Coping and anxiety symptoms in family carers of dependent older people: Mediation and moderation effects of subjective caregiver burden.

INTRODUCTION: Coping responses influence anxiety symptoms experienced by informal carers. However, only a few studies have investigated the longitudinal association between coping responses and anxiety symptoms in family carers. We also currently have limited knowledge on the mediating or moderating influence of subjective caregiver burden on this relationship over time. The aim of the present study was to investigate the longitudinal relationship between coping and anxiety symptoms in family carers of dependent older people, and examine the mediating or moderating role of subjective caregiver burden over time. DESIGN: Prospective longitudinal study. METHODS: We recruited and enrolled participants from a probability sample of 132 family carers of older dependent relatives. We measured coping strategies, anxiety symptoms, subjective caregiver burden, and several covariates (sex and intensity of care) at baseline and at 1-year follow-up. We used generalized estimating equations with multiple imputations to examine associations over time. RESULTS: Considering both direct and indirect effects through subjective burden, anxiety symptoms were positively associated with proactive coping (B = 0.13), planning (B = 0.15), self-distraction (B = 0.24), denial (B = 1.15), venting (B = 0.94) and self-blame (B = 0.90), and negatively associated with positive reframing (B = -0.83) and acceptance (B = -0.75). Subjective caregiver burden moderated the relationship between anxiety symptoms and planning, and the use of denial as a form of coping. CONCLUSIONS: Our results show that subjective caregiver burden is an important moderator and mediator of the longitudinal association between coping responses and anxiety symptoms in carers. CLINICAL RELEVANCE: Proactive coping and planning when subjective burden is low, self-distraction, denial, venting, and self-blame significantly increase levels of anxiety and caregiver burden in carers over time. Acceptance and positive reframing however as coping responses are associated with lower levels of anxiety and caregiver burden long-term. Our findings highlight the need for a multi-dimensional approach in future caregiving interventions.

Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity.

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.

Relationship between sense of coherence and health-related behaviours in adolescents and young adults: a systematic review.

BACKGROUND: The sense of coherence is developed through the learning process and contributes to the positioning of individuals in the health-disease continuum, facilitating successful and adaptive personal outcomes. Health-related behaviours represent a health determinant of utmost importance for public health and the development of adolescent and youth health promotion policies, as they are related to the main risk factors and problems of morbidity and mortality in our society. Previous studies have analysed the relationship between sense of coherence and only some individual health outcomes such as oral health, the relationship of sense of coherence with smoking and alcohol consumption, concluding that salutogenic factors are related to quality of life and preventive behaviours. The aim of this systematic review was to describe the relationship of sense of coherence with different health-related behaviours investigated so far in the adolescent and youth population. METHODS: A systematic review was carried out in databases (PubMed, CINAHL, Scopus and PsycInfo) and in the bibliographies of the retrieved articles, without limitation of time or language. Associations between sense of coherence and health-related behaviours have been assessed. RESULTS: A total of 1214 investigations were reviewed and 21 of them were included in this systematic review. The relationship between sense of coherence and eight health-related behaviours were identified (alcohol use, physical activity, tobacco use, eating habits, rest periods, use of illegal substances, behaviours related to oral health and time spent in games on the computer). CONCLUSIONS: Our results increase the available evidence and support the solid relationship of the sense of coherence with health behaviours both as a protective factor against risk behaviours and for its positive association with preventive and health promoting behaviours of adolescents, young adults and university students.

The mediating role of sense of coherence on mental health outcomes in carers of older dependent relatives: A longitudinal study.

BACKGROUND: Sense of coherence (SOC) is an important protective factor for carer well-being but research to date remains cross-sectional, focusing primarily on the direct effects of SOC on carers' mental health. The study's aim was to investigate the mediating role of SOC in the longitudinal relationship between caregiver strain and carers' psychological health, and its stability over time. METHODS: Prospective longitudinal study conducted in Jaén (Spain) with a probabilistic sample of 132 carers of older people, with data collected at baseline and at 1-year follow-up. We measured SOC, caregiver strain, anxiety and depressive symptoms, and several care-recipient characteristics and intensity of care provided. We used multiple linear regression modelling and the Sobel test to analyse mediation effects. RESULTS: SOC was significantly negatively longitudinally associated with both anxiety (ß = -0.38, p = 0.001) and depressive symptoms (ß = -0.28, p = 0.023), after controlling for several confounders. SOC mediated both the relationship between caregiver strain and anxiety, and caregiver strain and depressive symptoms (Sobel test: p < 0.001 for anxiety and p < 0.001 for depressive symptoms). Differences between baseline and 1-year follow-up SOC scores were not statistically significant (p = 0.617). CONCLUSIONS: SOC appears to buffer the impact of caregiver strain on symptoms of depression and anxiety in informal carers of older people. Our data showed that SOC is an important psychological resource for carers that remained relatively stable under non-experimental conditions over a period of 1 year in this sample. The findings suggest that interventions aimed at strengthening SOC may protect carer psychological well-being.

