Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma.

Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone

Development and validation of explainable machine learning models for risk of mortality in transcatheter aortic valve implantation: TAVI risk machine scores.

AIMS Identification of high-risk patients and individualized decision support based on objective criteria for rapid discharge after transcatheter aortic valve implantation (TAVI) are key requirements in the context of contemporary TAVI treatment. This study aimed to predict 30-day mortality following TAVI based on machine learning (ML) using data from the German Aortic Valve Registry. METHODS AND RESULTS Mortality risk was determined using a random forest ML model that was condensed in the newly developed TAVI Risk Machine (TRIM) scores, designed to represent clinically meaningful risk modelling before (TRIMpre) and in particular after (TRIMpost) TAVI. Algorithm was trained and cross-validated on data of 22 283 patients (729 died within 30 days post-TAVI) and generalisation was examined on data of 5864 patients (146 died). TRIMpost demonstrated significantly better performance than traditional scores [C-statistics value, 0.79; 95% confidence interval (CI)] [0.74; 0.83] compared to Society of Thoracic Surgeons (STS) with C-statistics value 0.69; 95%-CI [0.65; 0.74]). An abridged (aTRIMpost) score comprising 25 features (calculated using a web interface) exhibited significantly higher performance than traditional scores (C-statistics value, 0.74; 95%-CI [0.70; 0.78]). Validation on external data of 6693 patients (205 died within 30 days post-TAVI) of the Swiss TAVI Registry confirmed significantly better performance for the TRIMpost (C-statistics value 0.75, 95%-CI [0.72; 0.79]) compared to STS (C-statistics value 0.67, CI [0.63; 0.70]). CONCLUSION TRIM scores demonstrate good performance for risk estimation before and after TAVI. Together with clinical judgement, they may support standardised and objective decision-making before and after TAVI

A compact and portable deposition chamber to study nanoparticles in air-exposed tissue

BACKGROUND Epidemiological studies show that elevated levels of particulate matter in ambient air are highly correlated with respiratory and cardiovascular diseases. Atmospheric particles originate from a large number of sources and have a highly complex and variable composition. An assessment of their potential health risks and the identification of the most toxic particle sources would require a large number of investigations. Due to ethical and economic reasons, it is desirable to reduce the number of in vivo studies and to develop suitable in vitro systems for the investigation of cell-particle interactions. METHODS We present the design of a new particle deposition chamber in which aerosol particles are deposited onto cell cultures out of a continuous air flow. The chamber allows for a simultaneous exposure of 12 cell cultures. RESULTS Physiological conditions within the deposition chamber can be sustained constantly at 36-37°C and 90-95% relative humidity. Particle deposition within the chamber and especially on the cell cultures was determined in detail, showing that during a deposition time of 2 hr 8.4% (24% relative standard deviation) of particles with a mean diameter of 50 nm [mass median diameter of 100 nm (geometric standard deviation 1.7)] are deposited on the cell cultures, which is equal to 24-34% of all charged particles. The average well-to-well variability of particles deposited simultaneously in the 12 cell cultures during an experiment is 15.6% (24.7% relative standard deviation). CONCLUSIONS This particle deposition chamber is a new in vitro system to investigate realistic cell-particle interactions at physiological conditions, minimizing stress on the cell cultures other than from deposited particles. A detailed knowledge of particle deposition characteristics on the cell cultures allows evaluating reliable dose-response relationships. The compact and portable design of the deposition chamber allows for measurements at any particle sources of interest

Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland

Background: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. Methods: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. Results: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were “local recurrence and compression” (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. Conclusions: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT.ISSN:2072-669

Association Between Lifetime Marijuana Use and Cognitive Function in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

ImportanceMarijuana use is increasingly common in the United States. It is unclear whether it has long-term effects on memory and other domains of cognitive function.ObjectiveTo study the association between cumulative lifetime exposure to marijuana use and cognitive performance in middle age.Design, setting, and participantsWe used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of 5115 black and white men and women aged 18 to 30 years at baseline from March 25, 1985, to June 7, 1986 (year 0), and followed up over 25 years from June 7, 1986, to August 31, 2011, to estimate cumulative years of exposure to marijuana (1 year = 365 days of marijuana use) using repeated measures and to assess associations with cognitive function at year 25. Linear regression was used to adjust for demographic factors, cardiovascular risk factors, tobacco smoking, use of alcohol and illicit drugs, physical activity, depression, and results of the mirror star tracing test (a measure of cognitive function) at year 2. Data analysis was conducted from June 7, 1986, to August 31, 2011.Main outcomes and measuresThree domains of cognitive function were assessed at year 25 using the Rey Auditory Verbal Learning Test (verbal memory), the Digit Symbol Substitution Test (processing speed), and the Stroop Interference Test (executive function).ResultsAmong 3385 participants with cognitive function measurements at the year 25 visit, 2852 (84.3%) reported past marijuana use, but only 392 (11.6%) continued to use marijuana into middle age. Current use of marijuana was associated with worse verbal memory and processing speed; cumulative lifetime exposure was associated with worse performance in all 3 domains of cognitive function. After excluding current users and adjusting for potential confounders, cumulative lifetime exposure to marijuana remained significantly associated with worse verbal memory. For each 5 years of past exposure, verbal memory was 0.13 standardized units lower (95% CI, -0.24 to -0.02; P = .02), corresponding to a mean of 1 of 2 participants remembering 1 word fewer from a list of 15 words for every 5 years of use. After adjustment, we found no associations with lower executive function (-0.03 [95% CI, -0.12 to 0.07]; P = .56) or processing speed (-0.04 [95% CI, -0.16 to 0.08]; P = .51).Conclusions and relevancePast exposure to marijuana is associated with worse verbal memory but does not appear to affect other domains of cognitive function

