Multicenter Trial Research Articles

Optimizing aldosterone receptor antagonist therapy by sodium zirconium cyclosilicate in heart failure - OPRA-HF trial

Abstract Background Heart failure remains a significant health burden, characterized by disabling symptoms and mortality rates comparable to cancer. Mineralocorticoid antagonists (MRAs), pivotal in treating heart failure with reduced ejection fraction (HFrEF), are underutilized due to concerns of hyperkalemia. Sodium Zirconium Cyclosilicate (SZC) enables optimized MRA therapy by reducing hyperkalemia. However, prospective studies on the efficacy and safety of SZC in patients with HFrEF and high hyperkalemia risk are lacking, particularly in the context of contemporary heart failure quadruple-therapy including angiotensin receptor neprilysin inhibitor (ARNI) and Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. Purpose The OPRA-HF trial aims to assess the efficacy and safety of SZC in optimizing MRA treatment in symptomatic patients with HFrEF with risk for hyperkalemia on top of optimal guideline-directed medical therapy including ARNI and SGLT2 Inhibitors. Methods This investigator-initiated multicentred, randomized, placebo-controlled, and double-blinded trial include patients with HFrEF on suboptimal MRA treatment due to (1) history of hyperkalemia due to MRA, or (2) risk of hyperkalemia due to reduced renal function (eGFR 30-45 ml/min/m2) and current potassium 4.5-5-0 mmol/L. Patients undergo a Run-In phase with SZC, initiating or up-titrating MRA to target doses for 4-7 weeks and SZC was initiated in those patients that became hyperkalemic (K+>5 mEq/L. Those normokalemic and tolerating MRA ≥ 25 mg daily or at least 25 mg dose increase vs before run-in were randomized to SZC (5g or 10g) or placebo for 6 months. Study is powered to randomize 110 patients. Primary outcomes include maintaining daily MRA dose ≥ 25 mg or dose increase by 25 mg with normal potassium levels without rescue therapy. Secondary outcomes include evaluating the safety and tolerability of SZC as well as impact of SZC on quality of life. Results In this ongoing trial, so far 40 patients have been randomized. Of these, mean age was 74.3 years, 88.9% men. Most patients had ischemic etiology (54.2%), 36.1% had diabetes mellitus, 52.8% had hypertension.n. At screening 94.4% had beta-blockers, 35% ACEI/ARB, 60% ARNI and 72.2% had SGLT2 inhibitors, 33.3% had no MRAs and 35,6% of patients had less than 25 mg MRA daily,62,2% had 25 mg MRA daily, mean p-potassium was 4.7+0.4 mmol/L, and eGFR was 57.3 ml/min/1.73m². After run-in, 85.2% were on 50 mg MRA daily. A substantial number (51.2%) of eligible patients with previous hyperkalemia had Run-In failure as they now successfully tolerated target dose of MRA at 50 mg daily without recurrent hyperkalemia. SZC dosing was 5g once daily in 78.9% of patients. Conclusion This ongoing trial will provide evidence for the use of SZC to optimize MRA treatment in contemporary HFrEF patients. Preliminary findings suggest SZC effectively maintains normokalemia, enabling MRA optimization, potentially improving patients’ otcome.

Hypertensive myocardial disease screening in low-income settings using smartphone-based technologies: a prospective multicenter trial

