Multimorbidity and risk of falls, fractures, and joint replacements over two decades: Findings from the Hertfordshire Cohort Study.

AIM: To examine the relationship between level of morbidity burden and long-term risk of fractures, falls, and joint replacements in the community-dwelling participants of the Hertfordshire Cohort Study. METHODS: Data were analyzed from 2997 individuals (age 59-73 at baseline). Outcomes (fractures, falls, and lower limb joint replacements) were identified using ICD-10 and OPCS-4 codes from Hospital Episode Statistics data, available from baseline (1998-2004) until December 2018. Number of systems medicated (marker of morbidity level) in relation to risk of outcomes was examined using sex-stratified Cox regression. RESULTS: Among both men and women, a greater number of systems medicated was related to increased risk of falls (P < 0.001) and lower limb joint replacements (P < 0.003). More systems medicated was only related to increased risk of fracture among women (P-values for trend of <0.001 among women and 0.186 among men). CONCLUSIONS: Higher morbidity was associated with increased risk of adverse health outcomes related to poor musculoskeletal health, but these relationships varied according to the musculoskeletal outcome studied. Intervention strategies to reduce multimorbidity among middle-aged and older people may hence reduce the burden of musculoskeletal aging. Geriatr Gerontol Int 2024; ••: ••-••.

The impact of HIV infection on skeletal maturity in peripubertal children in Zimbabwe: a cross-sectional study.

INTRODUCTION: HIV infection and its treatment compromises skeletal development (growth and maturation). Skeletal maturity is assessed as bone age (BA) on hand and wrist radiographs. BA younger than chronological age (CA) indicates delayed development. We conducted a cross-sectional study to determine differences between BA and CA (i.e., skeletal maturity deviation [SMD]), and risk factors associated with SMD in peripubertal children with and without HIV established on antiretroviral therapy (ART) including use of tenofovir disoproxil fumarate (TDF). METHODS: Children with HIV taking ART for at least two years and a comparison group of HIV-negative children, aged 8-16 years and frequency-matched by age and sex, were recruited from HIV clinics and local schools in the same catchment area, in Harare, Zimbabwe. BA was assessed from non-dominant hand-wrist radiographs using the Tanner Whitehouse 3 method. Negative SMD values correspond to delayed development, i.e., BA younger than CA. Multivariable linear regression models determined factors associated with SMD overall, and in children with HIV. RESULTS: In total, 534 participants (54% males) were included; by design CA was similar in males and females, whether living with or without HIV. Mean (SD) SMD was more negative in CWH than in HIV-negative children in both males [-1.4(1.4) vs. -0.4(1.1) years] and females [-1.1(1.3) vs. -0.0(1.2) years]. HIV infection and weight-for-age Z-score<-2 were associated with more negative SMD in both males and females after adjusting for socio-economic status, orphanhood, pubertal stage, and calcium intake. Age at ART initiation was associated with SMD in both males and females with those starting ART later more delayed: starting ART aged 4-8 years 1.14 (-1.84, -0.43), or over 8 years 1.47 (-2.30, -0.65) (p-value for trend < 0.001). Similar non-significant trends were seen in males. TDF exposure TDF exposure whether < 4years or ≥ 4 years was not associated with delayed development. CONCLUSION: Perinatally-acquired HIV infection and being underweight were independently associated with delayed skeletal maturation in both males and females. Starting ART later was independently associated with skeletal maturation delay in CWH. Given the known effects of delayed development on later health, it is important to find interventions to ensure healthy weight gain through early years and in CWH to initiate ART as early as possible.

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

Mortality, bone density and grip strength: lessons from the past and hope for the future?

Objectives: Therapeutic advances in the management of osteoporosis and sarcopenia have occurred at different rates over the last 2 decades. Here we examine associations between grip strength and BMD with subsequent all-cause and cause-specific mortality in a UK community-dwelling cohort. Methods: Data from 495 men and 414 women from the Hertfordshire Cohort Study were analysed. Grip strength was assessed by grip dynamometry, femoral neck BMD was ascertained using DXA and deaths were recorded from baseline (1998-2004) until 31 December 2018. Grip strength and BMD in relation to mortality outcomes (all-cause, cardiovascular-related, cancer-related and mortality due to other causes) were examined using Cox regression with adjustment for age and sex. Results: The mean baseline age of participants was 64.3 years (s.d. 2.5) and 65.9 years (s.d. 2.6) in men and women, respectively. Lower grip strength was associated with increased risk of all-cause mortality [hazard ratio (HR) 1.30 (95% CI 1.06, 1.58), P = 0.010] and cardiovascular-related mortality [HR 1.75 (95% CI 1.20, 2.55), P = 0.004]. In contrast, BMD was not associated with any of the mortality outcomes (P > 0.1 for all associations). Conclusion: We report strong relationships between grip strength and mortality compared with BMD. We hypothesize that this may reflect better recognition and treatment of low BMD in this cohort.

