Identifying predictors of cognitive decline in long-term care: a scoping review.

BACKGROUND: Cognitive impairment can cause social, emotional, and financial burdens on individuals, caregivers, and healthcare providers. This is especially important in settings such as long-term care (LTC) homes which largely consist of vulnerable older adults. Thus, the objective of this study is to review and summarize current research examining risk factors of cognitive decline in older adults within LTC. METHODS: This scoping review includes primary observational research studies assessing within-person change in cognition over time in LTC or equivalent settings in high resource countries. A mean participant age of ≥ 65 years was required. Searches were conducted in Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PyscInfo on June 27th, 2022 and included articles published during or after the year 2000. Title, abstract, and full-text screening was performed by two independent reviewers using Covidence. Specific predictors along with their associated relation with cognitive decline were extracted by a team of reviewers into a spreadsheet. RESULTS: Thirty-eight studies were included in this review. The mean sample size was 14 620. Eighty-seven unique predictors were examined in relation to cognitive decline. Dementia was the most studied predictor (examined by 9 of 38 studies), and the most conclusive, with eight of those studies identifying it as a risk factor for cognitive decline. Other predictors that were identified as risk factors included arterial stiffness (identified by 2 of 2 studies), physical frailty (2 of 2 studies), sub-syndromal delirium (2 of 2 studies), and undergoing the first wave of COVID-19 lockdowns (2 of 2 studies). ADL independence was the most conclusive protective factor (3 of 4 studies), followed by social engagement (2 of 3 studies). Many remaining predictors showed no association and/or conflicting results. CONCLUSIONS: Dementia was the most common risk factor, while ADL independence was the most common protective factor associated with cognitive decline in LTC residents. This information can be used to stratify residents by risk severity and provide better personalized care for older adults through the targeted management of cognitive decline.

A Translational Randomized Trial of Perioperative Arginine Immunonutrition on Natural Killer Cell Function in Colorectal Cancer Surgery Patients.

BACKGROUND: Surgery results in severe impairment of natural killer (NK) cell cytotoxicity (NKC) and activity (NKA, cytokine secretion), and a dramatic drop in arginine levels. Postoperative immunosuppression is associated with increased complications and recurrence. Perioperative arginine is reported to reduce postoperative complications. Because arginine modulates NK cell function, this study aimed to determine whether perioperative consumption of arginine-enriched supplements (AES) can improve NK cell function in colorectal cancer (CRC) surgery patients. METHODS: This study randomized 24 CRC patients to receive the AES or isocaloric/isonitrogenous control supplement three times a day for five days before and after surgery. The AES contained 4.2 g of arginine per dose (12.6 g/day). The primary objective was to determine whether AES improved NKC by 50 % compared with the control group after surgery. RESULTS: On surgery day (SD) 1, NKC was significantly reduced postoperatively in the control group by 50 % (interquartile range [IQR], 36-55 %; p = 0.02) but not in the AES group (25 % reduction; IQR, 28-75 %; p = 0.3). Furthermore, AES had no benefit in terms of NKA or NK cell number. Compliance was much greater preoperatively (>91 %) than postoperatively (<46 %). However, despite excellent preoperative compliance, arginine was rapidly cleared from the blood within 4 h after consumption and therefore, did not prevent the postoperative drop in arginine. CONCLUSIONS: Oral consumption of arginine immunonutrition resulted in a modest improvement in NKC after surgery but was unable to prevent postoperative arginine depletion or the suppression of NKA (ClinicalTrials.gov NCT02987296).

Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review.

PURPOSE: Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1-2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted. METHODS: MEDLINE, Embase, and Cochrane databases were searched (1970-February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years. RESULTS: Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0-24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8-18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare. CONCLUSIONS: Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed. PROSPERO REGISTRATION NUMBER: CRD42019126813.

Why "Reply All" Can Push All the Wrong Buttons.