Abstract Background Mobile health technologies are revolutionizing cardiovascular (CV) medicine. However, more than 80% of heart disease related deaths occur in low-income settings, that are unable to take advantage of such technologies for healthcare awareness and prevention. Purpose To assess the feasibility of a pilot telemedicine-based CV screening campaign with D-Heart, a validated low-cost 8-lead smartphone portable ECG, coupled with blood-pressure (BP) monitoring in three regions of Africa. Methods A total of 950 patients (60%) men, age 29±21) were enrolled at 5 African rural dispensaries, 2 in Kenya, 2 in Senegal and at a hospital (Uganda). ECGs recording were obtained by community health workers with D- Heart smartphone ECG; BP was measured with a validated smartphone BP recorder. Global burden of ECG abnormalities was defined by a semi-quantitative score based on the sum of 9 criteria, identifying four classes of increasing severity. ECGs that were moderately and severely abnormal and from patients with severe hypertension, were sent for consultation via smartphone to D-Heart tele-cardiology centre: an advice on how to manage the patient was sent back to the community health worker’s smartphone within 15 minutes. If referral was needed, patients were sent to the local hospital. Results Mean BMI was 26.2 ± 8.5 (men 22.3±1.5 vs women 27.2±1.1, p<0.01). Active/recent history of smoking and alcohol intake were 327 (45%, 298 men) and 232/590 (40%, 198 men) respectively. A total of 142 (15%) patients had been previously diagnosed with diabetes, 199(25%) had known hypertension of whom 95/199 on treatment), whereas 43(4%) had a previous myocardial infarction. A total of 487 (51%) patients never had their blood pressure measured, whereas 798(91%) never received an ECG. Mean SBP/DBP were 138±31/71±12 mmHg respectively. Patients with normal BP were 304(32%), whereas 380(40%) were mildly-moderately hypertensive (SBP/DBP 148±7/91±5 mmHg) and 130 (29%) with severe hypertension (SBP/DBP 162±8/99±6 mmHg). D-Heart ECGs tracings were respectively classified as: normal: 361(38%); mildly abnormal: 332(35%); moderately abnormal: 199 (21%) and severely abnormal 58(6%). Most common ECG abnormality was a positive Romhilt-Estes index in 361, 38%. For 174(18%) patients smartphone tele-report advised referral to the local hospital, but only 121 69%) presented to the visit: 9 (8%) were found to have normal hearts, 57(47%) with hypertensive heart disease, 35 (29%) with rheumatic heart disease, 20 (16%) with HFrEF. Visit time was 8±2 minutes; cost of screening per patient was 1.10€: 0,30€ for consumable electrodes, 0.80€ for the community health worker visit time. Conclusions D-Heart ECG screening combined with smartphone BP measurement proved feasible and cost-effective. This should encourage to develop and extend low-cost/high-technology community-based CV screening programs in low-income settings.

Comparison of ridaforolimus-eluting and zotarolimus-eluting coronary stents: 5-Year outcomes from the BIONICS and NIREUS trials

Abstract Introduction Despite similarities between different modern drug eluting stents (DES), their comparative short and long-term safety and efficacy has generated much interest and yielded conflicting results. The BIONICS and the NIREUS randomized clinical trials showed non-inferiority of the Ridaforolimus eluting stent (RES) compared to the Zotarolimus-eluting stent (ZES) with respect to 1-year target lesion failure (TLF) and 6-month angiographic late lumen loss. Aim To evaluate clinical outcomes between treatment groups over 5 years follow-up Methods BIONICS and NIREUS were prospective, randomized, single-blind multicenter trials comparing RES and ZES in patients undergoing PCI. Patients were blinded to treatment assignment and randomized to RES or ZES in a 1:1 fashion in BIONICS, and in 2:1 fashion in NIREUS. Clinical events were assessed during hospital stay, at 30 days, 1 year, and yearly thereafter, up to 5 years. The The primary endpoint in the current study was the 5-year rate of target lesion failure (TLF). Results The study population included 2221 patients enrolled in the BIONICS (n=1919) and NIREUS (n=302) studies. Median follow-up was 1822 days (interquartile range 1783 to 1847 days). Mean age was 63.2±10.3 years, and most patients were men (79.7%). Clinical presentation with ACS was similar between groups (38.9% versus 37.9%, RES versus ZES, respectively, p=0.38). Procedural characteristics were similar for patients treated with RES and ZES. A mean of 1.6±0.9 and 1.5±0.8 stents were implanted in RES and ZES patients, respectively, p=0.08. Post dilatation was performed more frequently in the RES group (63.3% versus 60.1%, p=0.02) and procedure duration was longer in RES versus ZES patients (47.0±31.8 minutes versus 44.6±29.2 minutes, p=0.01). Device success was high in both groups but slightly higher in the ZES group (98.2% versus 99.5% for RES and ZES, respectively, p=0.002) yet with similar procedural success (97.9% versus 97.3%, p=0.49). At 5 years, the primary endpoint of TLF was similar between treatment groups (12.2% RES versus 11.3% ZES, p=0.52). Rates of TLR (7.6% RES versus 6.8% ZES, p=0.42), target vessel-related MI (4.8% RES versus 4.9% ZES, p=0.95) and stent thrombosis (0.9% RES versus 0.9% ZES, p=0.87), also did not differ between groups. Target vessel revascularization (TVR) and cardiac death were higher among the RES group (12.3% versus 9.5% p=0.037, and 3.6% versus 2.2 % p=0.042, respectively). However, after correction for baseline characteristics there was no significant difference in cardiac death between groups. Conclusions In a pooled analysis of two randomized trials, 5-year clinical outcomes were similar between patients undergoing PCI with RES and ZES. These results support the long-term safety and efficacy of RES for the treatment of patients with coronary artery disease.Central illustrationZES vs. RES

Diagnostic accuracy of automatic quantitative flow ratio for hemodynamic assessment of coronary artery stenosis: prospective observational study

