Caregiving During the COVID-19 Pandemic: A Cross-Sectional Study with Older Cisgender Sexual Minority Women in the United States.

Purpose: This study describes prevalence of caregiving before and after the onset of the COVID-19 pandemic among racially diverse older cisgender sexual minority women, examines factors associated with caregiving, and assesses relationships between caregiving and health. Methods: A convenience sample of participants aged ≥50 years completed self-administered online surveys assessing sociodemographic characteristics, caregiver status, self-rated health, and depressive symptoms. Bivariate statistics compared response variables by race, caregiver status, and timing of caregiving relative to the pandemic. Results: Of 365 participants, 82.7% identified as lesbian or gay and 41.1% as Black/African American; 40% were caregivers before (n = 32), during (n = 34), or both before and during (n = 80) the pandemic. A greater proportion of caregivers lived with a partner (45.9% vs. 35.6%, p = 0.06), were unemployed (37.7% vs. 29.7%, p = 0.07), and had high school or lower education (11.6% vs. 5%, p = 0.09). No differences were found in self-rated health by caregiver status; however, a higher proportion of Black (vs. White) caregivers reported good to excellent physical health (77.9% vs. 62.9%, p = 0.05). Caregivers more frequently reported depressive symptoms (28.1% vs. 17.8%, p = 0.03). Caregivers both before and during the pandemic had lower educational attainment than those who provided care only before or only during the pandemic (p = 0.04). Conclusion: Caregiving was common among older sexual minority women during the pandemic and experiences varied by race and other social factors. Consideration of these intersecting experiences is important for fully understanding caregiver experiences during COVID-19. Overall, caregiving was associated with depressive symptoms, underscoring the importance of psychosocial support for all caregivers.

Very late relapse in Hodgkin lymphoma: Characterizing an understudied population.

BACKGROUND: Very late relapse (VLR) occurring >5 years after initial diagnosis is an uncommon event in the management of Hodgkin lymphoma (HL). Limited information regarding risk factors and optimal therapy is available. PATIENTS AND METHODS: We reviewed patients treated for HL at Princess Margaret Cancer Centre, Toronto, Ontario Canada between January 01, 1999 and 31 December 31, 2018. RESULTS: Thirty-two patients experienced VLR. Median time to first relapse was 7.2 years. Most patients were treated with CMT both at initial diagnosis and relapse. Male gender (P = .04) and increased age at initial diagnosis (P = .008; HR 1.09 (95% CI: 1.02-1.15)) were identified as risk factors for inferior survival on univariate analysis. Stage, histology, treatment modality and risk assessment at diagnosis or relapse did not have a significant impact on survival outcomes. ASCT at first relapse had no impact on time to second progression (HR 1.72; 95% CI, 0.35-8.53; P = .51) or overall survival from first relapse (HR 1.55; 95% CI, 0.3-8.03; P = .6). CONCLUSION: Our data aligns with the limited information available in VLR HL suggesting the negative impact of age and male gender on this rare event. Additionally, our data did not show benefit of ASCT at first relapse in terms of survival outcomes in this population, though this analysis is limited by small sample size. Further study of optimal therapy to prevent and treat VL in the era of novel agents is critical.

Cell death proteins in sepsis: key players and modern therapeutic approaches.

Cell death proteins play a central role in host immune signaling during sepsis. These interconnected mechanisms trigger cell demise via apoptosis, necroptosis, and pyroptosis while also driving inflammatory signaling. Targeting cell death mediators with novel therapies may correct the dysregulated inflammation seen during sepsis and improve outcomes for septic patients.

Are we choosing mobilization regimens for autologous stem cell transplantation in multiple myeloma wisely: A single center comparison of GCSF+/-plerixafor vs cyclophosphamide/GCSF+/-plerixafor.

BACKGROUND: Autologous stem cell transplantation (ASCT) is a standard consolidation treatment for eligible patients with multiple myeloma (MM). There is no standardized mobilization regimen for collection of CD34+ stem cells, which is crucial to the success of ASCT. Cyclophosphamide/GCSF is an effective regimen, although reported associated toxicities include risk of febrile neutropenia (FN). Since plerixafor was introduced in Canada, this mobilization agent has been increasingly used as needed with GCSF at Kingston Health Science Centre (KHSC), with elimination of cyclophosphamide. This single center, retrospective, quality improvement study evaluates mobilization and ASCT outcomes of MM patients who had undergone stem cell mobilization at KHSC with cyclophosphamide/GCSF+/-plerixafor without antibiotics, cyclophosphamide/GCSF+/-plerixafor with antibiotics, and GCSF+/-plerixafor without antibiotics. METHODS: A retrospective chart review was conducted evaluating 137 patients. The primary outcome measure was FN rates with mobilization. Balancing measures include CD34+ cell collected, plerixafor usage, days of apheresis and transplant outcomes. Chi-square, ANOVA, or Kruskal-Wallis methods were used to test statistical significance where appropriate. RESULTS: Our study noted a higher total and day one CD34+ count in the two groups utilizing cyclophosphamide in mobilization. All nine cases of FN occurred in these two groups (P < .05). Addition of antibiotics decreased, but did not eliminate risk of FN. There were no significant differences in the rate of plerixafor usage and number of apheresis days. Difference in transplant outcomes, including engraftment and transfusion support, were statistically but not clinically significant. A larger sample size may be needed to explore this fully. There was no significant difference in length of transplant hospital stay. CONCLUSION: The elimination of cyclophosphamide from mobilization regimens for MM appears to significantly reduce FN rates, without increasing balancing measures such as total number of apheresis days, plerixafor usage, duration of transplant hospitalization or mortality outcomes.

Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study.

