The Abca7V1613M variant reduces Aß generation, plaque load, and neuronal damage.

BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Family carer experiences of hospice care at home: Qualitative findings from a mixed methods realist evaluation.

BACKGROUND: Hospice-at-home aims to enable patients approaching end-of-life to die at home and support their carers. A wide range of different service models exists but synthesised evidence on how best to support family carers to provide sustainable end-of-life care at home is limited. AIM: To explore what works best to promote family carers' experiences of hospice-at-home. DESIGN: Realist evaluation with mixed methods. This paper focuses on qualitative interviews with carers (to gain their perspective and as proxy for patients) and service providers from 12 case study sites in England. Interviews were coded and programme theories were refined by the research team including two public members. SETTING/PARTICIPANTS: Interviews with carers (involved daily) of patients admitted to hospice-at-home services (n = 58) and hospice-at-home staff (n = 78). RESULTS: Post bereavement, 76.4% of carers thought that they had received as much help and support as they needed and most carers (75.8%) rated the help and support as excellent or outstanding. Of six final programme theories capturing key factors relevant to providing optimum services, those directly relevant to carer experiences were: integration and co-ordination of services; knowledge, skills and ethos of hospice staff; volunteer roles; support directed at the patient-carer dyad. CONCLUSIONS: Carers in hospice-at-home services identified care to be of a higher quality than generic community services. Hospice staff were perceived as having 'time to care', communicated well and were comfortable with dying and death. Hands-on care was particularly valued in the period close to death.

Safety of influenza vaccination during pregnancy: a systematic review.

OBJECTIVE: We conducted a systematic review to evaluate associations between influenza vaccination during pregnancy and adverse birth outcomes and maternal non-obstetric serious adverse events (SAEs), taking into consideration confounding and temporal biases. METHODS: Electronic databases (Ovid MEDLINE ALL, Embase Classic+Embase and the Cochrane Central Register of Controlled Trials) were searched to June 2021 for observational studies assessing associations between influenza vaccination during pregnancy and maternal non-obstetric SAEs and adverse birth outcomes, including preterm birth, spontaneous abortion, stillbirth, small-for-gestational-age birth and congenital anomalies. Studies of live attenuated vaccines, single-arm cohort studies and abstract-only publications were excluded. Records were screened using a liberal accelerated approach initially, followed by a dual independent approach for full-text screening, data extraction and risk of bias assessment. Pairwise meta-analyses were conducted, where two or more studies met methodological criteria for inclusion. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess evidence certainty. RESULTS: Of 9443 records screened, 63 studies were included. Twenty-nine studies (24 cohort and 5 case-control) evaluated seasonal influenza vaccination (trivalent and/or quadrivalent) versus no vaccination and were the focus of our prioritised syntheses; 34 studies of pandemic vaccines (2009 A/H1N1 and others), combinations of pandemic and seasonal vaccines, and seasonal versus seasonal vaccines were also reviewed. Control for confounding and temporal biases was inconsistent across studies, limiting pooling of data. Meta-analyses for preterm birth, spontaneous abortion and small-for-gestational-age birth demonstrated no significant associations with seasonal influenza vaccination. Immortal time bias was observed in a sensitivity analysis of meta-analysing risk-based preterm birth data. In descriptive summaries for stillbirth, congenital anomalies and maternal non-obstetric SAEs, no significant association with increased risk was found in any studies. All evidence was of very low certainty. CONCLUSIONS: Evidence of very low certainty suggests that seasonal influenza vaccination during pregnancy is not associated with adverse birth outcomes or maternal non-obstetric SAEs. Appropriate control of confounding and temporal biases in future studies would improve the evidence base.

Cost-Effectiveness of Fractional Exhaled Nitric Oxide Suppression Testing as an Adherence Screening Tool Among Patients With Difficult-to-Control Asthma.