Could self-reported physical performance help predict individuals at the highest risk of mortality and hospital admission events in clinical practice? Findings from the Hertfordshire Cohort Study.

AIM: To consider how self-reported physical function measures relate to adverse clinical outcomes measured over 20 years of follow-up in a community-dwelling cohort (aged 59-73 at baseline) as compared with hand grip strength, a well-validated predictor of adverse events. BACKGROUND: Recent evidence has emphasized the significant association of physical activity, physical performance, and muscle strength with hospital admissions in older people. However, physical performance tests require staff availability, training, specialized equipment, and space to perform them, often not feasible or realistic in the context of a busy clinical setting. METHODS: In total, 2997 men and women were analyzed. Baseline predictors were measured grip strength (Jamar dynamometer) and the following self-reported measures: physical activity (Dallosso questionnaire); physical function score (SF-36 Health Survey); and walking speed. Participants were followed up from baseline (1998-2004) until December 2018 using UK Hospital Episode Statistics and mortality data, which report clinical outcomes using ICD-10 coding. Predictors in relation to the risk of mortality and hospital admission events were examined using Cox regression with and without adjustment for sociodemographic and lifestyle characteristics. FINDINGS: The mean age at baseline was 65.7 and 66.6 years among men and women, respectively. Over follow-up, 36% of men and 26% of women died, while 93% of men and 92% of women were admitted to hospital at least once. Physical activity, grip strength, SF-36 physical function, and walking speed were all strongly associated with adverse health outcomes in both sex- and fully adjusted analyses; poorer values for each of the predictors were related to greater risk of mortality (all-cause, cardiovascular-related) and any, neurological, cardiovascular, respiratory, any fracture, and falls admissions. SF-36 physical function and grip strength were similarly associated with the adverse health outcomes considered.

Sacral neuromodulation in nursing home residents: Predictors of success and complications in a national cohort of older adults.

AIMS: There is limited evidence to support the efficacy of sacral neuromodulation (SNM) for older adults with overactive bladder (OAB). This study aims to report outcomes following SNM among nursing home (NH) residents, a vulnerable population with high rates of frailty and comorbidity. METHODS: This is a retrospective cohort study of long-stay NH residents who underwent a trial of percutaneous nerve evaluation (PNE) or Stage 1 permanent lead placement (Stage 1) between 2014 and 2016. Residents were identified using the Minimum Data Set linked to Medicare claims. The primary outcome of this study was successful progression from trial to implant. Rates of 1-year device explant/revisions were also investigated. RESULTS: Trial of SNM was observed in 1089 residents (mean age: 77.9 years). PNE was performed in 66.9% of residents and 33.2% underwent Stage 1. Of Stage 1 procedures, 23.8% were performed with simultaneous device implant (single-stage). Overall, 53.1% of PNEs and 72.4% of Stage 1 progressed to device implant, which was associated with Stage 1 procedure versus PNE (adjusted relative risk [aRR]: 1.34; 95% confidence interval [95% CI]: 1.21-1.49) and female versus male sex (aRR: 1.26; 95% CI: 1.09-1.46). One-year explant/revision was observed in 9.3% of residents (6.3% for PNE, 10.5% for Stage 1, 20.3% single-stage). Single stage procedure versus PNE was significantly associated with device explant/revision (aRR: 3.4; 95% CI: 1.9-6.2). CONCLUSIONS: In this large cohort of NH residents, outcomes following SNM were similar to previous reports of younger healthier cohorts. Surgeons managing older patients with OAB should use caution when selecting patients for single stage SNM procedures.

Lifecourse correlates of self-rated health and associations with subsequent mortality: findings from the Hertfordshire Cohort Study.