Technology has changed the way medicine is practiced. This commentary considers the effect of digital communications and offers advice on e­mail etiquette.

Randomized window of opportunity trial evaluating high-dose vitamin D in breast cancer patients.

PURPOSE: Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol (vitamin D3) on breast tumour proliferation and apoptosis. METHODS: We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40,000 IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery. The primary outcome was the relative change in proliferation (Ki67) and apoptosis (cleaved caspase 3 apoptotic assay [CC3]) in primary breast cancer cells pre and post treatment. RESULTS: Of 83 patients randomized, 80 completed the study (43 (53.8%) vitamin D and 37 (46.3%) placebo). Mean duration of drug intake was 19 days (range 9-28 days). There were no significant differences between the control arm and the vitamin D arm in percent changes of either Ki67 index (1.6% vs. 16.7%, p = 0.25) or CC3 (- 55.9% vs. - 45.9%, p = 0.28). Serum 25-hydroxyvitamin D (25-OHD) levels were 3 times higher in the vitamin D arm (62 nmol/L vs. 246 nmol/L, p < 0.001). Adverse effects were minimal and all classified as grade 1. CONCLUSIONS: Despite significantly higher levels of serum 25-OHD in the vitamin D-treated group, this was not associated with any significant effects on tumour proliferation or apoptosis. These findings are consistent with the lack of benefit observed in prospective prevention trials. TRIAL REGISTRY: Trial registration clinicaltrials.gov NCT01948128.

A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients.

PURPOSE: Chloroquine has demonstrated anti-tumor activities through autophagy inhibition and cell cycle disruption. This study aimed to assess the effect of single-agent chloroquine on breast tumor cellular proliferation in a randomized, phase II, double-blind, placebo-controlled, pre-surgical window of opportunity trial. METHODS: Patients with newly diagnosed breast cancer were randomized 2:1 to chloroquine 500 mg daily or placebo for 2- to 6-weeks prior to their breast surgery. The primary outcome was the relative change in measures of proliferation (Ki67) in primary breast cancer cells pre- and post-treatment. Adverse events and toxicity profiles were also evaluated. RESULTS: From September 2015 to December 2016, 70 patients were randomized [46 (66%) chloroquine and 24 (34%) placebo]. Ten patients who were randomized to chloroquine withdrew from study due to adverse events. Mean duration of drug intake was 15 days (range 14-29 days). There were no significant differences between the chloroquine or placebo arms with respect to either the percentage change (- 0.4 vs. - 1.2, p = 0.088) or absolute change (- 2.0% vs. - 5.2%, p = 0.066) in Ki67 index pre- and post-drug treatment. Although adverse effects were minimal and all classified as grade 1, the effects were significant enough to cause nearly 15% of patients to discontinue therapy. CONCLUSIONS: Treatment with single-agent chloroquine 500 mg daily in the preoperative setting was not associated with any significant effects on breast cancer cellular proliferation. It was, however, associated with toxicity that may affect its broader use in oncology.

Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery.

BACKGROUND: Surgical stress results in a significant reduction in natural killer (NK) cell cytotoxicity (NKC), which has been linked to postoperative cancer metastases. However, few studies have measured the impact of surgical stress upon NK cell IFNγ secretion (NKA), a cytokine with essential roles in controlling infection and metastases. The objective of this study was to investigate the impact of surgical stress on NKA in colorectal cancer (CRC) surgery patients. METHODS: Peripheral blood was collected from CRC surgery patients (n = 42) preoperatively and on postoperative day (POD) 1, 3, 5, 28, and 56. Healthy donor blood (n = 27) was collected for controls. We assessed NKA by production of IFNγ following whole blood cytokine stimulation, NKC by 51Cr-release assay, and immune cell profiling by flow cytometry. RESULTS: The mean reduction in NKA on POD1 compared with baseline was 83.1% (standard deviation 25.2%; confidence interval 75-91), and therefore the study met the primary endpoint of demonstrating a > 75% decrease in a cohort of CRC surgery patients (p < 0.0001). The profound and universal suppression of NKA persisted with 65.5% (19/29) and 33.3% (4/12) of patients with levels measuring < 75% of baseline on POD28 and POD56 respectively. The NKC was significantly reduced on POD1, but the degree was less pronounced (24.6%, p = 0.0024). Immune cell profiling did not reveal differences in the absolute number of NK cells (CD3-CD56+) or the ratio of CD56dim-to-CD56bright subsets. CONCLUSIONS: NKA is significantly suppressed for up to two months following surgery in CRC patients, a degree of surgery-induced immunosuppression far worse than previously reported.