Abstract Background Quantitative flow ratio (QFR) is a method for evaluating fractional flow reserve (FFR) without the use of an invasive coronary pressure wire or pharmacological hyperemic agent. Automatic QFR (auto QFR) is a recently developed, simpler method of calculating QFR that uses a patient-specific TIMI (Thrombolysis in Myocardial Infarction) frame count, but with automatically specified start and end frames. Although the previous studies demonstrated that contrast QFR is more accurate than fixed QFR, there is no evidence for auto QFR. Purpose The aim of this study was to evaluate the diagnostic performance of auto QFR, fixed QFR, and contrast QFR for the diagnosis of hemodynamically significant coronary stenosis defined by FFR ≤0.80. Methods This prospective, multicentre trial enrolled patients suspected with coronary artery disease undergoing diagnostic coronary angiography with an indication for to perform invasive FFR. QFR was calculated at a blinded core laboratory. The primary endpoint was the diagnostic accuracy of auto QFR, fixed QFR, and contrast QFR to determine hemodynamically significant coronary stenosis using invasive FFR (≤0.80) as a reference standard. Results A total of 325 vessels from 274 patients were analysed. Mean FFR was 0.82±0.09, mean auto QFR was 0.80±0.12, and mean contrast QFR was 0.82±0.11, respectively. The overall diagnostic accuracy for identifying an FFR of ≤0.80 was highest by contrast QFR (81.5%), followed by fixed QFR (79.1%), and auto QFR (77.5%). The AUC was higher for contrast QFR (AUC 0.885; 95% CI: 0.845-0.925) than fixed QFR (AUC 0.856; 95% CI: 0.812-0.900) or auto QFR (AUC 0.854; 95% CI: 0.806-0.901), but did not differ significantly between fixed QFR and auto QFR (Figure). Conclusions There was no significant difference in AUC between fixed and auto QFR, but the accuracy of contrast QFR was significantly higher compared to both QFRs. Auto QFR has the advantage of faster computation time while using patient-specific coronary flow, but accuracy still needs to be improved.

Innovative Approaches for Personalized Cardiovascular Prevention: the INNOPREV multicentric trial

Abstract Background Cardiovascular diseases (CVD) represent a major global health concern, requiring innovative primary prevention strategies. Personalized prevention, through the use of digital technologies and genetic risk scores (PRS), holds promise but requires further investigation to assess clinical efficacy. Consequently, the INNOPREV trial aims to investigate the efficacy of PRS and/or digital technologies in the uptake of CV preventive behaviors uptakes. Methods The INNOPREV trial is a multicenter randomized controlled trial conducted in Italy across three hospital centers in Rome, Catania, and Palermo. It aims to recruit 1020 participants aged 40-69 with a high 10-year CVD risk. Participants are allocated to traditional CVD risk assessment, or genetic testing, or digital interventions, or a combination of both. The study involves comprehensive CV risk assessments at baseline and follow-up visits at one, five, and twelve months. Data analysis will utilize mixed-effects models to analyze longitudinally collected data and explore potential moderators and mediators of behavior change. Results Preliminary results indicate good progress in recruitment, which currently stands at 250 participants (25% of expected). Recruited females have a mean age of 59 ± 6 years, while males have a mean age of 58 ± 6 years. Currently, PRS analyses indicate that 77% of participants have intermediate scores, and 23% have low scores. Follow-up will be essential to evaluate the efficacy of the proposed interventions. Conclusions We expect that the INNOPREV trial will provide evidence towards integration of innovative approaches based on PRS and digital devices, in the traditional preventive approaches for CVDs. Expectations are high based on the limited effectiveness of the current approaches in CV risk reduction based on lifestyle advice. Key messages • INNOPREV trial examines PRS and digital technology for CVD prevention, aiming to enhance preventive efficacy. Initial findings suggest promising potential for innovative CVD prevention strategies. • The INNOPREV trial aims to investigate the efficacy of personalized prevention strategies, including PRS and digital technologies, in improving cardiovascular preventive behaviors.

Long-term follow-up after catheter ablation of atrial fibrillation and atrial tachycardia in patients with pulmonary hypertension

