Double-blind Study Research Articles

Esketamine administered epidurally as an adjuvant to epidural ropivacaine for labour analgesia: a prospective, double-blind dose-response study.

To investigate the efficacy of esketamine as an adjuvant to epidural ropivacaine for labour analgesia by determining its effect on the median effective concentration (EC50) in a 20 ml volume of ropivacaine. A prospective, double-blind dose-response study. This study was conducted in Women's Hospital, School of Medicine, Zhejiang University, China. One hundred and fifty parturients who requested epidural analgesia were recruited in this study to randomly receive epidural ropivacaine alone or with esketamine of 0.2 mg ml-1, 0.3 mg ml-1, 0.4 mg ml-1 or 0.5 mg ml-1, respectively. The primary outcome, EC50 of ropivacaine, was determined using an up-down sequential allocation technique. The secondary outcomes were analgesia characteristics, Ramsay Sedation Scale score, labour duration, caesarean section rate and adverse effects. The EC50 of ropivacaine with the addition of esketamine at concentrations of 0.3 mg ml-1, 0.4 mg ml-1 and 0.5 mg ml-1 resulted in significant reductions in the EC50 of ropivacaine to 0.050%, 0.044% and 0.043%, respectively, from baseline (esketamine 0 mg ml-1) (p<0.0001). However, reductions of the EC50 of ropivacaine were similar among the groups with esketamine of 0.3 mg ml-1, 0.4 mg ml-1 and 0.5 mg ml-1 (p>0.05). The Ramsay Sedation Scale score was higher and more dizziness was observed in the Group of esketamine 0.5 mg ml-1 compared with all other groups (p<0.0001). During the peripartum period, no differences in sensory blockade level, Bromage score, labour duration and percentage of caesarean delivery were found among the groups. Under the conditions of this study, the addition of epidural esketamine of 0.3 mg⋅mL-1, 0.4 mg⋅mL-1 and 0.5 mg⋅mL-1 offered a similar ropivacaine dose-sparing effect; 0.5 mg⋅mL-1 of esketamine produced more adverse effects. ChiCTR2100054348.

Effects of acepromazine, xylazine and propofol on spinal reflexes in healthy dogs.

In the neurological examination, it is crucial to identify the possible location of the lesion in order to determine the appropriate treatment process. In aggressive animals, chemical restraint may be necessary due to their non-cooperative behaviour. However, sedatives may distort the results of examinations. Therefore, a drug should be found that has minimal impact on the examination results. To investigate the effects of acepromazine, xylazine, and propofol on spinal reflexes in healthy dogs. In a randomized, blinded study, ten native adult mixed-breed dogs were participated in three groups with a 1-week washout period between each group. Before performing each step, the spinal reflexes were evaluated. Then, in the first group, acepromazine (0.05mg/kg, IM), in the second group, xylazine (1mg/kg, IM), and in the third group, propofol (3mg/kg, IV for initial bolus and 0.1mg/kg/min for maintenance) were injected for sedation. The spinal reflexes were reevaluated at maximum sedation and at 15, 30, and 45 min thereafter. Acepromazine increased the patellar reflex and decreased the panniculus reflex. Xylazine increased the cranial tibial reflex and decreased the panniculus reflex, while propofol decreased the withdrawal, and extensor carpi radialis reflexes, and suppressed the palpebral and gag reflexes. The drugs used in the present study did not have a significant impact on the most important reflexes evaluated in neurological examinations. Among the drugs, acepromazine has the least effects compared to other drugs, making it a suitable choice for sedation.

A phase II, randomized, double-blind study of the use of rucaparib versus placebo maintenance therapy in metastatic and recurrent endometrial cancer

A phase II, randomized, double-blind study of the use of rucaparib versus placebo maintenance therapy in metastatic and recurrent endometrial cancer

Comparison between 1.5 and 3-Tesla MRI findings in Ménière’s disease

Introduction3 T-MRI of the inner ear has been used to identify the endolymphatic hydrops (EH) phenomenon, and less frequently 1.5 T-MRI. The aim of this study was to assess whether there was agreement between findings of EH at 1.5 T MRI and those obtained at 3.0 T MRI in patients clinically diagnosed with definite Meniere disease (MD).MethodsCross-sectional, blinded study was conducted in a tertiary neurotology ambulatory practice. Thirty patients with clinical diagnosis of unilateral definite MD was included. Two MRI exams (1.5 T and 3.0 T) were performed for each patient and were evaluated by two examiners (E1, E2) who were blinded to the symptomatic ear. An analysis of intra-and inter-examiner agreement was performed. It was determined whether there was an association between MRI findings and disease duration, symptom severity, and MD clinical stage.ResultsE1 found EH at 3 T-MRI in 26 (86.66%) patients and at 1.5 T-MRI in 25 (83.33%). E2 found EH in 25 (83.33%) patients in 3 T-MRI and in 22 (73.33%) at 1.5 T-MRI. The agreement between the examiners’ assessments in relation to the EH was high (0.844) for the 3 T MRI and substantial for the 1.5 T, both statistically significant. There was no statistically significant relationship between EH imaging findings and clinical disease severity and course.Discussion1.5 T and 3.0 T MRI images agreed regarding the findings of absence or presence of cochlear hydrops (CH) and vestibular hydrops (VH). The degrees of CH and VH found at 3.0 T MRI in symptomatic ear were not associated with clinical aspects and the stage of disease.

