bluuebunny/crossref_metadata_2025 huggingface dataset:
Heart failure with improved ejection fraction (HFimpEF) in patients treated with sacubitril/valsartan (SV)
Authors: Kong M G , Suh J , Moon I K , Lee K Y , Jang H J , Kim J S , Choi I J
Published: October 2022

Introduction

Several studies demonstrated that patients with improvement of left ventricular ejection fraction (LVEF) and symptoms had good prognosis in heart failure with reduced ejection fraction (HFrEF). Based on these results, new classification of HF according to LVEF was currently proposed. Sacubitril/valsartan (SV) is recommended as one of the first-line therapy of HFrEF patients. SV reduced hospitalization for HF and cardiovascular mortality compared to enalapril in PARADIGM-HF trial. However, it is unclear that patients with improvement of LVEF also have better prognosis compared to patients without LVEF improvement among patients treated with SV.

Purpose

We aimed to evaluate the clinical characteristics and outcomes of heart failure with improved ejection fraction (HFimpEF) in heart failure with reduced ejection fraction (HFrEF) patients treated with SV.

Methods

We analyzed 230 patients with HFrEF taking SV in a multicenter retrospective cohort (RECORD-SV registry) from 2017 to 2019. Enrolled 230 patients were performed baseline and 1-year follow-up echocardiography. Based on 2 echocardiographic results, we defined “HFimpEF” as HF with a baseline LVEF ≤40%, ≥10% increase from baseline LVEF and a follow-up measurement of LVEF >40%. Others were defined as “Persistent HFrEF”. We analyzed and compared clinical characteristics and outcomes between two groups. Primary endpoint was a composite outcome of all-cause death and hospitalization for HF (HHF).

Results

From 230 patients, 65 patients with HFimpEF and 165 patients with Persistent HFrEF were analyzed. The median follow-up duration was 557 days (interquartile range 364 to 727 days). Patients with HFimpEF had a higher prevalence of female gender (50.8% vs. 30.3%) and de novo HF (44.6% vs. 21.2%). There were no significant differences for age, etiology (ischemic vs. non-ischemic), diabetes, atrial fibrillation, hypertension, and HF medications including SV dose between two groups. Patients with HFimpEF showed lower rate of all-cause death or HHF as a primary endpoint compared to patients with persistent HFrEF (6.2% vs. 22.4%; IPTW adjusted HR 0.24; 95% CI 0.13–0.46; p<0.001) (Table 1). It was also shown that HFimpEF patients had a reduced risk of primary endpoint in the Kaplan-Meier curves compared with persistent HFrEF (Log-rank p=0.045) (Figure 1). We demonstrated that Non-prior MI (adjusted OR 7.29; 95% CI 1.50–35.36; p=0.014) and de novo HF (adjusted OR 4.33; 95% CI 1.70–11.04; p=0.002) were independent prognostic factors of HFimpEF in HFrEF patients treated with SV.

Conclusions

HFimpEF patients had better clinical outcomes compared to those with persistent HFrEF in HFrEF patients treated with SV. Non-prior MI and de novo HF were independent predictors of HFimpEF in patients treated with SV.

Funding Acknowledgement

Type of funding sources: None.
Effects of angiotensin receptor-neprilysin inhibitors (ARNIs) on the glucose and fat metabolism biomarkers leptin and fructosamin
Authors: Ohnewein B , Shomanova Z , Jirak P , Topf A , Froeb E J , Pogoda C , Granitz C , Lichtenauer M , Hoppe U , Reinecke H , Pistulli R , Motloch L J
Published: October 2022

Background

Heart Failure with reduced ejection fraction (HFrEF) has a life time risk about 20% among adults aged 40 years or older and a 5-year mortality rate about 60% [1,2]. However novel therapies have shown to improve this outcome. One novel agent are angiotensin receptor-neprilysin inhibitors (ARNIs) that increase the BNP levels via inhibiting neprilsyin [3]. This has beneficial effects on heart failure by reducing preload, inflammation and fibrosis. Neprilysin also interacts with leptin and is known to correlate with the incidence and progression of heart failure if chronically elevated [4]. Furthermore beneficial affects of ARNI therapy on glucose metabolism were reported in a post-hoc analysis of the PARADIGM-HF trial [5]. In this study we aim to investigate the effect of ARNI therapy on the fat metabolism markers leptin and on the glucose metabolism marker fructosamin.

Methods

In total, we included 74 patients with HFrEF with ischemic (N=37) and non-ischemic (n=37) origin in the present study. The mean NYHA class was II–III, the mean BMI 28 (SD 6.3). Patients had well established heart failure therapy before starting ARNI therapy with sacubitril/valsartan. 88% of patients were on ACE-inhibitors, 86% on beta blockers and 68% on mineralocorticoid receptor antagonists. Serum samples were obtained and analyzed for leptin, fructosamin and pBNP before and 3–6 month after ARNI therapy. The clinical parameters LVEF and NYHA class were assessed before and 3–6 month after ARNI therapy.

Results

Baseline leptin level was 15.0 (SD 17.2), baseline fructosamin level was 370.1 (SD 167.7) and baseline pBNP level was 1494.9 (SD 1281.4). Under therapy a significant improvement of ejection fraction from 29,8% to 37,5% (7,7 SD 8,5 P≤0.001), an improvement of NYHA stadium from 2.46 (SD 0.62) to 1.96 (SD 0.63, p=0.005) and a significant decrease of pBNP (562.1 SD 1256.4, p=0.018) was found. Along with that, a significant increase in leptin levels (3.6 SD 8.85, p=0.012) and a significant increase in fructosamine levels (93.5 SD 160.6, p=0.013) was shown.