BACKGROUND: Rilpivirine (RPV) is a second-generation once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) which has shown non-inferior antiviral activity to efavirenz in treatment-naive patients. Data in treatment-experienced patients are more limited. We wished to assess the efficacy and safety of a switch to RPV-based regimens in well-suppressed treatment-experienced patients. METHODS: Between September 2012 and June 2013, all antiretroviral therapy (ART)-experienced HIV-1-infected patients with a plasma HIV RNA level <50 copies/ml, and switching to an RPV-based regimen, were analysed in this retrospective observational monocentric cohort study. The primary end point was the proportion of patients with virological success defined as a plasma HIV RNA level <50 copies/ml at 12 months using the FDA snapshot algorithm. RESULTS: A total of 281 participants were studied and 97% received a combination of RPV/tenofovir disoproxil fumarate/emtricitabine. At month 12, the rate of virological success was 59% and increased to 72% using available data beyond month 12. Sixteen (6%) patients experienced virological failure, which was associated with the presence of the M184V/I resistance mutation in prior genotypes (P=0.02) and the use of a non-NNRTI as third agent before the switch (P=0.03). RPV-based regimens were overall well tolerated and only 23 (8%) patients discontinued ART because of adverse events, mostly neuropsychiatric adverse events. Switching to RPV was associated with significant but modest improvement of the lipid profile. CONCLUSIONS: In patients fully suppressed on ART, a switch to an RPV-based regimen should only be considered in the absence of prior virological failure or resistance mutations to nucleoside reverse transcriptase inhibitors and NNRTIs to avoid virological failures.

Efficacy and safety of rilpivirine-based regimens in treatment-experienced HIV-1 infected patients: a prospective cohort study.

INTRODUCTION: Rilpivirine (RPV) is a new once-daily, non-nucleoside, reverse transcriptase inhibitor (NNRTI). In treatment-naïve patients, RPV has shown non-inferior antiviral activity to efavirenz but data in treatment-experienced patients are more limited. We assessed the efficacy and safety of RPV in treatment-experienced patients switching to a RPV-based regimen. METHODS: Between September 2012 and June 2013, all antiretroviral therapy (ART) experienced HIV-1 infected patients with a plasma HIV-RNA level <50 cp/mL, and switching to a RPV-based regimen, were enrolled in this prospective monocentric cohort study. Clinical and laboratory data were collected every 3 months to assess safety and efficacy. The primary endpoint was the proportion of patients with virologic success (HIV-RNA load <50 cp/mL) at 12 months using the FDA snapshot algorithm. RESULTS: A total of 281 patients (76% male, median age: 47 years, 56% MSM) were enrolled in this study. Median lymphocyte CD4 count at baseline was 640/mm(3). Patients have received ART for a median of 7 years and viral replication was fully suppressed for a median of 3 years. Before the switch, 39% patients were treated with NNRTI, 52% with protease inhibitor and 7% with integrase inhibitor-based regimens. Reasons for switch were simplification (176 cases), adverse events (AEs) (93 cases) and others (12 cases). At month 12 (database frozen on June 2014) in the snapshot analysis, 56% of patients met virologic success, 5% experienced virologic failure (n=14) and 39% had no data in the window period. In the LOCF analysis (using data from the previous available visit before month 12), 89% patients were suppressed, 5% had virologic failure and 6% had no data. Genotypic resistance analysis was performed in 7/14 patients at the time of virologic failure (3 of whom had previous NRTI/NNRTI resistance-associated mutations (RAMs)), and new NNRTI and NRTI RAMs emerged in 4 patients. RPV-based regimen was generally well tolerated and only 6% of patients discontinued treatment for AEs. Grade 2-4 treatment-related AEs occurred in 39 patients: 6 had rashes, 13 neuropsychiatric symptoms, 10 GI symptoms, 10 biological abnormalities. At month 12, significant changes from baseline were seen for total and LDL cholesterol (-0.5 and -0.28 mmol/L, respectively, p<0.05 for both), and plasma creatinine (+5.8 µmol/L, p<10-4). CONCLUSIONS: In patients fully suppressed on ART, switching to a RPV-based regimen in clinical practice was well tolerated and associated with few virologic failures.

Listeria phospholipases subvert host autophagic defenses by stalling pre-autophagosomal structures.

Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced autophagic flux and phosphatidylinositol 3-phosphate (PI3P) levels, causing pre-autophagosomal structure stalling and preventing efficient targeting of cytosolic bacteria. In co-infection experiments, wild-type Listeria protected PlcA/B-deficient bacteria from autophagy-mediated clearance. Thus, our results uncover a critical role for Listeria phospholipases C in the inhibition of autophagic flux, favouring bacterial escape from host autophagic defense.

Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program.

Autophagy, which targets cellular constituents for degradation, is normally inhibited in metabolically replete cells by the metabolic checkpoint kinase mTOR. Although autophagic degradation of invasive bacteria has emerged as a critical host defense mechanism, the signals that induce autophagy upon bacterial infection remain unclear. We find that infection of epithelial cells with Shigella and Salmonella triggers acute intracellular amino acid (AA) starvation due to host membrane damage. Pathogen-induced AA starvation caused downregulation of mTOR activity, resulting in the induction of autophagy. In Salmonella-infected cells, membrane integrity and cytosolic AA levels rapidly normalized, favoring mTOR reactivation at the surface of the Salmonella-containing vacuole and bacterial escape from autophagy. In addition, bacteria-induced AA starvation activated the GCN2 kinase, eukaryotic initiation factor 2α, and the transcription factor ATF3-dependent integrated stress response and transcriptional reprogramming. Thus, AA starvation induced by bacterial pathogens is sensed by the host to trigger protective innate immune and stress responses.