Protocol for a double-blind crossover randomised controlled trial to investigate inhalation CHallenge to assess Inducible Laryngeal Obstruction (CH-ILO)

Current ILO diagnosis is dependent on an individual being symptomatic. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.IntroductionInducible laryngeal obstruction (ILO) remains a poorly understood condition in part due to lack of understanding about the underlying neuronal mechanisms. Many suffer delayed confirmed diagnosis as no standardised assessment exists. Based on previous work, we propose citric acid (CA) is the most appropriate inhalation agent for inducing upper airway reflex responses, with a view to developing an inhalation challenge test for ILO.Methods and analysisA single-centre, double-blind crossover study. The primary objective is to identify if CA inhalation challenge provokes laryngeal obstruction in patients with confirmed ILO. We will recruit: 10 participants with ILO, 10 with refractory chronic cough (RCC), 10 healthy controls. Each will undergo two inhalation challenges during laryngoscopy, with ascending concentrations of citric acid or saline control; participants will be randomised sequentially by a computer-generated schedule to determine order of delivery. Follow up is a telephone consultation. Randomisation and preparation of challenge agents will be by an unblinded study team member, not involved in data analysis. Challenge agents will only be unblinded on study completion. Log10concentration of CA evoking ILO will be compared between patient groups using a one-way ANOVA, comparing participants with ILO and participants with RCC to healthy controls.ConclusionThis will be the first randomised controlled trial to investigate the role of inhalation challenge as an assessment tool to evoke laryngeal obstruction in patients with confirmed ILO. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.

Study the Immediate Effects of “Primal Reflex Release Technique™” Versus “Neural Tissue Mobilization” on Hip Flexor Tightness in Individuals with a Sedentary Lifestyle

Background: An inactive life can lead to various problems, such as tightness of muscles, decreased joint mobility, and decreased pliability, which can hinder daily activities. Prolonged sitting puts a lot of force on the muscles, increasing the risk of injury. Studies have shown that many people with desk jobs have tight iliopsoas muscles, resulting in lower strength, restricted hip movement, increased pelvic tilt, and excessive lower back curvature. Objective: This study investigates the immediate effectiveness of PRRT™ and NTM on hip flexor tightness in individuals with a sedentary lifestyle. The goal is to determine the most effective treatment approach to alleviate hip flexor tightness, thereby reducing associated risks and improving the quality of life for sedentary individuals. Study Design: Double-blinded Comparative Study Study Settings: In and around the Himalayan Institute of Medical Sciences, Dehradun Participants: 60 individuals with a sedentary lifestyle having tight hip flexors in the age group 18-45. Outcome measures: Hip Flexion Angle measured while performing Modified Thomas Test, Hip Extension Range. Result: A significant improvement is seen in hip flexion angle (p-value &lt;0.001) and prone hip extension range (p-value &lt;0.001) in both Groups A and B. However, on analysing and comparing the post-intervention results of both groups, no major difference was found in the outcome variables (p-value&gt;0.05). Conclusion: This study concluded that both techniques are equally effective in reducing hip flexor tightness with a sedentary lifestyle and can mitigate associated risks and enhance the quality of life for sedentary individuals. KEYWORDS: Hip Flexors, Iliopsoas, PRRT, Neural Tissue Mobilization, Sedentary Lifestyle, Tightness.

Low-dose and ultra-low-dose estradiol and dydrogesterone in postmenopause: an analysis by body mass index

Objective Oral, low-dose and ultra-low-dose continuous combined 17β-estradiol (E) plus dydrogesterone (D) reduce vasomotor symptoms (VMS) in postmenopausal women. Methods Two phase 3, double-blind studies were included. In the European study, postmenopausal women were randomized 2:1:2 to receive E0.5 mg/D2.5 mg (ultra-low dose), E1 mg/D5 mg (low dose) or placebo for 13 weeks. In the Chinese study, women were randomized 1:1 to receive E0.5 mg/D2.5 mg or placebo for 12 weeks. Post-hoc endpoints assessed in body mass index (BMI) subgroups (<25 kg/m2; ≥25 kg/m2) included number of hot flushes and moderate-to-severe hot flushes per day, and the proportion of women with amenorrhea. Results A total of 640 women were included. At the end of treatment, the mean (95% confidence interval) numbers of daily hot flushes were significantly lower (p ≤ 0.05) for all treatment groups versus placebo, with E0.5 mg/D2.5 mg (BMI < 25 kg/m2: 2.5 [1.9, 3.1]; BMI ≥ 25 kg/m2: 3.2 [2.5, 3.8]) and E1 mg/D5 mg versus placebo (BMI < 25 kg/m2: 2.7 [1.2, 4.2]; BMI ≥ 25 kg/m2: 2.3 [1.1, 3.5]) than with placebo (BMI < 25 kg/m2: 4.4 [3.8, 50]; BMI ≥ 25 kg/m2: 4.2 [3.6, 4.9]). A similar pattern was seen for moderate-to-severe hot flushes. The amenorrhea rate was high (79–98%) across both studies and BMI subgroups. Conclusion Oral, ultra-low-dose continuous combined E0.5 mg/D2.5 mg and low-dose continuous combined E1 mg/D5 mg alleviated postmenopausal VMS compared with placebo, irrespective of BMI.