Conclusion

Under therapy with ARNI we showed a sufficient therapy response with improvement of ejection fraction and decrease of pBNP in line with literature. Surprisingly metabolism biomarkers did significantly worsen under the first three to six month after new ARNI therapy. To distinguish between a side effect of ARNI therapy or consequence of heart failure itself further investigations are needed.

Funding Acknowledgement

Type of funding sources: None.
The effect of kidney dysfunction on introducing guideline-derived medical therapy and on mortality among hospitalized patients with heart failure with reduced ejection fraction
Authors: Muk B , Banfi-Bacsardi F , Majoros Z S , Vagany D , Borsanyi T , Lee S , Pilecky D , Duray G Z , Kiss R G , Nyolczas N
Published: October 2022

Introduction

Chronic kidney disease (CKD) is one of the main limiting factors of introducing and uptitrating guideline-derived medical therapy (GDMT) among patients with heart failure with reduced ejection fraction (HFrEF). Only few studies evaluated the success of implementation of pharmacotherapy in HFrEF and its effect on prognosis across the whole spectrum of CKD stages.

Aim

To analyze the implementation differences of mortality reducing triple therapy (ACEi/ARB/ARNI + BB + MRA) by severity of CKD among hospitalized HFrEF patients. Furthermore, we evaluated the association between mortality and CKD stages.

Patients and methods

257 consecutive, hospitalized HFrEF patients' data were analyzed retrospectively, who had been hospitalized at the Heart Failure Unit of a tertiary cardiological centre in 2019–2021 (male: 74%, age: 65 [56–73] years, ischemic: 45%, diabetes: 40%, hypertension 58%, atrial fibrillation 46%, LVEF: 25 [20–30] %, NT-proBNP at admission: 6086 [2757–11994] pg/ml). Median eGFR was 58 [39–74] ml/min/1.73 m2, 53% of patients had eGFR <60 ml/min/1.73 m2 (CKD stage: G1 – eGFR >90 ml/min/1.73 m2: 15%, G2 – eGFR = 60–90 ml/min/1.73 m2: 32%, G3A – eGFR = 45–59 ml/min/1.73 m2: 20%, G3B – eGFR = 30–44 ml/min/1.73 m2: 21%, G4 – eGFR = 15–29 ml/min/1.73 m2: 9%, G5 – eGFR <15 ml/min/1.73 m2: 3%). 1% of patients was on dialysis.

The success of implementing triple-therapy depending on CKD stages was investigated with Chi-square test, while mortality differences were analyzed with Kaplan-Meier method.

Results

The severity of CKD led to significantly (p<0.0001) lower implementation rate of triple-therapy (CKD stage G1–G2–G3A–G3B–G4–G5: 92 vs. 87 vs. 81 vs. 74 vs. 29 vs. 43%). However, only the ratio of RASi use showed significant difference (p<0.0001) among CKD subgroups (stage G1–G2–G3A–G3B–G4–G5: 100 vs. 100 vs. 92 vs. 87 vs. 42 vs. 43%), while BB (CKD stage G1–G2–G3A–G3B–G4–G5: 92 vs. 88 vs. 88 vs. 81 vs. 71 vs. 71%; p=0.162) and MRA (CKD stage G1–G2–G3A–G3B–G4–G5: 97 vs. 98 vs. 96 vs. 93 vs. 83 vs. 100%; p=0.0899) implementation was independent of renal function. All-cause 6-month mortality was 14% in the whole population. 6-months mortality rates proved to be higher (p=0.0083) in patients with more severe CKD (stage G1–G2–G3A–G3B–G4–G5: 8 vs. 11 vs. 8 vs. 20 vs. 35 vs. 29%).

Conclusions

Patients with advanced HFrEF and concomitant CKD are not equally treated with GDMT, even though kidney dysfunction is not an absolute contraindication of cornerstone HFrEF therapies. HFrEF patients with more severe CKD have poorer prognosis, thus implementation of mortality- and morbidity reducing drug therapy according to the guidelines is essential.

Funding Acknowledgement

Type of funding sources: None.
Effects of empagliflozin in patients with heart failure and preserved ejection fraction according to baseline diuretic use: results from the EMPEROR-Preserved trial
Authors: Butler J
Published: October 2022

Background

In the EMPEROR-Preserved trial, empagliflozin reduced the risk of hospitalizations for heart failure (HHF) or cardiovascular (CV) death in patients with heart failure and preserved ejection fraction (HFpEF). Almost one in five patients in the trial were not on baseline diuretic therapy.

Purpose

To evaluate the efficacy and safety of empagliflozin according to baseline diuretic treatment, as well as change in diuretic therapy after initiation of empagliflozin.

Methods

Patients were categorized into subgroups as no diuretic and furosemide-equivalent diuretic dose of <40, 40 and >40mg and were compared for first HHF or CV death, HHF, CV death, total HHF, change in eGFR slope, and change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Scores (KCCQ-CSS) between patients on empagliflozin vs. placebo. Changes in diuretic therapy in the two treatment groups were also compared.