Abstract Introduction Catheter ablation of atrial fibrillation and atrial tachycardia (AF / AT) is established treatment in selected population. Only limited data, including long-term results, exist in patients with pulmonary hypertension (PH). Recently published prospective multicentric trial showed that more extensive radiofrequency catheter ablation of the bi-atrial arrhythmogenic substrate instead of clinical arrhythmia ablation alone is not beneficial in terms of arrhythmia recurrence in patients with AF / AT and PH. Now, we present the results of an extended, long-term follow-up from one of the study centres. Methods Patients with combined post- and pre-capillary or isolated pre-capillary PH and AF / AT indicated to catheter ablation were enrolled and randomised 1:1 into two parallel treatment arms. Patients underwent either clinical arrhythmia ablation only (Limited ablation group) or clinical arrhythmia plus substrate-based ablation (Extended ablation group). The primary endpoint was arrhythmia recurrence >30 s without antiarrhythmic drugs after the 3-month blanking period. Results A total of 52 patients (median age 71 years (IQR 62-75); 27 males) were enrolled. The presumable clinical arrhythmia was AF in 20 and AT in 32 patients, including typical AFL in 22 patients. Limited and extended ablation group included 28 and 24 patients, respectively. During the extended follow-up period of median 31 (IQR: 18; 46) months, the primary endpoint occurred in 17 patients (71 %) vs. 13 patients (46 %) in the Extended vs. Limited ablation group (p = 0.096). In parallel, overall mortality was comparable between groups (9 [38 %] vs. 11 [39 %]). Only 2 patients had recurrence of AFL during the extended follow-up. However, new different arrhythmia was documented in another 7 patients after the AFL ablation. Conclusion In PH patients, recurrence of AF / AT after a catheter ablation is frequent and the recurrence rate increases with the duration of follow-up. Ablation strategy seems to have no impact on arrhythmia free survival. Patients with typical atrial flutter have significantly higher chance to maintain sinus rhythm after a catheter ablation compared to AF or other AT.

The interplay between coronary microvascular resistance, arterial reservoir function and coronary flow reserve: unravelling the significance of high microvascular resistance

Abstract Background Beyond the observation that patients with low CFR indicating presence of coronary microvascular dysfunction (CMD) have an unfavourable prognosis compared to patients with preserved CFR, recent large multicentre trials [1-2] have shown that increased minimal hyperaemic microvascular resistance (HMR or IMR) ,neither on top of the low CFR nor alone, does not play a role as a prognostic factor for ischemia in nonobstructive coronary artery disease (INOCA) patients. Purpose This study investigates the pathophysiological interactive processes in CMD and no-CMD groups with high and low HMR taking into account potential adaptive mechanisms that alter arterial reservoir function [3] associated with microvascular resistance and systemic vasomotor response in INOCA patients. Methods Analysis was conducted on 312 unique unobstructed vessels (FFR>0.80) from 258 patients (73% male) enrolled in the DEFINE-FLOW [4] study. CFR and HMR were quantified using intracoronary Doppler and pressure measurements. Vessels were categorized into four groups based on high and low CFR and HMR using the best available cut-off values (2.5 for both). Arterial reservoir capacity (ARC) and related parameters [3] were quantified using reservoir-excess pressure (Preservoir and Pexcess) analysis of averaged aortic and distal coronary pressure waveforms in CMD (CFR<2.5) and no-CMD (CFR≥2.5) subgroups. (Figure 1-2) Results Compared to vessels without CMD, functional and structural CMD have increased Pexcess (p:0.007) and a rapid decline in diastolic pressure (DRCcoronary p<0.001, DRCaortic, p<0.05), indicating the ongoing systemic hemodynamic superfluous state despite locally suppressed resting blood flow in the structural CMD. Higher baseline microvascular resistance (BMR) was associated with increased reservoir pressure (r:0.302, p<0.001). The vessels with preserved CFR despite high HMR are characterised by uniquely increased ARC (p:0.014), effectively diminished Pexcess (p:0.010), which parallels the local (highest BMR p<0.001) and global (lowest DRCaortic, p<0.05) vasomotor response, that normalizes the systemic and local hyperperfusion, and ultimately regains an adequate flow reserve (CFR) (p<0.001). The high HMR in this group was mainly due to increased resting tonus unlike structural CMD, evident by the highest RRR (BMR/HMR).(p<0.001) (Figure 1-2) Conclusion(s) The high HMR despite preserved CFR vessels form a unique-adaptive group, characterised by substantially increased arterial reservoir capacity and effectively diminished Pexcess, by means of an adaptive vasomotor response which manifests locally in the coronary bed as pronouncedly augmented BMR & RRR, and globally as reduced DRC in the aortic pressure waveform. This adaptive myogenic response normalising resting flow and ongoing systemic and local hyperperfusion ultimately regains an adequate flow reserve (CFR).Figure 1.Methods and Main FindingsFigure 2.Visual Abstract

Microaxial Flow Pump Use and Renal Outcomes in Infarct-Related Cardiogenic Shock - a Secondary Analysis of the DanGer Shock Trial.