4CMenB Breadth of Immune Response, Immunogenicity, and Safety: Results from a Phase 3 Randomized, Controlled, Observer Blind Study in Adolescents and Young Adults

Abstract Background Meningococcal serogroup B (MenB) strains are highly diverse. Breadth of immune response for the MenB vaccine, 4CMenB, administered at 0-2, 0-6, or 0-2-6 months, was demonstrated by endogenous complement-human serum bactericidal antibody (enc-hSBA) assay against an epidemiologically-relevant panel of 110 MenB strains. Methods In a phase 3 trial, 3651 healthy 10–25 year-old participants were randomized 5:5:9:1 to receive 4CMenB (0-6 schedule), 4CMenB (0-2-6 schedule), investigational MenABCWY vaccine, or control MenACWY-CRM vaccine. The primary objectives were to evaluate safety and demonstrate breadth of immune response by enc-hSBA assay against the MenB strain panel using test-based (percentage of samples without bactericidal activity against strains after 4CMenB versus control vaccination) and responder-based (percentage of participants whose post-vaccination sera kill ≥70% strains) approaches. Success was demonstrated with two-sided 97.5% confidence interval (CI) lower limit &amp;gt;65%. Immunogenicity was assessed by traditional hSBA assay against four indicator strains. Results Breadth of immune response (test-based) was 78.7% (97.5% CI 77.2%–80.1%), 81.8% (80.4%–83.1%), 83.2% (81.9%–84.4%) for the 0-2, 0-6, and 0-2-6 schedules, respectively, and (responder-based) 84.8% (81.8%–87.5%), 89.8% (87.2%–92.0%), and 93.4% (91.2%–95.2%), respectively. No clinically relevant differences in immunogenicity were observed across schedules. 4CMenB was well tolerated. Conclusions The two-dose (0-2, 0-6) 4CMenB schedules met pre-defined criteria for success for both breadth of immune response endpoints against a diverse MenB strain panel, had comparable immunogenicity, and safety in line with the established 4CMenB safety profile. The three-dose schedule provided no additional immunological benefit, supporting use of the 4CMenB 0-2 schedule. Clinical Trial Registration NCT04502693.

Chest compression quality decreases in hypoxic conditions simulating an airliner cabin at cruising altitude: a randomized, controlled, double-blind Manikin Study

AbstractAir traveler numbers are predicted to reach 4.0 billion in 2024. Between 1/15,000–50,000 passengers will experience acute medical problems inflight with cardiac arrests requiring cardiopulmonary resuscitation (CPR) accounting for 0.3% of medical emergencies. Hypoxia in airplane cabins could impair oxygenation and physical performance of caregivers. We conducted a randomized controlled, double-blind study to test the hypothesis that hypoxia decreases the effectiveness in performing CPR. We randomized 24 healthcare professionals to two different study arms, each consisting of two conditions: arm (1) ‘hypoxia (FiO2 15%, equivalent to 2400 m altitude)’ versus ‘normoxia’; arm (2) ‘hypoxia + supplemental oxygen’ versus ‘normoxia + supplemental oxygen’. The order of conditions was counterbalanced and a minimum wash-out period of 24 h was granted between conditions. In each condition participants performed a 5-min cardiac compression only CPR (CCO-CPR) using a full-body manikin after one, three and six hours in an altitude chamber. Mixed ANOVAs with post-hoc false-discovery-rate adjusted pairwise comparisons indicated that although compression frequency was maintained, the number of compressions with correct depth was decreased at all times during hypoxia compared to normoxia (all p &lt; 0.002). After 6 h hypoxia exposure, mean compression depth was below the recommended compression depth defined by ERC/AHA guidelines and reduced compared to normoxia (42.4 ± 12.6 mm vs. 54.6 ± 4.3 mm, p &lt; 0.0001). Supplemental oxygen during CCO-CPR in hypoxia prevented the decrease of compression-depth (55.3 ± 3 mm). Extended hypoxia exposure akin to conditions in airplane cabins can reduce quality of chest compressions during CPR. Supplemental oxygen for healthcare providers is an effective countermeasure.

