Associations Between Midlife Anticholinergic Medication Use and Subsequent Cognitive Decline: A British Birth Cohort Study.

BACKGROUND: Anticholinergic medication use is associated with cognitive decline and incident dementia. Our study, a prospective birth cohort analysis, aimed to determine if repeated exposure to anticholinergic medications was associated with greater decline, and whether decline was reversed with medication reduction. METHODS: From the Medical Research Council (MRC) National Survey of Health and Development, a British birth cohort with all participants born in a single week of March 1946, we quantified anticholinergic exposure between ages 53 and 69 years using the Anticholinergic Cognitive Burden Scale (ACBS). We used multinomial regression to estimate associations with global cognition, quantified by the Addenbrooke's Cognitive Examination, 3rd Edition (ACE-III). Longitudinal associations between ACBS and cognitive test results (Verbal memory quantified by the Word Learning Test [WLT], and processing speed quantified by the Timed Letter Search Task [TLST]) at three time points (age 53, 60-64 and 69) were assessed using mixed and fixed effects linear regression models. Analyses were adjusted for sex, childhood cognition, education, chronic disease count and severity, and mental health symptoms. RESULTS: Anticholinergic exposure was associated cross-sectionally with lower ACE-III scores at age 69, with the greatest effects in those with high exposure at ages 60-64 (mean difference - 2.34, 95% confidence interval [CI] - 3.51 to - 1.17). Longitudinally, both mild-moderate and high ACBS scores were linked to lower WLT scores, again with high exposure showing larger effects (mean difference with contemporaneous exposure - 0.90, 95% CI - 1.63 to - 0.17; mean difference with lagged exposure - 1.53, 95% CI - 2.43 to - 0.64). Associations remained in fixed effects models (mean difference with contemporaneous exposure -1.78, 95% CI -2.85 to - 0.71; mean difference with lagged exposure - 2.23, 95% CI - 3.33 to - 1.13). Associations with TLST were noted only in isolated contemporaneous exposure (mean difference - 13.14, 95% CI - 19.04 to - 7.23; p < 0.01). CONCLUSIONS: Anticholinergic exposure throughout mid and later life was associated with lower cognitive function. Reduced processing speed was associated only with contemporaneous anticholinergic medication use, and not historical use. Associations with lower verbal recall were evident with both historical and contemporaneous use of anticholinergic medication, and associations with historical use persisted in individuals even when their anticholinergic medication use decreased over the course of the study.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies.

BACKGROUND: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. METHODS: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). FINDINGS: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. INTERPRETATION: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. FUNDING: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.

CRISPR Advancements for Human Health.

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has emerged as a powerful gene editing technology that is revolutionizing biomedical research and clinical medicine. The CRISPR system allows scientists to rewrite the genetic code in virtually any organism. This review provides a comprehensive overview of CRISPR and its clinical applications. We first introduce the CRISPR system and explain how it works as a gene editing tool. We then highlight current and potential clinical uses of CRISPR in areas such as genetic disorders, infectious diseases, cancer, and regenerative medicine. Challenges that need to be addressed for the successful translation of CRISPR to the clinic are also discussed. Overall, CRISPR holds great promise to advance precision medicine, but ongoing research is still required to optimize delivery, efficacy, and safety.

CRISPR-Cas9 Genome Editing of Rat Embryos using Adeno-Associated Virus (AAV) and 2-Cell Embryo Electroporation.

Genome editing technology is widely used to produce genetically modified animals, including rats. Cytoplasmic or pronuclear injection of DNA repair templates and CRISPR-Cas reagents is the most common delivery method into embryos. However, this type of micromanipulation necessitates access to specialized equipment, is laborious, and requires a certain level of technical skill. Moreover, microinjection techniques often result in lower embryo survival due to the mechanical stress on the embryo. In this protocol, we developed an optimized method to deliver large DNA repair templates to work in conjunction with CRISPR-Cas9 genome editing without the need for microinjection. This protocol combines AAV-mediated DNA delivery of single-stranded DNA donor templates along with the delivery of CRISPR-Cas9 ribonucleoprotein (RNP) by electroporation to modify 2-cell embryos. Using this novel strategy, we have successfully produced targeted knock-in rat models carrying insertion of DNA sequences from 1.2 to 3.0 kb in size with efficiencies between 42% and 90%.

