [aHR]:1.40 (95% CI: 1.35-1.47) and 15% (aHR: 1.17 (95% CI: 1.11-1.19) increase in the risk of PASC compared with the robust, respectively. Vaccination and booster doses before infection were associated with a 27% (aHR: 0.73 (95% CI: 0.71-0.75) and 33% (aHR: 0.66 (95% CI: 0.63-0.69) reduction in the risk of developing PASC, respectively. CONCLUSIONS: Frailty was associated with an increased risk of developing PASC. Vaccination was associated with a decreased risk of PASC, further reduced by booster doses. Early recognition of frailty in patients with COVID-19 may assist in the early identification and management of PASC.

Perspectives on illness-related stigma and electronically sharing psychiatric health information by people with multiple sclerosis.

BACKGROUND: Electronic medical records (EMRs) facilitate more integrated and comprehensive care. Despite this, EMRs are used less frequently in psychiatry compared to other medical disciplines, in part due to concerns regarding stigma surrounding mental health. This paper explores the willingness to share medical information among patients with multiple sclerosis (MS), who experience higher rates of psychiatric comorbidities compared to the general population, and the role that stigma plays in patient preferences. METHODS: MS patients were surveyed about their co-occurring psychiatric and non-psychiatric diagnoses, willingness to share their health information electronically among their treating doctors, and levels of self and societal stigma associated with their diagnoses. RESULTS: Participants were slightly more willing to share their non-psychiatric medical information vs. psychiatric information. Despite the presence of stigma decreasing patient willingness to share medical records, those with psychiatric co-occurring disorders, compared to those without, endorsed significantly greater willingness to electronically share their health records. The majority of diagnoses for which participants experienced the greatest difference in self vs. societal stigmas were psychiatric ones, including substance use, eating and mood disorders. Societal stigma strongly correlated with decreased non-psychiatric medication sharing, while self stigma was strongly correlated with decreased psychiatric medications sharing. LIMITATIONS: Standardized scales were not used to assess patient stigma and there is a potential lack of generalizability of results beyond patients with MS. CONCLUSIONS: These insights into patient preferences toward sharing their medical information should inform decisions to implement EMRs, particularly for patient populations experiencing higher than average levels of psychiatric comorbidities.

Antigenic Stimulation of Kv1.3-Deficient Th Cells Gives Rise to a Population of Foxp3-Independent T Cells with Suppressive Properties.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS that has been linked with defects in regulatory T cell function. Therefore, strategies to selectively target pathogenic cells via enhanced regulatory T cell activity may provide therapeutic benefit. Kv1.3 is a voltage-gated potassium channel expressed on myelin-reactive T cells from MS patients. Kv1.3-knockout (KO) mice are protected from experimental autoimmune encephalomyelitis, an animal model of MS, and Kv1.3-KO Th cells display suppressive capacity associated with increased IL-10. In this article, we demonstrate that myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells exhibit a unique regulatory phenotype characterized by high CD25, CTLA4, pSTAT5, FoxO1, and GATA1 expression without a corresponding increase in Foxp3. These phenotypic changes result from increased signaling through IL-2R. Moreover, myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells can ameliorate experimental autoimmune encephalomyelitis following transfer to wild-type recipients in a manner that is partially dependent on IL-2R and STAT5 signaling. The present study identifies a population of Foxp3(-) T cells with suppressive properties that arises in the absence of Kv1.3 and enhances the understanding of the molecular mechanism by which these cells are generated. This increased understanding could contribute to the development of novel therapies for MS patients that promote heightened immune regulation.

Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice.

Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4(+) T cells. Characterization of this model reveals both Th1 and Th17 CD4(+) T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Fingolimod (FTY720) is a multiple sclerosis (MS) therapeutic that upon phosphorylation causes the internalization of sphingosine-1-phosphate receptors (S1PR) and traps CCR7+ T-cells in lymph nodes but relatively spares CCR7-effector T-cells. Nonetheless, FTY720-treated patients are more susceptible to viral infections, indicating a CD8 T-cell defect. Thus, the effects of FTY720 on CD8 T-cells were investigated. To this end, we utilized experimental autoimmune encephalomyelitis (EAE) and a murine influenza model. CD8 T-cell trafficking, IFNγ and Granzyme B (GrB) production were assessed by flow cytometry. CD8 T-cell cytotoxic function was assessed in vitro by an LDH release assay. FTY720 not only ameliorated EAE by sequestering T-cells, but also reduced IFNγ and Granzyme B (GrB) in splenic CD8 T-cells. Murine influenza infection was exacerbated and mortality was increased, as FTY720 inhibited CD8 T-cell GrB production and lung infiltration. Remarkably, only the unphosphorylated compound was able to reduce IFNγ and GrB levels in CD8 T-cells and inhibits their cytotoxic function in vitro. The phosphorylated moiety had no effect in vitro, indicating that CD8 T-cell suppression by FTY720 is independent of S1PR modulation. The addition of arachidonic acid rescued CD8 T-cell function, suggesting that this effect may be mediated via inhibition of cytosolic phospholipase A2. Herein, we demonstrate that FTY720 suppresses CD8 T-cells independently of its trafficking effects and S1PR modulation. This provides a novel explanation not only for the increased rate of viral infections in FTY720-treated patients, but also for its efficacy in MS, as CD8 T-cells have emerged as crucial mediators of MS pathogenesis.