Structural Mechanism of Regioselectivity in an Unusual Bacterial Acyl-CoA Dehydrogenase.

Terminal alkenes are easily derivatized, making them desirable functional group targets for polyketide synthase (PKS) engineering. However, they are rarely encountered in natural PKS systems. One mechanism for terminal alkene formation in PKSs is through the activity of an acyl-CoA dehydrogenase (ACAD). Herein, we use biochemical and structural analysis to understand the mechanism of terminal alkene formation catalyzed by an γ,δ-ACAD from the biosynthesis of the polyketide natural product FK506, TcsD. While TcsD is homologous to canonical α,ß-ACADs, it acts regioselectively at the γ,δ-position and only on α,ß-unsaturated substrates. Furthermore, this regioselectivity is controlled by a combination of bulky residues in the active site and a lateral shift in the positioning of the FAD cofactor within the enzyme. Substrate modeling suggests that TcsD utilizes a novel set of hydrogen bond donors for substrate activation and positioning, preventing dehydrogenation at the α,ß position of substrates. From the structural and biochemical characterization of TcsD, key residues that contribute to regioselectivity and are unique to the protein family were determined and used to identify other putative γ,δ-ACADs that belong to diverse natural product biosynthetic gene clusters. These predictions are supported by the demonstration that a phylogenetically distant homologue of TcsD also regioselectively oxidizes α,ß-unsaturated substrates. This work exemplifies a powerful approach to understand unique enzymatic reactions and will facilitate future enzyme discovery, inform enzyme engineering, and aid natural product characterization efforts.

[Motives and perceptions of family care for dependent elderly]. / Motivos y percepciones del cuidado familiar de mayores dependientes.

OBJECTIVE: To identify and analyze the motives that lead people to take care of a dependent relative and their perceptions of the care situation. DESIGN: Phenomenological qualitative study. LOCATION: The study was conducted in the Jaén-Norte Sanitary District, during 2013 and 2014. PARTICIPANTS: A total of 13 primary caregivers of dependent elderly relatives with a minimum experience of one year in care participated, selected by intentional sampling. METHOD: Discourse analysis of 13 in-depth interviews considering the semantic and pragmatic content and field notes. Triangulation was performed in the analysis to favor the credibility of the study. RESULTS: The motives for caring for a dependent relative are:'Familism','Material gains' and'Social pressure'. In turn, the'Familism' include 7 dimensions/motives:'Family obligation','Affection to the person taken care of','Return the received','Well-being of the person taken care of','Respect to the decision of the person taken care of','Agreement','Habit'. When the main motive to take care of is the'Family obligation', the'Material gains' or the'Social pressure' caregivers do not manifest positive perceptions for caring, and vice versa. CONCLUSION: This study has identified that'Familism','Material gains' and'Social pressure' are reasons why people care for a dependent relative in our sociocultural environment, as well as the relationship with the perception of the care situation. This will facilitate the identification of caregivers with greater predisposition to suffer negative consequences for caring and the development of interventions aimed at the prevention of such consequences.

The implementation of health promotion in primary and community care: a qualitative analysis of the 'Prescribe Vida Saludable' strategy.

