Evaluation and limitations of the novel chemiluminescent enzyme immunoassay technique for measuring total tau protein in the cerebrospinal fluid in patients with human prion disease: a 10-year prospective study (2011–2020) (preprint)

Background: Recently, the investigation of cerebrospinal fluid (CSF) biomarkers for diagnosing human prion diseases (HPD) has garnered significant attention. Reproducibility and accuracy are paramount in biomarker research, particularly in the measurement of total tau (t-tau) protein, which is a crucial diagnostic marker. Given the global impact of the coronavirus disease pandemic, the frequency of measuring this protein using one of the world's fully automated assays, chemiluminescent enzyme immunoassay (CLEA), has increased. At present, the diagnosis and monitoring of neurological diseases mainly rely on traditional methods, but their accuracy and responsiveness are limited.there is a limited knowledge on the accuracy of CLEA in Tau measurements. We aimed to measure t-tau protein using CLEA and to elucidate its merits and limitations. Methods: We analysed CSF samples obtained from 91 patients with rapidly progressive dementia using ELISA and CLEA. Additionally, we used western blotting to detect the presence of 14-3-3 protein and employed real-time quaking-induced conversion (RT-QuIC) assays to analyse the same set of samples. Furthermore, we examined the correlation coefficient between ELISA and CLEA results in a subset of 30 samples. Moreover, using CLEA, we evaluated the diurnal reproducibility, storage stability, dilutability, and freeze-thaw effects in three selected samples. Results:Among the 91 patients, a total of 45 (22 men and 23 women) tested positive for HPD in the RT-QuIC assay. In contrast, all CSF samples from the remaining 46 patients without HPD (23 men and 23 women) tested negative in the RT-QuIC assay. Both ELISA and CLEA showed perfect sensitivity and specificity (100%) in measuring t-tau protein levels. Furthermore, there was a strong correlation coefficient (R² = 0.9363) between ELISA and CLEA results. However, despite its advantages, CLEA analysis exhibited instability for certain samples with t-tau protein levels exceeding 2,000 pg/mL, leading to low reproducibility during dilution analysis. Conclusions: Our findings indicate that CLEA outperforms ELISA in terms of diurnal reproducibility, storage stability, and freeze-thaw effects. However, ELISA demonstrated superior performance in the dilution assay. Therefore, it is imperative to develop innovative approaches for the dilution of biomarker samples for CLEA measurements during clinical trials.

The Effectiveness of Socially Assistive Robots in Improving Children’s Pain and Negative Affectivity during Needle-based Invasive Treatment: A Systematic Review and Meta-analysis (preprint)

Background The ability of socially assistive robots (SARs) to treat dementia and Alzheimer’s disease has been verified. Currently, to increase the range of their application, there is an increasing amount of interest in using SARs to relieve pain and negative emotions among children in routine medical settings. However, there is little consensus regarding the use of these robots. Objective This study aimed to evaluate the effect of SARs on pain and negative affectivity among children undergoing invasive needle-based procedures. Design This study was a systematic review and meta-analysis of randomized controlled trials that was conducted in accordance with the Cochrane Handbook guidelines. Methods The PubMed, Embase, EBSCO, Web of Science, Cochrane Library, Embase, CNKI, and WanFang databases were searched from inception to January 2024 to identify relevant randomized controlled trials (RCTs). We used the Cochrane Risk of Bias tool 2.0 (RoB2.0) to assess the risk of bias among the included studies, and we used RevMan 6.3 software to conduct the meta-analysis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of the evidence. Results Ten RCTs involving 815 pediatric subjects were selected for this review and reported outcomes related to pain and emotions during IV placement, port needle insertion, flu vaccination, blood sampling, and dental treatment. Children undergoing needle-related procedures with SARs reported less anxiety (SMD= -0.36; 95% CI= -0.64, -0.09; P = 0.01) and fewer distressed avoidance behaviors (SMD= -0.67; 95% CI= -1.04, -0.30; P = 0.0004) than did those receiving typical care. There were nonsignificant differences between these groups in terms of in pain (SMD = -0.02; 95% CI = − 0.81, 0.78; P = 0.97) and fear (SMD = 0.38; 95% CI= -0.06, 0.82; P = 0.09). The results of exploratory subgroup analyses revealed no statistically significant differences based on the intervention type of robots or anesthetic use. Conclusions The use of SARs is a promising intervention method for alleviating anxiety and distress among children undergoing needle-related procedures. However, additional high-quality randomized controlled trials are needed to further validate these conclusions. Registrations The protocol of this study has been registered in the database PROSPERO (registration ID: CRD42023413279).