BACKGROUND: Approximately 50% of adults on long-term asthma medication are nonadherent. Current methods to detect nonadherence have had limited effect. Fractional exhaled nitric oxide suppression testing (FeNOSuppT) has demonstrated clinical effectiveness as an adherence screening tool to detect poor adherence to inhaled corticosteroids in difficult-to-control asthma prior to initiation of expensive biologic therapy. OBJECTIVE: Estimate the cost effectiveness and budget impact of FeNOSuppT as a screen prior to the initiation of biologic therapy among U.S. adults with difficult-to-control asthma and high fractional exhaled nitric oxide (≥45 ppb). METHODS: A decision tree simulated the progression of a cohort of patients over a 1-year time horizon into 1 of 3 states ([1] discharged from or [2] remain in specialist care; or [3] progress to biologics). Two strategies, with and without FeNOSuppT, were examined and the incremental net monetary benefit estimated using a discount rate of 3% and a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY). Sensitivity analysis and a budget impact analysis were also undertaken. RESULTS: In the baseline scenario, FeNOSuppT prior to the initiation of biologic therapy was associated with lower costs ($4,435/patient) and fewer QALYs (0.0023 QALY/patient) compared with no FeNOSuppT over 1 year and was considered cost effective (incremental net monetary benefit = $4,207). The FeNOSuppT was consistently found to be cost effective across a range of scenarios and in deterministic and probabilistic sensitivity analyses. Assuming differential levels of FeNOSuppT uptake (20%-100%), this was associated with budget savings ranging from USD $5 million to $27 million. CONCLUSIONS: The FeNOSuppT is likely to be cost effective as a protocol-driven, objective, biomarker-based tool for identifying nonadherence in difficult-to-control asthma. This cost effectiveness is driven by cost savings from patients not progressing to expensive biologic therapy.

How can the priorities of older, frail patients and their carers be used to inform policy and practice at the end of life? Insights from qualitative research across multiple settings.

OBJECTIVES: The paper reports on experiences from older patients and their carers of current provision of end-of-life care in England. It draws on data from a study that sought to explore the extent to which national policy for end-of-life care in England was aligned with the aspirations of stakeholders. Specifically, the study explored the balance between clinical healthcare vs social and relational care asking how this was aligned to patient priorities at this time of life. Here, we examine the extent to which the patient voice is attended to when health and social care services are delivered to older people and consider how the experiences of patients and carers could be used to improve outcomes. DESIGN: The work draws on data collected as part of a realist informed study using a case study approach to gather data. SETTING: Clinical Commissioning Groups were used as the boundaries of the three case studies and within these geographical areas data was collected in hospitals, care homes, hospices and patient homes. PARTICIPANTS: This paper reports on in-depth interviews conducted with 21 patients at the end of life and 22 relatives/carers (n=43). RESULTS: While the medical care patients received was generally praised, it was reported that relational care, particularly in respect to adult social care received at home, was fragmented and of varying quality. Relational and social support were key to the patient and carer experience yet appeared to be hard to access. CONCLUSION: The work highlights the misalignment between the availability of different types of care at the end of life and patient priorities. More attention should be paid to the voice of older patients and their carers, drawing on their experiences to influence the way policy is translated into practice.

Impacts of medical and non-medical cannabis on the health of older adults: Findings from a scoping review of the literature.