BACKGROUND: The impact of lifestyle on health is undeniable and effective healthy lifestyle promotion interventions do exist. However, this is not a fundamental part of routine primary care clinical practice. We describe factors that determine changes in performance of primary health care centers involved in piloting the health promotion innovation 'Prescribe Vida Saludable' (PVS) phase II. METHODS: We engaged four primary health care centers of the Basque Healthcare Service in an action research project aimed at changing preventive health practices. Prescribe Healthy Life (PVS from the Spanish "Prescribe Vida Saludable) is focused on designing, planning, implementing and evaluating innovative programs to promote multiple healthy habits, feasible to be performed in routine primary health care conditions. After 2 years of piloting, centers were categorized as having high, medium, or low implementation effectiveness. We completed qualitative inductive and deductive analysis of five focus groups with the staff of the centers. Themes generated through consensual grounded qualitative analysis were compared between centers to identify the dimensions that explain the variation in actual implementation of PVS, and retrospectively organized and assessed against the Consolidated Framework for Implementation Research (CFIR). RESULTS: Of the 36 CFIR constructs, 11 were directly related to the level of implementation performance: intervention source, evidence strength and quality, adaptability, design quality and packaging, tension for change, learning climate, self-efficacy, planning, champions, executing, and reflecting and evaluating, with -organizational tracking added as a new sub-construct. Additionally, another seven constructs emerged in the participants' discourse but were not related to center performance: relative advantage, complexity, patients' needs and resources, external policy and incentives, structural characteristics, available resources, and formally appointed internal implementation leaders. Our findings indicate that the success of the implementation seems to be associated with the following components: the context, the implementation process, and the collaborative modelling. CONCLUSIONS: Identifying barriers and enablers is useful for designing implementation strategies for health promotion in primary health care centers that are essential for innovation success. An implementation model is proposed to highlight the relationships between the CFIR constructs in the context of health promotion in primary care.

Feasibility of an implementation strategy for the integration of health promotion in routine primary care: a quantitative process evaluation.

BACKGROUND: Process evaluation is recommended to improve the understanding of underlying mechanisms related to clinicians, patients, context and intervention delivery that may impact on trial or program results, feasibility and transferability to practice. The aim of this study was to assess the feasibility of the Prescribe Healthy Life (PVS from the Spanish "Prescribe Vida Saludable") implementation strategy for enhancing the adoption and implementation of an evidence-based health promotion intervention in primary health care. METHODS: A descriptive study of 2-year implementation indicators for the PVS clinical intervention was conducted in four primary health care centers. A multifaceted collaborative modeling implementation strategy was developed to enhance the integration of a clinical intervention to promote healthy lifestyles into clinical practice. Process indicators were assessed for intervention reach, adoption, implementation, sustainability and their variability at center, practice, and patient levels. RESULTS: Mean rates of adoption by means of active collaboration among the three main professional categories (family physicians, nurses and administrative personnel) were 75% in all centers. Just over half of the patients that attended (n = 11650; 51.9%) were reached in terms of having their lifestyle habits assessed, while more than a third (33.7%; n = 7433) and almost 10% (n = 2175) received advice or a printed prescription for at least one lifestyle change, respectively. Only 3.7% of the target population received a repeat prescription. These process indicators significantly (p < 0.001) varied by center, lifestyle habit and patient characteristics. Sustainability of intervention components changed thorough the implementation period within centers. CONCLUSIONS: The implementation strategy used showed moderate-to-good performance on process indicators related to adoption, reach, and implementation of the evidence-based healthy lifestyle promotion intervention in the context of routine primary care. Sources of heterogeneity and instability in these indicators may improve our understanding of factors required to attain adequate program adoption and implementation through improved implementation strategies.

Metric properties of the "prescribe healthy life" screening questionnaire to detect healthy behaviors: a cross-sectional pilot study.

BACKGROUND: Feasible and valid assessment of healthy behaviors is the first step for integrating health promotion in routine primary care. Therefore, the aim of this study was to develop and evaluate the validity and reliability of the "prescribe healthy life" screening questionnaire, a brief tool for detecting physical activity levels, consumption of fruit and vegetables, tobacco use and patients' compliance with minimal recommendations. METHODS: An observational cross-sectional study to determine the reliability and validity of this questionnaire by means of mixed (qualitative and quantitative) methods. Thirteen healthcare professionals designed the questionnaire. One hundred and twenty-six patients from three primary care health centers within Osakidetza (Basque Health Service, Spain) filled in the "Prescribe Healthy Life" Screening Questionnaire and completed an accelerometry record, the PREDIMED Food Frequency Questionnaire and a co-oximetry as gold standards for physical activity, dietary intake and tobacco use, respectively. Correlations, sensitivities, specificities, likelihood ratios and test-retest reliability were calculated. Additionally, the feasibility and utility of the questionnaire were evaluated. RESULTS: Both reliability and concurrent validity for the consumption of fruit and vegetables (rspearman = 0.59, rspearman = 0.50) and tobacco use (rspearman = 0.76, r = 0.69) as their overall performance in the detection of unhealthy diet (accuracy = 76.8%, LR + = 3.1 and LR- = 0.31) and smokers (accuracy = 86.8%, LR + = 6.1 and LR- = 0.05) were good. Meanwhile, the reproducibility (0.38), the correlation between the minutes of physical activity (0.34) and LR+ (1.00) for detection of physical activity were low. On average the questionnaire was considered by patients easy to understand, easy to fill in, short (5-6 min) and useful. CONCLUSION: The "Prescribe Healthy Life" Screening Questionnaire, PVS-SQ, has proved to be a simple and practical tool for use in the actual context of primary care, with guarantees of validity and reliability for the diet and tobacco scales. However, the physical activity scale show unsatisfactory results, and alternative questions ought to be tested.

