Double-blind Study Research Articles

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 <130 and DBP <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 <130 and DBP <85 mmHg in FinnDiane, and as SBP <140 and DBP <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.

Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy.

Key Points Participants who completed a 36-week double-blind study of atacicept were eligible for a 60-week, open-label extension study.Atacicept 96-week treatment resulted in sustained reductions in galactose-deficient IgA1, hematuria, and urine protein-creatinine ratio.The slope of the eGFR was similar to that observed in the general population without kidney disease. Background B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell–mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks. Methods Participants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated. Results There were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received ≥1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean±SEM) in Gd-IgA1 (−66%±2%), percentage of participants with hematuria (−75%; 95% confidence intervals, −87 to −59; in participants with baseline hematuria), and UPCR (−52%±5%). The mean annualized slope of eGFR was −0.6±0.5 ml/min per 1.73 m2 through 96 weeks. Conclusions Atacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks. Clinical Trial registry name and registration number: Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

Combination of Intravenous Ondansetron and Intravenous Glycopyrrolate Versus Intravenous Ondansetron and Intramuscular Glycopyrrolate for Reduction of Post-spinal Hypotension in Cesaraen Section: A Randomized Double-Blinded Study

Combination of Intravenous Ondansetron and Intravenous Glycopyrrolate Versus Intravenous Ondansetron and Intramuscular Glycopyrrolate for Reduction of Post-spinal Hypotension in Cesaraen Section: A Randomized Double-Blinded Study

Acute Ear, Nose and Throat Pain in Children in Brazzaville

Objective: To evaluate the intensity of acute pain associated with ENT conditions during consultations and the effectiveness of the analgesic prescribed. Patients and Methods: We conducted a prospective, experimental, randomised, double-blind study in the ENT CCF department of the CHUB. The study took place over a period of 9 months (01 March to 30 November 2021) and involved only children aged 2-12 years presenting with an acute ENT complaint and having been treated in the ENT consultation department of the CHUB. Paracetamol and ibuprofen were administered after pain assessment. Results: During the study period, 60 patients presented with acute ENT complaints and were managed on an outpatient basis. The mean age was 7.7 +/- 31 years, with extremes ranging from 2 to 12 years. Tekes were the most represented ethnic group at 58.4%. Schoolchildren represented the most common school level. Acute pain affected patients' life activities. Acute pharyngitis was the most common pathology. Acute ENT pain. Paracetamol and ibuprofen were the molecules most frequently used, and pain was virtually absent on the 3rd day of use (96.7% and 75% respectively for paracetamol and ibuprofen). Conclusion : Acute pain in children is often underestimated or sometimes inadequately treated.

Circulating Chromogranin A as Surveillance Biomarker in Patients with Carcinoids - The CASPAR Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value > 100 ng/mL in the following CgA concentration was considered positive. 153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%-95·5%, p < 0·001), sensitivity 34·4% (25·6%-44·3%), positive predictive value 57·9% (45·0-69·8), negative predictive value (NPV) 84·3% (80·5-87·6), and area under the curve 0·73 (0·67-0·79). Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.

Magnetic Garments Promote Parasympathetic Dominance and Improve Sleep Quality in Male Long-Distance Runners Following a 30 km Run

This study aimed to investigate the effects of high-intensity running on the autonomic nervous system and sleep quality of male long-distance runners and to examine the impact of wearing magnetic garments on these parameters. Fifteen highly trained male collegiate long-distance runners participated in a randomized, double-blind crossover study. Participants completed two 30 km runs (30k-RUN) during a 10-day training camp. After each run, they wore either magnetic (MAG) or non-magnetic control (CTRL) garments. Sleep quality and heart rate variability (HRV) were assessed using a wrist-worn device before and after each 30k-RUN. Wearing MAG garments post-30k-RUN resulted in significantly longer deep sleep duration compared to CTRL. HRV analysis revealed that the MAG condition led to a significantly higher root mean square of successive RR interval differences and high-frequency power, indicating enhanced parasympathetic activity. The low-frequency to high-frequency ratio was significantly lower in MAG than in CTRL. Perceived recovery scores were significantly higher in MAG than in CTRL. The findings of this study suggest that wearing magnetic garments following high-intensity endurance running may promote parasympathetic dominance and improve sleep quality in male long-distance runners. These findings indicate that magnetic garments may be a practical method for enhancing recovery in athletes following intense training.

Preferences for oral and injectable PrEP among qualitative sub-study participants in HPTN 084.

