Metabolic Profile and Long-Term Risk of Depression, Anxiety, and Stress-Related Disorders.

Importance: Biomarkers of lipid, apolipoprotein, and carbohydrate metabolism have been previously suggested to be associated with the risk for depression, anxiety, and stress-related disorders, but results are inconsistent. Objective: To examine whether the biomarkers of carbohydrate, lipid, and apolipoprotein metabolism are associated with the risk of depression, anxiety, and stress-related disorders. Design, Setting, and Participants: This population-based cohort study with longitudinal data collection assessed 211 200 participants from the Apolipoprotein-Related Mortality Risk (AMORIS) cohort who underwent occupational health screening between January 1, 1985, and December 31, 1996, mainly in the Stockholm region in Sweden. Statistical analysis was performed during 2022 to 2023. Exposures: Lipid, apolipoprotein, and carbohydrate biomarkers measured in blood. Main Outcomes and Measures: The associations between biomarker levels and the risk of developing depression, anxiety, and stress-related disorders through the end of 2020 were examined using Cox proportional hazards regression models. In addition, nested case-control analyses were conducted within the cohort, including all incident cases of depression, anxiety, and stress-related disorders, and up to 10 control individuals per case who were individually matched to the case by year of birth, sex, and year of enrollment to the AMORIS cohort, using incidence density sampling. Population trajectories were used to illustrate the temporal trends in biomarker levels for cases and controls. Results: A total of 211 200 individuals (mean [SD] age at first biomarker measurement, 42.1 [12.6] years; 122 535 [58.0%] male; 188 895 [89.4%] born in Sweden) participated in the study. During a mean (SD) follow-up of 21.0 (6.7) years, a total of 16 256 individuals were diagnosed with depression, anxiety, or stress-related disorders. High levels of glucose (hazard ratio [HR], 1.30; 95% CI, 1.20-1.41) and triglycerides (HR, 1.15; 95% CI, 1.10-1.20) were associated with an increased subsequent risk of all tested psychiatric disorders, whereas high levels of high-density lipoprotein (HR, 0.88; 95% CI, 0.80-0.97) were associated with a reduced risk. These results were similar for male and female participants as well as for all tested disorders. The nested case-control analyses demonstrated that patients with depression, anxiety, or stress-related disorders had higher levels of glucose, triglycerides, and total cholesterol during the 20 years preceding diagnosis, as well as higher levels of apolipoprotein A-I and apolipoprotein B during the 10 years preceding diagnosis, compared with control participants. Conclusions and Relevance: In this cohort study of more than 200 000 participants, high levels of glucose and triglycerides and low levels of high-density lipoprotein were associated with future risk of depression, anxiety, and stress-related disorders. These findings may support closer follow-up of individuals with metabolic dysregulations for the prevention and diagnosis of psychiatric disorders.

Peripheral vertigo and subsequent risk of depression and anxiety disorders: a prospective cohort study using the UK Biobank.

BACKGROUND: Peripheral vertigo is often comorbid with psychiatric disorders. However, no longitudinal study has quantified the association between peripheral vertigo and risk of psychiatric disorders. Furthermore, it remains unknown how the white matter integrity of frontal-limbic network relates to the putative peripheral vertigo-psychiatric disorder link. METHODS: We conducted a cohort study including 452,053 participants of the UK Biobank with a follow-up from 2006 through 2021. We assessed the risks of depression and anxiety disorders in relation to a hospitalization episode involving peripheral vertigo using Cox proportional hazards models. We also examined the associations of peripheral vertigo, depression, and anxiety with MRI fractional anisotropy (FA) in a subsample with brain MRI data (N = 36,087), using multivariable linear regression. RESULTS: Individuals with an inpatient diagnosis of peripheral vertigo had elevated risks of incident depression (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.79-2.67) and anxiety (HR 2.11; 95% CI 1.71-2.61), compared to others, particularly within 2 years after hospitalization (HR for depression 2.91; 95% CI 2.04-4.15; HR for anxiety 4.92; 95% CI 3.62-6.69). Depression was associated with lower FA in most studied white matter regions, whereas anxiety and peripheral vertigo did not show statistically significant associations with FA. CONCLUSIONS: Individuals with an inpatient diagnosis of peripheral vertigo have increased subsequent risks of depression and anxiety disorders, especially within 2 years after hospitalization. Our findings further indicate a link between depression and lower microstructural connectivity as well as integrity beyond the frontal-limbic network.