In-silico analysis of SARS-CoV-2 N protein host interactors involved in Parkinson’s Disease and Dementia (preprint)

Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is a highly pathogenic and contagious coronavirus that first surfaced in late 2019. The genome encodes four major structural proteins, non-structural proteins and accessory proteins. The nucleocapsid (N) protein of SARS-CoV-2 is an evolutionarily conserved RNA-binding protein that is abundant and plays a critical role in packaging the viral genome. Researchers have explored its potential as a target for therapeutic purposes. People with pre-existing neurological conditions like Parkinson’s disease (PD) and dementia have been recognised as a high-risk population for severe COVID-19 illness as SARS-CoV-2 has been reported to cause deterioration of the symptoms of these diseases. This study aims to identify the shared human interactors of SARS-CoV-2 N protein, PD and dementia. Proteins involved were retrieved from databases, and protein-protein interaction networks were created and visualized in Cytoscape. Individual intersection networks of SARS-CoV-2 N protein with PD and dementia resulted in 46 and 26 proteins, respectively, while intersection networks of SARS-CoV-2 N protein, PD and dementia resulted in 15 common proteins. Seed proteins were identified from network clusters and their Gene Ontology (GO) analysis revealed their involvement in several biological processes. Valosin-containing-protein (VCP) was found to be the only seed protein involved during the co-occurrence of SARS-CoV-2 N protein infection, PD and dementia and is mainly concerned with the regulation of the ubiquitin-proteasome system (UPS). Further, gene enrichment analysis of the identified 15 common proteins was conducted using the DAVID tool, followed by the identification of 7 druggable targets using the Therapeutic Target Database (TTD) and DrugBank. Studying the biological functions of the identified host-protein interactors is crucial for understanding the progression of the disease at a molecular level. Moreover, approved therapeutic compounds against the potential drug target proteins can also be utilized to develop effective treatments.

Assessing COVID-19 Vaccine Effectiveness in Frail Long-Term Care Facilities Residents in a Middle-Income Country (preprint)

Background: During the COVID-19 pandemic, individuals residing in long-term care facilities (LTCF) are particularly vulnerable to adverse outcomes due to their higher rates of frailty, disabilities, cognitive impairment, dementia, and chronic illnesses. In low and middle-income nations, research on immunizing frail populations is lacking, while most studies on COVID-19 in LTCF come from wealthier nations and may not fully capture the situation in emerging countries.  Methods: We aimed to evaluate the effectiveness of first, second and third COVID-19 vaccine doses, against infections, hospitalizations, and deaths, and their association with frailty, age, sex and chronic disease, among older adults, in a social vulnerability context. This retrospective cohort study, comprises a total of 712 older adults, in a social vulnerability context, of 29 LTCF, in Brazil. Continuous variables were described by medians and interquartile ranges and categorical variables were represented by absolute and relative frequencies. The Mann-Whitney test was used. For evaluating the relation between categorical variables, Pearson's chi-square test was used. When comparing proportions, the Z test of proportion was applied. A significance level of 5% was considered.  Results: Median age was 81.37 years, 72.8% were female, 94.61% were frail, 79.97% had a cognitive impairment, 69.54% had a mobility impairment, 78.37% have, at least, one chronic disease and 72.73% use five or more medications per day. Before the vaccine, mobility impairment was associated with great contamination rates (p=.03); frailty (p=.02) and previous pulmonary disease (p=.03) with symptoms of gravity; frailty (p=.02), pulmonary disease (p=.04) and male sex (p=.02) with emergency care or hospital admission. After the third vaccine dose, only frailty remains associated with admissions (p=.03). The number of positive cases (p=.001), symptomatic patients (p<.001), admissions (p=.001) and deaths (p<.001) were substantially reduced after the three vaccine doses.  Conclusions and Implications: Even in a frail population, the vaccine was effective, in the reduction of positive cases, the number of symptomatic patients, admission to emergency or hospital care and deaths. Before the vaccine, frailty, previous pulmonary disease and male sex were associated with worse outcomes. After the vaccine, frailty remains associated with a major number of admissions.