BACKGROUND: Cannabis legalization has enabled increased consumption in older adults. Age-related mental, physical, and physiological changes may lead to differences in effects of cannabis in older adults compared to younger individuals. OBJECTIVE: To perform a scoping review to map the evidence regarding the health effects of cannabis use for medical and non-medical purposes in older adults. METHODS: Electronic databases (MEDLINE, Embase, PsycINFO, Cochrane Library) were searched for systematic reviews (SRs), randomized controlled trials (RCTs) and non-randomized/observational studies (NRSs) assessing the health effects and associations of cannabis use (medical or non-medical) in adults ≥ 50 years of age. Included studies met age-related inclusion criteria or involved a priori identified health conditions common among older adults. Records were screened using a liberal accelerated approach and data charting was performed independently by two reviewers. Descriptive summaries, structured tables, effect direction plots and bubble plots were used to synthesize study findings. FINDINGS: From 31,393 citations, 133 publications describing 134 unique studies (26 SRs, 36 RCTs, 72 NRSs) were included. Medical cannabis had inconsistent therapeutic effects in specific patient conditions (e.g., end-stage cancer, dementia), with a number of studies suggesting possible benefits while others found no benefit. For medical cannabis, harmful associations outnumbered beneficial, and RCTs reported more negative effects than NRSs. Cannabis use was associated with greater frequencies of depression, anxiety, cognitive impairment, substance use and problematic substance use, accidents/injuries, and acute healthcare use. Studies often were small, did not consistently assess harms, and did not adjust for confounding. DISCUSSION: The effects of medical cannabis are inconsistent within specific patient conditions. For older adults, generally, the available evidence suggests cannabis use may be associated with greater frequencies of mental health issues, substance use, and acute healthcare use, and the benefit-to-risk ratio is unclear. Studies with a balanced assessment of benefits and harms may guide appropriate public health messaging to balance the marketing pressures of cannabis to older adults.

Opioid-induced constipation: a stepwise treatment algorithm feasibility study.

BACKGROUND: Opioid-induced constipation (OIC) is frequently undertreated in patients with advanced cancer. Our hypothesis is that the use of a stepwise treatment algorithm, supported by regular patient-reported outcome measures, should improve the management of OIC. The aim of this feasibility study was to determine whether a definitive study could be successfully completed. METHODS: Patients with OIC (Rome Foundation diagnostic criteria positive), and a Bowel Function Index (BFI) score of ≥30, were recruited to the study. The study involved weekly assessments, and decisions about management were based on the current BFI score (and the tolerability of the current treatment). Management was based on a four-step treatment algorithm, developed from recent international guidelines. RESULTS: One hundred patients entered the study, and 79 patients completed the study. Fifty-seven (72%) participants responded to treatment, with 34 (43%) participants having a 'complete' response (ie, final BFI<30) and 23 (29%) participants having a 'partial' response (ie, change in BFI≥12). In participants with a complete response, 73.5% were prescribed conventional laxatives, 12% were prescribed a peripherally acting mu-opioid receptor antagonist (PAMORA) and 14.5% were prescribed a PAMORA and conventional laxative. DISCUSSION: The feasibility study suggests that a definitive study can be successfully completed. However, we will amend the methodology to try to improve participant recruitment, participant retention and adherence to the treatment algorithm. The feasibility study also suggests that the use of the BFI to monitor OIC, and the use of a treatment algorithm to manage OIC, can result in clinically important improvements in OIC.Trial registration number NCT04404933.

Alzheimer's disease-associated R47H TREM2 increases, but wild-type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss.

Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems. Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F.

Brain Cells Release Calreticulin That Attracts and Activates Microglia, and Inhibits Amyloid Beta Aggregation and Neurotoxicity.

Calreticulin is a chaperone, normally found in the endoplasmic reticulum, but can be released by macrophages into the extracellular medium. It is also found in cerebrospinal fluid bound to amyloid beta (Aß). We investigated whether brain cells release calreticulin, and whether extracellular calreticulin had any effects on microglia and neurons relevant to neuroinflammation and neurodegeneration. We found that microglia release nanomolar levels of calreticulin when inflammatory-activated with lipopolysaccharide, when endoplasmic reticulum stress was induced by tunicamycin, or when cell death was induced by staurosporine, and that neurons release calreticulin when crushed. Addition of nanomolar levels of extracellular calreticulin was found to chemoattract microglia, and activate microglia to release cytokines TNF-α, IL-6 and IL-1ß, as well as chemokine (C-C motif) ligand 2. Calreticulin blocked Aß fibrillization and modified Aß oligomerization, as measured by thioflavin T fluorescence and transmission electron microscopy. Extracellular calreticulin also altered microglial morphology and proliferation, and prevented Aß-induced neuronal loss in primary neuron-glial cultures. Thus, calreticulin is released by microglia and neurons, and acts: as an alarmin to recruit and activate microglia, as an extracellular chaperone to prevent Aß aggregation, and as a neuroprotectant against Aß neurotoxicity.