Results

Amongst 5815 patients with data on diuretic dose, 1179 (20%) were on no diuretic, 2039 (35%) were on <40mg, 1700 (29%) were on 40mg, and 897 (15%) were on >40mg at baseline. Patients on higher diuretic doses at baseline were more likely to be diabetic, had a higher body weight and NT-proBNP, and lower estimated glomerular filtration rate (eGFR) on average. Patients on higher diuretic doses also had worse health status based on NYHA class and KCCQ-CSS estimates. The reduction of the risk of CVD or HHF, total HHF, preservation of eGFR, and KCCQ-CSS improvement with empagliflozin were consistent across all doses of diuretics (Table 1). The findings for all outcomes were consistent in patients on diuretics (any dose) vs. not on diuretics. Treatment with empagliflozin was associated with decreased rates of initiation (HR: 0.73 [0.59,0.90; p=0.004) or intensification (HR: 0.74; [0.65, 0.84]; p<0.001) of diuretics, while there were increased rates in permanent discontinuation of diuretics (HR: 1.46 [1.17, 1.82]; p<0.001) or diuretic dose reduction (HR: 1.22 [1.06, 1.42]; p=0.007). The incidence of adverse events were similar between treatment arms, irrespective of baseline use of diuretics. Volume depletion events were more common with empagliflozin amongst patients treated with diuretics (7.4 vs 5.7 events per 100 patient-years for empagliflozin vs placebo).

Conclusion

Empagliflozin improved clinical outcomes and health status in patients with HFpEF irrespective of baseline use of diuretics. Additionally, empagliflozin was associated with increased de-escalation or discontinuation of diuretics and decreased chances of initiation or intensification.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance
Association of heart rate with heart failure outcomes and the effects of empagliflozin in patients with preserved ejection fraction – EMPEROR-Preserved trial
Authors: Boehm M , Anker S D , Mahfoud F , Filippatos G , Ferreira J P , Pocock S J , Brueckmann M , Linetzky B , Schueler E , Wanner C , Zannad F , Packer M , Butler J
Published: October 2022

Background and objective

High resting heart rate (HR) associates with cardiovascular death (CVD) and heart failure hospitalisation (HFH) in patients with reduced ejection fraction (HFrEF), but data are sparse in patients with preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction. Empagliflozin reduced the risk of CVD and HFH in HFpEF in the EMPEROR-Preserved trial. This study analyses the influence of HR on outcomes in patients with left ventricular ejection fraction (LVEF) >40% in EMPEROR-Preserved and evaluates the effects of empagliflozin across HR categories.

Methods

Patients (n=5988) with HFpEF (LVEF >40%) were categorised to HR <70 beats per minute (bpm), 70–75 bpm and >75 bpm. The composite of CVD or HFH (primary outcome), first HFH, CVD, recurrent HFH and all-cause mortality were studied in the HR groups and in patients separated by sinus rhythm (SR) or atrial fibrillation (AF) and true HFpEF (EF ≥50%) or HFmrEF (EF 40–49%).

Results

Empagliflozin did not influence HR over time. At HR >75 bpm, the primary outcome (hazard ratio: 1.31, 1.13–1.52, p=0.0003), time to first HFH (hazard ratio: 1.25, 1.04–1.49, p=0.02), recurrent HFH (hazard ratio: 1.29, 1.05–1.60, p=0.02), CVD (hazard ratio: 1.49, 1.21–1.84, p=0.0001) and all-cause mortality (hazard ratio: 1.49, 1.28–1.73, p<0.0001) were increased compared to HR of <70 bpm with HR 70–75 bpm showing intermediate results. The influence of HR on the primary outcome was only observed in SR (p trend=0.005), but not in AF (p trend=0.55). Patients with true HFpEF (≥50%) or HFmrEF (40–49%) showed similar effects. The treatment effects of empagliflozin to reduce the primary outcome, time to first HFH and recurrent HFH were not modified by HR.

Conclusions

HR in SR, but not in AF, predicts heart failure outcomes in HFpEF and HFmrEF, but the effects of empagliflozin were not modified by HR.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance
The effectiveness of ARNI medication in patients, non-responder to cardiac resynchronization therapy
Authors: Szabo K , Sandorfi G , Nagy L T , Nagy L , Clemens M , Toth A , Borbely A , Polik Z S , Raduly A , Csanadi Z
Published: October 2022

Introduction

Almost 30% of patients are non-responders to cardiac resynchronization therapy (CRT) with no improvement of heart failure (HF) symptoms and left ventricular ejection fraction (LVEF). Angiotensin Receptor Neprilysin Inhibitor (ARNI), a novel class of medication resulted in a significant improvement in HF with reduced ejection fraction (HFrEF) in recent trials. No data has been reported on the clinical effectiveness of ARNI in the specific HF patient cohort of CRT non-responders (CRT-NR).

Objective

Herein, we compared the efficacy of ARNI medication in a general HF patient population and in CRT-NR patients.

Method

CRT-NR patients on ARNI therapy initiated at least 6 months after CRT implantation in years 2019–2021 were enrolled. Criterium for CRT-NR was a no, or less than 10% improvement in LVEF measured with echocardiography 6 months post-implantation. HF patients on ARNI therapy from our HF Clinic were used as controls. Changes in LVEF, in NYHA functional class and in the level of NT-proBNP were compared before ARNI therapy initiation and 6 months thereafter in both groups.

Results

70 patients (age: 66,03±9.06 years, 9 women) were enrolled in the CRT-NR and 135 patients (age 62,36±11.26 years; 31 women) in the control group. LVEF increased from 25,25±5.70% to 29,47±6.73% (p<0.001), NYHA class decreased from 2,74±0.55 to 2.03±0.68 (p<0.001) and NT-proBNP from 3884.21±2503.95 to 2676,16±1745.94 (p<0.001) in CRT-NR patients after a 6-month treatment with ARNI. Similar improvement was demonstrated in all parameters in the control group: LVEF increased from 26,64±6.47% to 29,91±6.64% (p<0,001), NYHA class decreased from 2,97±0.54 to 2,18±0.58% (p<0,001) and NT-proBNP from 5355,17±1731.71 to 2062,66±1919.07 (p<0,001). During a mean follow-up of 20,55±11,36 months mortality rates were 17,14% in the CRT-NR group, and 18,51% in the control group.