Collaborating with pharmacists to improve medication use in dementia care: views from healthcare professionals in Sweden (preprint)

Background Dementia is a major global public health challenge, and with the growing elderly population, its prevalence is expected to increase in the coming years. In Sweden, municipalities are responsible for providing special housing for the elderly (SÄBO), which offers services and care for older individuals needing specific support. SÄBO is both the person´s home and a care environment and workplace. Polypharmacy in patients with dementia is common and increases the risk of medication interactions. Involving clinical pharmacists in medication reviews has been shown to result in safer medication use and more appropriate prescribing. However, less attention has been given to how other healthcare professionals view the implementation of such pharmacist services. Thus, this study aims to explore their views towards pharmacist-supported medication reviews for people with dementia.Methods This descriptive qualitative study used semi-structured interviews and qualitative content analysis to explore healthcare professionals’ views on pharmacist-supported medication reviews for people with dementia. The study was conducted in a southern Swedish special housing and included nurses, assistant nurses, general practitioners (GPs), and a pharmacist. Due to the COVID-19 pandemic, interviews were conducted over the phone. The Swedish Ethical Review Authority approved the study.Results The analysis revealed three main categories, and eleven subcategories.: 1) Approaches to safe medication use, 2) Approaches to work processes and 3) The role of the pharmacist. Nurses focused on non-pharmacological treatments, while GPs emphasized the importance of medication reviews in assessing the benefits and side-effects of prescribed medication. Pharmacists were valued for their reliable medication expertise, appreciated by GPs for saving time and providing recommendations prior to consultations with individuals with dementia and their next-of-kin. Although medication reviews were considered beneficial, there was skepticism about their ability to solve all medication-related problems associated with dementia care.Conclusions The healthcare professionals generally had a positive attitude towards collaborating with pharmacists. The study highlighted the importance of involving healthcare professionals in the implementation of new work processes to ensure employee commitment and successful adoption.

Viral Infections, a Trigger and Risk Factor of Alzheimer’s Disease? (preprint)

Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD. We will also extend beyond these mere associations by carefully analyzing the potential mechanisms by which viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, dysregulation of immune responses, and the impact on protein processing. Controversies and challenges of the viral-AD relationship emerge as we tease out these potential mechanisms considered. Looking forward, we emphasize the future directions the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development.

Syndromic case definitions for Lower Respiratory Tract Infection (LRTI) are less sensitive in older age: an analysis of symptoms among hospitalised adults (preprint)

Background Lower Respiratory Tract Infections (LRTI) pose a serious threat to older adults but may be underdiagnosed due to atypical presentations. Here we assess LRTI symptom profiles and syndromic (symptom-based) case ascertainment in older (≥65y) as compared to younger adults (<65y). Methods We included adults (≥18y) with confirmed LRTI admitted to two acute care Trusts in Bristol, UK from 1st August 2020- 31st July 2022.  Logistic regression was used to assess whether age ≥65y reduced the probability of meeting syndromic LRTI case definitions, using patients’ symptoms at admission. We also calculated relative symptom frequencies (log-odds ratios) and evaluated how symptoms were clustered across different age groups. Results Of 17,620 clinically confirmed LRTI cases, 8,487 (48.1%) had symptoms meeting the case definition. Compared to those not meeting the definition these cases were younger, had less severe illness and were less likely to have received a SARS-CoV-2 vaccination or to have active SARS-CoV-2 infection. Prevalence of dementia/cognitive impairment and levels of comorbidity were lower in this group. After controlling for sex, dementia and comorbidities, age ≥65y significantly reduced the probability of meeting the case definition (aOR=0.67, 95% CI:0.63-0.71). Cases aged ≥65y were less likely to present with fever and LRTI-specific symptoms (e.g., pleurisy, sputum) than younger cases, and those aged ≥85y were characterised by lack of cough but frequent confusion and falls. Conclusions LRTI symptom profiles changed considerably with age in this hospitalised cohort. Standard screening protocols may fail to detect older and frailer cases of LRTI based on their symptoms.