Effectiveness of building-level sewage surveillance during both community-spread and sporadic-infection phases of SARS-CoV-2 in a university campus population.

Pathogen surveillance within wastewater rapidly progressed during the SARS-CoV-2 pandemic and informed public health management. In addition to the successful monitoring of entire sewer catchment basins at the treatment facility scale, subcatchment or building-level monitoring enabled targeted support of resource deployment. However, optimizing the temporal and spatial resolution of these monitoring programs remains complex due to population dynamics and within-sewer physical, chemical, and biological processes. To address these limitations, this study explores the advancement of the building-scale network that monitored the on-campus residential population at the University of Colorado Boulder between August 2020 and May 2021 through a daily SARS-CoV-2 surveillance campaign. During the study period, SARS-CoV-2 infection prevalence transitioned from robust community spread in Fall 2020 to sporadic infections in Spring 2021. Temporally, these distinct phases enabled investigating the effectiveness of resource commitment by exploring subsets of the original daily sampling data. Spatially, select sampling sites were installed along the flow path of the pipe network, enabling the exploration of the conservation of viral concentrations within the wastewater. Infection prevalence and resource commitment for informed action displayed an inverted relationship: higher temporal and spatial resolution surveillance is more imperative during sporadic infection phases than during high prevalence periods. This relationship was reinforced when norovirus (two minor clusters) and influenza (primarily absent) were additionally surveilled at a weekly frequency. Overall, resource commitment should scale to meet the objectives of the monitoring campaign-providing a general prevalence estimate requires fewer resources than an early-warning and targeted-action monitoring framework.

Glucocorticoid toxicity reduction with mepolizumab using the Glucocorticoid Toxicity Index.

BACKGROUND: Reduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity. OBJECTIVES: To use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12 months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient-reported outcome measures (PROMs). METHODS: A longitudinal, real-world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a specialist UK regional severe asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12 months treatment (V2). RESULTS: There was significant reduction in oral glucocorticoid exposure (V1 median 4280 mg prednisolone per year (interquartile range 3083-5475 mg) versus V2 2450 mg prednisolone per year (1243-3360 mg), p<0.001). Substantial improvements in individual toxicities were observed, but did not correlate with oral glucocorticoid reduction. Mean±sd GTI aggregate improvement score (AIS) was -35.7±57.8 with a wide range in toxicity change at individual patient level (AIS range -165 to +130); 70% (71 out of 101) had a reduction in toxicity (AIS <0); 3% (three out of 101) had no change (AIS=0); and 27% (27 out of 101) an increase in overall toxicity. 62% (62 out of 101) of patients met the AIS minimally clinically important difference of ≤-10, but AIS did not correlate with glucocorticoid reduction or change in PROMs. CONCLUSION: Mepolizumab resulted in substantial oral glucocorticoid reduction, but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab.

How does English national end-of-life care policy impact on the experience of older people at the end of life? Findings from a realist evaluation.

AIM: To explore the extent to which national policy in end-of-life care (EOLC) in England influences and guides local practice, helping to ensure that care for older people at the EOL is of a consistently good quality. BACKGROUND: Whilst policy is recognised as an important component in determining the effectiveness of EOLC, there is scant literature which attempts to interrogate how this happens or to hypothesise the mechanisms linking policy to better outcomes. METHOD: This article reports on the second phase of a realist evaluation comprising three case studies of clinical commissioning groups, including 98 in-depth interviews with stakeholders, meeting observation and documentary analysis. FINDINGS: This study reveals the key contextual factors which need to be in place at micro, meso and macro levels if good quality EOLC for older people is to be achieved. The findings provide insight into rising local inequalities and reveal areas of dissonance between stakeholder priorities. Whilst patients privilege the importance of receiving care and compassion in familiar surroundings at EOL, there remains a clear tension between this and the medical drive to cure disease and extend life. The apparent devaluing of social care and subsequent lack of resource has impacted significantly on the way in which dying is experienced.Patient experience at EOL, shaped by the care received both formally and informally, is driven by a fragmented health and social care system. Whilst the importance of system integration appears to have been recognised, significant challenges remain in terms of shaping policy to adequately reflect this. This study highlights the priority attached by patients and their families to the social and relational aspect of death and dying and shines a light on the stark disparities between the health and social care systems which became even more evident at the height of the Covid-19 pandemic.