In the Danish-German Cardiogenic Shock (DanGer Shock) trial, use of a microaxial flow pump (mAFP) in patients with ST-segment elevation myocardial infarction (STEMI)-related CS led to lower all-cause mortality but higher rates of renal replacement therapy (RRT). In this prespecified analysis, rates and predictors of acute kidney injury (AKI) and RRT were assessed. In this international, randomized, open label, multicenter trial, 355 adult patients with STEMI-CS were randomized to mAFP (N=179) or standard care alone (N=176). AKI was defined according to Risk, Injury, and Failure, sustained Loss and End-stage kidney disease (RIFLE) criteria and assessed using logistic regression models. Use of RRT was assessed accounting for the competing risk of death using Fine-Gray subdistribution hazard models. AKI (RIFLE≥1) was recorded in 110 patients (61%) in mAFP group and 79 (45%) in control group (p<0.01); RRT was used in 75 (42%) and 47 (27%) patients, respectively (p<0.01). About 2/3 of the RRTs were initiated within the first 24h from admission (n=48 (64%) in mAFP group, n=31 (66%) in control group). Occurrence of AKI and RRT were associated with higher 180-day mortality in both study arms. At 180 days, all patients alive were free of RRT. mAFP use was associated with higher rates of RRT, even when accounting for competing risk of death (subdistribution hazard: 1.67 [1.18-2.35]). This association was largely consistent among prespecified subgroups. Allocation to mAFP was associated with lower 180-day mortality irrespective of AKI or RRT (p=0.8 for interaction). Relevant predictors of AKI in both groups comprised reduced left ventricular ejection fraction, baseline kidney function, shock severity, bleeding events, and positive fluid balance. In addition, predictors of AKI specific to mAFP were suction events, higher pump speed, and longer duration of support. Shock severity, allocation to mAFP, and device-related complications were associated with an increased risk of AKI. AKI was generally associated with higher mortality, but the allocation to mAFP consistently led to lower mortality rates at 180 days irrespective of the occurrence of AKI with or without RRT initiation.

Impact of semaglutide on weight and functional outcomes among obese heart failure patients: a propensity scores matching analysis

Background & objectivesObesity is a common comorbidity in heart failure, yet effective pharmacological options for weight loss in these patients are limited. Semaglutide, a glucagon-like peptide 1 receptor agonist, has shown promise for weight reduction in obese adults. This study aims to evaluate semaglutide’s impact on weight loss, functional status, and clinical outcomes in obese patients with heart failure.MethodsA retrospective analysis was conducted on all consecutive obese (BMI > 30 kg/m²) patients with heart failure at the University Hospital Bonn outpatient clinic from July 2019 to July 2022. Propensity score matching paired patients receiving semaglutide as an add-on therapy (SEMA) with those on medical therapy alone (Control).ResultsAmong 1,942 patients with heart failure screened, 26 matched pairs were identified. At one year, the SEMA group exhibited significant weight loss, with a mean BMI reduction of -2.91 kg/m² (95% CI: -4.27 to -1.55; p < 0.001), while the control group showed a non-significant mean change of -0.41 kg/m² (95% CI: -1.08 to 0.26; p = 0.22). The difference in BMI between the two groups was statistically significant (mean difference: 3.42 kg/m², 95% CI: 1.43 to 5.42; p = 0.001). Improvements by at least one NYHA class were observed in 65% of the SEMA group (p < 0.001) compared to 15% of the control group (p = 0.18). The SEMA group also showed a significant increase in 6-minute walk distance (6MWD), with a mean difference of 75 m between the groups at one year (95% CI: 0.53 to 150.02; p = 0.049). NT-proBNP levels significantly decreased in the SEMA group (p < 0.001) compared to the control group (p = 0.78), with a statistically significant difference in NT-proBNP between the groups (p = 0.048). Both improvements in 6MWD and reductions in NT-proBNP were significantly correlated with BMI percentage reductions.ConclusionsSemaglutide was associated with significant weight reduction in obese patients with heart failure, accompanied by improved NYHA classification and 6-minute walk distance. Larger, multi-center trials and prospective, randomized controlled trials are warranted. These studies should focus on assessing long-term outcomes, optimizing dosage, and exploring the potential cardiovascular benefits beyond weight reduction.

Cellular therapy for traumatic brain injury in adults: a meta-analysis of controlled clinical trials