Plasma proteomic evidence for increased Alzheimer's disease-related brain pathology after SARS-CoV-2 infection (preprint)

Viral infections have been linked to an increased risk for dementia. We investigated whether SARS-CoV-2 infection increases preclinical brain pathology associated with Alzheimer's disease (AD) by comparing changes in plasma biomarkers in UK Biobank participants with and without prior SARS-CoV-2 infection. We discovered an association between SARS-CoV-2 infection and reduced plasma A{beta}42:A{beta}40 concentration ratio. In older participants, SARS-CoV-2 infection was associated with both lower plasma A{beta}42 and higher plasma pTau-181. These biomarker changes, which have been associated with beta-amyloid accumulation and prodromal AD, were associated with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health and appeared to be greater in participants who had been hospitalised with COVID-19. Protein biomarker risk scores for other diseases were also raised among individuals who had past SARS-CoV-2 infections. Our data provide support for the hypothesis that viral infections can accelerate prodromal AD pathology and highlight biomarker profiles indicative of an increased risk of dementia and systemic diseases after SARS-CoV-2 infection, particularly in older people.

IMPACT OF METHYLPREDNISOLONE PULSE ON THE MORTALITY OF PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME SECONDARY TO COVID-19 (preprint)

Corticosteroids are the most important factor to reduce the mortality in patients with moderate-severe COVID-19. The aim of the study was to analyze the impact of methylprednisolone pulse (MPP) on in-hospital mortality of patients with acute respiratory distress syndrome (ARDS) due to COVID-19. We conducted a retrospective, single-center observational study We selected adult patients admitted to the hospital with the diagnosis of COVID-19 between March and June 2020. A total of 306 patients were analyzed. In-hospital crude mortality rate was 17%. Diabetes mellitus (HR 5.5, 95% CI 1.40–4.55), dementia (HR 7.7, 95% CI 4.25-13.87) and ARDS (HR 4.2, 95% CI 2.34-7.46) were associated with in -hospital mortality. In patients diagnosed of ARDS, the only in-hospital mortality risk factor was dementia (HR 5.2, 95% CI 2.44–11.07), whereas MPP was a protective factor (HR 0.2, 95% CI 0.09–0.63)

In-person and remote recruitment of people with dementia into a primary care-based cluster randomised controlled trial: lessons from the Dementia PersonAlised Care Team (D-PACT) feasibility study (preprint)

Background Recruiting individuals with dementia for clinical trials within primary care is complex, involving socio-cultural, psychological, geographical, and service-related factors. Phase 1 of the Dementia PersonAlised Care Team (D-PACT) study assessed the feasibility of evaluating a personalized dementia support intervention based in primary care in a cluster randomized controlled trial. COVID-19 necessitated a shift to remote working, providing the opportunity to compare in-person and remote capacity judgment and recruitment.Methods Using an inclusive multi-stage approach, in-person recruitment commenced September 2019 but was temporarily halted in March 2020 due to COVID-19. The study resumed recruitment remotely from September 2020 to March 2021. We analysed quantitative data comparing both periods, examining proportion of recruited GP practices and participants, participant recruitment rate per month and number of meetings/time required for consent and baseline. Qualitative interviews explored participants’ experiences of remote recruitment using thematic analysis.Results Pre-COVID-19, 61.5% (n = 8) of approached GP practices (n = 13) were recruited vs. 20% (n = 4) during COVID-19. In-person participant recruitment yielded 9.9% (22 recruited/228 approached), while remote recruitment achieved 17.2% (n = 34). 15 of the 34 had been approached prior to COVID-19, put on hold but re-approached/recruited remotely post-study pause. Even accounting for this, remote recruitment remained comparable at 9.6% (19/198). Monthly recruitment rate increased from 3.6 dyads in-person to 5.6 remotely. However mean time on recruitment was higher (9 hours per participant in-person vs.15 remotely), and time on specific activities differed: no travel time during COVID-19, offset by increased preparation/administration. Our multi-stage approach added to overall recruitment time but proved productive, achieving recruitment percentages of 40%, 39%, and 23% respectively from interested patients. Qualitative interviews (n = 13) indicated general acceptability of remote recruitment, with preferences tied to individual needs.Conclusions Our findings contribute to recruitment strategies for primary care trials by showing remotely judging capacity and recruiting people with dementia without specialist support using person-centred approaches is possible. While time-intensive, recruitment rates were not compromised. Researchers should consider flexible, hybrid approaches to increase participation. Understanding the time commitment essential for inclusive dementia recruitment will guide realistic target setting and study design. Funders should consider time and financial requirements in their decisions.Trial registration: ISRCTN80204146. Registration date 23/09/2019