Conclusion

ARNI therapy resulted in significant improvement in functional class, LVEF and HF biomarker level in CRT-NR patients, similarly to what was observed in a general HF patient cohort with no CRT.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Project no. TKP2021-EGA-18 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme.
Clinical determinants and barriers to cardiac rehabilitation enrolment of patients with heart failure with reduced ejection fraction
Authors: Alexandre A , Campinas A , Schmidt C , Magalhaes S , Preza-Fernandes J , Silveira J , Gomes C , Santos M , Torres S
Published: October 2022

Introduction

Cardiac rehabilitation (CR) is a recommended treatment for patients with heart failure with reduced ejection fraction (HFrEF). Despite the robust evidence supporting its safety and benefits, there is an incomplete understanding of the reasons of the underutilization of CR programs in HFrEF. These reasons are complex and probably encompass healthcare system- and patient-level barriers.

Purpose

To study the clinical determinants and barriers to enrolment in a CR program for HFrEF patients.

Methods

We conducted a study of consecutive heart failure patients followed at a dedicated HFrEF cardiology clinic from January 2019 to April 2021. Patients were divided according to previous enrolment in CR program. Data were collected from electronic health records, and in case of missing data patients were asked by telephone about the reason for not participating in CR using a structured and validated questionnaire for this purpose.

Results

Of 228 patients with HFrEF, 60% had not been enrolled in a CR program; they were older (63 vs 58 years; p<0.01) and more likely to have comorbidities such as hypertension (56% vs 41%; p=0.03) or concomitant chronic obstructive pulmonary disease (20% vs 8%; p=0.01). Conversely, patients enrolled in CR programs were more likely to have a previous history of acute myocardial infarction (34% vs 20%; p=0.02). Regarding heart failure-related clinical features (NYHA functional class, LVEF, ICD/CRT), we did not find any significant differences between groups. The main reasons for not being enrolled in CR programs were: no medical referral (31%), concomitant medical problems (27%) such as musculoskeletal problems, patient refusal (11%) and geographical distance to the hospital (9%).

Conclusion

Despite the high proportion (40%) of HFrEF patients who underwent CR program compared to previous studies, the enrolment to CR can be further improved. The main barriers are related to health professionals (no referral), healthcare system (geographical distance to the hospital) and patients (concomitant noncardiac problems). Innovative strategies should target these factors to increase the delivery of CR program in HFrEF.

Funding Acknowledgement

Type of funding sources: None.
Progression of aerobic and anaerobic thresholds in cardiac rehabilitation: heart failure vs coronary artery disease
Authors: Custodio P M , Santos A R , Moreno L , Mendes M
Published: October 2022

Background

Cardiac rehabilitation (CR) aims at the maintenance and potential recovery of cardiovascular function through an exercise program. Programs may be started with cardiopulmonary exercise test (CPET) in order to assess aerobic and anaerobic thresholds (VT1 and VT2), and to optimize the exercise prescription. In our center, most CR programs are in-hospital for the first 3–6 months, after which patients undertake another CPET to evaluate the progression and follow up with a home-based training schedule.

Aim

To compare the progression in aerobic and anaerobic thresholds after CR program in patients with heart failure (HF) or post-acute event in coronary artery disease (CAD). Stratify the results based on ejection fraction to see which patients show the most benefit.

Methods

A retrospective single center study using data from patients that were included in a CR program between January 2016 and December 2020. Patients without measurable ventilatory thresholds 1 and 2 (VT 1 and VT2) at both CPET were excluded as were those that didn't complete the CR program. VT 1 and VT2 progression was compared among patients referred to the CR program due to HF and CAD.

A sub-analysis was performed based on having reduced ejection fraction (rEF) (<50% on echocardiogram).

Results and discussion

A total of 136 patients were included (57,51±13,47 YO; 80,9% (n=110) male; 44,2% (n=60) had reduced ejection fraction. 46 patients were referred to CR due to HF and 90 due to CAD. Most patients referred to CR due to CAD underwent complete revascularization (82,2%) beforehand. The average time between the acute coronary event and the beginning of the CR program was 208 days. Even though the stunned myocardial phase would be expected to be resolved by the time the CR program was started, patients with CAD showed the steepest progression in VT1 and VT2 thresholds. Patients with CAD with preserved ejection fraction are the subgroup with the most robust progression in VT1 and VT2 when compared with rEF. This difference was statistically significant when the two etiologies were compared (p value = 0,047 for VT1 and 0,031 for VT2) – Table 1.

Conclusion

Patients with CAD and preserved ejection fraction exhibit the faster progression in aerobic and anaerobic thresholds in CR when compared to HF patients.

Funding Acknowledgement

Type of funding sources: None.
Comparative effectiveness of exercise-based cardiac rehabilitation for heart failure: a Bayesian network analysis of 44 randomized trials and 5896 patients
Authors: Jiang L , Wan R X , Li J T , Yan Y
Published: October 2022

Introduction

The prevalence of heart failure (HF) is increasing nowadays. Exercise-based cardiac rehabilitation (CR) reduces mortality and further improves the outcome of patients with HF. However, the effect of different types of CR on HF remains unclear. Data comparing these CR have not been synthesized. Thus, the purpose of this study is to determine the relative efficacy of different types of exercise-based CR for individuals with HF using a Bayesian network meta-analysis.

Methods

We followed a pre-specified protocol (PROSPERO: CRD42021278351). We conducted a systematic literature review of any randomized controlled trials which evaluated exercise-based CR for patients with HF. Databases including Embase, Medline, the Cochrane Central Register of Controlled Trials, and Web of Science were screened up to 31 December 2021. The primary outcomes focus on functional capacity (peak oxygen uptake and 6-minute walk distance) and health-related quality of life (hr-QOL). The main analysis was complemented by network subanalysis, standard pairwise comparisons, and subgroup and sensitivity analyses. The pooled estimates were quantified as mean differences (MD) or standardized mean difference (SMD)where appropriate, at 95% confidence intervals (CI).

