Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial.

Importance: An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. Objective: To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants: This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Intervention: Dapagliflozin, 10 mg per day, or placebo. Main Outcomes and Measures: In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Results: Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Conclusions and Relevance: Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Long-term cardiovascular events, graft failure, and mortality in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients are at increased risks of cardiovascular events, but contemporary risk estimates are sparse. Using the Danish nationwide administrative databases, we quantified 1- and 5-year risks of cardiovascular disease and kidney failure among all first-time kidney transplant recipients (2005-2018) and age- and sex-matched controls (1:10 ratio). METHODS: Cumulative 1- and 5-year incidence of cardiovascular events (myocardial infarction, stroke, or heart failure), kidney failure (re-transplantation or need for dialysis >30 days post-transplant), and mortality following transplantation were calculated until maximally Dec 31, 2018. RESULTS: A total of 2,565 kidney transplant recipients (median age 50.5 [25-75th percentile 40.2-60.7] years, 37 % females) and 25,650 controls were included. 1-year cumulative incidence of myocardial infarction, stroke, or heart failure was 2.6 % (95 % confidence interval 1.9 %-3.2 %) among kidney transplant recipients versus 0.5 % (0.4 %-0.5 %) in controls. Cumulative 5-year risk estimates for the same endpoints were 8.3 % (7.1 %-9.5 %) for the transplant patients, and 2.6 % (2.3 %-2.8 %) among controls, respectively. For the kidney transplant cohort, cumulative mortality was 2.2 % (1.7 %-2.8 %) and 10.3 % (9.0 %-11.6 %) at 1- and 5 years, respectively, versus 0.5 % (0.4 %-0.6 %) and 3.0 % (2.7 %-3.2 %) for controls. The cumulative incidence of dialysis and re-transplantation was 6.1 % (5.2 %-7.1 %) at 1 year and 16.3 % (14.7 %-17.9 %) at 5 years, respectively. CONCLUSIONS: Despite the benefits of transplantation, kidney transplant recipients continue to have significant long-term cardiovascular disease, end-stage kidney disease, and mortality risks even with contemporary medical management. Better cardiovascular preventive strategies are warranted to improve prognosis in this segment of patients.

Active involvement of people with lived experience of suicide in suicide research: a Delphi consensus study.

BACKGROUND: The importance and value of involvement of people with lived experience of suicide has been recognized in suicide research and prevention. Nonetheless, clear guidance on research collaboration and co-production is lacking. This study aimed to address this gap by developing a set of guidelines on active involvement of people with lived experience of suicide in suicide studies., i.e., conducting research with or by people with lived experience, rather than to, about or for them. METHODS: The Delphi method was used to determine statements on best practice for the active involvement of people with lived experience of suicide in suicide research. Statements were compiled through a systematic search of the scientific and grey literature, and reviewing qualitative data from a recent related study conducted by the authors. Two expert panels: people with lived experience of suicide (n = 44) and suicide researchers (n = 29) rated statements over three rounds of an online survey. Statements endorsed by at least 80% of panellists of each panel were included in the guidelines. RESULTS: Panellists endorsed 96 out of 126 statements in 17 sections covering the full research cycle from deciding on the research question and securing funding, to conducting research and disseminating and implementing outcomes. Overall, there was a substantial level of agreement between the two panels regarding support from research institutions, collaboration and co-production, communication and shared decision making, conducting research, self-care, acknowledgment, and dissemination and implementation. However, panels also disagreed on specific statements regarding representativeness and diversity, managing expectations, time and budgeting, training, and self-disclosure. CONCLUSIONS: This study identified consensus recommendations on active involvement of people with lived experience of suicide in suicide research, including co-production. Support from research institutions and funders, and training on co-production for researchers and people with lived experience, are needed for successful implementation and uptake of the guidelines.

Sense of purpose interventions for depression and anxiety in youth: A scoping review and cross-cultural youth consultation.