Surgeon Factors and Trends Associated With the Use of Subacromial Decompression at the Time of Rotator Cuff Repair.

PURPOSE: Subacromial decompression (SAD) has historically been described as an essential part of the surgical treatment of rotator cuff disorders. However, investigations throughout the 21st century have increasingly questioned the need for routine SAD during rotator cuff repair (RCR). Our purpose was to assess for changes in the incidence of SAD performed during RCR over a 12-year period. In addition, we aimed to characterize surgeon and practice factors associated with SAD use. METHODS: Records from two large tertiary referral systems in the United States from 2010 to 2021 were reviewed. All cases of RCR with and without SAD were identified. The outcome of interest was the proportion of SAD performed during RCR across years and by surgeon. Surgeon-specific characteristics included institution, fellowship training, surgical volume, academic practice, and years in practice. Yearly trends were assessed using binomial logistic regression modeling, with a random effect accounting for surgeon-specific variability. RESULTS: During the study period, 37,165 RCR surgeries were performed by 104 surgeons. Of these cases, 71% underwent SAD during RCR. SAD use decreased by 11%. The multivariable model found that surgeons in academic practice, those with lower surgical volume, and those with increasing years in practice were significantly associated with increased odds of performing SAD. Surgeons with fellowship training were significantly more likely to use SAD over time, with the greatest odds of SAD noted for sports medicine surgeons (odds ratio = 3.04). CONCLUSIONS: Although SAD use during RCR appears to be decreasing, multiple surgeon and practice factors (years in practice, fellowship training, volume, and academic practice) are associated with a change in SAD use. CLINICAL RELEVANCE: These data suggest that early-career surgeons entering practice are likely driving the trend of declining SAD. Despite evidence suggesting limited clinical benefits, SAD remains commonly performed; future studies should endeavor to determine factors associated with practice changes among surgeons.

The Impact of Pre-Operative Benzodiazepine Use on Post-Operative Opioid Use in Total Shoulder Arthroplasty.

BACKGROUND: As the rate of total shoulder arthroplasty (TSA) and preoperative benzodiazepine use rise, there is an increased need to understand the impact of preoperative benzodiazepine use on postoperative opioid consumption following TSA, especially amid the current opioid epidemic. The relationship between preoperative benzodiazepine use and chronic opioid use postoperatively has been well-described following other orthopedic procedures, however, the impact on patients undergoing TSA remains unclear. This study aims to identify the impact of preoperative benzodiazepine use on opioid use following TSA. METHODS: A retrospective chart review of 4,488 patients undergoing primary TSA (CPT code 23472) at a single institution from 2014-2022 was performed. Patient demographics, surgical variables, comorbidities, distressed communities index score (DCI), and clinical outcomes, including readmission and revision, were collected. The Charlson Comorbidity Index (CCI) was used to assess preoperative health status. Opioid use in morphine milligram equivalents (MME) and benzodiazepine use were also recorded using the Prescription Drug Monitoring Program Database. Opioid use was collected at 30-, 60-, and 90-day intervals both before and after each patient's date of surgery. Statistical analysis included stepwise logistic regression to identify variables independently affecting benzodiazepine use pre- and postoperatively. RESULTS: Overall, 16% of patients utilized benzodiazepines within 90 days before their date of surgery. Of those patients, 46.4% were also utilizing preoperative opioids, compared to just 30.0% of patients who were benzodiazepine-naïve (p<0.001). Preoperative benzodiazepine use was also associated with increased pre- and postoperative total opioid use in MME and the number of opioid prescriptions across all time points when compared to benzodiazepine-naïve patients (p<0.001). Furthermore, 37.4% of preoperative benzodiazepine users went on to prolonged opioid use (filled prescriptions >30 days after surgery) compared to 19.0% of those who were benzodiazepine-naïve (p<0.001). CONCLUSION: This study demonstrates a significant association between preoperative benzodiazepine use and increased and prolonged opioid use following TSA. Further exploration of risk factors contributing to preoperative benzodiazepine use may help to reduce overall opioid use in patients undergoing TSA.

Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Comparison of Thermal and Mechanical Pain Testing Modalities in Sprague Dawley and Fischer 344 Rats (Rattus norvegicus).

While rodents are used extensively for studying pain, there is a lack of reported direct comparisons of thermal and mechanical pain testing methods in rats of different genetic backgrounds. Understanding the range of interindividual variability of withdrawal thresholds and thermal latencies based on these testing methods and/or genetic background is important for appropriate experimental design. Testing was performed in two common rat genetic backgrounds: outbred Sprague-Dawley (SD) and inbred Fischer 344 (F344). Male and female, 10- to 14-wk-old F344 and SD rats were used to assess withdrawal thresholds in 3 different modalities: the Randall-Selitto test (RST), Hargreaves test (HT), and tail flick test (TFT). The RST was performed by using an operator-controlled handheld instrument to generate a noxious pressure stimulus to the left hind paw. The HT and the TFT used an electronically controlled light source to deliver a noxious thermal stimulus to the left hind paw or tail tip, respectively. Rats of each sex and genetic background underwent one type of test on day 0 and day 7. Withdrawal thresholds and thermal latencies were compared among tests. No significant differences were observed. Our findings can serve as a guide for researchers considering these nociceptive tests for their experiments.

Increasing midtarsal joint stiffness reduces triceps surae metabolic costs in walking simulations but has little effect on total stance limb metabolic cost.

The human foot's arch is thought to be beneficial for efficient gait. This study addresses the extent to which arch stiffness changes alter the metabolic energy requirements of human gait. Computational musculoskeletal simulations of steady state walking using direct collocation were performed. Across a range of foot arch stiffnesses, the metabolic cost of transport decreased by less than 1% with increasing foot arch stiffness. Increasing arch stiffness increased the metabolic efficiency of the triceps surae during push-off, but these changes were almost entirely offset by other muscle groups consuming more energy with increasing foot arch stiffness.

Delirium is more common and associated with worse outcomes in Parkinson's disease compared to older adult controls: results of two prospective longitudinal cohort studies.

BACKGROUND: Inpatient prevalence of Parkinson's disease (PD) delirium varies widely across the literature. Delirium in general older populations is associated with adverse outcomes, such as increased mortality, dementia, and institutionalisation. However, to date there are no comprehensive prospective studies in PD delirium. This study aimed to determine delirium prevalence in hospitalised PD participants and the association with adverse outcomes, compared to a control group of older adults without PD. METHODS: Participants were hospitalised inpatients from the 'Defining Delirium and its Impact in Parkinson's Disease' and the 'Delirium and Cognitive Impact in Dementia' studies comprising 121 PD participants and 199 older adult controls. Delirium was diagnosed prospectively using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria. Outcomes were determined by medical note reviews and/or home visits 12 months post hospital discharge. RESULTS: Delirium was identified in 66.9% of PD participants compared to 38.7% of controls (p < 0.001). In PD participants only, delirium was associated with a significantly higher risk of mortality (HR = 3.3 (95% confidence interval [CI] = 1.3-8.6), p = 0.014) and institutionalisation (OR = 10.7 (95% CI = 2.1-54.6), p = 0.004) 12 months post-discharge, compared to older adult controls. However, delirium was associated with an increased risk of developing dementia 12 months post-discharge in both PD participants (OR = 6.1 (95% CI = 1.3-29.5), p = 0.024) and in controls (OR = 13.4 (95% CI = 2.5-72.6), p = 0.003). CONCLUSION: Delirium is common in hospitalised PD patients, affecting two thirds of patients, and is associated with increased mortality, institutionalisation, and dementia. Further research is essential to understand how to accurately identify, prevent and manage delirium in people with PD who are in hospital.

