Purpose We have previously demonstrated that ritonavir targeting of glycolysis is growth inhibitory and cytotoxic in a subset of multiple myeloma cells. In this study, our objective was to investigate the metabolic basis of resistance to ritonavir and to determine the utility of cotreatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism. Experimental Design We determined combination indices for ritonavir and metformin, impact on myeloma cell lines, patient samples, and myeloma xenograft growth. Additional evaluation in breast, melanoma, and ovarian cancer cell lines was also performed. Signaling connected to suppression of the prosurvival BCL-2 family member MCL-1 was evaluated in multiple myeloma cell lines and tumor lysates. Reliance on oxidative metabolism was determined by evaluation of oxygen consumption, and dependence on glutamine was assessed by estimation of viability upon metabolite withdrawal in the context of specific metabolic perturbations. Results Ritonavir-treated multiple myeloma cells exhibited increased reliance on glutamine metabolism. Ritonavir sensitized multiple myeloma cells to metformin, effectively eliciting cytotoxicity both in vitro and in an in vivo xenograft model of multiple myeloma and in breast, ovarian, and melanoma cancer cell lines. Ritonavir and metformin effectively suppressed AKT and mTORC1 phosphorylation and prosurvival BCL-2 family member MCL-1 expression in multiple myeloma cell lines in vitro and in vivo. Conclusions FDA-approved ritonavir and metformin effectively target multiple myeloma cell metabolism to elicit cytotoxicity in multiple myeloma. Our studies warrant further investigation into repurposing ritonavir and metformin to target the metabolic plasticity of myeloma to more broadly target myeloma heterogeneity and prevent the reemergence of chemoresistant aggressive multiple myeloma.

Background During the COVID-19 pandemic, health care workers are sharing their challenges, including sleep disturbances, on social media; however, no study has evaluated sleep in predominantly US frontline health care workers during the COVID-19 pandemic. Objective The aim of this study was to assess sleep among a sample of predominantly US frontline health care workers during the COVID-19 pandemic using validated measures through a survey distributed on social media. Methods A self-selection survey was distributed on Facebook, Twitter, and Instagram for 16 days (August 31 to September 15, 2020), targeting health care workers who were clinically active during the COVID-19 pandemic. Study participants completed the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI), and they reported their demographic and career information. Poor sleep quality was defined as a PSQI score ≥5. Moderate-to-severe insomnia was defined as an ISI score >14. The Mini-Z Burnout Survey was used to measure burnout. Multivariate logistic regression tested associations between demographics, career characteristics, and sleep outcomes. Results A total of 963 surveys were completed. Participants were predominantly White (894/963, 92.8%), female (707/963, 73.4%), aged 30-49 years (692/963, 71.9%), and physicians (620/963, 64.4%). Mean sleep duration was 6.1 hours (SD 1.2). Nearly 96% (920/963, 95.5%) of participants reported poor sleep (PSQI). One-third (288/963, 30%) reported moderate or severe insomnia. Many participants (554/910, 60.9%) experienced sleep disruptions due to device use or had nightmares at least once per week (420/929, 45.2%). Over 50% (525/932, 56.3%) reported burnout. In multivariable logistic regressions, nonphysician (odds ratio [OR] 2.4, 95% CI 1.7-3.4), caring for patients with COVID-19 (OR 1.8, 95% CI 1.2-2.8), Hispanic ethnicity (OR 2.2, 95% CI 1.4-3.5), female sex (OR 1.6, 95% CI 1.1-2.4), and having a sleep disorder (OR 4.3, 95% CI 2.7-6.9) were associated with increased odds of insomnia. In open-ended comments (n=310), poor sleep was mapped to four categories: children and family, work demands, personal health, and pandemic-related sleep disturbances. Conclusions During the COVID-19 pandemic, nearly all the frontline health care workers surveyed on social media reported poor sleep, over one-third reported insomnia, and over half reported burnout. Many also reported sleep disruptions due to device use and nightmares. Sleep interventions for frontline health care workers are urgently needed.

Between February 1 and July 1, 2020, SARS-CoV-2 killed over 120,000 people in the United States alone. Nearly 80% of deaths occurred in those 65 years and older; by contrast, this age group constituted only 65% of deaths from influenza during the same time period. 1 Though the reasons for these differences have not been completely elucidated, one thing is abundantly clear: Our nation's oldest and most frail have been among the most likely to die of COVID-19. With an estimated mortality rate of 4.7% in the United States, we are fortunate that most infected patients survive 2,3 ; however, many survivors require an exceptionally long hospital stay in isolation. Hospitalizations for patients with COVID-19 are distinct and confer a high risk for hospital-associated disability (HAD). HAD, defined as a new loss of ability to complete one or more activities of daily living (ADLs) without assistance after hospital discharge, occurs in approximately one-third of all hospitalized patients. 4 In this perspective, we explore why HAD might be worse in patients with COVID-19 and offer new models for delivery of physical and occupational therapy to help them with functional recovery during and after hospitalization.

Appropriate use of inpatient physical therapy services is important for preventing hospital-associated disability (HAD). We assessed potential overutilization of physical therapy consults on hospital medicine services using the Activity Measure-Post Acute Care (AM-PAC) score. Our sample included 3592 unique admissions (mean age, 66 years; 48% women) at a large academic medical center. Based on an AM-PAC cutoff of >43.63 (raw score, 18) in patients who were discharged to home, 38% of physical therapy consults were considered “potential overutilization.” Combined with age <65 years, 18% of consults remained “potential overutilization.” After adjustment for age, sex, and length of stay, patients admitted with high mobility scores were 5.38 times more likely to be discharged to home (95% CI, 4.36-2.89) compared with those with low mobility scores. Being more judicious with physical therapy consults and reserving skilled therapy for at-risk patients could help prevent HAD while also having a positive impact on healthcare systems.

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