Background: Poor self-rated health (SRH) has been shown to predict adverse health outcomes among older people, however these associations have traditionally only been considered at one point in the lifecourse, usually midlife or later. Here we examined lifecourse correlates of SRH in early, mid and later life, relating these to subsequent risk of mortality in a community-dwelling cohort. Methods: 2989 men and women from the Hertfordshire Cohort Study (HCS) were included in this study. The HCS was initially retrospective and linked contemporary health outcome data to early life data available from health ledgers but investigations from baseline (1998-2004, aged 59-73) onwards have been prospective. At baseline, participants completed an initial clinic visit, which included questionnaire assessment of SRH, reported as 'excellent', 'very good', 'good', 'fair', or 'poor'. Socioeconomic, lifestyle, mental health and demographic information was also collected. Deaths were recorded from baseline to 31/12/2018. Baseline characteristics in relation to SRH were examined using sex-stratified ordinal logistic regression; these factors were examined in relation to mortality using sex-stratified Cox regression. Statistically significant exposures were then included in sex-stratified mutually-adjusted models. Results: In mutually-adjusted analysis, numerous contemporaneous correlates of poorer SRH in the seventh decade were identified and included obesity, lower physical activity, greater comorbidity and higher levels of depression among men and women. For example, odds ratios for being in a lower category of SRH were as follows: obese (BMI≥30) vs underweight/healthy (BMI<25) (men 1.60 (1.21, 2.11), women 1.65 (1.25, 2.17)) and per additional system medicated (men 1.62 (1.47, 1.77), women 1.53 (1.41, 1.66)). By contrast, factors earlier in the lifecourse (early growth, age left full-time education) were not associated with SRH in late adulthood. 36% of men and 26% of women died during follow-up. Hazard ratios (95% CI) for mortality per lower category of SRH were 1.22 (1.10,1.36) among men and 1.17 (1.01,1.35) among women after adjustment for age, BMI, smoking, physical activity, diet quality, education, home ownership status, comorbidity level and depression levels, suggesting residual confounding by other unrecorded factors that are related to SRH. Conclusions: Poorer SRH in the seventh decade was a risk factor for mortality. Importantly modifiable adverse health behaviours in the seventh decade, such as low physical activity, were associated with poorer SRH and later mortality after adjustment for socioeconomic factors and comorbidity level. By contrast early growth and education were not related to later SRH. These data suggest that attention to lifestyle in late midlife may be associated with better SRH and subsequent health outcomes, highlighting the value of intervention at this stage of the lifecourse.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Fracture Risk and Health Profiles Differ According to Relationship Status: Findings from the Hertfordshire Cohort Study.

Registry studies have suggested associations between relationship status and fracture risk. We considered associations between relationship status and incident fracture in the Hertfordshire Cohort Study, comprising community-dwelling older adults, and explored associations between socioeconomic and lifestyle factors with relationship status. 2997 participants completed a baseline questionnaire (1998-2004) and clinic visit. Participants were followed up until December 2018 using Hospital Episode Statistics, which report clinical outcomes using codes from the 10th revision of the International Classification of Diseases (ICD-10); these codes were used to ascertain incident fractures. Relationship status (not currently married/cohabiting vs currently married/cohabiting) at baseline was examined in relation to incident fracture using Cox regression. Associations between baseline characteristics and relationship status were examined using logistic regression. Mean baseline age was 66.2 years. 80% were married/cohabiting at baseline; 15% had an incident fracture (mean (SD) follow-up duration: 14.4 (4.5) years). The following were related to greater likelihood of not being married/cohabiting: older age (women only); higher BMI (women only); current smoking; high alcohol consumption (men only); poorer diet quality (men only); lower physical activity; leaving school before age 15 (women only); and not owning one's home. Those not married/cohabiting had greater risk of incident fracture compared to those who were (age-adjusted hazard ratios (95% CI) 1.58 (1.06, 2.38) among men, 1.35 (1.06, 1.72) among women); associations were attenuated after accounting for the above factors associated with relationship status in the corresponding sex. This suggests that differences in health profiles and lifestyle according to relationship status may explain the association between relationship status and fracture risk.

General self-efficacy, not musculoskeletal health, was associated with social isolation and loneliness in older adults during the COVID-19 pandemic: findings from the Hertfordshire Cohort Study.