HPTN 084 compared the safety and efficacy of long-acting injectable cabotegravir (CAB) to daily oral TDF/FTC for prevention of HIV-1 in uninfected African women. Like a similar trial in MSM/TGW (HPTN 083), the trial was stopped early for efficacy, expediting the need to consider introduction strategies for different populations. We examine survey and qualitative data from a four-country sub-study to examine oral and injectable PrEP acceptability and considerations for CAB access among African women. Participants completed baseline and follow-up surveys on HIV risk perception, sexual behavior. product acceptability and adherence during the blinded trial. Additionally, up to two in-depth interviews each with 73 sub-study participants explored product use and trial-related experiences, during the blinded and unblinded study periods. Using survey data, we classified participants as: engaged in female sex work (FSW), having multiple non-transactional partners, or monogamous. A study statistician identified participants' assigned study arm. We followed a thematic analysis process to read transcripts, develop a codebook and apply codes in NVivo to transcripts with intermittent intercoder reliability checks; using Excel matrices to explore differences across risk categories and study arms. Participants overwhelmingly preferred injections to pills, appreciating the ease, convenience, and privacy of a long-acting formulation. Many participants described challenges with contraceptive and/or study pill adherence, impeded by late night work, unexpected travel, or heavy drinking. Women in the TDF/FTC arm were more likely to describe side effects, compared to those in the CAB arm. Pain also varied widely by study arm. When considering post-trial access to CAB, limited PrEP knowledge, cost and concerns around stigma and poor service quality were potential access barriers. Women's desire for privacy and ease of use outweighed injectable concerns, resulting in a strong preference for CAB. Cost and accessibility will need to be addressed by implementation programs.

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease

BackgroundVariants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.MethodsPreclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.ResultsIn cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.ConclusionsThese findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.Trial registrationClinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047.

Efficacy and Safety of Upadacitinib vs Dupilumab in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: Week 16 results of an Open-label, Randomized, Efficacy Assessor-Blinded Head-to-Head Phase 3b/4 Study (Level Up).

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Some patients continue to experience flares and substantial clinical burden despite ongoing systemic treatment. This study assessed the efficacy and safety of once-daily upadacitinib (UPA), initiated at 15 mg and dose-escalated to 30 mg based on clinical response, compared with dupilumab (DUPI) per its label. Week 16 primary analysis results are presented. Level Up is a phase 3b/4 global, randomized, open-label, efficacy assessor blinded study evaluating UPA vs DUPI in adolescents and adults with moderate-to-severe AD who had inadequate response to systemic therapy or when use was inadvisable. Patients were randomized to UPA or DUPI for 16 weeks of treatment (Period 1). Patients on UPA started on 15 mg and were dose-escalated to 30 mg if they did not achieve an Eczema Area and Severity Index reduction of at least 50% (EASI 50) or a ≥4-point Worst Pruritus Numerical Rating Scale (WP-NRS) improvement on/after Week 4, or EASI 75 on/after Week 8. The primary endpoint was simultaneous achievement of EASI 90 and WP-NRS 0/1 at Week 16. Ranked secondary endpoints included skin and itch responses at varying response levels and timepoints. Safety measures were assessed throughout the study. Superior efficacy in achieving simultaneous EASI 90 and WP-NRS 0/1 response at Week 16 was demonstrated with UPA vs DUPI (19.9% vs 8.9%, respectively; p<0.0001). UPA showed superiority vs DUPI for all ranked secondary endpoints, with post-hoc analyses exhibiting higher itch response rates as early as Day 2. No new safety signals were identified during this period. Treatment of moderate-to-severe AD with UPA, initiated at 15 mg and dose escalated based on clinical response, demonstrated superiority vs DUPI per its label for the primary endpoint of simultaneous achievement of near complete skin clearance (EASI 90) and little to no itch (WP-NRS 0/1) at Week 16, with all ranked secondary endpoints demonstrating superiority at varying skin and itch response levels and timepoints. There were no new safety signals identified compared to the previously reported safety profiles of UPA and DUPI.

The Application of Untargeted Metabolomic Approaches for the Search of Common Bioavailable Metabolites in Human Plasma Samples from Lippia citriodora and Olea europaea Extracts.

Lippia citriodora and Olea europaea are known for their shared common bioactivities. Although both matrices are rich in similar families of bioactive compounds, their specific phytochemical compounds are mostly different. Since these compounds can be metabolized in the organism, this study hypothesized that common bioavailable metabolites may contribute to their similar bioactive effects. To test this, an acute double-blind intervention study in humans was conducted with blood samples collected at multiple time points. Using an untargeted metabolomic approach based on HPLC-ESI-QTOF-MS, 66 circulating metabolites were detected, including 9 common to both extracts, such as homovanillic acid sulfate and glucuronide derivates, hydroxytyrosol sulfate, etc. These common metabolites displayed significantly different Tmax values depending on the source, suggesting distinct metabolization pathways for each extract. The study highlights how shared bioavailable metabolites may underlie similar bioactivities observed between these two plant sources.