Results

We identified 44 randomized controlled trials with a total of 5896 HF participants. Among 23 studies that compared exercise-based CR and usual care, participants in center-based CR (CBCR) had improvement of peak oxygen uptake (MD: 2.30 mL/kg per minute; 95% CI, 0.43–4.40) and 6-minute walk distance (MD: 33 meters; 95% CI, 11.00–58.00).18 studies that compared exercise-based CR with usual care showed that CBCR and cardiac telerehabilitation (CTR) had greater improvements in hr-QOL (SMD: −0.38; 95% CI, −0.49 to −0.15 and SMD: −0.18,95% CI, −0.36 to −0.00 respectively). Treatment ranking indicated CTR has the highest probability (46.0%, 50.2%) of being the most effective CR for peak oxygen uptake and hr-QOL elevation respectively. CBCR was similarly indicated as the most effective treatment for 6-min walk distance (38.7%).

Conclusion

Exercise-based CR programs provide broader cardiovascular benefits compared with UC. CBCR significantly improved functional capacity. CBCR and CTR have favorable effects on hr-QOL.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): China Scholarship Council
General practitioners’ perceptions of pharmacists working in general practice: a qualitative interview study
Authors: Hurley Eoin , Walsh Elaine , Foley Tony , Heinrich Clara H , Byrne Stephen , Dalton Kieran
Published: October 2022

Background

Pharmacists are being increasingly employed as part of general practice teams globally, and their input has been associated with several clinical and economic benefits. However, there is a paucity of research focussing on general practitioners’ (GPs’) perceptions of pharmacist integration into practices in countries where this novel role for pharmacists is yet to become commonplace.

Objective

To explore GPs’ perceptions of integrating pharmacists into general practices and to identify the behavioural determinants of GPs integrating pharmacists into practices.

Methods

Semistructured interviews were conducted with GPs practising in Ireland, who were sampled using a combination of purposive, convenience, and snowball sampling. Interviews were audio-recorded and transcribed verbatim, which then were analysed using conventional content analysis and directed content analysis employing the Theoretical Domains Framework (TDF).

Results

Seventeen GPs were interviewed between November 2021 and February 2022. Seven TDF domains were identified as predominant in influencing GPs’ perceptions of pharmacist integration into general practices. These perceptions were mostly positive, especially regarding patient outcomes, cost savings, and improving access to care. However, there were concerns about funding the role, affecting others’ workloads, and pharmacists’ training needs to work in practices.

Conclusion

This study’s theory-informed insight provides a deeper understanding of GPs’ perceptions of pharmacists working in general practice and behaviours which can be targeted to help optimize integration. These findings should be utilized in future service development to preempt and address GPs’ concerns ahead of pharmacist integration, as well as to inform the development of general practice-based pharmacist roles going forward.
Facial Trustworthiness Perception Across the Adult Life Span
Authors: Pehlivanoglu Didem , Lin Tian , Lighthall Nichole R , Heemskerk Amber , Harber Alexandria , Wilson Robert C , Turner Gary R , Spreng R Nathan , Ebner Natalie C
Published: October 2022

Objectives

Trust is crucial for successful social interaction across the life span. Perceiver age, facial age, and facial emotion have been shown to influence trustworthiness perception, but the complex interplay between these perceiver and facial characteristics has not been examined.

Method

Adopting an adult life-span developmental approach, 199 adults (aged 22–78 years) rated the trustworthiness of faces that systematically varied in age (young, middle-aged, and older) and emotion (neutral, happy, sad, fearful, angry, and disgusted) from the FACES Lifespan Database.

Results

The study yielded three key results. First, on an aggregated level, facial trustworthiness perception did not differ by perceiver age. Second, all perceivers rated young faces as the most trustworthy, and middle-aged and older (but not young) perceivers rated older faces as least trustworthy. Third, facial emotions signaling threat (fear, anger, and disgust) relative to neutral, happy, and sad expressions moderated age effects on facial trustworthiness perception.

Discussion

Findings from this study highlight the impact of perceiver and facial characteristics on facial trustworthiness perception in adulthood and aging and have potential to inform first impression formation, with effects on trait attributions and behavior. This publication also provides normative data on perceived facial trustworthiness for the FACES Lifespan Database.
Toward Quantification of Agitation in People With Dementia Using Multimodal Sensing
Authors: Davidoff Hannah , Van den Bulcke Laura , Vandenbulcke Mathieu , De Vos Maarten , Van den Stock Jan , Van Helleputte Nick , Van Hoof Chris , Van Den Bossche Maarten J A
Published: October 2022

Background and Objectives

Agitation, a critical behavioral and psychological symptom in dementia, has a profound impact on a patients’ quality of life as well as their caregivers’. Autonomous and objective characterization of agitation with multimodal systems has the potential to capture key patient responses or agitation triggers.

Research Design and Methods

In this article, we describe our multimodal system design that encompasses contextual parameters, physiological parameters, and psychological parameters. This design is the first to include all three of these facets in an n > 1 study. Using a combination of fixed and wearable sensors and a custom-made app for psychological annotation, we aim to identify physiological markers and contextual triggers of agitation.

Results

A discussion of both the clinical as well as the technical implementation of the to-date data collection protocol is presented, as well as initial insights into pilot study data collection.