Recommendations following a modified UK-Delphi consensus study on best practice for referral and management of severe asthma.

INTRODUCTION: Severe asthma affects an estimated 3%-5% of people with asthma and is associated with frequent exacerbations, poor symptom control and significant morbidity from the disease itself, as well as high dose of inhaled and systemic steroids used to treat it. The introduction of specialist asthma services across the UK has attempted to improve quality of care and ensure that patients undergo a full systematic assessment prior to initiation of advanced biological therapies. However, improvements are required in the patient pathway to minimise avoidable harm. OBJECTIVES: To define standards of care in areas where the evidence base is lacking through patient and healthcare professional (HCP) consensus. METHODS: The precision UK National Working Group of asthma experts identified 42 statements formed from 7 key themes. An online four-point Likert scale questionnaire was sent to HCPs working in asthma throughout the UK to assess agreement (consensus) with these statements; a subset of the statements formed a patient questionnaire. Consensus was defined as high if ≥75% and very high if ≥90% of respondents agreed with a statement. RESULTS: A total of 117/197 responses (59.3% response rate) were received from severe asthma patients (n=15) and HCPs (n=102) including respiratory physicians, respiratory nurse specialists, respiratory pharmacists, specialist physiotherapists and general practitioners. Consensus was very high in 25 (60%) statements, high in 12 (29%) statements and was not achieved in 5 (12%) statements. Based on the consensus scores, the precision UK National Working Group derived 10 key recommendations. These focus on referrals from primary and secondary care, accessing specialist asthma services, homecare provision for severe asthma patients and outcome measures. CONCLUSIONS: Implementation of these 10 recommendations across the severe asthma pathway in the UK has the potential to improve outcomes for patients by reducing delays to assessment and initiation of advanced phenotype-specific therapies.

Utility of fractional exhaled nitric oxide suppression as a prediction tool for progression to biologic therapy.

RATIONALE: The utility of fractional exhaled nitric oxide (F ENO) suppression (FeNOSuppT) to identify non-adherence to inhaled corticosteroid (ICS) treatment has previously been reported, but whether it can predict clinical outcome remains unclear. OBJECTIVES: We examined the utility of FeNOSuppT in prediction of progression to biologic agents or discharge from specialist care. METHODS: FeNOSuppT was measured at home using remote monitoring technology of inhaler use alongside daily F ENO measurement over 7 days. Long-term clinical outcomes in terms of progression to biologic agent or discharge from specialist care were compared for non-suppressors and suppressors. MEASUREMENTS AND MAIN RESULTS: Of the 162 subjects, 135 successfully completed the test with 81 (60%) positive F ENO suppression tests. Subjects with a negative FeNOSuppT were more likely to proceed to biologic therapy (39 of 54 patients, 72%) compared to those with a positive FeNOSuppT (35 of 81 patients, 43%, p=0.001). In subjects with a positive FeNOSuppT, predictors of progression to biologic therapy included higher dose of maintenance steroid at initial assessment and prior intensive care unit admission. These subjects had a significant rise in F ENO between post-suppression test and follow-up (median, 33 (IQR 25-55) versus 71 (IQR 24-114); p=0.009), which was not explained by altered corticosteroid dose. CONCLUSIONS: A negative FeNOSuppT correlates with progression to biologic therapy. A positive FeNOSuppT, with subsequent maintenance of "optimised" F ENO, predicts a subgroup of patients in whom asthma control is preserved with adherence to high-dose ICS/long-acting ß2 agonist and who can be discharged from specialist care.