Increase in serum TTR levels observed with acoramidis treatment in patients with transthyretin amyloid cardiomyopathy (ATTR-CM): insights from ATTRibute-CM and its open-label extension

Abstract Background/Introduction Patients with ATTR-CM can have lower circulating TTR levels, which is associated with worsening of cardiac function and increased risk of cardiovascular mortality.[1] Acoramidis has been shown to reduce cardiovascular mortality and hospitalization, while increasing circulating TTR levels, in the ATTRibute-CM phase 3 study.[2] Purpose I. Evaluate serum TTR levels in participants (pts) receiving acoramidis vs those who received tafamidis in the placebo group in ATTRibute-CM at Month 30. II. Evaluate serum TTR levels in pts who transitioned from placebo+tafamidis to acoramidis in the open-label long term extension (OLE) study. Methods ATTRibute-CM study: Eligible pts with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis or placebo for 30 months. Pts in both groups had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Upon completion of Month 30, pts were invited to participate in the OLE study. In OLE, pts who had previously received acoramidis continued acoramidis, and those who had previously received placebo+tafamidis were switched to acoramidis-only treatment. All pts in the OLE study received acoramidis only. Change in serum TTR levels in ATTRibute-CM and OLE at data cutoff (Oct 9, 2023) are summarised using descriptive statistics. Results In the phase 3 study, efficacy analyses were performed in 611 pts, of which 61 of 409 (14.9%) and 46 of 202 (22.8%) received tafamidis in acoramidis and placebo groups, respectively. The median time until tafamidis initiation was 17.8 and 16.1 months, respectively; median exposure duration was 11.6 and 10.5 months, for acoramidis and placebo groups, respectively.[3] Change from baseline (CFB) in serum TTR levels remained unchanged at Month 30 in the placebo-only group (mean [SD] = –0.4 [4.92] mg/dL). Characteristics of pts analysed are described in Fig. 1. A total of 380/611 pts (62.2%) entered the OLE study (229 pts continued acoramidis only, and 23 switched from placebo+tafamidis to acoramidis). At the time of data cutoff, 214 pts who had received acoramidis only completed Month 6 in OLE versus 18 who switched from placebo+tafamidis to acoramidis. At Month 30 in ATTRibute-CM, CFB in serum TTR levels were higher for patients who received acoramidis only than those receiving placebo+tafamidis (Fig 2A). Serum TTR levels increased further in pts who switched from placebo+tafamidis to acoramidis in OLE (Fig. 2B). The OLE study is ongoing, and this analysis includes pts who completed the Month 6 visit at time of data-cut. Conclusion(s) CFB in serum TTR levels were higher in pts receiving acoramidis only than those receiving placebo+tafamidis at Month 30 in the double-blind study. A further significant increase in serum TTR levels was observed in those who received placebo+tafamidis and switched to acoramidis in OLE.

The impact of exogenous ketone body suppletion on energy and pH balance in skeletal muscle during exercise in chronic heart failure patients: a prospective randomized double-blind cross-over study

Abstract Background Heart Failure (HF) is characterized by impediments in exercise capacity. Disruptions in the energy metabolism of skeletal muscle contribute to this condition. Pre-clinical and clinical evidence showed that reductions in carbohydrate and FA metabolism in HF may be partially overcome by a compensatory increase in ketone body oxidation and suggest that suppletion of ketone bodies (KB) may improve energy metabolism in HF. Purpose We tested the effect of exogenous KB suppletion on energy and pH balance during cycling exercise using 31P Magnetic Resonance (MR) Spectroscopy of the exercising quadriceps muscle in patients with HF. Methods In a randomized, double-blind, placebo-controlled cross-over study, 14 stable HF patients with reduced ejection fraction and diminished exercise capacity underwent maximal exercise testing in a MR scanner fitted with a cycling ergometer after KB or placebo treatment. Phosphocreatine (PCr) and inorganic phosphate (Pi) resonance amplitudes and frequencies were measured continuously in the quadriceps muscle during rest, exercise and recovery using in-vivo 31P MR spectroscopy (Figure 1). Results Patients had a median age of 66 [53 – 75] years, were 14% female, had a median LVEF of 37% [27 – 40] and circulating NT-pro BNP levels of 411 [182 – 946] pg/mL. Peak oxygen uptake (VO2) was 18.2 [15.2 – 20.3] ml/kg/min, which is 68% [62 – 78%] of predicted. After treatment, exercise performance in terms of cycling duration and workload were comparable between treatment arms (Figure 2). Quadriceps acidification during exercise was larger after KB suppletion compared to placebo (ΔpH: -0.2 [-0.3 - -0.1] vs -0.1 [-0.3 - -0.1] respectively; p=0.041) while quadriceps energy depletion during exercise was not altered by treatment (ΔPi/PCr 0.77 [0.55 – 2.51] vs 0.66 [0.46 – 0.81] respectively; p=0.087). Post-exercise mitochondrial oxidative function was similar between treatment arms (KB: PCr resynthesis rate 48 sec [25 – 59] versus placebo: 42 sec [36 – 63]; p=0.767). Conclusions Ketone body suppletion increased acidification and did not improve energy balance in skeletal muscle during exercise or mitochondrial function during recovery in patients with chronic HF. These results question the value of ketone bodies as treatment to boost muscular energy metabolism during exercise in HF.31P MRS Spectrum during exercise in HFExercise and energy parameters