Suicide attempt and death by suicide among parents of young individuals with cancer: A population-based study in Denmark and Sweden.

BACKGROUND: The psychological toll on parents of a child receiving a cancer diagnosis is known to be high, but there is a knowledge gap regarding suicidal behavior among these parents. The aim of this study was to investigate the risk of suicide attempt and death by suicide in relation to having a child with cancer. METHODS AND FINDINGS: We performed a binational population-based and sibling-controlled cohort study, including all parents with a child diagnosed with cancer in Denmark (1978 to 2016) or Sweden (1973 to 2014), 10 matched unexposed parents per exposed parent (population comparison), and unaffected full siblings of the exposed parents (sibling comparison). Suicide attempt was identified through the Patient Register and the Psychiatric Central Register in Denmark and the Patient Register in Sweden, whereas death by suicide was identified through the Danish Causes of Death Register and the Swedish Causes of Death Register. In population comparison, we used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of suicide attempt and death by suicide associated with cancer diagnosis of a child, adjusting for sex, age, country of residence, calendar year, marital status, highest attained educational level, household income, history of cancer, history of psychiatric disorder, and family history of psychiatric disorder. The sibling comparison was performed to assess the role of familial confounding in the studied associations. The population comparison consisted of 106,005 exposed parents and 1,060,050 matched unexposed parents, with a median age of 56 at cohort entry and 46.9% male. During the median follow-up of 7.3 and 7.2 years, we observed 613 (incidence rate [IR], 58.8 per 100,000 person-years) and 5,888 (IR, 57.1 per 100,000 person-years) cases of first-onset suicide attempt among the exposed and unexposed parents, respectively. There was an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis (HR, 1.15; 95% CI, [1.03, 1.28]; p = 0.01), particularly when the child was 18 or younger at diagnosis (HR, 1.25; 95% CI, [1.08, 1.46]; p = 0.004), when the child was diagnosed with a highly aggressive cancer (HR, 1.60; 95% CI, [1.05, 2.43]; p = 0.03), or when the child died due to cancer (HR, 1.63; 95% CI, [1.29, 2.06]; p < 0.001). The increased risk did not, however, maintain thereafter (HR, 0.86; 95% CI: [0.75, 0.98]; p = 0.03), and there was no altered risk of parental death by suicide any time after the child's cancer diagnosis. Sibling comparison corroborated these findings. The main limitation of the study is the potential residual confounding by factors not shared between full siblings. CONCLUSIONS: In this study, we observed an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis, especially when the child was diagnosed during childhood, or with an aggressive or fatal form of cancer. There was, however, no altered risk of parental death by suicide at any time after a child's cancer diagnosis. Our findings suggest extended clinical awareness of suicide attempt among parents of children with cancer, especially during the first few years after cancer diagnosis.

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

The relationship of publication language, study population, risk of bias, and treatment effects in acupuncture related systematic reviews: a meta-epidemiologic study.