Effectiveness of physical activity promotion interventions in primary care: A review of reviews.

OBJECTIVE: The present review aims to summarize the evidence about the effectiveness of physical activity (PA) promotion interventions in primary care (PC) and the intervention or sample characteristics associated with greater effectiveness. METHODS: MEDLINE, EMBASE, and Cochrane Library were searched to identify systematic reviews and meta-analyses published from 2002 to 2012 that assessed the effectiveness of PA-promoting interventions in PC. Information was extracted and recorded about each of the selected studies and their reported results. Methodological and evidence quality was independently rated by two reviewers using the nine-item OQAQ scale and the SIGN classification system. RESULTS: Ten of the 1664 articles identified met the inclusion criteria: five meta-analyses, three systematic reviews, and two literature reviews. Overall, PA promotion interventions in PC showed a small to moderate positive effect on increasing PA levels. Better results were obtained by interventions including multiple behavioral change techniques and those targeted to insufficiently active patients. No clear associations were found regarding intervention intensity or sample characteristics. CONCLUSION: Although several high-quality reviews provided clear evidence of small but positive effects of PA intervention in PC settings, evidence of specific strategies and sample characteristics associated with greater effectiveness is still needed to enhance the implementation of interventions under routine clinical conditions.

Learned response dynamics reflect stimulus timing and encode temporal expectation violations in superficial layers of mouse V1.

The ability to recognize ordered event sequences is a fundamental component of sensory cognition and underlies the capacity to generate temporally specific expectations of future events based on previous experience. Various lines of evidence suggest that the primary visual cortex participates in some form of predictive processing, but many details remain ambiguous. Here we use two-photon calcium imaging in layer 2/3 (L2/3) of the mouse primary visual cortex (V1) to study changes to neural activity under a multi-day sequence learning paradigm with respect to prediction error responses, stimulus encoding, and time. We find increased neural activity at the time an expected, but omitted, stimulus would have occurred but no significant prediction error responses following an unexpected stimulus substitution. Sequence representations became sparser and less correlated with training, although these changes had no effect on decoding accuracy of stimulus identity or timing. Additionally, we find that experience modifies the temporal structure of stimulus responses to produce a bias towards predictive stimulus-locked activity. Finally, we find significant temporal structure during intersequence rest periods that was largely unchanged by training.

Visual stimulation drives retinotopic acetylcholine release in the mouse visual cortex.

Cholinergic signaling is involved with a variety of brain functions including learning and memory, attention, and behavioral state modulation. The spatiotemporal characteristics of neocortical acetylcholine (ACh) release in response to sensory inputs are poorly understood, but a lack of intra-region topographic organization of cholinergic projections from the basal forebrain has suggested diffuse release patterns and volume transmission. Here, we use mesoscopic imaging of fluorescent ACh sensors to show that visual stimulation results in ACh release patterns that conform to a retinotopic map of visual space in the mouse primary visual cortex, suggesting new modes of functional cholinergic signaling in cortical circuits.x.

A systematic review and meta-analysis of the association between anxiety symptoms and coping in family carers of dependent people aged 18 and over.