Beneficial clinical effects of honey from bees fed with specific plant extracts

Abstract Background Our team has demonstrated in a number of pre-clinical studies that special bees fed with syrups containing natural plant extracts contain a number of active substances that have beneficial effects on the human body. We have previously reported that bees fed with green walnut have beneficial effects on sugar metabolism, lowering serum glucose levels and reducing insulin resistance. Methods We conducted a prospective double-blind functional food study with 45 healthy volunteers using a strict inclusion and exclusion criteria with ethical approval. Participants ate 30 gramms of honey layered under 150 ml of yoghurt twice a day for 3 weeks. Fifteen participants consumed honey from bees fed with green walnut extract, while 15 participants consumed honey from bees fed with sea buckthorn extract, and 15 participants in the control group consumed acacia honey. Sleep quality was assessed with the SQS questionnaire, and quality of life with the SF-36, EORTC Q-C30 and EQ-5D tests on days 0 and 22 of the study. Results Consumption of both specific honey resulted improvements in the life quality parameters and in the sleep quality. ‘Buckthorn honey’ showed significant differences after the 3rd week: physical function improved (25.3±0.5 vs 27.4±2.8; p = 0.04), anxiety-depression decreased (1.4±3.6 vs 1±0.3; p = 0.03), complex physical status (84.1±9.7 vs 88.7±6.9; p = 0. 04), while ‘green walnut honey’ improved EQ-5D complex quality of life (84.1±9.7 vs 88.9±6.9; p = 0.01), overall quality of life functioning (90.6±14.9 vs 99.2±4.2; p = 0.03), EORTC Q-C30 total score (467.1±30.6 vs 487.4±21.4; p = 0.03).No such positive effects were confirmed in the control group. Conclusions Honey from bees fed with sea buckthorn extract has many beneficial physiological effects on the human body, improving physical well-being and reducing anxiety and depression. Honey from bees fed with green walnut extract improves the complex quality of life. Key messages • Improving the quality of life with nutrition is an increasingly important research field, playing a key role in our life. • Our research has shown that honey from bees fed with green walnut and sea buckthorn extract improves several parameters in the quality of life.

Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in preclinical individuals with an HCM sarcomeric gene mutation

Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic gene variants, i.e. mutations in genes encoding sarcomere proteins. Previous studies have shown that preclinical asymptomatic individuals with a heterozygous sarcomere mutation have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Purpose In the ENERGY trial, preclinical individuals with an HCM sarcomere gene mutation without hypertrophy were treated with the metabolic anti-anginal drug trimetazidine (TMZ) to determine whether the reduced MEE can be corrected at an early pre-hypertrophic disease stage. Methods 40 MYBPC3 and MYH7 asymptomatic mutation carriers without hypertrophy were treated for eight weeks with TMZ or placebo in a double-blind randomized study design. Directly before and after treatment, study participants underwent an [11C]-acetate PET/CT-scan and cardiac magnetic resonance imaging to measure MEE. A cardio-pulmonary exercise test was performed to measure the influence of TMZ on exercise parameters. Results Eight weeks of treatment with TMZ 20mg three times daily did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3±3.8 percent to 29.8±4.3 percent in the placebo group and from 30.1±4 percent to 29.1±4 percent in the TMZ group. After adjustment for baseline, the TMZ group did not have a significantly different MEE (95% CI, -2.863 to 1.986, P=0.68) compared to placebo. Exercise parameters VO2max and respiratory exchange ratio were not significantly altered by treatment with TMZ. Conclusion The ENERGY trial is the first proof-of-concept randomized controlled trial with well-matched (age, sex, mutation) groups to test the hypothesis that TMZ improves MEE at a preclinical disease stage. We conclude that metabolic therapy does not correct reduced MEE in an early disease stage of HCM.methodsprimary outcome