BACKGROUND: There are debates in acupuncture related systematic reviews and meta-analyses on whether searching Chinese databases to get more Chinese-language studies may increase the risk of bias and overestimate the effect size, and whether the treatment effects of acupuncture differ between Chinese and non-Chinese populations. METHODS: In this meta-epidemiological study, we searched the Cochrane library from its inception until December 2021, and identified systematic reviews and meta-analyses with acupuncture as one of the interventions. Paired reviewers independently screened the reviews and extracted the information. We repeated the meta-analysis of the selected outcomes to separately pool the results of Chinese- and non-Chinese-language acupuncture studies and presented the pooled estimates as odds ratios (OR) with 95% confidence interval (CI). We calculated the Ratio of ORs (ROR) by dividing the OR of the Chinese-language trials by the OR of the non-Chinese-language trials, and the ROR by dividing the OR of trials addressing Chinese population by the OR of trials addressing non-Chinese population. We explored whether the impact of a high risk of bias on the effect size differed between studies published in Chinese- and in non-Chinese-language, and whether the treatment effects of acupuncture differed between Chinese and non-Chinese population. RESULTS: We identified 84 Cochrane acupuncture reviews involving 33 Cochrane groups, of which 31 reviews (37%) searched Chinese databases. Searching versus not searching Chinese databases significantly increased the contribution of Chinese-language literature both to the total number of included trials (54% vs. 15%) and the sample size (40% vs. 15%). When compared with non-Chinese-language trials, Chinese-language trials were associated with a larger effect size (pooled ROR 0.51, 95% CI 0.29 to 0.91). We also observed a higher risk of bias in Chinese-language trials in blinding of participants and personnel (97% vs. 51%) and blinding of outcome assessment (93% vs. 47%). The higher risk of bias was associated with a larger effect estimate in both Chinese-language (allocation concealment: high/unclear risk vs. low risk, ROR 0.43, 95% CI 0.21 to 0.87) and non-Chinese-language studies (blinding of participants and personnel: high/unclear risk vs. low risk, ROR 0.41, 95% CI 0.23 to 0.74). However, we found no evidence that the higher risk of bias would increase the effect size of acupuncture in Chinese-language studies more often than in non-Chinese-language studies (the confidence intervals of all ROR in the high-risk group included 1, Table 3). We further found acupuncture appeared to be more effective in Chinese than in non-Chinese population (Table 4). CONCLUSIONS: The findings of this study suggest the higher risk of bias may lead to an overestimation of the treatment effects of acupuncture but would not increase the treatment effects in Chinese-language studies more often than in other language studies. The difference in treatment effects of acupuncture was probably associated with differences in population characteristics. TRIAL REGISTRATION: We registered our protocol on the Open Science Framework (OSF) ( https://doi.org/10.17605/OSF.IO/PZ6XR ).

Loss of a child and the risk of atrial fibrillation: a Danish population-based prospective cohort study.

BACKGROUND: Several studies suggest that bereavement is associated with increased risks of ischaemic heart disease, heart failure, stroke and cardiovascular mortality. Knowledge regarding the link between bereavement and the risk of atrial fibrillation (AF) is limited. We investigated whether the death of a child, one of the most severe forms of bereavement, is associated with AF. METHODS: We conducted a population-based cohort study involving parents of live-born children during 1973-2016 from the Danish Medical Birth Register (n=2 804 244). Information on children's death, parental AF and sociodemographic and other health-related characteristics was obtained by individual-level linkage between several Danish population-based registers. We analysed the association between loss of a child and AF using Poisson regression. RESULTS: During the up to 39 years follow-up, 64 216 (2.3%) parents lost a child and 74 705 (2.7%) had an AF. Bereaved parents had a higher risk of AF than the non-bereaved; the corresponding incidence rate ratio (IRR) and 95% CI were 1.12 (1.08 to 1.17). The association was present both when the child died of cardiovascular diseases (IRR (95% CI): 1.42 (1.20 to 1.69)), and of other causes (IRR (95% CI): 1.11 (1.06 to 1.16)), tended to be U-shaped according to the deceased child's age at loss, but did not differ substantially according to the number of remaining live children at loss, the number of deceased children or the time since the loss. CONCLUSIONS: The death of a child was associated with a modestly increased risk of AF. Bereaved parents may benefit from increased support from family members and health professionals.

Bereavement in childhood and young adulthood and the risk of atrial fibrillation: a population-based cohort study from Denmark and Sweden.

BACKGROUND: Adverse childhood life events are associated with increased risks of hypertension, ischemic heart disease, and stroke later in life. Limited evidence also suggests that stress in adulthood may increase the risk of atrial fibrillation (AF). Whether childhood adversity may lead to the development of AF is unknown. We investigated whether the loss of a parent or sibling in childhood is associated with an increased risk of AF and compared this effect to that of similar losses in young adulthood. METHODS: We studied 6,394,975 live-born individuals included in the Danish (1973-2018) and Swedish Medical Birth Registers (1973-2014). We linked data from several national registers to obtain information on the death of parents and siblings and on personal and familial sociodemographic and health-related factors. We analyzed the association between bereavement and AF using Poisson regression. RESULTS: Loss of a parent or sibling was associated with an increased AF risk both when the loss occurred in childhood and in adulthood; the adjusted incident rate ratios and 95% confidence intervals were 1.24 (1.14-1.35) and 1.24 (1.16-1.33), respectively. Bereavement in childhood was associated with AF only if losses were due to cardiovascular diseases or other natural causes, while loss in adulthood was associated with AF not only in case of natural deaths, but also unnatural deaths. The associations did not differ substantially according to age at loss and whether the deceased was a parent or a sibling. CONCLUSIONS: Bereavement both in childhood and in adulthood was associated with an increased AF risk.

