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.

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.

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.

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.

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.

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.

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.

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.

Perceptions, Motivations, and Empowerment Strategies of Midwives in Rural and Remote Areas of Northern Morocco.

The shortage of midwives is a problem in rural and remote areas. This is mainly the consequence of job insecurity and difficult living conditions. The present study aimed to identify and analyse the perceptions and motivations of midwives in rural and remote areas of northern Morocco on the quality of their working life and the motivational factors and empowerment strategies they use to maintain and develop their work. It is a qualitative study that follows Van Manen's hermeneutic phenomenology approach. Three focus groups and in-depth interviews were conducted with 15 midwives from rural and remote areas. The results indicate that midwives in rural and remote areas have a negative perception of the quality of the work and their personal life because of the scarcity of basic resources, unfavourable working conditions, and the personal sacrifices they have to make to support themselves. However, some factors favour their efforts. Therefore, there is a need to promote intersectoral policies that focus on improving material and human resources, as well as the working and personal conditions of midwives and the factors that support and empower them.

PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages.

BACKGROUND: The immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163+ M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear. METHODS: To model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14+ peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings. RESULTS: We observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163+ M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells. CONCLUSION: This study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.

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 relationship between perceived social support and psychological distress in carers of older relatives: A longitudinal cross-lagged analysis.

BACKGROUND AND OBJECTIVES: Although a large body of research has examined the relationship between social support and psychological health of family carers of frail older people, the exact nature and direction of this relationship is not well understood with most research to date being cross-sectional. This longitudinal study explored the relationship between perceived social support and psychological distress in carers of older relatives. METHODS: We used data from two longitudinal cohorts which included a total of 332 family carers of frail older people. We used cross-lagged panel analysis to investigate the longitudinal association between perceived social support and carer psychological distress controlling for a number of covariates over time. RESULTS: Fully-adjusted Generalised Estimating Equations (GEE) and cross-lagged models indicated that higher social support was significantly associated with lower carer psychological distress over time (regression coefficient [B] = -0.178, standard error [SE] = 0.028), with levels of perceived social support exerting an effect on psychological distress rather than vice versa (ß = 0.03, p = 0.32). LIMITATIONS: All observations were based on self-report data, and there may be other variables that may explain the results that we did not account for. DISCUSSION AND IMPLICATIONS: Our study finds that the directionality of the relationship appears to be from perceived social support to carer psychological distress suggesting that social support directly affects carer psychological health but not vice versa. This finding has important implications for the provision of social support interventions for carers of frail older people at risk of experiencing psychological distress.

Subjective caregiver burden and anxiety in informal caregivers: A systematic review and meta-analysis.

There is increasing evidence that subjective caregiver burden is an important determinant of clinically significant anxiety in family carers. This meta-analysis aims to synthesise this evidence and investigate the relationship between subjective caregiver burden and anxiety symptoms in informal caregivers. We searched PubMed, CINAHL and PsycINFO up to January 2020. Combined estimates were obtained using a random-effects model. After screening of 4,312 articles, 74 studies (with 75 independent samples) were included. There was a large, positive association between subjective caregiver burden and anxiety symptoms (r = 0.51; 95% CI = 0.47, 0.54; I2 = 0.0%). No differences were found in subgroup analyses by type of study design (cross-sectional vs. longitudinal), sampling, control of confounders or care-recipient characteristics. Subjective caregiver burden is an important risk factor for anxiety in informal caregivers. Targeting subjective caregiver burden could be beneficial in preventing clinically significant anxiety for the increasing number of family carers worldwide.

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.

Modelos teóricos de promoción de la salud en la práctica habitual en atención primaria de salud / Theoretical models of health promotion in primary healthcare everyday practice

OBJETIVO: Comprender a qué modelos teóricos se ajusta la práctica actual de la prevención primaria y promoción de la salud en atención primaria de salud en diferentes centros de salud de siete comunidades autónomas de España, según los/las profesionales de distintas disciplinas de este ámbito asistencial. MÉTODO: Investigación cualitativa descriptiva en la que participaron 145 profesionales de 14 centros de salud de siete comunidades autónomas de España. El muestreo fue teórico. Se realizaron 14 grupos de discusión. El análisis de datos se realizó siguiendo procedimientos del análisis de contenido temático y de acuerdo con siete modelos teóricos de promoción de la salud a nivel micro, meso y macro. RESULTADOS: Las prácticas de los profesionales de los centros participantes en relación con las actividades de prevención primaria y promoción de la salud se adhieren principalmente a modelos intrapersonales, centrándose en ayudar a que las personas se empoderen aumentando la conciencia de riesgo y de los beneficios del cambio en los comportamientos, y guiándolas en la implementación de un comportamiento saludable. Algunos/as profesionales realizan actividades que encajan en modelos interpersonales, implicando a la familia y al propio profesional en las estrategias. Solo en algunos casos las prácticas actuales encajan en modelos comunitarios de promoción de la salud. CONCLUSIONES: Las prácticas de prevención primaria y promoción de la salud de los profesionales de atención primaria siguen principalmente modelos intrapersonales, en algunos casos modelos interpersonales y más puntualmente modelos comunitarios. Es necesario potenciar la participación de la ciudadanía y la orientación comunitaria de los servicios de atención primaria de salud

OBJECTIVE: To understand which theoretical models apply to current primary care practice of primary prevention and health promotion in a sample of primary health centres of seven autonomous regions in Spain according to the various professionals involved. METHOD: Descriptive qualitative research with the participation of 145 professionals from 14 primary health centres of seven autonomous regions in Spain. Theoretical sampling was used and 14 discussion groups were carried out. Data analysis followed thematic contents analysis procedures and was based on seven health promotion theoretical models at micro-, meso- and macro-level. RESULTS: Current practice of primary prevention and health promotion activities mainly follow intrapersonal models, which focus on assisting the empowerment of patients by means of raising awareness of risk and benefits of behavioural change and on guiding the adoption of the new healthy behaviour. To a lesser degree, the activities of some professionals adhere to interpersonal models, which involve also the family and the health professional. In only a few instances community models of health promotion were used. CONCLUSIONS: Primary prevention and health promotion practice of primary healthcare professionals follow mainly intrapersonal models, few cases use interpersonal models and community models are only occasionally employed. Advance of public participation and community orientation in primary healthcare services is needed

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.