Beneficial effect of honey from algae extract-fed bees on quality of life

Abstract Background Our team has been researching and developing special honeys from bees fed with syrups containing natural plant extracts for decades. Several pre-clinical studies have demonstrated that honey from bees fed with Chlorella algae extract contains a number of algal active ingredients with beneficial effects on the human body. Methods We conducted a prospective double-blind functional food study with 30 healthy volunteers with ethical approval. Based on strict inclusion and exclusion criteria, 30 gramms of honey has been eaten twice a day for 3 weeks under 150 ml of yoghurt. 15 people were fed honey from bees with special algae extract, while 15 concerned - as a control group - consumed acacia honey. Before and after the study, sleep quality was assessed by the SQS questionnaire, and quality of life by the SF-36, EORTC Q-C30 and EQ-5D tests. Results The specific algae extract contained honey improved the people’s sleep quality, their EQRTC parameters, their appetite, their digestion, and it also significantly reduced pain (p = 0.01), boosted the patients cognitive function, and reduced both constipation and diarrhoea. Significant differences in SF-36 parameters: pain decreased (12.9±1.6vs 6.6±1.1; p = 0.01), physical function (21.2±6.3vs 27.1±3.6; p = 0.01) and energy (11.2±2.7vs 13.9±1.4; p = 0.01) improved. No such changes occurred in control group. Conclusions Honey from bees fed with algae extract has a number of beneficial physiological effects on the human body, improving many parameters of quality of life. Key messages • The consumption of honey from bees fed with algae extract improves sleep, reduces pain, and has a positive effect on digestive and gastrointestinal symptoms. • Within public health, quality of life is an increasingly important issue and improving it with functional foods is an important area of research.

Blood pressure polygenic risk scores associate with resistant hypertension in individuals with type 1 diabetes

Abstract Background Hypertension is a major risk factor of global disease burden, but treatment goals are often not met. A subset of individuals with hypertension is affected by treatment-resistant hypertension (RHTN), and they suffer from increased cardiovascular morbidity and mortality. Early identification of individuals at risk of RHTN could lead to more efficient antihypertensive drug treatment. Purpose The aim of this study was to investigate whether polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP) predict RHTN in individuals with or without type 1 diabetes (T1D). Methods We performed association analyses between PRSs and RHTN in two Finnish cohorts: The Finnish Diabetic Nephropathy Study (FinnDiane) and the Finnish individuals of the LIFE Study (LIFE-Fin). FinnDiane is an ongoing, observational nationwide study aiming to identify genetic and clinical risk factors for complications of T1D. We included data from 778 adults (476 with RHTN and 302 with controlled hypertension). LIFE is a randomized, double-blind study evaluating long-term effects of losartan compared with atenolol in patients with signs of left ventricular hypertrophy. We used SBP and DBP data from 378 Finnish individuals (173 with RHTN and 205 with controlled hypertension) at the four-year visit of the study. In FinnDiane, RHTN was defined as SBP ≥130 or DBP ≥85 mmHg and the use of three or more antihypertensive drugs, or SBP &amp;lt;130 and DBP &amp;lt;85 mmHg and the use of four or more antihypertensive drugs. In LIFE-Fin, RHTN was defined as SBP ≥140 or DBP ≥90 mmHg and the use of three or more antihypertensive drugs. Controlled hypertension was defined as the use of three or fewer antihypertensive drugs and SBP &amp;lt;130 and DBP &amp;lt;85 mmHg in FinnDiane, and as SBP &amp;lt;140 and DBP &amp;lt;90 mmHg in LIFE-Fin. We calculated a PRS for each participant using genome-wide association study data for 1,098,015 genetic variants; the variant-specific data were derived from UK Biobank based PRS-CS-method computed PRSs (1). Results We observed significant associations of SBP and DBP PRSs with RHTN in FinnDiane (OR 1.56 [1.30; 1.87], P = 1.8e-6, and OR 1.25 [1.04; 1.50], P = 0.02, per one-SD increase of the PRS value) when adjusted for age, sex, estimated glomerular filtration rate and body mass index. The association between SBP PRS and RHTN remained significant when T1D individuals with or without albuminuria were analysed separately. Neither SBP nor DBP PRSs were significantly associated with RHTN in LIFE-Fin. Conclusion Higher SBP PRSs associate with higher risk of RHTN in individuals with T1D, with or without albuminuria, but not in nondiabetic individuals with hypertension. It remains to be investigated whether general blood pressure genetics contribute to RHTN in the general population.

Efficacy of vortioxetine versus desvenlafaxine in the treatment of functional impairment in patients with major depressive disorder: Results from the multinational VIVRE study.

In VIVRE (NCT04448431), vortioxetine was associated with significantly higher rates of symptomatic and functional remission, better daily and social functioning, and greater treatment satisfaction than desvenlafaxine in patients with major depressive disorder (MDD) and partial response to selective serotonin reuptake inhibitor (SSRI) therapy. This analysis further explored the relative improvement in patient functioning with vortioxetine versus desvenlafaxine. VIVRE was a randomized, double-blind study of vortioxetine (10 or 20mg/day) versus desvenlafaxine (50mg/day) in adults with MDD and partial response to initial SSRI monotherapy. Mean percentage changes from baseline to week 8 in Functioning Assessment Short Test (FAST) total and domain scores were analyzed by treatment group in the overall population and in working patients. In the overall population, the mean reduction in FAST total score from baseline after 8weeks of treatment was 37.2% in vortioxetine-treated patients versus 31.8% in desvenlafaxine-treated patients (P=0.04). Significantly greater improvements versus desvenlafaxine were seen in vortioxetine-treated patients for FAST autonomy, cognitive functioning, and interpersonal-relationships scores (all P<0.05). In working patients, the mean reduction in FAST total score from baseline at week 8 was 38.7% versus 32.1% in the vortioxetine and desvenlafaxine groups, respectively (P=0.04). Significant correlations were seen between absolute changes in patient functioning, and those in depression severity and health-related quality of life. Vortioxetine was significantly better than desvenlafaxine in improving overall functioning as well as daily, social, and cognitive functioning in patients with MDD with inadequate response to prior SSRI therapy.