Discussion and Implications

The ongoing data collection moves us toward improved agitation quantification and subsequent prediction, eventually enabling just-in-time intervention.
Perceived COVID-19 vaccine attributes associated with early adoption among adults in rural Indiana
Authors: Hunter-Mullis Kristina , Macy Jonathan T , Greene Alison , Simon Kosali
Published: October 2022

2019 Novel coronavirus (COVID-19) vaccination rates in the United States have plateaued in specific populations, including rural areas. To improve COVID-19 vaccination rates and to encourage early vaccine uptake in future pandemics, this study aimed to examine vaccine attributes associated with early adoption. Data are from an anonymous online survey of adults using targeted Facebook pages of rural southern Indiana towns in January and February 2021 (n = 286). The diffusion of innovation theory states that the rate of adoption of a product in a specific population is explained by five perceived attributes: relative advantage, compatibility, observability, complexity and trialability. Binary logistic regression analyses were used to examine the association of Diffusion of Innovation theory attributes of the COVID-19 vaccine on early adoption. Results indicated that trialability [odds ratio (OR) = 3.307; 95% confidence interval (CI) = 1.964–5.571; P < 0.001], relative advantage (OR = 2.890; 95% CI = 1.789–4.667; P < 0.001) and compatibility (OR = 2.606; 95% CI = 1.476–4.601; P < 0.001) showed significant independent associations with early adoption. Furthermore, age and political ideology were significant moderators of complexity and relative advantage, respectfully. Health education strategies for early vaccine uptake should focus on building trust in vaccine safety, increasing short-term benefits of vaccination and promoting relatability to personal values.
Health-Related Quality of Life Outcomes With Tofacitinib Treatment in Patients With Ulcerative Colitis in the Open-Label Extension Study, OCTAVE Open
Authors: Biedermann Luc , Dubinsky Marla C , Vermeire Séverine , Fellmann Marc , Gardiner Sean , Hur Peter , Mundayat Rajiv , Panés Julian , Rubin David T
Published: October 2022

Background

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We report health-related quality of life (HRQoL) outcomes in patients with ulcerative colitis in the phase 3 open-label, long-term extension study, OCTAVE Open.

Methods

The Inflammatory Bowel Disease Questionnaire (IBDQ), EuroQoL-5 Dimensions Health Questionnaire, and 36-Item Short Form Survey scores were analyzed up to month (M) 72 in 4 subpopulations: patients in remission at baseline (maintenance remitters) assigned tofacitinib 5 mg twice daily and patients not in remission at baseline (maintenance nonremitters, maintenance treatment failures, and induction nonresponders [IndNRs]) assigned tofacitinib 10 mg twice daily in OCTAVE Open. Data were analyzed overall and stratified by corticosteroid use at baseline, prior tumor necrosis factor inhibitor failure, and prior immunosuppressant failure.

Results

Among maintenance remitters and nonremitters, HRQoL outcomes were maintained up to M72: 80.0% and 100.0% of patients had an IBDQ total score ≥170, respectively. At baseline, 7.4% of maintenance treatment failures had an IBDQ total score ≥170, and this increased to 54.3% and 75.0% at M2 and M72, respectively. Corresponding values for IndNRs were 22.6%, 51.0%, and 86.0%. HRQoL outcomes were independent of treatment history. Among patients not in remission at baseline, improvement in EuroQoL-5 Dimensions Health Questionnaire and 36-Item Short Form Survey scores was maintained or achieved by M2, and steady to M72 or M33, with maintenance treatment failures and IndNR subpopulations undergoing the biggest improvements from baseline.

Conclusions

A continued favorable impact on HRQoL was revealed with long-term tofacitinib treatment in OCTAVE Open, regardless of baseline remission status or treatment history. (ClinicalTrials.gov; number: NCT01470612).
In silico analysis of metabolic effects of bipolar disorder on prefrontal cortex identified altered GABA, glutamate-glutamine cycle, energy metabolism and amino acid synthesis pathways
Authors: Karakurt Hamza Umut , Pir Pınar
Published: October 2022

Bipolar disorder (BP) is a lifelong psychiatric condition, which often disrupts the daily life of the patients. It is characterized by unstable and periodic mood changes, which cause patients to display unusual shifts in mood, energy, activity levels, concentration and the ability to carry out day-to-day tasks. BP is a major psychiatric condition, and it is still undertreated. The causes and neural mechanisms of bipolar disorder are unclear, and diagnosis is still mostly based on psychiatric examination, furthermore the unstable character of the disorder makes diagnosis challenging. Identification of the molecular mechanisms underlying the disease may improve the diagnosis and treatment rates. Single nucleotide polymorphisms (SNP) and transcriptome profiles of patients were studied along with signalling pathways that are thought to be associated with bipolar disorder. Here, we present a computational approach that uses publicly available transcriptome data from bipolar disorder patients and healthy controls. Along with statistical analyses, data are integrated with a genome-scale metabolic model and protein–protein interaction network. Healthy individuals and bipolar disorder patients are compared based on their metabolic profiles.