BACKGROUND/OBJECTIVES: To investigate the effectiveness, feasibility, and acceptability of sense of purpose (SOP) interventions in preventing or reducing anxiety or depression in youth aged 14-24 years. METHODS: A systematic search was conducted of the academic (PubMed/MEDLINE, PsycINFO, EMBASE) and grey literature. We also consulted two SOP experts and an Australian and Indian youth advisory group with lived experience of anxiety and/or depression. Consultations focused on the feasibility and acceptability of reviewed interventions. RESULTS: The search identified 25 studies reporting on 4408 participants from six countries (64.0 % of studies in the US). Multi-component interventions targeting several SOP components (i.e., value clarification, goal setting, gratitude enhancement) reported, on average, moderate reductions in depression and anxiety symptoms in youth. Interventions were generally more effective at reducing depression than anxiety symptoms. In terms of sub-populations or groups, there was some evidence for greater intervention effectiveness among youth with prior therapy experience, extraverted personalities, and those with already elevated anxiety/depression symptoms. Youth advisors and experts opined that group interventions were most acceptable to young people. LIMITATIONS: This review was limited to a recent 10-year timeframe and publications in English, potentially excluding relevant studies published prior to 2011 or in other languages. CONCLUSIONS: Fostering SOP can lead to better psychological wellbeing in youth. Potential harms resulting from interventions can occur without adequate consideration for a person's readiness for purpose discovery, environmental barriers, and familial and cultural settings. Further research in more diverse populations is required to determine who benefits and in what contexts.

Disclosure of Mental Health Problems or Suicidality at Work: A Systematic Review.

Many adults experience mental health problems or suicidality. Mental health and suicidality are associated with stigma and discrimination. Little is known about disclosure of mental health or suicidality problems in workplaces and the role of stigma and discrimination in affecting disclosure. To address this gap, we conducted a systematic review following the PRISMA guidelines. Searches for peer-reviewed articles in MedLINE, CINAHL, Embase and PsycINFO identified 26 studies, including sixteen qualitative, seven quantitative and three mixed-methods studies. No studies were excluded based on quality assessment. All studies reported on mental health disclosure; none reported on disclosure of suicidal thoughts or behaviours. The narrative synthesis identified four overarching themes relating to disclosure of mental health problems in workplaces. Themes included beliefs about stigma and discrimination, workplace factors (including supports and accommodation), identity factors (including professional and personal identity, gender and intersectionality) and factors relating to the disclosure process (including timing and recipients), with all influencing disclosure decision making. Significantly, this review found that there is a gap in the existing literature relating to suicidality disclosure in workplaces, with none of the included studies investigating disclosure of suicidal thoughts and behaviours.

Informing and Sustaining Participation of Lived Experience in the Suicide Prevention Workforce.

BACKGROUND: Currently, there is no comprehensive study focused on identifying what is needed to support ongoing participation within the suicide prevention lived experience workforce (LEW). It is unclear what specific factors may impede or support ongoing participation in the LEW. The aim of this study was to explore the experiences of suicide prevention LEW in terms of its sustainability. METHOD: A qualitative interview method was utilised, with a purposive sample of participants who had engaged in the LEW for at least 12 months. The sample comprised 13 individuals (nine females, four males) who engaged in multiple LEW roles, with over half (54%) working in the LEW for more than 5 years. Data were analysed using thematic analysis. RESULTS: Five main themes were identified: support, passion, personal impact, training, and work diversity. Each theme offers perspectives about the challenges participants face within the suicide prevention LEW. CONCLUSION: Challenges faced are both similar to those found in the broader MH sector and unique to suicide prevention. Findings suggest that managing expectations of the LEW is important and can inform the creation of guidelines for a supported and sustainable suicide prevention LEW.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction. Objective: To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants: This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m2 or higher. Interventions: Dapagliflozin, 10 mg, per day or placebo. Main Outcomes and Measures: Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2; end-stage kidney disease; death from kidney causes). Results: A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001). Conclusions and Relevance: Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER.

Importance: In 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes. Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. Design, Setting, and Participants: This was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression. Results: Of 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI. Conclusions and Relevance: In a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124, NCT03619213.

Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. OBJECTIVES: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. METHODS: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. RESULTS: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. CONCLUSIONS: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure.

AIMS: Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin-neprilysin inhibition in a pooled analysis of 13 195 patients with heart failure with reduced and preserved EF. METHODS AND RESULTS: We combined data from PARADIGM-HF (EF ≤40%; n = 8399) and PARAGON-HF (EF ≥45%; n = 4796) in a pre-specified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in estimated glomerular filtration rate (eGFR), ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 ml/min/1.73 m2 in PARADIGM-HF and 63 ± 19 ml/min/1.73 m2 in PARAGON-HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of 6601 patients (1.9%) in the valsartan or enalapril group (hazard ratio 0.56, 95% confidence interval [CI] 0.42-0.75; p < 0.001). The mean eGFR change was -1.8 (95% CI -1.9 to -1.7) ml/min/1.73 m2 /year for the sacubitril/valsartan group, compared with -2.4 (95% CI -2.5 to -2.2) ml/min/1.73 m2 /year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (p-interaction = 0.64), but was most pronounced in those with baseline EF between 30% and 60% (p-interaction = 0.001). CONCLUSIONS: In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function.