High-resolution within-sewer SARS-CoV-2 surveillance facilitates informed intervention.

To assist in the COVID-19 public health guidance on a college campus, daily composite wastewater samples were withdrawn at 20 manhole locations across the University of Colorado Boulder campus. Low-cost autosamplers were fabricated in-house to enable an economical approach to this distributed study. These sample stations operated from August 25th until November 23rd during the fall 2020 semester, with 1512 samples collected. The concentration of SARS-CoV-2 in each sample was quantified through two comparative reverse transcription quantitative polymerase chain reactions (RT-qPCRs). These methods were distinct in the utilization of technical replicates and normalization to an endogenous control. (1) Higher temporal resolution compensates for supply chain or other constraints that prevent technical or biological replicates. (2) The data normalized by an endogenous control agreed with the raw concentration data, minimizing the utility of normalization. The raw wastewater concentration values reflected SARS-CoV-2 prevalence on campus as detected by clinical services. Overall, combining the low-cost composite sampler with a method that quantifies the SARS-CoV-2 signal within six hours enabled actionable and time-responsive data delivered to key stakeholders. With daily reporting of the findings, wastewater surveillance assisted in decision making during critical phases of the pandemic on campus, from detecting individual cases within populations ranging from 109 to 2048 individuals to monitoring the success of on-campus interventions.

Models of provider care in long-term care: A rapid scoping review.

INTRODUCTION: One of the current challenges in long-term care homes (LTCH) is to identify the optimal model of care, which may include specialty physicians, nursing staff, person support workers, among others. There is currently no consensus on the complement or scope of care delivered by these providers, nor is there a repository of studies that evaluate the various models of care. We conducted a rapid scoping review to identify and map what care provider models and interventions in LTCH have been evaluated to improve quality of life, quality of care, and health outcomes of residents. METHODS: We conducted this review over 10-weeks of English language, peer-reviewed studies published from 2010 onward. Search strategies for databases (e.g., MEDLINE) were run on July 9, 2020. Studies that evaluated models of provider care (e.g., direct patient care), or interventions delivered to facility, staff, and residents of LTCH were included. Study selection was performed independently, in duplicate. Mapping was performed by two reviewers, and data were extracted by one reviewer, with partial verification by a second reviewer. RESULTS: A total of 7,574 citations were screened based on the title/abstract, 836 were reviewed at full text, and 366 studies were included. Studies were classified according to two main categories: healthcare service delivery (n = 92) and implementation strategies (n = 274). The condition/ focus of the intervention was used to further classify the interventions into subcategories. The complex nature of the interventions may have led to a study being classified in more than one category/subcategory. CONCLUSION: Many healthcare service interventions have been evaluated in the literature in the last decade. Well represented interventions (e.g., dementia care, exercise/mobility, optimal/appropriate medication) may present opportunities for future systematic reviews. Areas with less research (e.g., hearing care, vision care, foot care) have the potential to have an impact on balance, falls, subsequent acute care hospitalization.

CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer's disease-protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion.

CD33 is a Siglec (sialic acid-binding immunoglobulin-type lectin) receptor on microglia. Human CD33 can be alternatively spliced into two isoforms: the long isoform (CD33M) and a shorter isoform (CD33m) that lacks the sialic acid-binding site. CD33m appears to protect against Alzheimer's disease; however, it remains unclear how. To investigate potential mechanisms by which CD33m may confer protection, we expressed the CD33m and CD33M isoforms of human CD33 in mouse BV-2 and human CHME3 microglial cells and assessed microglia functions. In the BV-2 cells, CD33M inhibited microglial phagocytosis of beads, synapses, debris and dead cells, while CD33m increased phagocytosis of beads, debris and cells. RNAi knockdown of the endogenous mouse CD33 increased phagocytosis and prevented CD33m's (but not CD33M's) effect on phagocytosis. CD33M increased cell attachment but inhibited cell proliferation, while CD33m did the opposite. We also found that CD33M inhibited cell migration. In human CHME3 cells, CD33M increased cell attachment, but inhibited phagocytosis, proliferation and migration, whereas CD33m did the opposite. We conclude that CD33M inhibits microglial phagocytosis, inhibits migration and increases adhesion, while CD33m increases phagocytosis, proliferation and inhibits adhesion. Thus, CD33m might protect against Alzheimer's disease by increasing microglial proliferation, movement and phagocytosis of debris and dead cells.