We hypothesize that energy metabolism alterations in bipolar disorder relate to perturbations in amino-acid metabolism and neuron-astrocyte exchange reactions. Due to changes in amino acid metabolism, neurotransmitters and their secretion from neurons and metabolic exchange pathways between neurons and astrocytes such as the glutamine-glutamate cycle are also altered. Changes in negatively charged (−1) KIV and KMV molecules are also observed, and it indicates that charge balance in the brain is highly altered in bipolar disorder. Due to this fact, we also hypothesize that positively charged lithium ions may stabilize the disturbed charge balance in neurons in addition to its effects on neurotransmission. To the best of our knowledge, our approach is unique as it is the first study using genome-scale metabolic models in neuropsychiatric research.
Effects of mat feeding on the growth performance, removal, and mortality of pigs after weaning
Authors: Wensley Madie R , Potter Megan L , Tokach Mike D , Woodworth Jason C , Goodband Robert D , DeRouchey Joel M , Gebhardt Jordan T , Menegat Mariana B , Allerson Matt W
Published: October 2022

Four experiments were conducted to determine the effect of mat feeding strategy on the growth performance, removal, and mortality of pigs after weaning. In exp. 1, 1,392 weanling pigs (initially 7.0 kg; approximately 24 d of age) were randomly allotted to 1 of 2 mat feeding treatments (mat feed vs. no mat feed). Overall, mat fed pigs had a tendency for improved ADG (P = 0.065) and G:F (P = 0.060) compared to pigs not offered mat feed. Mat fed pigs had fewer removals (P = 0.013) compared to pigs not offered mat feed. In exp. 2, 2,912 weanling pigs (initially 5.5 kg; approximately 21 d of age) were randomly allotted to 1 of 2 mat feeding treatments (mat feed vs. no mat feed). Overall, no differences in growth performance were observed. However, mat fed pigs had decreased (P < 0.026) final body weights compared to pigs not offered mat feed. This may be related to removal rates as mat fed pigs had fewer removals (P = 0.026). In exp. 3, 3,264 weanling pigs (initially 5.5 kg; approximately 21 d of age) were randomly allotted to 1 of 4 treatments in a 2 × 2 factorial with main effects of diet form (pellet or crumble) and mat feeding (mat feed vs. no mat feed). No interactions between diet form and mat feeding were observed. No differences were observed in overall growth performance for the main effect of mat feeding. Pigs offered pelleted feed had decreased overall ADFI (feed disappearance from the feeder and feed placed on the mat; P = 0.013) and improved G:F (P < 0.001) compared to pigs offered crumble feed. No differences were observed in removals or mortalities for the main effect of mat feeding or diet form. In exp. 4, 3,227 weanling pigs (initially 5.1 kg; approximately 21 d of age) were randomly allotted to 1 of 3 treatments consisting of mat feeding small (3.2 mm) pellets, mat feeding large (12.7 mm) pellets, or no mat feeding. Overall, no differences were observed in ADG or G:F. Mat fed pigs had increased ADFI (P < 0.001) compared to pigs not offered mat feed. Given the shorter duration of this experiment, the extra feed provided with mat feeding had a greater impact on overall feed usage than exp. 1, 2, and 3. No differences were observed in removals or mortalities. When combining the removal and mortality data for the four experiments, mat fed pigs had fewer removals (P = 0.002) compared to pigs not offered mat feed. In summary, mat feeding may encourage earlier feeding behavior, therefore reducing the removal rate of pigs post-weaning.
In vitro genotoxicity assessment of French fries from mass catering companies: a preliminary study
Authors: Sanz-Serrano Julen , Garayoa Roncesvalles , Vitas Ana Isabel , López de Cerain Adela , Azqueta Amaya
Published: October 2022

It is generally assumed that French fries are likely to have weak in vitro mutagenic activity, but most studies thereof have only assessed gene mutations. In this article, the genotoxicity of 10 extracts of French fries was assessed using the in vitro micronucleus test (following the principles of the OECD 487 guidelines). Each sample was obtained from a different mass catering company in Navarra (Spain). This assay, together with the Ames test, is recommended in the basic in vitro phase included in the European Food Safety Authority Opinion on Genotoxicity Testing Strategies Applicable to Food and Feed Safety Assessment. Eight of 10 samples from mass catering companies induced chromosomal aberrations in the in vitro micronucleus test. Moreover, French fries deep-fried in the laboratory for different periods of time (0, 3, 5, 10, 20, 30 min) were assessed using the in vitro micronucleus test. Genotoxicity was observed in all time periods from 3 min on. The biological relevance of these results must be further explored.
Clozapine Therapy and COVID-19: A Systematic Review of the Prevalence Rates, Health Outcomes, Hematological Markers, and Patient Perspectives
Authors: Giles Grace , Varghese Sunny , Shymko Gordon , Nguyen Thinh , Waters Flavie
Published: October 2022

Background/Objectives

There have been concerns that clozapine treatment may undermine the capacity of the body to fight infection and increase the vulnerability to contracting COVID-19. This review of recent cohort studies investigated (1) whether people with a severe psychiatric disorder are at increased risk of COVID-19 and complications, (2) the immunological response of clozapine-users who contract COVID-19, and (3) patients’ perspectives on COVID-19 and the pandemic response.

Methods

A systematic search of EMBASE, Medline, Pubmed, and PsycINFO databases using PRISMA guidelines using “COVID-19”, “clozapine”, and “vaccination” terms.

Results

18 studies (out of 330 identified) met all criteria (N = 119 054 including 8045 on clozapine). There was no strong evidence that clozapine users may be at increased risk of contracting COVID-19 or developing complications after adjusting for medical comorbidities. Hematological studies showed temporary reductions in neutrophils in COVID-19-positive patients and vaccination suggesting a clozapine effect in defence against infection. Vaccination studies did not report major adverse effects. Increased plasma levels of clozapine and neutropenia however point to COVID-19-related interference of clozapine metabolism. Patient surveys reported limited impact on mental health and positive attitudes regarding pandemic response.

