Cardiovascular Considerations in the Management of People With Suspected Long COVID.

Approximately 15% of adult Canadians with SARS-CoV-2 infection develop lingering symptoms beyond 12 weeks after acute infection, known as post-COVID condition or long COVID. Some of the commonly reported long COVID cardiovascular symptoms include fatigue, shortness of breath, chest pain, and palpitations. Suspected long-term cardiovascular complications of SARS-CoV-2 infection might present as a constellation of symptoms that can be challenging for clinicians to diagnose and treat. When assessing patients with these symptoms, clinicians need to keep in mind myalgic encephalomyelitis/chronic fatigue syndrome, postexertional malaise and postexertional symptom exacerbation, dysautonomia with cardiac manifestations such as inappropriate sinus tachycardia, and postural orthostatic tachycardia syndrome, and occasionally mast cell activation syndrome. In this review we summarize the globally evolving evidence around management of cardiac sequelae of long COVID. In addition, we include a Canadian perspective, consisting of a panel of expert opinions from people with lived experience and experienced clinicians across Canada who have been involved in management of long COVID. The objective of this review is to offer some practical guidance to cardiologists and generalist clinicians regarding diagnostic and treatment approaches for adult patients with suspected long COVID who continue to experience unexplained cardiac symptoms.

Bedspacing and clinical outcomes in general internal medicine: A retrospective, multicenter cohort study.

BACKGROUND: Admitting hospitalized patients to off-service wards ("bedspacing") is common and may affect quality of care and patient outcomes. OBJECTIVE: To compare in-hospital mortality, 30-day readmission to general internal medicine (GIM), and hospital length-of-stay among GIM patients admitted to GIM wards or bedspaced to off-service wards. DESIGN, PARTICIPANTS, AND MEASURES: Retrospective cohort study including all emergency department admissions to GIM between 2015 and 2017 at six hospitals in Ontario, Canada. We compared patients admitted to GIM wards with those who were bedspaced, using multivariable regression models and propensity score matching to control for patient and situational factors. KEY RESULTS: Among 40,440 GIM admissions, 10,745 (26.6%) were bedspaced to non-GIM wards and 29,695 (73.4%) were assigned to GIM wards. After multivariable adjustment, bedspacing was associated with no significant difference in mortality (adjusted hazard ratio 0.95, 95% confidence interval [CI]: 0.86-1.05, p = .304), slightly shorter median hospital length-of-stay (-0.10 days, 95% CI:-0.20 to -0.001, p = .047) and lower 30-day readmission to GIM (adjusted OR 0.89, 95% CI: 0.83-0.95, p = .001). Results were consistent when examining each hospital individually and outcomes did not significantly differ between medical or surgical off-service wards. Sensitivity analyses focused on the highest risk patients did not exclude the possibility of harm associated with bedspacing, although adverse outcomes were not significantly greater. CONCLUSIONS: Overall, bedspacing was associated with no significant difference in mortality, slightly shorter hospital length-of-stay, and fewer 30-day readmissions to GIM, although potential harms in high-risk patients remain uncertain. Given that hospital capacity issues are likely to persist, future research should aim to understand how bedspacing can be achieved safely at all hospitals, perhaps by strengthening the selection of low-risk patients.

A review of antimicrobial stewardship training in medical education.

OBJECTIVES: We reviewed the published literature on antimicrobial stewardship training in undergraduate and postgraduate medical education to determine which interventions have been implemented, the extent to which they have been evaluated, and to understand which are most effective. METHODS: We searched Ovid MEDLINE and EMBASE from inception to December 2016. Four thousand three hundred eighty-five (4385) articles were identified and underwent title and abstract review. Only those articles that addressed antimicrobial stewardship interventions for medical trainees were included in the final review. We employed Kirkpatrick's four levels of evaluation (reaction, learning, behaviour, results) to categorize intervention evaluations. RESULTS: Our review included 48 articles. The types of intervention varied widely amongst studies worldwide. Didactic teaching was used heavily in all settings, while student-specific feedback was used primarily in the postgraduate setting. The high-level evaluation was sparse, with 22.9% reporting a Kirkpatrick Level 3 evaluation; seventeen reported no evaluation. All but one article reported positive results from the intervention. No articles evaluated the impact of an intervention on undergraduate trainees' prescribing behaviour after graduation. CONCLUSIONS: This study enhances our understanding of the extent of antimicrobial stewardship in the context of medical education. While our study demonstrates that medical schools are implementing antimicrobial stewardship interventions, rigorous evaluation of programs to determine whether such efforts are effective is lacking. We encourage more robust evaluation to establish effective, evidence-based approaches to training prescribers in light of the global challenge of antimicrobial resistance.

Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response.

PURPOSE: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. EXPERIMENTAL DESIGN: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method. RESULTS: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106). CONCLUSION: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.

AMPK regulates metabolism and survival in response to ionizing radiation.

BACKGROUND AND PURPOSE: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. METHODS: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK α1/α2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK α1/α2 shRNA mediated knockdown. RESULTS: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. CONCLUSIONS: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.