Anxiety symptoms are prevalent in family carers of dependent people. Despite accumulating evidence in the area, there are still inconsistent findings on the association between carer anxiety symptoms and coping strategies. The aim of our study was to systematically analyse the relationship between anxiety symptoms and coping strategies in carers of dependent adults aged 18 years and older, and examine possible sources of heterogeneity in the results. The study design was a systematic review and meta-analysis. We searched several international databases (Pubmed, CINAHL, PsycINFO and LILACS) from June 2022 up to February 2023. We followed the preferred reporting items for systematic reviews and meta-analyses statement and performed several subgroup analyses to examine whether study design, cause of dependency and whether or not controlling for various biases influenced results. Forty-one studies were included in the review. We found significant associations between greater use of dysfunctional coping and higher anxiety symptoms. Greater use of problem-focused coping was associated with lower anxiety symptoms in carers of frail older people, but higher anxiety in carers of people surviving cancer. Emotion-focused coping and some of its individual strategies, such as acceptance and positive reappraisal, in probabilistic samples, were associated with lower anxiety symptoms across all groups. Most of the studies included in this review were cross-sectional. Evidence overall indicates that only specific dimensions and strategies of coping are significantly associated with anxiety symptoms in family carers. These findings should be considered when developing future interventions supporting carers.

Subjective caregiver burden and coping in family carers of dependent adults and older people: A systematic review and meta-analysis.

Subjective caregiver burden is highly prevalent in family caregivers. Despite several studies investigating the relationship between subjective caregiver burden and coping strategies, results remain inconsistent. The aim of our study was to systematically review current literature on the relationship between subjective caregiver burden and coping in family carers of dependent adults and older people. A secondary objective was to analyse possible sources of heterogeneity in the estimated effect. The study design was a systematic review with meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We searched several international databases (CINAHL, LILACS, PsycINFO and PubMed) up to February 2024. We performed several subgroup analyses to examine whether study design, methodological quality or care recipient dependency influenced results. Of the 1064 records identified in our search, a total of 80 studies met inclusion criteria. We found a significant association between greater use of dysfunctional coping and higher levels of subjective caregiver burden ( r ‾ $\overline{r}$  = 0.400; 95% CI = 0.315, 0.478); higher use of second-order active coping was significantly associated with lower caregiver burden ( r ‾ $\overline{r}$  = -0.213; 95% CI = -0.316, -0.105). Problem-focused coping showed no statistically significant association with levels of subjective burden; emotion-focused coping was associated with caregiver burden only after controlling for confounding variables ( r ‾ $\overline{r}$  = -0.258; 95% CI = -0.441, -0.055); several individual strategies of this dimension such as acceptance ( r ‾ $\overline{r}$  = -0.135; 95% CI = -0.238, -0.028), positive reappraisal ( r ‾ $\overline{r}$  = -0.178; 95% CI = -0.255, -0.099) and religious coping ( r ‾ $\overline{r}$  = -0.083; 95% CI = -0.162, -0.002), were associated with lower burden. We found that several dimensions of coping strategies are significantly associated with levels of subjective caregiver burden experienced by carers. These results can inform future research evaluating the effectiveness of interventions aimed at improving carers' mental health.

PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .

Monitoring steady flow effects on cell distribution in engineered valve tissues by magnetic resonance imaging.

In heart valve tissue engineering, assessment of cell migration under dynamic states can provide insights on the evolving tissue structure. We labeled human vascular smooth muscle (SMCs), endothelial (ECs), and bone marrow-derived mesenchymal stem cells (BMSCs) with superparamagnetic iron oxide (SPIO) microparticles and visualized them using magnetic resonance imaging (MRI) under steady flow. We determined that vascular cells were able to remain reasonably viable and proliferate well after being labeled with SPIO microparticles (200 µg/mL) for 48 hours. SPIO-labeled cells were successfully visualized using T2* contrast. When physiologically representative shear stresses (5-6 dynes/cm2) were applied to SMC-EC coculture-seeded scaffolds, hypointense regions seemed to have decreased after 2 weeks in some locations, whereas others revealed sustained levels of T2* contrast; similar observations were seen in the case of BMSC-seeded scaffolds. This could be attributable to increased out-of-plane cell migratory activity, which occurred from the fluid-induced mechanical cues received, which was not previously evidenced in static culture. Vascular cells and BMSCs were labeled with remarkably high concentrations of SPIO. Moreover, steady fluid flow enhanced intrascaffold cell migration of vascular SMCs and ECs as well as BMSCs, which, in turn, significantly improved construct cellularity and extracellular collagen content.

The Relationship between Social Support and Anxiety Symptoms in Informal Carers: A Systematic Review and Meta-Analysis.

