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ImportanceThe frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood.ObjectiveTo evaluate the 5-year incidence, clinical outcomes, and predictors of hemodynamic SVD in patients undergoing self-expanding TAVI or surgery.Design, Setting, and ParticipantsThis post hoc analysis pooled data from the CoreValve US High Risk Pivotal (n = 615) and SURTAVI (n = 1484) randomized clinical trials (RCTs); it was supplemented by the CoreValve Extreme Risk Pivotal trial (n = 485) and CoreValve Continued Access Study (n = 2178). Patients with severe aortic valve stenosis deemed to be at intermediate or increased risk of 30-day surgical mortality were included. Data were collected from December 2010 to June 2016, and data were analyzed from December 2021 to October 2022.InterventionsPatients were randomized to self-expanding TAVI or surgery in the RCTs or underwent self-expanding TAVI for clinical indications in the nonrandomized studies.Main Outcomes and MeasuresThe primary end point was the incidence of SVD through 5 years (from the RCTs). Factors associated with SVD and its association with clinical outcomes were evaluated for the pooled RCT and non-RCT population. SVD was defined as (1) an increase in mean gradient of 10 mm Hg or greater from discharge or at 30 days to last echocardiography with a final mean gradient of 20 mm Hg or greater or (2) new-onset moderate or severe intraprosthetic aortic regurgitation or an increase of 1 grade or more.ResultsOf 4762 included patients, 2605 (54.7%) were male, and the mean (SD) age was 82.1 (7.4) years. A total of 2099 RCT patients, including 1128 who received TAVI and 971 who received surgery, and 2663 non-RCT patients who received TAVI were included. The cumulative incidence of SVD treating death as a competing risk was lower in patients undergoing TAVI than surgery (TAVI, 2.20%; surgery, 4.38%; hazard ratio [HR], 0.46; 95% CI, 0.27-0.78; P = .004). This lower risk was most pronounced in patients with smaller annuli (23 mm diameter or smaller; TAVI, 1.32%; surgery, 5.84%; HR, 0.21; 95% CI, 0.06-0.73; P = .02). SVD was associated with increased 5-year all-cause mortality (HR, 2.03; 95% CI, 1.46-2.82; P < .001), cardiovascular mortality (HR, 1.86; 95% CI, 1.20-2.90; P = .006), and valve disease or worsening heart failure hospitalizations (HR, 2.17; 95% CI, 1.23-3.84; P = .008). Predictors of SVD were developed from multivariate analysis.Conclusions and RelevanceThis study found a lower rate of SVD in patients undergoing self-expanding TAVI vs surgery at 5 years. Doppler echocardiography was a valuable tool to detect SVD, which was associated with worse clinical outcomes.Trial RegistrationClinicalTrials.gov Identifiers: NCT01240902, NCT01586910, and NCT01531374

Introduction The variety, time patterns and long-term prognosis of persistent COVID-19 symptoms (long COVID-19) in patients who suffered from mild to severe acute COVID-19 are incompletely understood. Cohort studies will be combined to describe the prevalence of long COVID-19 symptoms, and to explore the pathophysiological mechanisms and impact on health-related quality of life. A prediction model for long COVID-19 will be developed and internally validated to guide care in future patients. Methods and analysis Data from seven COVID-19 cohorts will be aggregated in the longitudinal multiple cohort CORona Follow Up (CORFU) study. CORFU includes Dutch patients who suffered from COVID-19 at home, were hospitalised without or with intensive care unit treatment, needed inpatient or outpatient rehabilitation and controls who did not suffer from COVID-19. Individual cohort study designs were aligned and follow-up has been synchronised. Cohort participants will be followed up for a maximum of 24 months after acute infection. Next to the clinical characteristics measured in individual cohorts, the CORFU questionnaire on long COVID-19 outcomes and determinants will be administered digitally at 3, 6, 12, 18 and 24 months after the infection. The primary outcome is the prevalence of long COVID-19 symptoms up to 2 years after acute infection. Secondary outcomes are health-related quality of life (eg, EQ-5D), physical functioning, and the prevalence of thromboembolic complications, respiratory complications, cardiovascular diseases and endothelial dysfunction. A prediction model and a patient platform prototype will be developed. Ethics and dissemination Approval was obtained from the medical research ethics committee of Maastricht University Medical Center+ and Maastricht University (METC 2021-2990) and local committees of the participating cohorts. The project is supported by ZonMW and EuroQol Research Foundation. Results will be published in open access peer-reviewed scientific journals and presented at (inter)national conferences. Trial registration number NCT05240742 .

Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N 1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level ( P < 5 × 10 −8 ) mapped to 16q12.2 ( IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10 −8 ). We used Fisher’s combined probability tests weighted by sample size to perform a meta-analysis ( N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS ( N 2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 ( IGF2BP3: P = 3.2 × 10 −8 ), 14q13.3 ( PAX9: P = 1.9 × 10 −8 ), and 16q12.2 ( IRX5: P = 1.2 × 10 −9 ) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children ( N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.

Abstract Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.

AbstractIntroductionDespite important advances in many areas of hepatobiliary surgical practice during the past decades, posthepatectomy liver failure (PHLF) still represents an important clinical challenge for the hepatobiliary surgeon. The aim of this review is to present the current body of evidence regarding different aspects of PHLF.MethodsA literature review was conducted to identify relevant articles for each topic of PHLF covered in this review. The literature search was performed using Medical Subject Heading terms on PubMed for articles on PHLF in English until May 2022.ResultsUniform reporting on PHLF is lacking due to the use of various definitions in the literature. There is no consensus on optimal preoperative assessment before major hepatectomy to avoid PHLF, although many try to estimate future liver remnant function. Once PHLF occurs, there is still no effective treatment, except liver transplantation, where the reported experience is limited.DiscussionStrict adherence to one definition is advised when reporting data on PHLF. The use of the International Study Group of Liver Surgery criteria of PHLF is recommended. There is still no widespread established method for future liver remnant function assessment. Liver transplantation is currently the only effective way to treat severe, intractable PHLF, but for many indications, this treatment is not available in most countries.

PURPOSE At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS). METHODS CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression. RESULTS At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%). CONCLUSION D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

Abstract Durable overall response rate (ORR) remains a meaningful endpoint in recurrent GBM; however, the target ORR for single arm recurrent GBM trials has not been based on historic information or tied to patient outcomes. The current study reviewed past trials in recurrent GBM in order to judiciously define target ORRs for use in recurrent GBM trials. After reviewing 69 treatment arms comprising 4,971 patients, ORR was 6.1%[95% CI 4.23; 8.76%] for cytotoxic chemotherapies (ORR=7.59% for CCNU, 7.57% for TMZ, 0.64% for CPT-11, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for immunotherapies (select trials), and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2=0.4078, P&lt; 0.0001), biologics (R2=0.4003, P=0.0003), and immunotherapy trials (R2=0.8994, P&lt; 0.0001), but not anti-angiogenic agents (R2=0, P=0.8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2=0.3164, P&lt; 0.0001; mOS[weeks]=0.6xORR+28.9), suggesting an ORR &gt;20% results in an mOS of &gt; 40.9 weeks, which is double the survival estimate of a treatment with ORR=0% and ≥ 2 months longer than treatments with ORR=5%. Assuming an ineffective therapy (control) has ORR=5%, a trial of 32 patients with a target ORR=20% leads to the 95% confidence interval higher than the control group. We conclude that single arm phase II studies in recurrent GBM with ≥ 32 patients should have a target ORR ≥ 20%. This was associated with a median OS of approximately 1 year. Importantly, durability of response should also be considered and was not assessed in the current meta-analysis.