Microglial phagocytosis of neurons in neurodegeneration, and its regulation.

There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA-seq and genome-wide association (GWAS) studies have linked multiple phagocytic genes to neurodegenerative diseases, and knock-out of phagocytic genes has been found to protect against neurodegeneration in animal models, suggesting that excessive microglial phagocytosis contributes to neurodegeneration. Here, we review recent evidence that microglial phagocytosis of live neurons and synapses causes neurodegeneration in animal models of Alzheimer's disease and other tauopathies, Parkinson's disease, frontotemporal dementias, multiple sclerosis, retinal degeneration and neurodegeneration induced by ischaemia, infection or ageing. We also review factors regulating microglial phagocytosis of neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin-3, Apolipoprotein E, phagocytic receptors, Siglec receptors, cytokines, microglial epigenetics and expression profile. Some of these factors may be potential treatment targets to prevent neurodegeneration mediated by excessive microglial phagocytosis of live neurons and synapses.

Fractional exhaled nitric oxide and asthma treatment adherence.

PURPOSE OF REVIEW: Despite increased clinician awareness, nonadherence to inhaled corticosteroid treatment presents a major challenge to successful asthma management and risks inappropriate treatment escalation, particularly in severe disease. In patients with Type-2 mediated biology, fractional exhaled nitric oxide (FeNO) has a role in assessment and monitoring of adherence to inhaled corticosteroids. RECENT FINDINGS: Asthmatic patients with elevated FeNO are at an increased risk of exacerbation. High FeNO is often secondary to suboptimal adherence to inhaled corticosteroid treatment, whether intentional or nonintentional. FENO-suppression can 'unmask' underlying adherence issues and is a useful test in the presence of Type-2 biology in the 'difficult-to-control' asthma population. Identification of nonadherence can improve asthma control and prevent inappropriate commencement of costly biologic therapies. SUMMARY: Assessment of adherence and FeNO response to monitored inhaled corticosteroid in Type-2 biomarker high asthmatic individuals may prevent unnecessary escalation to biologic therapy. Establishing an 'optimised' FeNO may alert clinicians to the possibility of underlying nonadherence at future clinical assessments.

Hospice at Home services in England: a national survey.

OBJECTIVE: Hospice at Home (HAH) services aim to enable patients to be cared for and die at home, if that is their choice and achieve a 'good death'. A national survey, in 2017, aimed to describe and compare the features of HAH services and understand key enablers to service provision. METHODS: Service managers of adult HAH services in the 'Hospice UK' and National Association for Hospice at Home directories within England were invited to participate. Information on service configuration, referral, staffing, finance, care provision and enablers to service provision were collected by telephone interview. RESULTS: Of 128 services invited, 70 (54.7%) provided data. Great diversity was found. Most services operated in mixed urban/rural (74.3%) and mixed deprivation (77.1%) areas and provided hands-on care (97.1%), symptom assessment and management (91.4%), psychosocial support (94.3%) and respite care (74.3%). Rapid response (within 4 hours) was available in 65.7%; hands-on care 24 hours a day in 52.2%. Charity donations were the main source of funding for 71.2%. Key enablers for service provision included working with local services (eg, district nursing, general practitioner services), integrated health records, funding and anticipatory care planning. Access to timely medication and equipment was critical. CONCLUSION: There is considerable variation in HAH services in England. Due to this variation it was not possible to categorise services into delivery types. Services work to supplement local care using a flexible approach benefitting from integration and funding. Further work defining service features related to patient and/or carer outcomes would support future service development.