BACKGROUND: Social isolation and loneliness are prevalent among older adults. This study investigated factors influencing worsening social isolation and loneliness in community-dwelling older adults during the COVID-19 pandemic, focusing on musculoskeletal conditions, falls, and fractures. METHODS: We studied 153 participants from the Hertfordshire Cohort Study. Baseline assessments (2019-20) included osteoporosis, clinical osteoarthritis, fractures after age 45 years, falls in previous year, and lifestyle factors. Self-efficacy was assessed using a shortened General Self-Efficacy Scale. Social isolation was assessed using the 6-item Lubben Social Network Scale. Follow-up (2020-21) assessments included social isolation and loneliness using the 6-item De Jong-Gierveld scale for emotional, social, and overall loneliness. RESULTS: Baseline median age was 83.1 years. A history of smoking predicted worsening social isolation (p = 0.046). Being married (p = 0.026) and higher self-efficacy scores (p = 0.03) predicted reduced social isolation at follow-up. Greater alcohol consumption was associated with higher overall loneliness (p = 0.026). Being married was related to a 36% (95% CI: 3%, 58%) reduction in emotional loneliness (p = 0.037). No musculoskeletal condition was associated with social isolation or loneliness. However, we observed a 22% (14%, 30%; p < 0.001) reduction in emotional loneliness and a 12% (4%, 20%; p = 0.003) reduction in overall loneliness per unit increase in self-efficacy score. CONCLUSIONS: No musculoskeletal condition was associated with increased social isolation or loneliness, but longitudinal studies in larger samples are required. Greater self-efficacy was associated with reduced social isolation and reduced loneliness. Interventions promoting self-efficacy in older adults may reduce isolation and loneliness in this age group.

Musculoskeletal health and life-space mobility in older adults: Findings from the Hertfordshire Cohort Study.

This study explores the relationship between musculoskeletal conditions of ageing and life-space mobility (LSM) in 1110 community-dwelling older adults from the Hertfordshire Cohort Study. LSM is a novel measure which captures ability to mobilise within the home, locally and more widely. Among men, older age, care receipt, not driving a car, lower wellbeing, and reduced physical function were associated with lower LSM, while in women only driving status and physical function were associated with LSM. Osteoporosis, arthritis, and fractures had no significant associations with LSM in either gender. These findings provide support for sex-specificity in the determinants of LSM and inform novel approaches to improving mobility and health in older age.

Do lifestyle, anthropometric and demographic factors associated with muscle strength differ in a UK and Japanese cohort? An exploratory analysis.

BACKGROUND: Muscle weakness is associated with adverse clinical outcomes including disability and mortality. We report demographic, anthropometric and lifestyle correlates of grip strength in UK and Japanese population-based cohorts. AIM: To report prevalence of low grip strength according to 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and 2019 Asian Working Group for Sarcopenia (AWGS 2019) thresholds and to consider correlates of grip strength in Eastern and Western populations. METHODS: UK (1572 men; 1415 women) and Japanese (519 men; 1027 women) participants were recruited from two cohorts harmonised by consensus. Muscle strength was measured by grip strength dynamometry. Potential correlates of grip strength were examined using sex-stratified linear regression; univariate correlates (p < 0.05) were included in mutually adjusted models. RESULTS: Mean (SD) age was 66.2 (2.8) and 65.8 (12.3) in UK and Japanese cohorts, respectively. Prevalence of low grip strength was higher in Japanese participants (EWGSOP2 5.4% versus 2.4%, AWGS 2019 9.0% versus 3.7%). In both cohorts and sexes, univariate correlates of lower grip strength were older age, shorter height, not consuming alcohol, leaving education earlier and greater comorbidity. Apart from older age and shorter height, the only factors related to lower grip strength in mutually adjusted analyses were greater comorbidity among UK participants (kg difference in grip strength (95%CI) per additional comorbidity - 0.60(- 0.98, - 0.21) among men and - 0.50(- 0.86, - 0.13) among women) and not consuming alcohol among Japanese men (- 1.33(- 2.51, - 0.15)). DISCUSSION: Correlates of muscle strength were similar in both cohorts. CONCLUSIONS: A global approach to age-related muscle weakness prevention may be appropriate.

DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.

BACKGROUND: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. METHODS: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. RESULTS: Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. CONCLUSIONS: These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR.

Standard versus short stem cemented Exeter® when used for primary total hip arthroplasty: a survivorship analysis.