Influence of blood pressure targets on inflammation and associations between inflammatory markers and vasopressor usage after cardiac arrest - a substudy of a randomized clinical trial

Abstract Background Following resuscitation from cardiac arrest, a profound systemic inflammatory response may develop. In observational studies of critically ill patients an association between levels of inflammation and vasopressor usage has been found. Higher levels of inflammation may lead to higher vasopressor needs due to vasoplegia and cardiac dysfunction, however, catecholamines, including vasopressors also have immune modulatory effects. In the Blood Pressure and Oxygenation Targets in Post resuscitation Care (BOX) trial patients were randomized to a high or low blood pressure target, and vasopressor usage was increased in the high blood pressure target group. Therefore, the inflammatory response evoked by cardiac arrest, may have been altered by differences in vasopressor usage according to blood pressure target in this trial. Purpose To determine if differences in vasopressor and inotropy usage associated with randomization to a high compared to a low blood pressure target affects the inflammatory response after OHCA, and to investigate the association between inflammation and vasopressor and inotropy usage. Methods In the BOX trial, comatose OHCA patients with a presumed cardiac etiology were randomized to a blinded intervention of either a high (77mmHg) or a low blood pressure target (63mmHg). The inflammatory markers of leukocytes and CRP were measured at 0, 24, 48, and 72 hours. The average Vasoactive-Inotropic Score (VIS) was determined during initial 72 hours. The associations between average CRP, leukocytes, and VIS during initial 72 hours were determined by Spearman’s correlation analysis. Results The BOX trial included 789 resuscitated comatose OHCA patients, and 788 patients had at least 1 measurement of leukocytes and CRP. The median age was 64 (IQR 54-73), females constituted 19%, 1 year mortality was 36%. There was no difference in leukocytes and CRP at admission between the high and low blood pressure target groups (Figure 1). Leukocytes were slightly higher at 24 hours (p&amp;lt;0.01) in the high blood pressure target group, but no group differences were found at 48 and 72 hours, and CRP levels did not differ at 24, 48, or 72 hours. The average VIS was 19 (11-32) and 11 (5-19), p&amp;lt;0.01, in the two groups, with VIS being consistently higher at all timepoints beyond ICU admission (all p&amp;lt;0.01, data not shown) in patients with a high blood pressure target. Both average CRP and leukocytes were weakly correlated with average VIS at 0-72 hours for both blood pressure targets, r=0.17 and r=0.20, respectively for a high target (both p&amp;lt;0.01), and r=0.17 and r=0.20, respectively for a low target (both p&amp;lt;0.01). Conclusions In conclusion, increased vasopressor and inotropy usage in this randomized, blinded study of blood pressure targets after OHCA, did not lead to clinically relevant changes in inflammation. Inflammatory markers and VIS were correlated to a similar degree for both blood pressure targets.Figure 1, LeukocytesFigure 2, CRP

Challenging endomyocardial biopsies' gold standard status in rejection screening: a prospective blinded study on cardiovascular magnetic resonance in heart transplant patients

