Frontline daratumumab-based triplet and quadruplet standard-of-care regimens have demonstrated improved survival outcomes in newly diagnosed multiple myeloma (NDMM). For patients with transplant-ineligible NDMM, triplet therapy with either daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, lenalidomide and dexamethasone (VRd) is the current standard of care. This phase 3 trial evaluated subcutaneous daratumumab plus VRd (D-VRd) in patients with transplant-ineligible NDMM or for whom transplant was not planned as the initial therapy (transplant deferred). Some 395 patients with transplant-ineligible or transplant-deferred NDMM were randomly assigned to eight cycles of D-VRd or VRd followed by D-Rd or Rd until progression. The primary endpoint was overall minimal residual disease (MRD)-negativity rate at 10-5 by next-generation sequencing. Major secondary endpoints included complete response (CR) or better (≥CR) rate, progression-free survival and sustained MRD-negativity rate at 10-5. At a median follow-up of 58.7 months, the MRD-negativity rate was 60.9% with D-VRd versus 39.4% with VRd (odds ratio, 2.37; 95% confidence interval (CI), 1.58-3.55; P < 0.0001). Rates of ≥CR (81.2% versus 61.6%; P < 0.0001) and sustained MRD negativity (≥12 months; 48.7% versus 26.3%; P < 0.0001) were significantly higher with D-VRd versus VRd. Risk of progression or death was 43% lower for D-VRd versus VRd (hazard ratio, 0.57; 95% CI, 0.41-0.79; P = 0.0005). Adverse events were consistent with the known safety profiles for daratumumab and VRd. Combining daratumumab with VRd produced deeper and more durable MRD responses versus VRd alone. The present study supports D-VRd quadruplet therapy as a new standard of care for transplant-ineligible or transplant-deferred NDMM. ClinicalTrials.gov registration: NCT03652064 .
- Publikační typ
- časopisecké články MeSH
Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.
- MeSH
- databáze genetické MeSH
- exom genetika MeSH
- genom lidský genetika MeSH
- genomika * metody MeSH
- lidé MeSH
- rodokmen MeSH
- výpočetní biologie metody MeSH
- vzácné nemoci * genetika diagnóza MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
Ovarian lesions are common and often incidentally detected. A critical shortage of expert ultrasound examiners has raised concerns of unnecessary interventions and delayed cancer diagnoses. Deep learning has shown promising results in the detection of ovarian cancer in ultrasound images; however, external validation is lacking. In this international multicenter retrospective study, we developed and validated transformer-based neural network models using a comprehensive dataset of 17,119 ultrasound images from 3,652 patients across 20 centers in eight countries. Using a leave-one-center-out cross-validation scheme, for each center in turn, we trained a model using data from the remaining centers. The models demonstrated robust performance across centers, ultrasound systems, histological diagnoses and patient age groups, significantly outperforming both expert and non-expert examiners on all evaluated metrics, namely F1 score, sensitivity, specificity, accuracy, Cohen's kappa, Matthew's correlation coefficient, diagnostic odds ratio and Youden's J statistic. Furthermore, in a retrospective triage simulation, artificial intelligence (AI)-driven diagnostic support reduced referrals to experts by 63% while significantly surpassing the diagnostic performance of the current practice. These results show that transformer-based models exhibit strong generalization and above human expert-level diagnostic accuracy, with the potential to alleviate the shortage of expert ultrasound examiners and improve patient outcomes.
- MeSH
- deep learning MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory vaječníků * diagnostické zobrazování MeSH
- neuronové sítě (počítačové) * MeSH
- retrospektivní studie MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- ultrasonografie * metody MeSH
- umělá inteligence MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- validační studie MeSH
The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .
- MeSH
- dospělí MeSH
- Leishmania major * imunologie MeSH
- leishmanióza kožní * imunologie parazitologie patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- parazitární zátěž MeSH
- Phlebotomus parazitologie imunologie MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
Gastric cancer is a leading cause of cancer-related deaths in China. Affecting more than 40% of the world's population, Helicobacter pylori is a major risk factor for gastric cancer. While previous clinical trials indicated that eradication of H. pylori could reduce gastric cancer risk, this remains to be shown using a population-based approach. We conducted a community-based, cluster-randomized, controlled, superiority intervention trial in Linqu County, China, with individuals who tested positive for H. pylori using a 13C-urea breath test randomly assigned to receiving either (1) a 10-day, quadruple anti-H. pylori treatment (comprising 20 mg of omeprazole, 750 mg of tetracycline, 400 mg of metronidazole and 300 mg of bismuth citrate) or (2) symptom alleviation treatment with a single daily dosage of omeprazole and bismuth citrate. H. pylori-negative individuals did not receive any treatment. We examined the incidence of gastric cancer as the primary outcome. A total of 180,284 eligible participants from 980 villages were enrolled over 11.8 years of follow-up, and a total of 1,035 cases of incident gastric cancer were documented. Individuals receiving anti-H. pylori therapy showed a modest reduction in gastric cancer incidence in intention-to-treat analyses (hazard ratio 0.86, 95% confidence interval 0.74-0.99), with a stronger effect observed for those having successful H. pylori eradication (hazard ratio 0.81, 95% confidence interval 0.69-0.96) than for those who failed treatment. Moderate adverse effects were reported in 1,345 participants during the 10-day treatment. We observed no severe intolerable adverse events during either treatment or follow-up. The findings suggest the potential for H. pylori mass screening and eradication as a public health policy for gastric cancer prevention. Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000979 .
- MeSH
- antibakteriální látky terapeutické užití aplikace a dávkování MeSH
- dospělí MeSH
- Helicobacter pylori * účinky léků MeSH
- infekce vyvolané Helicobacter pylori * farmakoterapie epidemiologie mikrobiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metronidazol terapeutické užití aplikace a dávkování MeSH
- nádory žaludku * prevence a kontrola epidemiologie mikrobiologie MeSH
- omeprazol * terapeutické užití aplikace a dávkování MeSH
- organokovové sloučeniny terapeutické užití aplikace a dávkování MeSH
- senioři MeSH
- tetracyklin terapeutické užití aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Čína epidemiologie MeSH
- Názvy látek
- antibakteriální látky MeSH
- metronidazol MeSH
- omeprazol * MeSH
- organokovové sloučeniny MeSH
- tetracyklin MeSH
Clinical outcomes of catheter ablation for atrial fibrillation (AF) are suboptimal due, in part, to challenges in achieving durable lesions. Although focal point-by-point ablation allows for the creation of any required lesion set, this strategy necessitates the generation of contiguous lesions without gaps. A large-tip catheter, capable of creating wide-footprint ablation lesions, may increase ablation effectiveness and efficiency. In a randomized, single-blind, non-inferiority trial, 420 patients with persistent AF underwent ablation using a large-tip catheter with dual pulsed field and radiofrequency energies versus ablation using a conventional radiofrequency ablation system. The primary composite effectiveness endpoint was evaluated through 1 year and included freedom from acute procedural failure and repeat ablation at any time, plus arrhythmia recurrence, drug initiation or escalation or cardioversion after a 3-month blanking period. The primary safety endpoint was freedom from a composite of serious procedure-related or device-related adverse events. The primary effectiveness endpoint was observed for 73.8% and 65.8% of patients in the investigational and control arms, respectively (P < 0.0001 for non-inferiority). Major procedural or device-related complications occurred in three patients in the investigational arm and in two patients in the control arm (P < 0.0001 for non-inferiority). In a secondary analysis, procedural times were shorter in the investigational arm as compared to the control arm (P < 0.0001). These results demonstrate non-inferior safety and effectiveness of the dual-energy catheter for the treatment of persistent AF. Future large-scale studies are needed to gather real-world evidence on the impact of the focal dual-energy lattice catheter on the broader population of patients with AF. ClinicalTrials.gov identifier: NCT05120193 .
- MeSH
- fibrilace síní * chirurgie terapie MeSH
- jednoduchá slepá metoda MeSH
- katetrizační ablace * metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- recidiva MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.
- MeSH
- fibrilace síní * chirurgie terapie MeSH
- katetrizační ablace * škodlivé účinky metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- pooperační komplikace epidemiologie etiologie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