Risk of Psychiatric Disorders Among Spouses of Patients With Cancer in Denmark and Sweden.

Importance: There is emerging evidence that spouses of patients with cancer may have a higher prevalence of mental illness, but these studies have been limited by pre-post designs, focus on a single mental illness, and short follow-up periods. Objectives: To assess the overall burden of psychiatric disorders among spouses of patients with cancer vs spouses of individuals without cancer and to describe possible changes in this burden over time. Design, Setting, and Participants: This population based cohort study included spouses of patients with cancer (diagnosed 1986-2016 in Denmark and 1973-2014 in Sweden; exposed group) and spouses of individuals without cancer (unexposed group). Members of the unexposed group were individually matched to individuals in the exposed group on the year of birth, sex, and country. Spouses with and without preexisting psychiatric morbidity were analyzed separately. Data analysis was performed between May 2021 and January 2022. Exposures: Being spouse to a patient with cancer. Main Outcomes and Measures: The main outcome was a clinical diagnosis of psychiatric disorders through hospital-based inpatient or outpatient care. Flexible parametric models and Cox models were fitted to estimate hazard ratios (HRs) with 95% CIs, adjusted for sex, age and year at cohort entry, country, household income, and cancer history. Results: Among 546 321 spouses in the exposed group and 2 731 574 in the unexposed group who had no preexisting psychiatry morbidity, 46.0% were male participants, with a median (IQR) age at cohort entry of 60 (51-68) years. During follow-up (median, 8.4 vs 7.6 years), the incidence rate of first-onset psychiatric disorders was 6.8 and 5.9 per 1000 person-years for the exposed and unexposed groups, respectively (37 830 spouses of patients with cancer [6.9%]; 153 607 of spouses of individuals without cancer [5.6%]). Risk of first-onset psychiatric disorders increased by 30% (adjusted HR, 1.30; 95% CI, 1.25-1.34) during the first year after cancer diagnosis, especially for depression (adjusted HR, 1.38; 95% CI, 1.30-1.47) and stress-related disorders (adjusted HR, 2.04; 95% CI, 1.88-2.22). Risk of first-onset psychiatric disorders increased by 14% (adjusted HR, 1.14; 95% CI, 1.13-1.16) during the entire follow-up, which was similar for substance abuse, depression, and stress-related disorders. The risk increase was more prominent among spouses of patients diagnosed with a cancer with poor prognosis (eg, pancreatic cancer: adjusted HR, 1.41; 95% CI, 1.32-1.51) or at an advanced stage (adjusted HR, 1.31; 95% CI, 1.26-1.36) and when the patient died during follow-up (adjusted HR, 1.29; 95% CI, 1.27-1.31). Among spouses with preexisting psychiatric morbidity, the risk of psychiatric disorders (first-onset or recurrent) increased by 23% during the entire follow-up (adjusted HR, 1.23; 95% CI, 1.20-1.25). Conclusions and Relevance: In this cohort study of 2 populations in Denmark and Sweden, spouses of patients with cancer experienced increased risk of several psychiatric disorders that required hospital-based specialist care. Our results support the need for clinical awareness to prevent potential mental illness among the spouses of patients with cancer.

Application of continuous renal replacement therapy combined with extracorporeal carbon dioxide removal in children with acute respiratory failure / 中华急诊医学杂志