Conclusion

This review did not find compelling evidence that the immune system of clozapine users put them at risk of COVID-19 and further complications. Evidence of drug–infection interactions however points to the importance of adhering to consensus guidelines about clozapine therapy during the pandemic. More evidence using longitudinal designs is required to examine the longer-term effects of COVID-19 and vaccination in this vulnerable population.
Diagnostic Value of 18F-FACBC PET/MRI in Brain Metastases
Authors: Øen Silje Kjærnes , Johannessen Knut , Pedersen Lars Kjelsberg , Berntsen Erik Magnus , Totland Jon Andre , Johansen Håkon , Bogsrud Trond Velde , Solheim Tora S. , Karlberg Anna , Eikenes Live
Published: October 2022

Purpose

The study aims to evaluate whether combined 18F-FACBC PET/MRI could provide additional diagnostic information compared with MRI alone in brain metastases.

Patients and Methods

Eighteen patients with newly diagnosed or suspected recurrence of brain metastases received dynamic 18F-FACBC PET/MRI. Lesion detection was evaluated on PET and MRI scans in 2 groups depending on prior stereotactic radiosurgery (SRS group) or not (no-SRS group). SUVs, time-activity curves, and volumetric analyses of the lesions were performed.

Results

In the no-SRS group, 29/29 brain lesions were defined as “MRI positive.” With PET, 19/29 lesions were detected and had high tumor-to-background ratios (TBRs) (Dmax MR, ≥7 mm; SUVmax, 1.2–8.4; TBR, 3.9–25.9), whereas 10/29 lesions were undetected (Dmax MR, ≤8 mm; SUVmax, 0.3–1.2; TBR, 1.0–2.7). In the SRS group, 4/6 lesions were defined as “MRI positive,” whereas 2/6 lesions were defined as “MRI negative” indicative of radiation necrosis. All 6 lesions were detected with PET (Dmax MR, ≥15 mm; SUVmax, 1.4–4.2; TBR, 3.6–12.6). PET volumes correlated and were comparable in size with contrast-enhanced MRI volumes but were only partially congruent (mean DSC, 0.66). All time-activity curves had an early peak, followed by a plateau or a decreasing slope.

Conclusions

18F-FACBC PET demonstrated uptake in brain metastases from cancer of different origins (lung, gastrointestinal tract, breast, thyroid, and malignant melanoma). However, 18F-FACBC PET/MRI did not improve detection of brain metastases compared with MRI but might detect tumor tissue beyond contrast enhancement on MRI. 18F-FACBC PET should be further evaluated in recurrent brain metastases.
Umbilical Endometriosis Mimicking Malignancy on 18F-FDG PET/CT
Authors: Deng Yujiao , Xie Hongjun , He Limeng , Ding Zhiling , Zhang Wei
Published: October 2022

Umbilical endometriosis is a rare event. A 44-year-old woman complained of a palpable abdominal mass with bloody secretion and chronic abdominal pain for 2 months. 18F-FDG PET/CT images demonstrated multiple foci of increased tracer uptake indicating malignant tumor with metastases in the region of umbilicus and lower segment of the esophagus. Unexpectedly, the subsequent histology and immunohistochemistry of the umbilical lesion demonstrated endometriosis.
Socially Integrated Polysubstance (SIP) system: an open-source solution for continuous monitoring of polysubstance fluid intake in group housed mice
Authors: Wong Katrina , Wang Ziheng Christina , Patarino Makenzie , Baskin Britahny , Lee Suhjung Janet , Schindler Abigail G.
Published: October 2022

Despite impressive results from neuroscience research using rodent models, there is a paucity of successful translation from preclinical findings to effective pharmacological interventions for treatment of substance use disorder (SUD) in humans. One potential reason for lack of translation from animal models is difficulty in accurately replicating the lived experience of people who use drugs. Aspects of substance use in humans that are often not modeled in animal research include but are not limited to 1) voluntary timing and frequency of substance intake, 2) social environment during substance use, and 3) access to multiple substances and multiple concentrations of each substance. Critically, existing commercial equipment that allows for social housing and voluntary polysubstance use (e.g., home cage monitoring system) is prohibitively expensive and no open-source solutions exist. With these goals in mind, here we detail development of the Socially Integrated Polysubstance (SIP) system, an open-source and lower cost solution that allows for group housed rodents to self-administer multiple substances with continuous monitoring and measurement. In our current setup, each SIP cage contains four drinking stations, and each station is equipped with a RFID sensor and sipper tube connected to a unique fluid reservoir. Using this system, we can track which animal (implanted with unique RFID transponder) visits which drinking location and the amount they drink during each visit (in 20 ul increments). Using four flavors of Kool-Aid, here we demonstrate that the SIP system is reliable and accurate with high temporal resolution for long term monitoring of substance intake and behavior tracking in a social environment. The SIP cage system is a first step towards designing an accessible and flexible rodent model of substance use that more closely resembles the experience of people who use drugs.
A Natural Language Processing Pipeline to Study Disparities in Cannabis Use and Documentation Among Children and Young Adults A Survey of 21 Years of Electronic Health Records
Authors: Tavabi Nazgol , Raza Marium , Singh Mallika , Golchin Shahriar , Singh Harsev , Hogue Grant D. , Kiapour Ata M.
Published: October 2022

The legalizations of medical and recreational cannabis have generated a great deal of interest in studying the health impacts of cannabis products. Despite increases in cannabis use, its documentation during clinical visits is not yet mainstream. This lack of information hampers efforts to study cannabis effects on health outcomes. A clear and in-depth understanding of current trends in cannabis use documentation is necessary to develop proper guidelines to screen and document cannabis use. Here we have developed and used a hierarchical natural language processing pipeline (AUROC=0.94) to evaluate the trends and disparities in cannabis documentation on more than 23 million notes from a large cohort of 370,087 patients seen in a high-volume multi-site pediatric and young adult clinic over a period of 21 years. Our findings show a very low but growing rate of cannabis use documentation (<2%) in electronic health records with significant demographic and socioeconomic disparities in both documentation and use, which requires further attention.