BACKGROUND: Providing care can be challenging for informal carers and increases the risk of mental health problems, such as experiencing clinical symptoms of anxiety. While strengthening social support for informal carers is a common recommendation to reduce this risk, no systematic review or meta-analysis to date has examined the relationship between social support and anxiety symptoms in informal carers. The aim of our study was to systematically review the current evidence on the association between perceived and received social support and anxiety symptoms in informal carers of dependent adults and older people, and to comment on the quality of the evidence. METHODS: We searched PubMed, CINAHL (EBSCO), PsycINFO (ProQuest), Scopus, and LILACS up to 31 March 2021 for articles reporting on the association between caregiver anxiety symptoms and social support. A random-effects model was used to pool estimates, and each study was rated for quality using pre-specified criteria. Publication bias was assessed using a funnel plot and Egger's regression test, which was adjusted using trim and fill analysis. RESULTS: From the 2180 identified articles, 35 studies met our inclusion criteria, reporting on 5036 informal carers in total. We found a moderate negative association between perceived social support and caregiver anxiety symptoms (r = -0.31, 95% CI = -0.35, -0.27) and a small, negative association between received social support and caregiver anxiety (r = -0.15, 95% CI = -0.22, -0.08). CONCLUSION: The levels of perceived social support showed a significant negative association with caregiver anxiety symptoms. Policymakers and those working directly with informal carers should consider the development of targeted social support interventions that specifically enhance the levels of perceived social support to reduce symptoms of anxiety in informal carers.

Association between Social Support and Depressive Symptoms in Informal Caregivers of Adult and Older Dependents: A Systematic Review and Meta-Analysis.

Social support is an important determinant of a carer's mental health. In recent decades, despite many studies reporting on the relationship between social support and depressive symptoms in informal caregivers of adult and older dependents, there are no systematic reviews synthesizing the available evidence. The purpose of the present study was to perform a systematic review and meta-analysis on the relationship between social support and depressive symptoms in informal caregivers of adults and older dependent people. We searched PubMed, CINAHL (EBSCO), PsycINFO (ProQuest), and Scopus, up to 15 January 2023 for studies. We applied no date or language limits to our search. A random-effects model was used to pool effect estimates. The included studies were also independently assessed for quality. Publication bias was evaluated by funnel plots, Egger's regression test, and the Trim and Fill method. Ninety-three studies were included in the review, reporting on a total of 15,431 informal caregivers. We found a moderate negative association between perceived social support and caregiver depressive symptoms (78 studies; r = -0.35, 95% CI = -0.39, -0.31; low heterogeneity and low risk of publications bias) and a small negative association between received social support and caregiver self-reported depressive symptoms (12 studies; r = -0.14, 95% CI = -0.20, -0.07; low heterogeneity and low risk of publications bias). Our results indicate that social support is a clinically relevant construct for carer well-being and an important protective factor for depressive symptoms in informal caregivers of adult and older dependents.

Coping and depressive symptoms in family carers of dependent adults aged 18 and over: A systematic review and meta-analysis.

Being a family carer is associated with increased risk of experiencing depressive symptoms. Despite many decades of research investigating the association between coping strategies and depressive symptoms in carers results across studies remain contradictory. The objective of this study was to systematically review evidence on the association between depressive symptoms and coping strategies in carers of dependent people aged 18 and over and investigate potential sources of heterogeneity of findings. The study design was a systematic review and meta-analysis. We searched Pubmed, CINAHL, PsycINFO and LILACS up to April 2021. We performed meta-analyses following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement and several subgroup analyses to investigate whether cause of caring dependency, study design, and controlling for several biases influenced results. Fifty-nine studies met our inclusion criteria. We found a robust and statistically significant association between greater use of dysfunctional coping and higher depressive symptoms. Greater use of emotion-focussed coping was associated with fewer depressive symptoms only in studies controlling for confounding bias. Use of problem-focussed coping was related to fewer depressive symptoms in carers of frail older people. The combined use of both problem-focussed and emotion-focussed coping was associated with lower symptoms of depression. Our review concludes that the broad domain of dysfunctional coping is consistently associated with higher levels of depressive symptoms in carers. After controlling for confounders, emotion-focussed coping and several of its individual strategies were consistently associated with fewer depressive symptoms. Whilst problem-focussed coping and some of its individual strategies are also associated with lower depressive symptoms, these strategies may not be as helpful in all caregiving groups.

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 tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer ( NCT05225363 ). Preclinically, we found that CAR T cell-mediated IFNγ production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.