IntroductionTraumatic brain injury (TBI) has got no effective treatment. Cellular therapy is the transfer of autologous or allogeneic cells or cellular material into patient(s) for treatment, showed better outcomes in TBI in several clinical and preclinical studies. We performed a meta-analysis on published articles on the topic of cellular therapy for the treatment of TBI in adult patients.Material and MethodsThe literature search was done via selected database with no restrictions on publication year. Studies were included based on selection criteria and quality assessment. The following data were extracted from included articles; author names, publication year and place, type of study, number, sex and age of participants, type of cells used, and post-treatment follow up. The required data related to Fugl-Meyer Motor Scale (FMMS), Disability Rating Scale (DRS) and patients. Overall improvement was pooled and analyzed using RevMan (Ver.5.4.1).ResultsFive studies that met the selection criteria and considered as high quality, containing 367 participants, with an average follow up time of (7.58±6.93) months, were included in meta-analysis. The results showed that cellular therapy significantly improves (OR=0.26; 95% CI=0.15 to 0.48; P=0.0001) the overall performance of the patients. Moreover, the improvements in FMMS (MD=3.79; 95% CI= -2.53 to 10.10; P=0.24) and DRS (MD= -0.16; 95% CI= -1.51 to 1.19; P=0.82) were not statically significant, but they are obviously clinically significant.ConclusionsThis meta-analysis suggests that cellular therapy improves the condition of TBI patients in clinic. Larger, multi-central trials are required to further confirm and detail the use of stem cells in TBI.

Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review

Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.

Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use forr/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.

Breast and endometrial safety of micronised progesterone versus norethisterone acetate in menopausal hormone therapy (PROBES): study protocol of a double-blind randomised controlled trial

IntroductionData suggest that micronised progesterone (mP) in menopausal hormone therapy is safer for the breast than synthetic progestins, while protection of the endometrium appears to be less effective. However, comparative...

Physiotherapists working with pessaries

Pessaries and the physiotherapy profession have evolved over the past 10 years, and pelvic health physiotherapists can now prescribe vaginal pessaries. Pelvic, Obstetric and Gynaecological Physiotherapy (POGP) is developing ways to support members with these skills. Globally, up to 50% of women will suffer from pelvic organ prolapse (POP) (Carroll et al. 2022), and this condition costs the UK National Health Service £45 million every year (PCWHF 2019). The most common symptom is a vaginal bulge. The National Institute for Health and Care Excellence guidelines recommend either doing nothing, or pelvic floor muscle exercises (PFMEs), vaginal pessaries or surgery (NICE 2019). Pessary services are provided in dedicated clinics, usually in general practice or secondary care. There has been an increase in physiotherapists delivering pessary care over the past decade: in 2013, it was reported that 1.4% were part of the pessary workforce compared to 5% in 2020 (Bugge et al. 2013; Brown et al. 2021). Currently, ineffective patient pathways, poor service provision and lack of training are barriers to treatment. Poorly designed patient pathways are frustrating, and women are often required to return to primary or secondary care to get a referral to a pessary clinic. Physiotherapists are well placed to offer a pessary alongside PFMEs since it is part of the range of conservative treatment options. They also build strong a rapport with their patients because of the therapeutic nature of the treatment sessions, and typically, offer longer appointments than postnatal period. A prospective multicentre trial demonstrated the acceptability of and compliance with using a pessary immediately after childbirth irrespective of any pelvic floor dysfunction or mode of delivery (Baessler et al. 2019). The majority of women used the pessary to treat the symptoms of POP. Further work is required to investigate pessary use and the prevention of pelvic floor dysfunction in this cohort of women. The results of the TOPSY [Treatment Of Prolapse with Self-care pessarY] trial (Hagen et al. 2023) highlighted that pessary self-management is cost-effective and reduces complications. This is excellent news because physiotherapists are well placed to teach women pessary self-management because of: generally longer appointments; and the well-established rapport built up over time while teaching PFMEs. Despite women reporting that pessary use during exercise relieves their symptoms, this is an under-researched area. The impact of exercise on POP, and whether there are any protective factors involved that prevent its progression, are not fully understood. There also remains a gap in the evidence with regard to the use of PFMEs and vaginal pessaries. Research proposals are currently in development to address this. A pessary course is being developed by POGP, and this will be launched in 2024 alongside a mentoring programme as part of the pessary accreditation scheme jointly written with the United Kingdom Continence Society. Further governance documents have been created by the Physiotherapists Working with Pessaries subgroup of POGP, including a standard operating procedure, emergency out-of-hours statement, note proformas and template letters (POGP 2024).

A study of intersphincteric resection rate following robotic-assisted total mesorectal excision versus laparoscopic-assisted total mesorectal excision for patients with middle and low rectal cancer: study protocol for a multicenter randomized clinical trial

