The influence of the framework core residues on the biophysical properties of immunoglobulin heavy chain variable domains

Antibody variable domains differ considerably in stability. Single-chain Fv (scFv) fragments derived from natural repertoires frequently lack the high stability needed for therapeutic application, necessitating reengineering not only to humanize their sequence, but also to improve their biophysical properties. The human VH3 domain has been identified as having the best biophysical properties among human subtypes. However, complementarity determining region (CDR) grafts from highly divergent VH domains to huVH3 frequently fail to reach its superior stability. In previous experiments involving a CDR graft from a murine VH9 domain of very poor stability to huVH3, a hybrid VH framework was obtained which combines the lower core residues of muVH9 with the surface residues of huVH3. It resulted in a scFv with far better biophysical properties than the corresponding grafts to the consensus huVH3 framework. To better understand the origin of the superior properties of the hybrid framework, we constructed further hybrids, but now in the context of the consensus CDR-H1 and -H2 of the original human VH3 domain. The new hybrids included elements from either murine VH9, human VH1 or human VH5 domains. From guanidinium chloride-induced equilibrium denaturation measurements, kinetic denaturation experiments, measurements of heat-induced aggregation and comparison of soluble expression yield in Escherichia coli, we conclude that the optimal VH framework is CDR-dependent. The present work pinpoints structural features responsible for this dependency and helps to explain why the immune system uses more than one framework with different structural subtypes in framework 1 to optimally support widely different CDR

Diagnostic performance of quantitative coronary artery disease assessment using computed tomography in patients with aortic stenosis undergoing transcatheter aortic-valve implantation.

BACKGROUND Computed tomography angiography (CTA) is a cornerstone in the pre- transcatheter aortic valve replacement (TAVI) assessment. We evaluated the diagnostic performance of CTA and coronary artery calcium score (CACS) for CAD evaluation compared to invasive coronary angiography in a cohort of TAVI patients. METHODS In consecutive TAVI patients without prior coronary revascularization and device implants, CAD was assessment by quantitative analysis in CTA. (a) Patients with non-evaluable segments were classified as obstructive CAD. (b) In patients with non-evaluable segments a CACS cut-off of 100 was applied for obstructive CAD. The reference standard was quantitative invasive coronary angiography (QCA, i.e. ≥ 50% stenosis). RESULTS 100 consecutive patients were retrospectively included, age was 82.3 ± 6.5 years and 30% of patients had CAD. In 16% of the patients, adequate visualization of the entire coronary tree (all 16 segments) was possible with CTA, while 84% had at least one segment which was not evaluable for CAD analysis due to impaired image quality. On a per-patient analysis, where patients with low image quality were classified as CAD, CTA showed a sensitivity of 100% (95% CI 88.4-100.0), specificity of 11.4% (95% CI 5.1-21.3), PPV of 32.6% (95% CI 30.8-34.5), NPV of 100% and diagnostic accuracy of 38% (95% CI 28.5-48.3) for obstructive CAD. When applying a combined approach of CTA (in patients with good image quality) and CACS (in patients with low image quality), the sensitivity and NPV remained at 100% and obstructive CAD could be ruled out in 20% of the TAVI patients, versus 8% using CTA alone. CONCLUSION In routinely acquired pre-TAVI CTA, the image quality was insufficient in a high proportion of patients for the assessment of the entire coronary artery tree. However, when adding CACS in patients with low image quality to quantitative CTA assessment in patients with good image quality, obstructive CAD could be ruled-out in 1/5 of the patients and may therefore constitute a strategy to streamline pre-procedural workup, and reduce risk, radiation and costs in selected TAVI patients without prior coronary revascularization or device implants

Transcatheter Aortic Valve Replacement in Patients With Multivalvular Heart Disease.

As transcatheter aortic valve replacement becomes a more dominant treatment option across all risk profiles, the frequency of encountering patients with multivalvular disease will increase. Furthermore, percutaneous interventions to treat other valvular lesions are also evolving. Understanding the clinical implications and treatment options for a second valvular lesion is becoming increasingly important to guide heart team decisions, and this paper aims to review the evidence around these situations. Diagnosis of multivalvular disease can be challenging because of changes in physiology. There are little randomized data to guide therapy in multivalvular disease. Multidisciplinary heart team decisions can be invaluable in integrating the plethora of clinical, hemodynamic, and imaging data on which an optimal management strategy can be planned. Prospective studies to assess the role of structural valve interventions in the transcatheter aortic valve replacement era would greatly help improve outcomes for structural heart patients

Discharge Location and Outcomes after Transcatheter Aortic Valve Implantation.