Augmented Fixation in Transverse Midshaft Humerus Fractures Using a Nitinol Staple: Surgical Technique and Case Series.

Maintaining the reduction of a transverse humeral shaft fracture can be particularly challenging while applying a compression plate for definitive fixation. Nitinol compression staples are being increasingly utilized in orthopedic surgery due to their unique ability to apply continuous compression between staple legs at body temperature. We have found them to be particularly useful in the maintenance of the reduction of transverse humeral shaft fractures before compression plate application. This simple technique allows for the removal of reduction clamps and precise plate placement. We describe our technique for using nitinol compression staples to augment fracture fixation in transverse humeral shaft fractures as well as our experience using this technique in a case series of 4 patients.

Behavioral characterization of G-protein-coupled receptor 160 knockout mice.

ABSTRACT: Neuropathic pain is a devastating condition where current therapeutics offer little to no pain relief. Novel nonnarcotic therapeutic targets are needed to address this growing medical problem. Our work identified the G-protein-coupled receptor 160 (GPR160) as a potential target for therapeutic intervention. However, the lack of small-molecule ligands for GPR160 hampers our understanding of its role in health and disease. To address this void, we generated a global Gpr160 knockout (KO) mouse using CRISPR-Cas9 genome editing technology to validate the contributions of GPR160 in nociceptive behaviors in mice. Gpr160 KO mice are healthy and fertile, with no observable physical abnormalities. Gpr160 KO mice fail to develop behavioral hypersensitivities in a model of neuropathic pain caused by constriction of the sciatic nerve. On the other hand, responses of Gpr160 KO mice in the hot-plate and tail-flick assays are not affected. We recently deorphanized GPR160 and identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a potential ligand. Using Gpr160 KO mice, we now report that the development of behavioral hypersensitivities after intrathecal or intraplantar injections of CARTp are dependent on GPR160. Cocaine- and amphetamine-regulated transcript peptide plays a role in various affective behaviors, such as anxiety, depression, and cognition. There are no differences in learning, memory, and anxiety between Gpr160 KO mice and their age-matched and sex-matched control floxed mice. Results from these studies support the pronociceptive roles of CARTp/GPR160 and GPR160 as a potential therapeutic target for treatment of neuropathic pain.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Delirium detection tools show varying completion rates and positive score rates when used at scale in routine practice in general hospital settings: A systematic review.

BACKGROUND: Multiple short delirium detection tools have been validated in research studies and implemented in routine care, but there has been little study of these tools in real-world conditions. This systematic review synthesized literature reporting completion rates and/or delirium positive score rates of detection tools in large clinical populations in general hospital settings. METHODS: PROSPERO (CRD42022385166). Medline, Embase, PsycINFO, CINAHL, and gray literature were searched from 1980 to December 31, 2022. Included studies or audit reports used a validated delirium detection tool performed directly with the patient as part of routine care in large clinical populations (n ≥ 1000) within a general acute hospital setting. Narrative synthesis was performed. RESULTS: Twenty-two research studies and four audit reports were included. Tools used alone or in combination were the Confusion Assessment Method (CAM), 4 'A's Test (4AT), Delirium Observation Screening Scale (DOSS), Brief CAM (bCAM), Nursing Delirium Screening Scale (NuDESC), and Intensive Care Delirium Screening Checklist (ICDSC). Populations and settings varied and tools were used at different stages and frequencies in the patient journey, including on admission only; inpatient, daily or more frequently; on admission and as inpatient; inpatient post-operatively. Tool completion rates ranged from 19% to 100%. Admission positive score rates ranged from: CAM 8%-51%; 4AT 13%-20%. Inpatient positive score rates ranged from: CAM 2%-20%, DOSS 6%-42%, and NuDESC 5-13%. Postoperative positive score rates were 21% and 28% (4AT). All but two studies had moderate-high risk of bias. CONCLUSIONS: This systematic review of delirium detection tool implementation in large acute patient populations found clinically important variability in tool completion rates, and in delirium positive score rates relative to expected delirium prevalence. This study highlights a need for greater reporting and analysis of relevant healthcare systems data. This is vital to advance understanding of effective delirium detection in routine care.

Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU: 2023.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care hospitals have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes (PICO) format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation Approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among unselected patients. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system. CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Executive Summary: Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care facilities have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based clinical practice guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among "unselected" patients due to the absence of data regarding the benefit and the potential harms of false positive alarms, the risk of alarm fatigue, and cost. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system (GPS). CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Prostaglandin E2 impacts multiple stages of the natural killer cell antitumor immune response.

Tumor immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumors can produce prostaglandin E2 (PGE2 ), an inflammatory mediator that directly acts on Natural killer (NK) cells to inhibit antitumor immunity. However, precisely how PGE2 influences NK cell tumor-restraining functions remains unclear. Here, we report that following PGE2 treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to degranulate and kill cancer targets. Transcriptional analysis uncovered that PGE2 also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE2-treated NK cells exhibited decreased migration to CXCL10 but increased ability to migrate toward CXCL12. Using live cell imaging, we showed that in the presence of PGE2 , NK cells were slower and less likely to kill cancer target cells following conjugation. Imaging the sequential stages of NK cell killing revealed that PGE2 impaired NK cell polarization, but not the re-organization of synaptic actin or the release of perforin itself. Together, these findings demonstrate that PGE2 affects multiple but select NK cell functions. Understanding how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.

Drug-induced orthostatic hypotension: Cluster analysis of co-prescription patterns in older people in UK primary care.

PURPOSE: Over 250 medications are reported to cause orthostatic hypotension, associated with serious adverse outcomes in older adults. Studies suggest a harmful cumulative risk of orthostatic hypotension with multiple medication use. However, there is limited evidence on the potential for harm in practice, particularly which drugs is co-prescribed and may increase risk of orthostatic hypotension. METHODS: Retrospective cohort study and cluster analysis using general practice data from IQVIA Medical Research Data (IMRD) in patients aged ≥50 contributing data between 1 January 2018 and 31 December 2018. Thirteen drug groups known to be associated with orthostatic hypotension by mechanism, were analyzed and clusters generated by sex and age-band. RESULTS: A total of 602 713 individuals aged ≥50 with 283 912 (47%) men and 318 801 (53%) women were included. The most prevalent prescriptions that might contribute to orthostatic hypotension were ACE inhibitors, calcium-channel blockers, beta-blockers, selective serotonin reuptake inhibitors and uroselective alpha-blockers. We identified distinct clusters of cardiovascular system (cardiovascular system) drugs in men and women at all ages. cardiovascular system plus psychoactive drug clusters were common in women at all ages, and in men aged ≤70. cardiovascular system plus uroselective alpha-blockers were identified in men aged ≥70. CONCLUSIONS: Distinct clusters of drugs associated with orthostatic hypotension exist in practice, which change over the life course. Our findings highlight potentially harmful drug combinations that may cause cumulative risk of orthostatic hypotension in older people. This may guide clinicians about the potential of synergistic harm and to monitor for orthostatic hypotension if using combinations of cardiovascular system drugs, cardiovascular system plus psychoactive drugs and/or alpha-blockers-particularly in patients aged ≥70 or at high-risk due to comorbidity. Future research should consider quantifying the risk of drug-induced orthostatic hypotension with such drug combinations.