IntroductionRobotic-assisted complete mesorectal excision (RATME) is increasingly being used by colorectal surgeons. Most surgeons consider RATME a safe method, and believe it can facilitate total mesorectal excision (TME) in rectal cancer, and may potentially have advantages over intersphincteric resection (ISR) and anus preservation. Therefore, this trial was designed to investigate whether RATME has technical advantages and can increase the ISR rate compared with laparoscopic-assisted TME (LATME) in patients with middle and low rectal cancer.Methods and analysisThis is a multicenter, superiority, randomized controlled trial designed to compare RATME and LATME in middle and low rectal cancer. The primary endpoint is the ISR rate. The secondary endpoints are coloanal anastomosis (CAA) rate, conversion to open surgery, conversion to transanal TME (TaTME), abdominoperineal resection (APR) rate, postoperative morbidity and mortality within 30 days, pathological outcomes, long-term survival outcomes, functional outcomes, and quality of life. In addition, certain measurements will be conducted to ensure quality and safety, including centralized photography review and semiannual assessment.DiscussionThis trial will clarify if RATME improves ISR and promotes anus preservation in patients with mid- and low-rectal cancer. Furthermore, this trial will provide evidence on the optimal treatment strategies for RATME and LATME in patients with mid- and low-rectal cancer regarding improved operational safety.Trial registrationClinicalTrials.gov NCT06105203. Registered on October 27, 2023.

Diabetes Mellitus Is Not a Risk Factor for Difficult Intubation Among Critically Ill Adults: A Secondary Analysis of Multicenter Trials

Objectives: Diabetes mellitus has been associated with greater difficulty of tracheal intubation in the operating room. This relationship has not been examined for tracheal intubation of critically ill adults. We examined whether diabetes mellitus was independently associated with the time from induction of anesthesia to intubation of the trachea among critically ill adults. Design: A secondary analysis of data from five randomized trials completed by the Pragmatic Critical Care Research Group (PCCRG). Setting: Emergency departments (EDs) or ICUs at 11 centers across the United States that enrolled in randomized trials of a pre-intubation checklist, fluid bolus administration, bag-mask ventilation between induction and laryngoscopy, and intubation using a bougie vs. stylet. Patients: Critically ill adults undergoing tracheal intubation with a laryngoscope in an ED or an ICU. Interventions: None. Measurements and Main Results: A total of 2654 patients were included in this analysis, of whom 638 (24.0%) had diabetes mellitus. The mean time from induction of anesthesia to intubation of the trachea was 169 seconds (sd, 137s). Complications occurred during intubation in 1007 patients (37.9%). Diabetes mellitus was not associated with the time from induction of anesthesia to intubation of the trachea (–4.4 s compared with nondiabetes; 95% CI, –17.2 to 8.3 s; p = 0.50). Use of a video vs. direct laryngoscope did not modify the association between diabetes mellitus and the time from induction to intubation (p for interaction = 0.064). Diabetes mellitus was not associated with the probability of successful intubation on the first attempt (85.6% vs. 84.3%; p = 0.46) or complications during intubation (39.8% vs. 37.4%; p = 0.52). Conclusions: Among 2654 critically ill patients undergoing tracheal intubation in an ED or an ICU, diabetes mellitus was not independently associated with the time from induction to intubation, the probability of successful intubation on the first attempt, or the rate of complications during intubation.

Early minimally invasive image-guided endoscopic evacuation of intracerebral hemorrhage (EMINENT-ICH): a randomized controlled trial

BackgroundSpontaneous supratentorial intracerebral hemorrhage is the deadliest form of stroke with mortality rates over 50%. Currently, no sufficiently effective treatment to improve both mortality and functional outcome rates exists. However, it seems that minimally invasive surgery, especially endoscopic surgery, might be beneficial in improving survival and functional outcome rates, yet large confirmatory studies thereof are lacking. The aim of this trial is to compare whether early minimally invasive endoscopic surgery leads to improved functional outcome rates compared to the best medical treatment.MethodsThis is a prospective, parallel-arm, outcome assessor blinded multicenter trial across Switzerland. Endoscopic surgery will be compared to the best medical treatment in a 1:1 randomization over a total time of 12 months. The primary outcome is defined as improved functional outcome (mRS < 3) after 6 months; secondary outcomes include mortality and morbidity rates as well as patient reported outcomes and the temporal evolution of serum biomarkers for brain damage.DiscussionCurrently, large, randomized trials assessing the role and potential effect of early endoscopic surgery in intracerebral hemorrhage are lacking. Potential practical and methodological issues faced in this trial are patient enrollment, adherence to the hematoma evacuation technique used, potential patient cross-over, and the adaptive Bayesian statistical design. Nonetheless, this trial would be among the first to research the effects of early minimally invasive endoscopic surgery for SSICH and can provide class I evidence for future treatment options in intracerebral hemorrhage.Trial registrationClinicalTrials.gov NCT05681988. Registered on January 3, 2023.

Brain Stimulation in Alzheimer's Disease Trials.