The relationship between discharge location and outcomes after transcatheter aortic valve implantation (TAVI) is largely unknown. Thus, the objective of this study was to investigate the impact of discharge location on clinical outcomes after TAVI. Between August 2007 and December 2018, consecutive patients undergoing transfemoral TAVI at Bern University Hospital were grouped according to discharge location. Clinical adverse events were adjudicated according to VARC-2 endpoint definitions. Of 1,902 eligible patients, 520 (27.3%) were discharged home, 945 (49.7%) were discharged to a rehabilitation clinic and 437 (23.0%) were transferred to another institution. Compared with patients discharged to a rehabilitation facility or another institution, patients discharged home were younger (80.8±6.5 vs. 82.9±5.4 and 82.8±6.4 years), less likely female (37.3% vs. 59.7% and 54.2%) and at lower risk according to STS-PROM (4.5±3.0% vs. 5.5±3.8% and 6.6±4.4%). At 1 year follow-up, patients discharged home had similar rates of all-cause mortality (HRadj 0.82; 95%CI 0.54-1.24), cerebrovascular events (HRadj 1.04; 95%CI 0.52-2.08) and bleeding complications (HRadj 0.93; 95%CI 0.61-1.41) compared to patients discharged to a rehabilitation facility. Patients discharged home or to rehabilitation were at lower risk for death (HRadj 0.37; 95%CI 0.24-0.56 and HRadj 0.44; 95%CI 0.32-0.60) and bleeding (HRadj 0.48; 95%CI 0.30-0.76 and HRadj 0.66; 95%CI 0.45-0.96) during the first year after hospital discharge compared to patients transferred to another institution. In conclusion, discharge location is associated with outcomes after TAVI with patients discharged home or to a rehabilitation facility having better clinical outcomes than patients transferred to another institution. Clinical Trial Registration: https://www.clinicaltrials.gov. NCT01368250

Relationship of Neighbourhood Social Deprivation and Ethnicity on Access to Transcatheter and Surgical Aortic Valve A

BackgroundWide geographic variation in access to transcatheter (TAVR) and surgical (SAVR) aortic valve replacement exists, but the impact of socioethnic factors on the geographic variation of AS management in Ontario, Canada, is unknown.MethodsNeighbourhood rates of AS admissions, as a proxy for AS burden, and downstream TAVR and SAVR referrals and procedures were estimated for the 76 subregions in Ontario. To determine if the socioethnic geographic variations in referrals and procedures were concordant or discordant with AS burden, we calculated Pearson correlation coefficients to determine the relationship between AS burden and each of TAVR referrals, TAVR procedures, SAVR referrals, or SAVR procedures. We developed generalised linear models to determine the association between social deprivation indices captured in the Ontario Marginalization index and the rates of AS burden as well as TAVR/SAVR referral and procedures.ResultsThere was wide geographic variation that was concordant between AS burden and the referral and procedure rates for TAVR and SAVR (correlation coefficients 0.86-0.96). Increased dependency was associated with higher rates of both TAVR/SAVR referrals and procedures (rate ratios 1.63-2.22). Neighbourhoods with a higher concentration of ethnic minorities were associated with lower AS burden as well as lower rates of both SAVR and TAVR referrals and procedures (rate ratios 0.57-0.85).ConclusionsAn important ethnic gradient exists in AS burden and in both referral and completion of TAVR and SAVR in Ontario. Further research is necessary to understand if this gradient is appropriate or requires mitigation

Validation of the 2019 Expert Consensus Algorithm for the Management of Conduction Disturbances After TAVR.

OBJECTIVES The aim of this study was to validate the 2019 consensus algorithm in a large cohort of contemporary transcatheter aortic valve replacement (TAVR) patients. BACKGROUND The optimal management of patients with atrioventricular conduction disturbances after TAVR is unknown. Guidance was consolidated in an expert consensus algorithm in 2019. METHODS In a retrospective analysis of a prospective registry, patients were classified according to the 2019 consensus algorithm as eligible for early discharge (day 1 or 2 after TAVR), higher risk for high-degree atrioventricular block (HAVB) or complete heart block (CHB) or in need for a permanent pacemaker (PPM). The primary endpoint was the incidence of PPM implantation for HAVB or CHB within 30 days after TAVR. Patients with prior PPM or implantable cardioverter-defibrillator implantation, valve-in-valve procedures, or incomplete electrocardiographic data were excluded. RESULTS Among 1,439 patients undergoing TAVR between January 2014 and December 2019, the 2019 consensus algorithm classified 73% as eligible for early discharge, 21% as at higher risk for HAVB or CHB, and 6% as in need of PPM. PPM implantation for HAVB or CHB occurred in 234 patients (16%) within 30 days after TAVR. The incidence of PPM implantation was 2.7% in the early discharge group, 41% in the group with higher risk for HAVB or CHB, and 100% in the PPM group. CONCLUSIONS The 2019 consensus algorithm safely identifies patients with no need for PPM implantation. This strategy allows more uniform management of TAVR patients and facilitates early discharge of low-risk patients without prolonged monitoring in 3 of 4 patients. However, the algorithm is less precise in the identification of high-risk patients

True believers: the recption of Descartes's meditations by Malebranche and Huet

Both Nicholas Malebranche and Pierre-Daniel Huet were at first positively influenced by Descartes's Meditations, and both came to perceive shortcomings in that work. With respect to mind-body dualism, Malebranche attempted to strengthen Descartes's position by jettisoning clarity and distinctness basing it instead on a principle of intentionality. Huet jettisoned the whole position in favor of skepticism. The source of their different responses lay in their different estimations of Descartes's integrity.<br>Tanto Nicholas Malebranche como Pierre-Daniel Huet foram inicialmente positivamente influenciados pelas Meditações de Descartes e ambos terminaram por perceber falhas nesta obra. No que concerne o dualismo mente e corpo, Malebranche buscou fortalecer a posição cartesiana abandonando o critério de clareza e distinção em favor de um princípio de intencionalidade. Huet abandonou o cartesianismo como um todo em favor do ceticismo. A fonte destas respostas diversas está nas avaliações distintas que fizeram da integridade de Descartes