AIMS: The aims were to compare the survival of the cemented standard (150 mm) with the short (DDH [35.5 mm offset or less], number 1 short stem [125 mm options of 37.5 mm, 44 mm, 50 mm offset] and revision [44/00/125]) Exeter® V40 femoral stems when used for primary total hip arthroplasty (THA). METHODS: Patients were retrospectively identified from an arthroplasty database. A total of 664 short stem Exeter® variants were identified, of which 229 were DDH stems, 208 number 1 stems and 227 revision stems were implanted between 2011 and 2020. A control group of 698 standard Exeter® stems used for THA was set up, and were followed up for a minimum of 10 years follow-up (implanted 2011). All-cause survival was assessed for THA and for the stem only. Adjusted analysis was undertaken for age, sex and ASA grade. RESULTS: The median survival time for the short stems varied according to design: DDH had a survival time of 6.7 years, number 1 stems 4.1 years, and revision stems 7.2 years. Subjects in the short stem group (n = 664) were significantly younger (mean difference 5.1, P < 0.001) and were more likely to be female (odds ratio 1.89, 95% CI 1.50 to 2.39, P < 0.001), compared to the standard group. There were no differences in THA (P = 0.26) or stem (P = 0.35) survival at 5 years (adjusted THA: 98.3% vs. 97.2%; stem 98.7% vs. 97.8%) or 10 years (adjusted THA 97.0% vs. 96.0 %; stem 96.7% vs. 96.2%) between standard and short stem groups, respectively. At 5 years no differences were found in THA (DDH: 96.7%, number 1 97.5%, revision 97.3%, standard 98.6%) or stem (DDH: 97.6%, number 1 99.0%, revision 97.3%, standard 98.2%) survival between/among the different short stems or when compared to the standard group. CONCLUSION: The Exeter® short stems offer equivocal survival when compared to the standard stem at 5- to 10-year follow-up, which does not seem to be influenced by the short stem design.

Mental Health among Geriatric Healthcare Workers in Italy during the COVID-19 Pandemic: Results from a National Survey.

OBJECTIVES: This study aimed to investigate the psychological impact of the COVID-19 pandemic on healthcare workers (HCWs) in geriatric settings. DESIGN: Online cross-sectional survey. SETTINGS AND PARTICIPANTS: 394 geriatric HCWs in Italy. MEASUREMENTS: The survey was developed by a multidisciplinary team and disseminated in April 2022 to the members of two geriatric scientific societies (Italian Society of Geriatrics and Gerontology and Italian Association of Psychogeriatrics). The survey examined the experiences related to the COVID-19 pandemic, as well as psychological burden and support. Work-related anxiety and distress related to the pandemic were studied using the SAVE-9 scale (Stress and Anxiety to Viral Epidemics). RESULTS: Three hundred sixty-four participants (92.4%) changed their job activity during the pandemic and about half (50.9%) failed to cope with this change, 58 (14.7%) had increased work-related anxiety, and 39 (9.9%) work-related stress levels. Three hundred forty (86.3%) participants reported acute stress reaction symptoms, including irritability, depressed mood, headache, anxiety, and insomnia, and 262 (66.5%) required psychological support, mainly from friends/relatives (57.9%) and/or colleagues (32.5%). Furthermore, 342 participants (86.8%) recognized they would benefit from informal and formal psychological support in case of future similar emergencies. CONCLUSIONS: This study highlights the high psychological burden experienced by geriatric HCWs in Italy during the COVID-19 pandemic and emphasizes the need for supportive interventions.

Hospital admissions and mortality over 20 years in community-dwelling older people: findings from the Hertfordshire Cohort Study.

BACKGROUND: Demographic changes worldwide are leading to pressures on health services, with hospital admissions representing an important contributor. Here, we report admission types experienced by older people and examine baseline risk factors for subsequent admission/death, from the community-based Hertfordshire Cohort Study. METHODS: 2997 participants (1418 women) completed a baseline questionnaire and clinic visit to characterize their health. Participants were followed up from baseline (1998-2004, aged 59-73 years) until December 2018 using UK Hospital Episode Statistics and mortality data, which report clinical outcomes using ICD-10 coding. Baseline characteristics in relation to the risk of admission/death during follow-up were examined using sex-stratified univariate logistic regression. RESULTS: During follow-up, 36% of men and 26% of women died and 93% of men and 92% of women had at least one hospital admission; 6% of men and 7% of women had no admissions and were alive at end of follow-up. The most common types of admission during follow-up were cardiovascular (ever experienced: men 71%, women 68%) and respiratory (men 40%, women 34%). In both sexes, baseline risk factors that were associated (p < 0.05) with admission/death during follow-up were older age, poorer SF-36 physical function, and poorer self-rated health. In men, manual social class and a history of smoking, and in women, higher BMI, not owning one's home, and a minor trauma fracture since age 45, were also risk factors for admission/death. CONCLUSIONS: Sociodemographic factors were related to increased risk of admission/death but a small proportion experienced no admissions during this period, suggesting that healthy ageing is achievable.

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.