Association Between Lifetime Marijuana Use and Cognitive Function in Middle Age

IMPORTANCE: Marijuana use is increasingly common in the US. It is unclear whether it has long term effects on memory and other domains of cognitive function. OBJECTIVE: To study the association between cumulative lifetime exposure to marijuana use and cognitive performance in mid-life. DESIGN, SETTING AND PARTICIPANTS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a cohort of black and white men and women 18 to 30 years of age at baseline in 1986 (Year 0) and followed over 25 years, to estimate cumulative years of exposure to marijuana (=365 days of marijuana use) using repeated measures and to assess associations with cognitive function at Year 25. Linear regression was used to adjust for demographic factors, cardiovascular risk factors, tobacco smoking and alcohol, illicit drugs, physical activity, depression, and Mirror Star Tracing Test (a measure of cognitive function) at Year 2. MAIN OUTCOME MEASURES: Three domains of cognitive function were assessed at Year 25 using the Rey Auditory Verbal Learning Test (verbal memory), the Digital Symbol Substitution Test (processing speed) and the Stroop Interference Test (executive function). RESULTS: Among 3385 Year 25 CARDIA participants with cognitive function measurements, 2852 (84%) reported past marijuana use, but only 392 (9%) continued to use marijuana into middle age. Current use of marijuana was associated with worse verbal memory and processing speed; cumulative lifetime exposure was associated with all three domains of cognitive function. After excluding current users and adjusting for potential confounders, cumulative lifetime exposure to marijuana remained strongly associated with verbal memory. For each 5 years of past exposure, verbal memory was 0.13 standardized units lower (95% confidence interval (CI):−0.24 to −0.02, p=0.02), corresponding to 1 of 2 participants on average remembering one word less from a list of 15 words for every 5 years of use. After adjustment, we found no associations with lower executive function (−0.03, 95%CI: −0.12 to 0.07) or processing speed (−0.04, 95%CI: −0.16 to 0.08). CONCLUSION AND RELEVANCE: Past exposure to marijuana is associated with worse verbal memory, but does not appear to impact other domains of cognitive function

Final 3-Year Outcomes of a Randomized Trial Comparing a Self-Expanding to a Balloon-Expandable Transcatheter Aortic Valve.

BACKGROUND In the SCOPE I trial (Safety and Efficacy of the Symetis ACURATE Neo/TF Compared to the Edwards SAPIEN 3 Bioprosthesis), transcatheter aortic valve implantation with the self-expanding ACURATE neo (NEO) did not meet noninferiority compared with the balloon-expandable SAPIEN 3 (S3) device regarding a composite end point at 30 days due to higher rates of prosthetic valve regurgitation and acute kidney injury. Data on long-term durability of NEO are scarce. Here, we report whether early differences between NEO and S3 translate into differences in clinical outcomes or bioprosthetic valve failure 3 years after transcatheter aortic valve implantation. METHODS Patients with severe aortic stenosis were randomized to transfemoral transcatheter aortic valve implantation with NEO or S3 at 20 European centers. Clinical outcomes at 3 years are compared using Cox proportional or Fine-Gray subdistribution hazard models by intention-to-treat. Bioprosthetic valve failure is reported for the valve-implant cohort. RESULTS Among 739 patients, 84 of 372 patients (24.3%) had died in the NEO and 85 of 367 (25%) in the S3 group at 3 years. Comparing NEO with S3, the 3-year rates of all-cause death (hazard ratio, 0.98 [95% CI, 0.73-1.33]), stroke (subhazard ratio, 1.04 [95% CI, 0.56-1.92]), and hospitalization for congestive heart failure (subhazard ratio, 0.74 [95% CI, 0.51-1.07]) were similar between the groups. Aortic valve reinterventions were required in 4 NEO and 3 S3 patients (subhazard ratio, 1.32 [95% CI, 0.30-5.85]). New York Heart Association functional class ≤II was observed in 84% (NEO) and 85% (S3), respectively. Mean gradients remained lower after NEO at 3 years (8 versus 12 mm Hg; P<0.001). CONCLUSIONS Early differences between NEO and S3 did not translate into significant differences in clinical outcomes or bioprosthetic valve failure throughout 3 years. REGISTRATION URL: https://clinicaltrials.gov, Unique identifier: NCT03011346