Objective:To explore the role of continuous renal replacement therapy (CRRT) combined with extracorporeal carbon dioxide removal (ECCO 2R) in the treatment of children with respiratory failure. Methods:The clinical data of 12 children with respiratory failure who were treated with CRRT+ECCO 2R in PICU of Jinan Children's Hospital from July 2020 to August 2022 were collected and analyzed retrospectively. The outcomes and the external pipeline usage of the patients were observed, and the blood gas analysis and ventilator parameters before 1 h and after 1, 6, 12 and 24 h of the treatment were compared by one-way ANOVA with LSD post hoc correction. Results:Six patients successfully withdrew from CRRT+ECCO 2R and mechanical ventilation, three patients were transferred to ECMO treatment. Three cases died after voluntary withdrawal of treatment, and two cases died due to treatment failure. The mortality rate was 41.7%. After continuous treatment of CRRT+ECCO 2R for 15 to 112 h, two cases experienced extracorporeal circuit obstruction. After 1 h of treatment, PaCO 2 decreased from (64.67±24.4) mmHg to (49.42±15.54) mmHg, pH increased from (7.28±0.20) to (7.38±0.11), FiO 2 decreased from (0.85±0.13) to (0.78±0.15), PC decreased from (19.42±4.34) cmH 2O to (17.75±4.00) cmH 2O. After 24 h of treatment, PaCO 2 decreased to (39.2±5.55) mmHg, pH increased to (7.41±0.04), FiO 2 decreased to (0.46±0.11), and PC decreased to (13.8±3.36) cmH 2O, and the differences were statistically significant compared with before treatment ( P < 0.05). Conclusions:The combination of CRRT and ECCO 2R therapy can safely substitute for partial lung ventilation/perfusion function, and play a role in protecting right heart function and improving lung-kidney interaction. It can be considered as an option for extracorporeal respiratory, circulatory, and renal support, and consequently has broad prospects.

Bereavement and Prognosis After a First Acute Myocardial Infarction: A Swedish Register-Based Cohort Study.

BACKGROUND Despite accumulating evidence suggesting that bereavement is associated with increased risks of cardiovascular morbidity and mortality, the association between bereavement and prognosis after acute myocardial infarction (AMI) has not been well documented. We investigated the association by using Swedish register data. METHODS AND RESULTS We studied 266 651 patients with a first AMI included in the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) quality register from 1991 to 2018. We obtained information on bereavement (ie, death of a partner, child, grandchild, sibling, or parent), on primary (nonfatal recurrent AMI and death attributed to ischemic heart disease) and secondary outcomes (total mortality, heart failure, and stroke) and on covariates from several national registers. The association was analyzed using Poisson regression. The bereaved patients had a slightly increased risk of the primary outcome; the corresponding risk ratio (RR) was 1.02 (95% CI, 1.00-1.04). An increased risk was noted any time bereavement occurred, except if the loss was in the year after the first AMI. The association was strongest for the loss of a partner, followed by the loss of a child, grandchild, sibling, or parent. We also observed increased risks for total mortality (RR, 1.14 [95% CI, 1.12-1.16]), heart failure (RR, 1.05 [95% CI, 1.02-1.08]), and stroke (RR, 1.09 [95% CI, 1.05-1.13]) following bereavement. CONCLUSIONS Bereavement was associated with an increased risk of poor prognosis after a first AMI. The association varied by the relationship to the deceased.

Preventive strategies of cancer therapeutics-related cardiotoxicity in childhood cancer survivors: a protocol of systematic review.

INTRODUCTION: Five-year survival in childhood cancer has been improved markedly in the past decades. Childhood cancer survivors are at high risk of cardiovascular diseases due to anticancer therapy-induced cardiotoxicity. The comprehensive evidence for the prevention of anticancer therapy-induced cardiovascular disease is, however, sparse. The systematic review described in the protocol aims to summarise the effect of current prevention for anticancer therapy-induced cardiotoxicity among childhood cancer survivors. METHODS AND ANALYSIS: This protocol is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols checklist. We will search PubMed (via Medline), Embase and the Cochrane Library and include the studies investigating the effect of prevention against anticancer therapy-induced cardiotoxicity of childhood cancer. To assess the risk of bias, we will use the Cochrane Collaboration's risk of bias tool for randomised control trials and the Newcastle-Ottawa Scale for cohort studies and case-control studies. Furthermore, we will conduct meta-analyses if there is no substantial clinical heterogeneity between included studies. The Grading of Recommendations, Assessment, Development and Evaluation will be used to evaluate the quality of evidence. ETHICS AND DISSEMINATION: Ethical approval is not needed for systematic review of published data. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42022333877.

Cardiovascular disease and risk of lung cancer incidence and mortality: A nationwide matched cohort study.