Abstract Background The detection of rejection is crucial for graft survival after heart transplantation. Endomyocardial biopsies (EMBs) serve as the gold standard for rejection surveillance despite its limitations, while cardiac magnetic resonance (CMR), in conjunction with donor-derived cell-free DNA (dd-cfDNA) analysis, holds promise as a non-invasive approach. Purpose In this prospective blinded study, our aim was to evaluate feasibility of CMR for rejection screening, validating it against EMB, dd-cfDNA, and clinical status. Methods We blindly analyzed 250 studies involving CMR, EMB, dd-cfDNA, and clinical data in 58 heart transplant recipients (17 children and 41 adults). Of these 250 studies, 239 (96%) were assessed within 1 to 28 months after transplantation, and 11 studies (4%) 3-14 years post-transplant. In CMR T1- and T2-mapping analyses, acute rejection was defined by T1 or T2 times exceeding the specified thresholds (T1 ≥ 1060 ms, T2 ≥ 55 ms) in at least 2/16 heart segments. EMB findings were graded according to the ISHLT criteria (2005 and 2013), and acute cellular rejection (ACR) grade ≥ 2 or antibody-mediated rejection (AMR) grade ≥ 1 were considered significant. The cutoff for abnormal dd-cfDNA was set at 0.2%. Solely clinical rejection included patients with absent or normal EMB (ACR grade 0-1 and AMR grade 0), but with symptoms or ECG/echocardiographic findings indicative of acute rejection. Results Our study revealed 22 acute rejections, with 15 confirmed through EMB and 7 diagnosed solely based on clinical indicators. Among the EMB-confirmed cases, 3/15 exhibited AMR grade 1, 10/15 demonstrated ACR grade 2 and 2/15 ACR grade 3. CMR identified rejection in 77% (17/22) of cases. Specifically, it successfully identified rejection in 67% (10/15) of EMB-confirmed cases and 100% (7/7) of solely clinically diagnosed cases. Examining the concordance between CMR findings and dd-cfDNA levels, 35% (6/17) of the CMR-identified rejection cases exhibited abnormal dd-cfDNA, while 30% (5/17) showed normal levels. Notably, in one case, despite normal CMR results, both EMB and dd-cfDNA indicated rejection. Conversely, in four instances where EMB indicated acute rejection, both CMR and dd-cfDNA levels were normal. These findings highlight a potential discrepancy in the diagnostic accuracy of EMB, suggesting its tendency to both over- and underdiagnose acute heart transplant rejection. The integration of CMR and dd-cfDNA in the diagnostic process may provide a more comprehensive and reliable assessment of rejection episodes, offering valuable insights for clinical decision-making in heart transplant recipients. Conclusions EMB presents challenges in both under- and overdiagnosing rejection in heart transplant surveillance. A strategy based on CMR, combined with dd-cfDNA analyses, shows promise as a new gold standard for rejection screening.Flowchart

Adverse cardiovascular events in patients with cancer: a biomarker-enhanced clinical risk score

Abstract Background/Introduction Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but reliable tools for cardiovascular risk prediction remain unavailable (1). Purpose To assess a broad panel of cardiovascular biomarkers and clinical risk factors and to provide a novel risk score for the prediction of MACE in cancer patients. Methods Among 2’192 patients with newly diagnosed or recurrent cancer, a broad panel of cardiovascular biomarkers, including NT-proBNP, P-/E-/L-selectins, ICAM-1, VCAM-1, sLOX-1, CRP, and Lp(a) were measured by blinded study personnel. Patients were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death (2,3). Uni- and multivariable competing risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with MACE, and a risk score was developed. Results Beyond clinical risk factors, ICAM-1, P-/E-/L-selectins and NT-proBNP levels were independently linked to 2-year MACE risk, though shape of associations differed markedly. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age ≥60 years, and +2 points for ASCVD history, yielding a bootstrapped C-statistic of 0.76 (95%CI:0.71-0.81). Implementation of cardiovascular biomarkers conferred improved performance (0.83, 95%CI:0.78-0.88). A simplified model, solely informed by clinical variables and readily available NT-proBNP (+1 point for NT-proBNP≥230pg/mL), achieved similar performance (0.80, 95%CI:0.74-0.86), with a cumulative 2-year MACE incidence of 0% in low- and 11.0% in high-risk patients. Conclusions Cancer patients are at substantial MACE risk. The herein presented first-of-its-kind risk score, integrating traditional cardiovascular risk factors and biomarkers, including NT-proBNP, effectively predicts 2-year MACE and 5-year cardiovascular death.

Intensity-Dependent Effects of Low-Frequency Subthreshold rTMS on Primary Motor Cortex Excitability and Interhemispheric Inhibition in Elderly Participants: A Randomized Trial.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) protocols targeting primary motor cortex (M1) are used in rehabilitation of neurological diseases for their therapeutic potential, safety, and tolerability. Although lower intensity LF-rTMS can modulate M1 neurophysiology, results are variable, and a systematic assessment of its dose effect is lacking. To determine the dose-response of LF-rTMS on stimulated and non-stimulated M1. In a sham-controlled randomized double-blind crossover study the effect of LF-TMS protocols were determined in 20 right-handed older healthy participants. In 3 sessions, 1 Hz rTMS at 80% (rTMS80), 90% (rTMS90) of motor threshold or sham stimulation were applied to left upper extremity M1. Outcome measures were curve parameters of the stimulus-response curve (maximum motor evoked potential [MEPMAX], slope and the intensity to evoke 50% MEPMAX), short-interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI). Within LF-rTMS sessions, rTMS90, increased MEPMAX in the stimulated M1. Furthermore, rTMS90, increased the slope in the non-stimulated M1. LF-rTMS effects on SICI were dependent on the participants' baseline SICI, hemisphere, and intensity of conditioning pulse. Finally, rTMS90 increased whereas rTMS80 decreased IHI, for both IHI directions. These changes were dependent on baseline IHI and hemisphere and were no longer significant when baseline IHI was accounted for. Intensity of subthreshold LF-rTMS has differential effects on excitation and inhibition of stimulated and non-stimulated M1. The effects were small and were only demonstrated within the LF-rTMS sessions but were not different when compared to sham. rTMS related changes in SICI and IHI were dependent on baseline level. NCT02544503, NCT01726218.