Access to Long-Term Care for Minority Populations: A Systematic Review.

It has been shown that there is disparity in access to long-term care and other services for minority populations. This study assessed long-term care access among older individuals belonging to minority populations including visible, ethnocultural, linguistic, and sexual minorities. Barriers and facilitators influencing admission were identified and evaluated.A search for articles from 10 databases published between January 2000 and January 2021 was conducted. Included studies evaluated factors affecting minority populations' admission to long-term care, and non-residents' perceptions of future admission. This review was registered with PROSPERO: CRD42018038662. Sixty included quantitative and qualitative studies, ranging in quality from fair to excellent. Findings suggest minority status is associated with reduced admission to long-term care, controlling for confounding variables. Barriers identified include discordant language, fear of discrimination, lack of information, and family obligations. Findings suggest that minority populations experienced barriers accessing long-term care and had unmet cultural and language needs while receiving care in this setting.

Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer.

A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.

A randomised trial of 4- versus 12-weekly administration of bone-targeted agents in patients with bone metastases from breast or castration-resistant prostate cancer.

BACKGROUND: Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. PATIENTS AND METHODS: Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. RESULTS: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. CONCLUSION: These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option.

Health Outcomes of Immigrants in Nursing Homes: A Population-Based Retrospective Cohort Study in Ontario, Canada.

OBJECTIVE: Older adults account for a significant portion of Canadian immigrants, yet characteristics and health outcomes of older immigrants in nursing homes have not been studied. We aimed to describe the prevalence of immigrants living in nursing homes, their characteristics, and their hospitalization and mortality rates compared to long-term residents in the first year of entry to nursing homes. DESIGN: Population-based, retrospective cohort study using linked health administrative databases. SETTING AND PARTICIPANTS: We assessed all incident admissions into publicly funded nursing homes in Ontario between April 2013 and March 2016. Immigrants were defined as those who arrived in Canada after 1985; long-term residents are those who arrived before 1985 or are Canadian-born. METHODS: The primary outcome was all-cause hospitalization and mortality rates within 1 year of nursing home entry. Nested Cox proportional hazards models were estimated to explore the associations of facility, demographic, and clinical characteristics to the primary outcomes. RESULTS: Immigrants comprised 4.4% of residents in Ontario's nursing homes, compared to 13.9% in the general population. The majority were from East and Southeast Asia (52.2%), and more than half (53.9%) had no competency in either official language on arrival in Canada. At the time of nursing home entry, immigrants were younger than long-term residents but had greater functional and cognitive impairments. Immigrants had a lower rate of mortality [hazard ratio 0.58, 95% confidence interval (CI) 0.51, 0.68; P < .001] but were more likely to be hospitalized (hazard ratio 1.14, 95% CI 1.06, 1.23; P < .001). Adjusting for language ability, the effect of immigrant status on hospitalization was not statistically significant. CONCLUSIONS AND IMPLICATIONS: Despite greater functional and cognitive impairments, immigrants in nursing homes had lower mortality than long-term residents, potentially reflecting the "healthy immigrant effect." Inability to speak English was associated with increased risk of hospitalization, highlighting the need for strategies to overcome communication barriers.