Purpose: Previous studies have suggested a link between cardiovascular disease (CVD) and the subsequent development of lung cancer. However, empirical evidence on the association of CVDs, particularly type-specific CVDs, with lung cancer incidence and survival remains limited. Methods: The cohort study included 306,285 patients with CVD and 1,222,140 individuals without CVD. We performed stratified Cox regression to estimate the hazard ratio (HR). Results: During up to 42 years of follow-up, 243 (0.08%) and 537 (0.04%) participants were diagnosed with lung cancer among CVD patients and matched individuals, respectively. Patients with CVD had a 67% increased risk of lung cancer (HR: 1.67, 95% confidence interval [CI]: 1.42-1.96). The increased risks were observed in patients with heart disease (1.93, 1.30-2.85), vascular disease (1.88, 1.35-2.61), and hypertensive disease (1.46, 1.15-1.85), respectively. Patients with CVD had a 95% increased risk of lung cancer mortality (1.95, 1.50-2.55), particularly vascular disease (3.24, 1.74-6.02) and heart disease (2.29, 1.23-4.26). Patients with CVD diagnosed in middle adulthood (>40 years old) tended to have a higher incidence risk (3.44, 2.28-5.19) and mortality (3.67, 1.80-7.46) than those diagnosed at younger ages. Conclusions: Our findings on the association of CVD diagnosis, especially heart and vascular disease, with increased risk of lung cancer incidence and mortality suggest that CVD contributes to the development and worsening of lung cancer survival. In particular, people with CVD diagnosed in middle adulthood (>40 years old) would benefit from early preventive evaluation and screening for lung cancer.

Bereavement and Prognosis in Heart Failure: A Swedish Cohort Study.

BACKGROUND: The role of stress in the prognosis of heart failure (HF) is unclear. This study investigated whether the death of a close family member, a severe source of stress, is associated with mortality in HF. OBJECTIVES: This study assessed whether the death of a close family member is associated with mortality in HF. METHODS: Patients from the Swedish Heart Failure Registry during 2000-2018 and/or in the Swedish Patient Register with a primary diagnosis of HF during 1987-2018 (N = 490,527) were included in this study. Information was obtained on death of family members (children, partner, grandchildren, siblings, and parents), mortality, sociodemographic variables, and health-related factors from several population-based registers. The association between bereavement and mortality was analyzed by using Poisson regression. RESULTS: Loss of a family member was associated with an increased risk of dying (adjusted relative risk: 1.29; 95% CI: 1.27-1.30). The association was present not only in case of the family member's cardiovascular deaths and other natural deaths but also in case of unnatural deaths. The risk was higher for 2 losses than for 1 loss and highest in the first week after the loss. The association between bereavement and an increased mortality risk was observed for the death of a child, spouse/partner, grandchild, and sibling but not of a parent. CONCLUSIONS: Death of a family member was associated with an increased risk of mortality among patients with HF. Further studies are needed to investigate whether less severe sources of stress can also contribute to poor prognosis in HF and to explore the mechanisms underlying this association.

Development of hydrogen sulfide donors for anti-atherosclerosis therapeutics research: Challenges and future priorities.

Hydrogen sulfide (H2S), a gas transmitter found in eukaryotic organisms, plays an essential role in several physiological processes. H2S is one of the three primary biological gas transmission signaling mediators, along with nitric oxide and carbon monoxide. Several animal and in vitro experiments have indicated that H2S can prevent coronary endothelial mesenchymal transition, reduce the expression of endothelial cell adhesion molecules, and stabilize intravascular plaques, suggesting its potential role in the treatment of atherosclerosis (AS). H2S donors are compounds that can release H2S under certain circumstances. Development of highly targeted H2S donors is a key imperative as these can allow for in-depth evaluation of the anti-atherosclerotic effects of exogenous H2S. More importantly, identification of an optimal H2S donor is critical for the creation of H2S anti-atherosclerotic prodrugs. In this review, we discuss a wide range of H2S donors with anti-AS potential along with their respective transport pathways and design-related limitations. We also discuss the utilization of nano-synthetic technologies to manufacture H2S donors. This innovative and effective design example sheds new light on the production of highly targeted H2S donors.

Death of a Parent and the Risk of Ischemic Heart Disease and Stroke in Denmark and Sweden.