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19 (preprint)

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble alpha-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that alpha-synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-alpha-Syn and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes, when present, in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimer's-linked tauopathy and declined with progression of age in COVID19+ patients.

Olfactory and Cognitive Decrements in 1991 Gulf War Veterans (preprint)

Background Prominent symptoms of Gulf War illness (GWI), the disorder related to military service in the 1991 Gulf War (GW), include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI symptom, anecdotally some veterans reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans.Methods Eighty deployed GW veterans (mean age: 59.9 ± 7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from age-matched healthy controls (HC) were downloaded from the Parkinson’s Progression Markers Initiative (PPMI) study for comparison.Results GW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9–37) and a mean MoCA score of 25.3 ± 2.8 (range 19–30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman’s ρ = 0.39, p < 0.001). There was no significant difference in UPSIT or MoCA scores between GW veterans with and without history of COVID and with and without Kansas GWI exclusionary conditions.Conclusions We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

RCT-based Social Return on Investment (SROI) of a home exercise programme for people with early dementia comparing in-person and blended delivery before and during the COVID-19 pandemic (preprint)

Background: Regular exercise and community engagement may slow the rate of function loss for people with dementia. However, the evidence is uncertain regarding the cost-effectiveness and social return on investment (SROI) of home exercise with community referral for people with dementia. This study aimed to compare the social value generated from the in-person PrAISED programme delivered before March 2020 with a blended PrAISED programme delivered after March 2020. Methods: SROI analysis was conducted alongside a randomised controlled trial (RCT). Of 205 patient participants and their carers who completed cost data, 61 completed an in-person programme before March 2020. Due to COVID-19 pandemic restrictions, 144 patient participants completed a blended programme consisting of a combination of in-person visits, phone calls and video conferencing with multidisciplinary team (MDT) members. SROI analysis compared in-person and blended delivery formats. Five relevant and material outcomes were identified: three outcomes for patient participants (fear of falling, health-related quality of life, and social connection); one outcome for carer participants (carer strain index), and one outcome for the NHS (health service resource use). Data were collected at baseline and a 12-month follow-up. Results: The in-person PrAISED programme generated SROI ratios ranging from 0.58 Great Britain Pound (GBP) to 2.33 GBP for every 1 GBP invested. In-person PrAISED patient participants gained social value from improved health-related quality of life, social connection, and less fear of falling. In-person PrAISED carer participants acquired social value from less carer strain. The NHS gained benefit from less health care service resource use. However, the blended PrAISED programme generated lower SROI ratios ranging from a negative ratio to 0.08 GBP : 1 GBP. Conclusion: Compared with the blended programme, the PrAISED in-person programme generated higher SROI ratios for people with early dementia. During the COVID-19 pandemic and its restrictions, a blended delivery of the programme and the curtailment of community activities resulted in lower SROI ratios during this period. An in-person PrAISED intervention with community referral is likely to provide better value for money than a blended one with limited community referral, despite the greater costs of the former.

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19 (preprint)

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF- and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-19, was associated with lower levels of CXCL10, CCL8, and CCL2 - molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

Understanding Health Service Utilisation Patterns for Care Home Residents During the COVID-19 Pandemic using Routinely Collected Healthcare Data (preprint)