Alzheimer's disease (AD) continues to lack definitive curative therapies, necessitating an urgent exploration of innovative approaches. This review provides a comprehensive analysis of recent clinical trials focusing on invasive and non-invasive brain stimulation techniques as potential interventions for AD. Deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are evaluated for their therapeutic efficacy, safety, and applicability. DBS, though invasive, has shown promising results in mitigating cognitive decline, but concerns over surgical risks and long-term effects persist. On the other hand, non-invasive methods like rTMS, tDCS, and tACS have demonstrated potential in enhancing cognitive performance and delaying disease progression, with minimal side effects, but with varied consistency. The evidence hints towards an individualized, patient-centric approach to brain stimulation, considering factors such as disease stage, genetic traits, and stimulation parameters. The review also highlights emerging technologies and potential future directions, emphasizing the need for larger, multi-center trials to confirm preliminary findings and establish robust clinical guidelines. In conclusion, while brain stimulation techniques present a promising avenue in AD therapy, further research is imperative for more comprehensive understanding and successful clinical implementation. Through this review, we aim to catalyze the scientific discourse and stimulate further investigation into these novel interventions for AD.

Differences in sex and age response to single pill combination based antihypertensive therapy reflecting in blood pressure and arterial stiffness.

There are noticeable sex differences in the treatment response to antihypertensives, with limited data on the response to single pill combinations. The aim of the PRECIOUS trial was to assess the treatment response to perindopril/amlodipine and perindopril/amlodipine/indapamide dual and triple single-pill combination in men and women. Four hundred and forty adults with essential hypertension were assessed in the 16-week interventional, open-label, prospective, international, multicentre trial. Based on the previous antihypertensive therapy, patients were assigned to either perindopril/amlodipine 4/5 mg or perindopril/amlodipine/indapamide 4/5/1.25 mg, with the initial dose up-titrated in 4-week intervals in case of uncontrolled blood pressure. An additional analysis was performed for sex- and age-related differences on the blood pressure response and arterial stiffness in men and women aged 35-74 years. Women achieved better overall blood pressure control in all age groups, except for the 35-44 age group. Women presented higher average 24 h aortic augmentation indexes than men, but had more pronounced decreasing trends. The pulse wave velocity was only age-dependent, with reductions slightly greater in women. Both the aortic augmentation index and pulse wave velocity were significantly decreased in all groups compared to baseline. The results of the PRECIOUS trial contribute significant data to the expanding body of evidence on sex differences in hypertension, including the aspect of age-related changes during the life course of women. The differences between same-aged men and women tend to be smaller with advancing age, but with a greater treatment response in women in all age groups for all observed blood pressure parameters and arterial stiffness. ClinicalTrials.gov identifier NCT03738761.

A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of Tongmai Yangxin pill on ventricular remodeling in acute anterior STEMI patients after primary PCI

BackgroundAcute ST-segment elevation myocardial infarction (STEMI) is a severe form of coronary heart disease and a leading cause of mortality and morbidity. This can mainly be ascribed to adverse ventricular remodeling (VR). However, the efficacy of existing treatment strategies for STEMI is not entirely satisfactory. Tongmai Yangxin Pill (TMYX), a patented traditional Chinese medicine (TCM), has been approved for treating various cardiovascular diseases. PurposeThe purpose was to assess the effect of TMYX on VR in acute STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Study DesignA multicenter, randomized, double-blinded, and placebo-controlled trial conducted across 11 hospitals in China. MethodA total of 270 patients with acute anterior STEMI, undergoing PPCI within 10 days of symptom onset were enrolled and randomly assigned to receive either a placebo or TMYX, in addition to guideline-directed treatments for STEMI. The primary endpoint was a change in left ventricular end-diastolic volume index (LVEDVI) at 12 weeks. ResultAmong the 270 randomized patients, 218 (TMYX: 109 and placebo: 109) were included in the per-protocol analysis. At 4 and 12 weeks, TXMY significantly improved LVEDVI than the placebo group ([-2.17(-9.24, 8.28) vs. 3.76(-2.38, 11.48), p < 0.05] and [-1.17 (-12.19, 12.88) vs. 4.46 (-2.89, 11.99), p < 0.05]). Changes in left ventricular end-diastolic volume (LVEDV) at 4 weeks were superior in the TMYX group than the placebo group (-4.37 (-17, 13.99) vs. 7.41 (-4.56, 21.79), p < 0.05). Cardiac magnetic resonance imaging (CMRI) showed that left ventricular ejection fraction (LVEF) was significantly greater in the TMYX group than in the placebo group at 4 weeks. There were no statistically significant differences between groups for left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), 6 min walking distance (6MWD), and major adverse cardiac and cerebrovascular events (MACCEs) (p > 0.05). ConclusionTMYX, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly delayed VR in patients with acute anterior STEMI undergoing PPCI within 10 days of symptom onset.