Importance: Increasing evidence suggests that parental death is associated with unhealthy behaviors and mental ill-health. Knowledge regarding the link between parental death and the risk of ischemic heart disease (IHD) and stroke remains limited. Objectives: To investigate whether parental death is associated with an increased risk of IHD and stroke and whether these associations differ by the characteristics of the loss. Design, Setting, and Participants: This population-based cohort study, involving linkages between several nationwide registers, included 3 766 918 individuals born between 1973 and 1998 in Denmark and between 1973 and 1996 in Sweden. Participants were followed up until 2016 in Denmark and 2014 in Sweden. Data were analyzed from December 2019 to May 2021. Exposures: Death of a parent. Main Outcomes and Measures: Diagnosis with or death due to IHD or stroke. Poisson regression was used to analyze the associations between parental death and IHD and stroke risk. Results: Altogether, 48.8% of the participants were women, and 42.7% were from Denmark. A total of 523 496 individuals lost a parent during the study period (median age at loss, 25 years; IQR, 17-32 years). Parental death was associated with a 41% increased risk of IHD (incidence rate ratio [IRR], 1.41; 95% CI, 1.33-1.51) and a 30% increased risk of stroke [IRR, 1.30; 95% CI, 1.21-1.38). The associations were observed not only if the parent died because of cardiovascular or other natural causes but also in cases of unnatural deaths. The associations were stronger when both parents had died (IHD: IRR, 1.87; 95% CI, 1.59-2.21; stroke: IRR, 1.64; 95% CI, 1.35-1.98) than when 1 parent had died (IHD: IRR, 1.37; 95% CI, 1.28-1.47; stroke: IRR, 1.27; 95% CI, 1.19-1.36) but did not differ substantially by the offspring's age at loss or the deceased parents' sex. The risk of acute myocardial infarction was highest in the first 3 months after loss. Conclusions and Relevance: In this cohort study, parental death in the first decades of life was associated with an increased risk of IHD and stroke. The associations were observed not only in cases of parental cardiovascular and other natural deaths but also in cases of unnatural deaths. Family members and health professionals may need to pay attention to the cardiovascular disease risk among parentally bereaved individuals.

Death of a Child and the Risk of Stroke: A Binational Cohort Study from Denmark and Sweden.

BACKGROUND AND OBJECTIVES: The death of a child is an extreme life event with potentially long-term health consequences. Accumulating evidence suggests that parents who lost a child have increased risks of cardiovascular diseases, including ischemic heart disease and atrial fibrillation. Whether bereaved parents have an increased risk of stroke is unclear and was investigated in this study. METHODS: We conducted a population-based cohort study including parents who had a child born during 1973-2016 or 1973-2014 and recorded in the Danish and the Swedish Medical Birth Registers, respectively. We obtained information on child's death, parent's stroke, and socioeconomic and health-related characteristics through linkage between several population-based registers. We used Poisson regression to examine the association between the death of a child and the risk of stroke. RESULTS: Of the 6,711,955 study participants, 128,744 (1.9%) experienced the death of a child and 141,840 (2.1%) had a stroke during the follow-up. Bereaved parents had an increased risk of stroke; the corresponding incidence rate ratio (95% CI) was 1.23 (1.19-1.27). The association was present for all analyzed categories of causes of child death (cardiovascular, other natural, and unnatural death) and did not differ substantially according to the age of the deceased child, but was stronger if the parent had no or ≥3 than 1-2 live children at the time of the loss. The association was similar for ischemic and hemorrhagic stroke. The risk for hemorrhagic stroke was highest immediately after the death of a child and decreased afterwards. In contrast, there was no clear pattern over time in case of ischemic stroke. DISCUSSION: The death of a child was associated with a modestly increased risk of stroke. The finding that an association was observed in case of unnatural deaths is suggestive of the explanation that bereavement-related stress may contribute to the development of stroke. Although the death of a child often cannot be avoided, an understanding of its health-related consequences may highlight the need for improved support and attention from family members and health care professionals.

Death of a child and the risk of heart failure: a population-based cohort study from Denmark and Sweden.