Reasons for living among those with lived experience entering the suicide prevention workforce.

This study explored reasons for living among those with lived experience of suicide entering the suicide prevention workforce. The study recruited 110 participants from two Roses in the Ocean training programs (79% female, mean age 46.5). Responses to open-ended survey questions about reasons for living were analyzed using qualitative content analysis method. Connection to others and service were the most commonly stated reasons for living. Other categories included orientation toward future, life, self, pleasure, and spiritual reasons and values. These findings can be used in further research and design of support programs for peer specialists.

Excess mortality in solid organ transplant recipients hospitalized with COVID-19: A large-scale comparison of SOT recipients hospitalized with or without COVID-19.

BACKGROUND: Solid-organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) have higher risk of adverse outcomes compared to the general population. Whether hospitalized SOT recipients with COVID-19 are at higher risk of mortality than SOT recipients hospitalized for other causes, including non-COVID-19 pneumonia, remains unclear. METHODS: We used logistic regression to compare outcomes of SOT recipients hospitalized with COVID-19 to non-COVID-19 related admissions and with non-COVID-19 pneumonia. RESULTS: Of 17,012 hospitalized SOT recipients, 1682 had COVID-19. Those with COVID-19 had higher odds of ICU admission (adjusted odds ratio [aOR] 2.12 [95%CI: 1.88-2.39]) and mechanical ventilation (aOR 3.75 [95%CI: 3.24-4.33]). COVID-19 was associated with higher odds of in-hospital death, which was more pronounced earlier in the pandemic (aOR 9.74 [95%CI: 7.08-13.39] for April/May vs. aOR 7.08 [95%CI: 5.62-8.93] for June through November 2020; P-interaction = .03). Compared to SOT recipients hospitalized with non-COVID-19 pneumonia, odds of in-hospital death were higher in SOT recipients with COVID-19 (aOR 2.44 [95% CI: 1.90-3.13]), regardless of time of hospitalization (P-interaction > .40). CONCLUSIONS: In this large cohort of SOT recipients, hospitalization with COVID-19 was associated with higher odds of complications and in-hospital mortality than non-COVID-19 related admissions, and 2.5-fold higher odds of in-hospital mortality, compared to SOT recipients with non-COVID-19 pneumonia.

Preliminary Evaluation of Lived Experience of Suicide Training: Short-, Medium- and Longer-Term Impacts of Our Voices in Action Training.

Despite increased participation and multiple workforce roles of those with lived experience in suicide prevention, there are no evaluated training programs to support this population. This study evaluated a training program aimed to prepare people for these important roles. Survey data at pre-, post- and at three- and 12-month follow-up were used measuring knowledge, attitudes, and self-efficacy, as well as psychological distress as a safety measure. Participants experienced significant gains in knowledge after training, although not all aspects of knowledge were maintained at follow-up. Self-efficacy was examined through confidence and empowerment. Confidence gains were significant at immediate and longer-term follow-up but gains in empowerment were not maintained over time. Participants' positive attitudes improved but this was not significant. There was no indication of increases in psychological distress in participants throughout the training and follow-up periods. Implications of these outcomes are discussed.

Donor-derived Cryptococcus gattii sensu stricto infection in two kidney transplant recipients, southeastern United States.

Cryptococcus gattii infection is a rare cause of severe pulmonary disease and meningoencephalitis that has only recently been detected in the southeastern United States. We describe an organ transplant-associated outbreak of C. gattii infection involving an HIV-negative immunosuppressed donor in this region who died following new-onset headache and seizure of unknown cause. Retrospective cryptococcal antigen (CrAg) testing of donor serum was positive. Two of the three transplant recipients developed severe C. gattii infection 11 and 12 weeks following transplantation. One recipient died from severe pulmonary infection, identified on autopsy, and the other ill recipient survived following treatment for cryptococcal meningitis. This outbreak underscores the importance of considering cryptococcosis in patients with clinical findings suggestive of subacute meningitis or other central nervous system (CNS) pathology, and the potential benefit of routine pre-transplant donor CrAg screening using lateral flow assay to guide recipient antifungal prophylaxis. The case also adds to emerging evidence that C. gattii is a potential threat in the southeastern United States.

Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). METHODS: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. RESULTS: At randomization, eGFR was 63±19 mL·min-1·1.73 m-2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min-1·1.73 m-2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min-1·1.73 m-2 per year). CONCLUSIONS: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

AIMS: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies. METHODS AND RESULTS: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA. CONCLUSIONS: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.

Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation.

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.