BackgroundHealthcare in care homes during the COVID-19 pandemic required a balance, providing treatment while minimising exposure risk. Policy for how residents should receive care changed rapidly throughout the pandemic. A lack of accessible data on care home residents over this time meant policy decisions were difficult to make and verify. This study investigates common patterns of healthcare utilisation for care home residents in relation to COVID-19 testing events, and associations between utilisation patterns and resident characteristics. MethodsLinked datasets including secondary care, community care and a care home telehealth app are used to define daily healthcare utilisation sequences for care home residents. We derive four 10-day sets of sequences related to Pillar 1 COVID-19 testing; before [1] and after [2] a residents first positive test and before [3] and after [4] a residents first test. These sequences are clustered, grouping residents with similar healthcare patterns in each set. Association of individual characteristics (e.g. health conditions such as diabetes and dementia) with healthcare patterns are investigated. ResultsWe demonstrate how routinely collected health data can be used to produce longitudinal descriptions of patient care. Clustered sequences [1,2,3,4] are produced for 3,471 care home residents tested between 01/03/2020-01/09/2021. Clusters characterised by higher levels of utilisation were significantly associated with higher prevalence of diabetes. Dementia is associated with higher levels of care after a testing event, and appears to be correlated with a hospital discharge after a first test. Residents discharged from inpatient care within 10 days of their first test had the same mortality rate as those who stayed in hospital. ConclusionWe provide longitudinal, resident-level data on care home resident healthcare during the COVID-19 pandemic. We find that vulnerable residents were associated with higher levels of healthcare usage despite the additional risks. Implications of findings are limited by the challenges of routinely collected data. However, this study demonstrates the potential for further research into healthcare pathways using linked, routinely collected datasets.

Seven Epidemic Waves of COVID-19 in a Hospital in Madrid. Analysis of Severity and Associated Factors (preprint)

(1) Background: Since the onset of the SARS-CoV-2 pandemic, seven epidemic waves have been described in Spain. Our objective was to study mortality and severity, and associated factors in our hospitalized patients; (2) Method: Retrospective cohort study was conducted on COVID-19 patients admitted to the Hospital de Fuenlabrada (Madrid, Spain) from the beginning of the pandemic until December 31, 2022; (3) Results: A total of 5,510 admissions for COVID-19 were recorded. First wave accounted for 1,823 (33%) and exhibited the highest proportion of severe patients (lowest mean oxygen saturation, 88.2%; elevated levels of CRP, IL-6, D-dimer and ferri-tin), but a below-average percentage of intubated patients (5% vs. 6.5%). Overall mortality rate was 10.3%, higher during the first wave (11.5%) and the two winter waves (third: 11.3%, sixth: 12%), although the first wave represented 39% of the total. Variables associated with mortality were age (OR 1.08,1.07-1.09), need for high-flow oxygen (OR 6.10,4.94-7.52), oncological disease (OR 1.88,1.53-2.60), dementia (OR 1.82,1.2-2.75), Charlson index (OR 1.38,1.31-1.47), and maxi-mum IL-6 levels (OR 1.001,1.000-1.001); (4) Conclusions: Variables associated with mortality in-cluded age, comorbidity, respiratory failure, and inflammation. Differences on baseline charac-teristics of patients admitted explained differences on mortality in each wave

COVID-19 government measures and their impact on mental health: a cross-sectional study of older primary care patients in Germany.

Background: With the outbreak of COVID-19, government measures including social distancing and restrictions of social contacts were imposed to slow the spread of the virus. Since older adults are at increased risk of severe disease, they were particularly affected by these restrictions. These may negatively affect mental health by loneliness and social isolation, which constitute risk factors for depressiveness. We aimed to analyse the impact of perceived restriction due to government measures on depressive symptoms and investigated stress as mediator in an at-risk-population in Germany. Methods: Data were collected in April 2020 from the population of the AgeWell.de-study, including individuals with a Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score ≥9, using the depression subscale of the Brief Symptom Inventory (BSI-18) and the Perceived Stress Scale (PSS-4). Feeling restricted due to COVID-19 government measures was surveyed with a standardized questionnaire. Stepwise multivariate regressions using zero-inflated negative binomial models were applied to analyse depressive symptoms, followed by a general structural equation model to assess stress as mediator. Analysis were controlled for sociodemographic factors as well as social support. Results: We analysed data from 810 older adults (mean age = 69.9, SD = 5). Feeling restricted due to COVID-19 government measures was linked to increased depressiveness (b = 0.19; p < 0.001). The association was no longer significant when adding stress and covariates (b = 0.04; p = 0.43), while stress was linked to increased depressive symptoms (b = 0.22; p < 0.001). A final model confirms the assumption that the feeling of restriction is mediated by stress (total effect: b = 0.26; p < 0.001). Conclusion: We found evidence that feeling restricted due to COVID-19 government measures is associated with higher levels of depressive symptoms in older adults at increased risk for dementia. The association is mediated by perceived stress. Furthermore, social support was significantly associated with less depressive symptoms. Thus, it is of high relevance to consider possible adverse effects of government measures related to COVID-19 on mental health of older people.