Prospective randomised controlled trial using the REthinking Clinical Trials (REaCT) platform and National Surgical Quality Improvement Program (NSQIP) to compare no preparation versus preoperative oral antibiotics alone for surgical site infection rates in elective colon surgery: a protocol.

INTRODUCTION: Despite 40 randomised controlled trials (RCTs) investigating preoperative oral antibiotics (OA) and mechanical bowel preparation (MBP) to reduce surgical site infection (SSI) rate following colon surgery, there has never been an RCT published comparing OA alone versus no preparation. Of the four possible regimens (OA alone, MBP alone, OA plus MBP and no preparation), randomised evidence is conflicting for studied groups. Furthermore, guidelines vary, with recommendations for OA alone, OA plus MBP or no preparation. The National Surgical Quality Improvement Program (NSQIP) has automated data collection for surgical patients. Similarly, the 'REthinking Clinical Trials' (REaCT) platform increases RCT enrolment by simplifying pragmatic trial design. In this novel RCT protocol, we combine REaCT and NSQIP to compare OA alone versus no preparation for SSI rate reduction in elective colon surgery. To our knowledge, this is the first published RCT protocol that leverages NSQIP for data collection. In our feasibility study, 67 of 74 eligible patients (90%) were enrolled and 63 of 67 (94%) were adherent to protocol. The 'REaCT-NSQIP' trial design has great potential to efficiently generate level I evidence for other perioperative interventions. METHODS AND ANALYSIS: SSI rates following elective colorectal surgery after preoperative OA or no preparation will be compared. We predict 45% relative rate reduction of SSI, improvement in length of stay, reduced costs and increased quality of life, with similar antibiotic-related complications. Consent, using the 'integrated consent model', and randomisation on a mobile device are completed by the surgeon in a single clinical encounter. Data collection for the primary end point is automatic through NSQIP. Analysis of cost per weighted case, cost utility and quality-adjusted life years will be done. ETHICS AND DISSEMINATION: This study is approved by The Ontario Cancer Research Ethics Board. Results will be disseminated in surgical conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03663504; Pre-results, recruitment phase.

A Randomized Controlled Trial Comparing Alloderm-RTU with DermACELL in Immediate Subpectoral Implant-Based Breast Reconstruction.

BACKGROUND: The effectiveness of different acellular dermal matrices (ADM) used for implant-based reconstruction immediately following mastectomy is an important clinical question. A prospective randomized clinical trial was performed to evaluate the superiority of DermACELL over Alloderm-RTU in reducing drain duration. METHODS: Patients undergoing mastectomy with subpectoral immediate and permanent implant-based breast reconstruction were randomized to Alloderm-RTU or DermACELL. The primary outcome was seroma formation, measured by the duration of postoperative drain placement. Secondary outcomes included: post drain removal seroma aspiration, infection, redbreast syndrome, wound dehiscence, loss of the implant, and unplanned return to the operating room. RESULTS: 62 patients were randomized for 81 mastectomies (41 Alloderm-RTU, 40 DermACELL). Baseline characteristics were similar. There was no statistically significant difference in mean drain duration (p = 0.16), with a trend towards longer duration in the Alloderm-RTU group (1.6 days; 95%CI, 0.7 to 3.9). The overall rate of minor and major complications were statistically similar between the two groups; although patients with Alloderm-RTU had 3 times as many infections requiring antibiotics (7.9% vs. 2.5%) with a risk difference of 5.4 (95%CI -4.5 to 15.2), and twice as many unplanned returns to the operating room (15.8% vs. 7.5%) with a risk difference of 8.3 (95% CI -5.9 to 22.5) as DermACELL. CONCLUSION: This is the first prospective randomized clinical trial comparing the two most commonly used human-derived ADMs. There was no statistically significant difference in drain duration, minor, or major complications between DermACELL over Alloderm-RTU in immediate subpectoral permanent implant-based breast reconstruction post-mastectomy.