Exploring the Impact of Age, Frailty, and Multimorbidity on the Effect of ICU Interventions: A Systematic Review of Randomized Controlled Trials.

OBJECTIVES: To date, age, frailty, and multimorbidity have been used primarily to inform prognosis in older adults. It remains uncertain, however, whether these patient factors may also predict response to critical care interventions or treatment outcomes. DATA SOURCES: We conducted a systematic search of top general medicine and critical care journals for randomized controlled trials (RCTs) examining critical care interventions published between January 1, 2011, and December 31, 2021. STUDY SELECTION: We included RCTs of critical care interventions that examined any one of three subgroups-age, frailty, or multimorbidity. We excluded cluster RCTs, studies that did not report interventions in an ICU, and studies that did not report data examining subgroups of age, frailty, or multimorbidity. DATA EXTRACTION: We collected study characteristics (single vs. multicountry enrollment, single vs. multicenter enrollment, funding, sample size, intervention, comparator, primary outcome and secondary outcomes, length of follow-up), study population (inclusion and exclusion criteria, average age in intervention and comparator groups), and subgroup data. We used the Instrument for assessing the Credibility of Effect Modification Analyses instrument to evaluate the credibility of subgroup findings. DATA SYNTHESIS: Of 2037 unique citations, we included 48 RCTs comprising 50,779 total participants. Seven (14.6%) RCTs found evidence of statistically significant effect modification based on age, whereas none of the multimorbidity or frailty subgroups found evidence of statistically significant subgroup effect. Subgroup credibility ranged from very low to moderate. CONCLUSIONS: Most critical care RCTs do not examine for subgroup effects by frailty or multimorbidity. Although age is more commonly considered, the cut-point is variable, and relative effect modification is rare. Although interventional effects are likely similar across age groups, shared decision-making based on individual patient preferences must remain a priority. RCTs focused specifically on critically ill older adults or those living with frailty and/or multimorbidity are crucial to further address this research question.

Resident Burnout on the Internal Medicine Ward.

BACKGROUND: Burnout is common among medical trainees. Whether brief periods of training on the internal medicine ward leads to resident burnout is unknown. METHODS: A survey-based study was conducted at a single academic institution. Medical residents undertaking four-week rotations on the internal medicine ward were included. Burnout was measured at the beginning and end of each rotation using the Maslach Burnout Inventory - Human Services Survey. Burnout was defined as either an emotional exhaustion score of ≥ 27 or a depersonalization score of ≥ 10. Self-reported workplace conditions, behaviors and attitudes were recorded. RESULTS: The survey response rate was 71% and included 148 participants. The overall prevalence of burnout was 17% higher at the end of the rotation compared to the beginning of the rotation (71% vs. 54%; P < 0.001). Forty-three percent of residents without pre-rotation burnout developed post-rotation burnout. Residents with post-rotation burnout were more likely to report at least one suboptimal behavior or attitude related to patient care or professionalism (84% vs. 35%; P < 0.001). Respondents with new onset burnout were less likely to report being appreciated for their work, having their role as a learner emphasized, and receiving satisfactory support from allied healthcare professionals. New onset burnout was inversely associated with completing a second consecutive internal medicine ward rotation (adjusted OR 0.19; 95% CI, 0.04-0.90; P = 0.04). CONCLUSION: Seven in ten residents are in a state of burnout after completing internal medicine ward rotations. Interventions to mitigate burnout development during periods of high intensity clinical training are needed.

Restraint Practices in Incapable Wandering Patients During COVID-19: Ethics and Best Practice Recommendations.

Patients who wander as one of their psychological and behavioural symptoms of dementia are often unable to follow or recall Infection Prevention and Control precautions, putting them at risk of contracting or spreading COVID-19. Physical and chemical restraints have been used to limit the risk of transmission to wandering patients and their care providers, but restraints are not the standard of care for wandering behaviour in non-pandemic scenarios. Although provincial policies on restraint use are available, their guidance may not provide the context-dependent information necessary for individual patient decisions. To address this knowledge gap, we reviewed the medical, ethical, and legal considerations through an interdisciplinary approach including nurses, physicians, ethicists, hospital leadership, risk management, and legal counsel. We present an ethical framework that front-line health-care workers can use to create a balanced patient-centred care plan for incapable wandering patients who are at risk of contracting or spreading COVID-19.

Assessing the Short-Term Global Health Experience: A Cross-Sectional Study of Demographics, Socioeconomic Factors, and Disease Prevalence.