Navigating the Complexities of Dementia Care: The Lived Experiences of Black American Family Caregivers.

Black American individuals have a higher rate of Alzheimer's disease and related dementias (ADRD) diagnoses compared to other racial/ethnic groups, and their family caregiver population is expected to increase rapidly over the next 2 decades. The current study aimed to explore Black American women's experiences caring for family members with ADRD. An interpretative phenomenology approach was used to gain a deeper understanding of the caregiving experiences of Black American women. Participants in the study were all Black American married women aged 63 to 81 years (mean = 71.3 years, SD = 6.6 years). Key themes that emerged from the study included: (a) Family Care Obligation, (b) Caregiving Journey, (c) Prioritizing Health Concerns, (d) Coping Behaviors, and (e) Support Needs and Challenges. Family caregivers require ongoing support, education, and guidance. Implications for nursing practice include focusing on family assessments, increased education and awareness, and collaboration with interdisciplinary teams to provide the best resources. [Journal of Gerontological Nursing, 49(6), 19-26.].

Exploring challenges and best practice in Memory Assessment Services in England and Wales – a national survey and case study approach (preprint)

Background: To explore the design, delivery models and identify good and innovative practices in Memory Assessment Services (MAS) in England and Wales. Methods: A two-stage service evaluation comprising 1) on-line survey of MAS providers to identify features of the commissioning models, service design, delivery, and challenges alongside examples of good/innovative practice; 2) qualitative case studies using video/telephone interviews with key staff and people who had used the service. Results: The 49 respondents to the survey reported a shift in delivery of MAS services post COVID and identified key areas for improvement, including need for specialist staff, support for MCI and rarer dementias, and capacity for post diagnostic support. The 15 case studies illustrated good practice and innovation focusing on post diagnostic support, equity of access, working with external services/service location, MCI and rarer dementia and involving specialist staff. Conclusions: The evaluation speaks to the importance of (re)evaluation of services to identify local need and the importance of commissioning based on local need and innovative approaches that my sit outside of ‘typical’ MAS pathways.

Statistical analysis plan for HOMESIDE: a randomised controlled trial for home-based family caregiver-delivered music and reading interventions for people living with dementia.

BACKGROUND: Most people with dementia live in the community, not in residential care. Therefore, quality informal care for them is critical for managing behavioural and psychological symptoms of dementia (BPSD). Music therapy has been shown to reduce BPSD. However, no randomised controlled trial has examined the effects of music interventions delivered by caregivers in home settings. The HOME-based caregiver-delivered music intervention for people living with dementia (HOMESIDE) trial aims to evaluate the effectiveness of a 12-week music intervention in addition to standard care for BPSD. This article describes the statistical analysis plan. METHODS AND ANALYSIS: HOMESIDE is a large, pragmatic international three-arm parallel-group randomised controlled trial. Dyads (persons with dementia and caregiver) in Australia, Germany, the UK, Poland and Norway were randomised to receive music and standard care, reading and standard care or standard care alone. The primary outcome is BPSD (proxy) of the person living with dementia, measured using the Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 90 and 180 days post-randomisation. Longitudinal analysis will compare NPI-Q severity between music and standard care versus standard care alone. Secondary outcomes include quality of life and depression (both person with dementia and caregiver), cognition (person with dementia only), distress, resilience, competence and caregiver-patient relationship (caregiver only). Treatment effects will be obtained at 90 and 180 days post-randomisation, where applicable. Safety outcomes (adverse events, hospitalisations, deaths) will be summarised. DISCUSSION: This statistical analysis plan provides a detailed methodology for the analysis of HOMESIDE and will improve the validity of the study and reduce the potential for bias. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618001799246. Registered on November 05, 2018. CLINICALTRIALS: gov NCT03907748. Registered on April 09, 2019.