AIMS: We aimed to investigate whether the death of a child, one of the most severe stressors, is associated with the risk of heart failure (HF). METHODS AND RESULTS: We conducted a population-based cohort study involving parents of live-born children recorded in the Danish and Swedish Medical Birth Registers during 1973-2016 and 1973-2014, respectively (n = 6 717 349). We retrieved information on child death, HF diagnosis and sociodemographic characteristics of the parents from several nationwide registries. We performed Poisson regression models to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for HF in relation to bereavement. A total of 129 829 (1.9%) parents lost at least one child during the follow-up. Bereaved parents had a 35% higher risk of HF than the non-bereaved (IRR 1.35, 95% CI 1.29-1.41; p < 0.001). The increased HF risk was observed not only when the child died due to cardiovascular or other natural causes, but also when the loss was due to unnatural causes. The association tended to be U-shaped when we categorized the exposed parents by the number of remaining live children at loss or by the age of the deceased child. CONCLUSION: We found that the death of a child was associated with an increased risk of HF. The finding that not only cardiovascular and other natural deaths, but also unnatural deaths were associated with HF suggests that stress-related mechanisms may contribute to the development of HF.

Dual-specificity phosphatase 15 (DUSP15) in the nucleus accumbens is a novel negative regulator of morphine sensitization / 西安交通大学学报(医学版)

【Objective】 To study the role of dual-specificity phosphatase 15 （DUSP15） in mouse nucleus accumbens （NAc） in morphine sensitization. 【Methods】 The distance was recorded by open field test （OFT）， and morphine sensitization behavior was observed by acute morphine administration. The protein expressions of extracellular regulated protein kinases （ERK）， p-ERK and DUSP15 were tested using Western blotting. DUSP15-overexpressed virus （AAV-DUSP15） was injected into mouse NAc by brain stereotactic injection. Immunofluorescence staining confirmed viral expression. Western blotting was used to detect the effect of AAV-DUSP15 on the expressions of DUSP15， ERK and P-ERK. OFT was used to observe morphine sensitization behavior. 【Results】 The sensitization behavior was induced by intraperitoneal injection of 10 mg/kg morphine （continuous injection of 1 dose/day， for 7 doses） and withdrawal of morphine for 1 week. Compared with the saline control group， p-ERK was found to be increased and DUSP15 was found to be decreased. Intra-NAc infusions of AAV-DUSP15 （overexpression） not only inhibited the expression of p-ERK but also prevented morphine sensitization behavior. 【Conclusion】 DUSP15 negatively regulates ERK activation level in mouse NAc. DUSP15 agonist has a potential therapeutic effect on drug addiction.

Death of an offspring and parental risk of ischemic heart diseases: A population-based cohort study.

BACKGROUND: The death of a child is an extreme life event with potentially long-term health consequences. Knowledge about its association with ischemic heart diseases (IHDs) and acute myocardial infarction (AMI), however, is very limited. We investigated whether the death of an offspring is associated with the risk of IHD and AMI. METHODS AND FINDINGS: We studied parents of live-born children recorded in the Danish (1973 to 2016) and the Swedish (1973 to 2014) Medical Birth Registers (n = 6,711,952; mean age at baseline 31 years, 53% women). We retrieved information on exposure, outcomes, and covariates by linking individual-level information from several nationwide registers. We analyzed the abovementioned associations using Poisson regression. A total of 126,522 (1.9%) parents lost at least 1 child during the study period. Bereaved parents had a higher risk of IHD and AMI than the nonbereaved [incidence rate ratios (IRRs) (95% confidence intervals (CIs)): 1.20 (1.18 to 1.23), P < 0.001 and 1.21 (1.17 to 1.25), P < 0.001, respectively]. The association was present not only in case of losses due to CVD or other natural causes, but also in case of unnatural deaths. The AMI risk was highest in the first week after the loss [IRR (95% CI): 3.67 (2.08 to 6.46), P < 0.001], but a 20% to 40% increased risk was observed throughout the whole follow-up period. Study limitations include the possibility of residual confounding by socioeconomic, lifestyle, or health-related factors and the potentially limited generalizability of our findings outside Scandinavia. CONCLUSIONS: The death of an offspring was associated with an increased risk of IHD and AMI. The finding that the association was present also in case of losses due to unnatural causes, which are less likely to be confounded by cardiovascular risk factors clustering in families, suggests that stress-related mechanisms may also contribute to the observed associations.