Interest in short-term global health experiences to underserviced populations has grown rapidly in the last few decades. However, there remains very little research on what participants can expect to encounter. At the same time, it has been suggested that in order for physicians and workers to provide safe and effective care, volunteers should have a basic understanding of local culture, health systems, epidemiology, and socioeconomic needs of the community before arriving. Our objective was to add to the limited literature on what short-term global health trips can expect to encounter through a cross-sectional study of patient demographics, socioeconomic markers, and the prevalence of diseases encountered on a short-term medical service trip to Lima, Peru. Descriptive analysis was conducted on clinic data collected from patients living in Pamplona Alta and Pamplona Baja, Lima, Peru, in July 2015. We found that volunteers encountered mainly female patients (70.8%), and that there were significant socioeconomic barriers to care including poverty, poor housing, environmental exposures, and lack of continuity of health care. Analysis of the disease prevalence found a high proportion of acute and chronic musculoskeletal pain in the adult populations (18.8% and 11.4%, respectively), and a high presentation of upper respiratory tract infections (25.4%) and parasites (22.0%) in the pediatric group. These findings can be used by future short-term medical service trips to address potential gaps in care including the organization of weekend clinics to allow access to working men, and the use of patient education and nonpharmacological management of acute and chronic disease.

Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma.

BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases. Silencing of Snail and its associate member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. METHODS: Live cell sialidase, WST-1 cell viability and immunohistochemistry assays were used to evaluate sialidase activity, cell survival and the expression levels of tumor E-cadherin, N-cadherin, VE-cadherin, and host endothelial CD31+(PECAM-1) cells in archived paraffin-embedded ovarian A2780, A2780 Snail shRNA GIPZ lentiviral knockdown (KD) and A2780 Slug shRNA GIPZ lentiviral KD tumors grown in RAGxCγ double mutant mice. RESULTS: Oseltamivir phosphate (OP), anti-Neu1 antibodies and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 ovarian epithelial carcinoma cells. Silencing Snail in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to A2780 and A2780 Slug KD cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD50 of 7 and 4 µm, respectively, after 48 h of incubation. Heterotopic xenografts of A2780 and A2780 Slug KD tumors developed robust and bloody tumor vascularization in RAG2xCγ double mutant mice. OP treatment at 50 mg/kg daily intraperitoneally did not significantly impede A2780 tumor growth rate but did cause a significant reduction of lung metastases compared with the untreated and OP 30mg/kg cohorts. Silencing Snail in A2780 tumor cells completely abrogated tumor vascularization, tumor growth and spread to the lungs in RAGxCγ double mutant mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells, while A2780 Snail KD tumors expressed E-cadherin and reduced host CD31+ cells. OP 50mg/kg cohort tumors had reduced numbers of host CD31+ cells compared to a higher expression levels of CD31+ cells in tumors from the untreated control and OP 30mg/kg cohorts. CONCLUSION: Snail transcriptional factor is an important intermediate player in human ovarian tumor neovascularization.

A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer.

Epidermal growth factor (EGF)-induced EGFR tyrosine kinase receptor activation in cancer cell survival responses has become a strategic molecular-targeting clinical therapeutic intent, but the failures of these targeted approaches in the clinical setting demand alternate strategies. Here, we uncover a novel neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with GPCR neuromedin B, which is essential for EGF-induced receptor activation and cellular signaling. Neu1 and MMP-9 form a complex with EGFR on the cell surface. Tamiflu (oseltamivir phosphate), anti-Neu1 antibodies, broad range MMP inhibitor galardin (GM6001), neuromedin B GPCR specific antagonist BIM-23127, the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 and MMP-9 specific inhibitor dose-dependently inhibited Neu1 activity associated with EGF stimulated 3T3-hEGFR cells. Tamiflu, anti-Neu1 antibodies and MMP9i attenuated EGFR phosphorylation associated with EGF-stimulated cells. Preclinical data provide the proof-of-evidence for a therapeutic targeting of Neu1 with Tamiflu in impeding human pancreatic cancer growth and metastatic spread in heterotopic xenografts of eGFP-MiaPaCa-2 tumors growing in RAGxCγ double mutant mice. Tamiflu-treated cohort exhibited a reduction of phosphorylation of EGFR-Tyr1173, Stat1-Tyr701, Akt-Thr308, PDGFRα-Tyr754 and NFκBp65-Ser311 but an increase in phospho-Smad2-Ser465/467 and -VEGFR2-Tyr1175 in the tumor lysates from the xenografts of human eGFP-MiaPaCa-2 tumor-bearing mice. The findings identify a novel promising alternate therapeutic treatment of human pancreatic cancer.