An automated calculation pipeline for differential pair interaction energies with molecular force fields using the Tinker Molecular Modeling Package.

An automated pipeline for comprehensive calculation of intermolecular interaction energies based on molecular force-fields using the Tinker molecular modelling package is presented. Starting with non-optimized chemically intuitive monomer structures, the pipeline allows the approximation of global minimum energy monomers and dimers, configuration sampling for various monomer-monomer distances, estimation of coordination numbers by molecular dynamics simulations, and the evaluation of differential pair interaction energies. The latter are used to derive Flory-Huggins parameters and isotropic particle-particle repulsions for Dissipative Particle Dynamics (DPD). The computational results for force fields MM3, MMFF94, OPLS-AA and AMOEBA09 are analyzed with Density Functional Theory (DFT) calculations and DPD simulations for a mixture of the non-ionic polyoxyethylene alkyl ether surfactant C10E4 with water to demonstrate the usefulness of the approach.Scientific ContributionTo our knowledge, there is currently no open computational pipeline for differential pair interaction energies at all. This work aims to contribute an (at least academically available, open) approach based on molecular force fields that provides a robust and efficient computational scheme for their automated calculation for small to medium-sized (organic) molecular dimers. The usefulness of the proposed new calculation scheme is demonstrated for the generation of mesoscopic particles with their mutual repulsive interactions.

Optimizing cancer patient care with a robust assay for 5-fluorouracil quantification and in-vitro stability in human blood for therapeutic drug monitoring.

Background: The plasma concentration of 5-Fluorouracil (5-FU) is affected by numerous factors, thereby limiting its efficacy. The current therapeutic regimen's doses based on body surface area (BSA) are linked to increased toxicity and sometimes inadequate drug exposure. Aim and objectives: The study aims to develop an in-vitro assay to monitor 5-Fluorouracil's therapeutic efficacy in cancer patients' blood samples, focusing on pharmacokinetics to improve therapy precision. Materials and methods: Drug levels were determined from standards, quality controls, and experimental samples using protein precipitation, liquid-liquid extraction, and separation using a C18 analytical column with an isocratic program. Result: In EXP-1A, the mean concentration of 5-Fluorouracil was 1.15 µg/ml; in EXP-1B, it was 1.16 µg/ml, while in EXP-1C, the mean concentration was 0.9 µg/ml. The percentage difference in mean 5-Fluorouracil concentration between the experiment sample containing a DPD inactivator and EXP-1C (without a DPD inactivator) was 21.5 % higher for EXP-1A and 0.68 % higher for EXP-1B. In the second phase of the experiment, the overall stability of 5-Fluorouracil in samples containing a DPD inactivator was 24.5 % superior compared to samples without a DPD inactivator. Conclusion: A modified extraction technique has been developed to accurately measure 5-Flourouracil concentration in blood, preserving its stability and concentration by adding a DPD inactivator.

Transthyretin amyloid cardiomyopathy in patients with unexplained increased left ventricular wall thickness.

Amyloid cardiomyopathy (CA) was previously considered a rare disease; however, rapid advancements in imaging modalities have led to an increased frequency of its diagnosis. The aim of this prospective study was to assess the prevalence and clinical phenotype of transthyretin amyloidosis (ATTR) cardiomyopathy in patients exhibiting unexplained increased left ventricular (LV) wall thickness. From 2020 to 2022, we enrolled 100 consecutive adults with unexplained increased LV wall thickness in the study. The analysis included clinical data, electrocardiography, transthoracic echocardiography, single-photon emission computed tomography/computed tomography with 3,3-disphono-1,2-propanodicarboxylic acid, genetic testing. Overall, 18% of patients were diagnosed with CA, comprising 5% with light-chain amyloidosis, and 12% with ATTR. To evaluate associations with the ATTR diagnosis, a LOGIT model and multivariate analysis were applied. Notably, age, polyneuropathy, gastropathy, carpal tunnel syndrome, lumbar spine stenosis, low voltage, ventricular arrhythmia, LV mass, LV ejection fraction, global longitudinal strain (GLS), E/A, E/E', right ventricle (RV) thickness, right atrium area, RV VTI, TAPSE, apical sparing, ground glass appearance of myocardium, thickening of interatrial septum, thickening of valves, and the "5-5-5" sign were found to be significantly associated with ATTR (p < 0.05). The best predictive model for ATTR diagnoses exhibited an area under the curve of 0.99, including LV mass, GLS and RV thickness. This study, conducted at a cardiology referral center, revealed that a very considerable proportion of patients with unexplained increased LV wall thickness may suffer from underlying CA. Moreover, the presence of ATTR should be considered in patients with increased LV mass accompanied by reduced GLS and RV thickening.

Prognostic Value of [99mTc]Tc-DPD Quantitative SPECT/CT in Patients with Suspected and Confirmed Amyloid Transthyretin-Related Cardiomyopathy and Preserved Left Ventricular Function.

Quantitative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD) SPECT may be used for risk-stratifying patients with amyloid transthyretin-related cardiomyopathy (ATTR-CM). We aimed to analyze the predictive value of quantitative [99mTc]Tc-DPD SPECT/CT in suspected and confirmed ATTR-CM according to different disease stages. Methods: The study enrolled consecutive patients with suspected ATTR-CM who were referred to a single tertiary center and underwent quantitative [99mTc]Tc-DPD SPECT/CT allowing SUVmax and SUVpeak analysis. Patients were divided into 2 groups according to left ventricular ejection fraction (LVEF) at baseline (i.e., ≥50% and <50%). Clinical, laboratory, and echocardiographic parameters and major adverse cardiac events (i.e., all-cause death, sustained ventricular tachyarrhythmia, hospitalization for heart failure, implantation of a cardioverter defibrillator) were investigated for any correlation with quantitative uptake values. Results: In total, 144 patients with suspected ATTR-CM were included in the study (98 with LVEF ≥ 50% and 46 with LVEF < 50%), of whom 99 were diagnosed with ATTR-CM (68.8%; 69 with LVEF ≥ 50% and 30 with LVEF < 50%). A myocardial SUVmax of at least 7 was predictive of major adverse cardiac events at 21.9 ± 13.0 mo of follow-up (hazard ratio, 2.875; 95% CI, 1.23-6.71; P = 0.015) in patients with suspected or confirmed ATTR-CM (global χ2 = 6.892, P = 0.02) and an LVEF of at least 50%. SUVmax was not predictive in patients with an LVEF of less than 50% and suspected or confirmed ATTR-CM. Conclusion: In patients with suspected or confirmed ATTR-CM and preserved LVEF, representing an early disease stage, quantitative [99mTc]Tc-DPD SPECT should be considered to improve early-stage risk stratification.

A Simulation of the Mechanical Testing of the Cell Membrane and Cytoskeleton.

Cell models play a crucial role in analyzing the mechanical response of cells and quantifying cellular damage incurred during micromanipulation. While traditional models can capture the overall mechanical behavior of cells, they often lack the ability to discern among distinct cellular components. Consequently, by employing dissipative particle dynamics, this study constructed a triangular network-like representation of the cell membrane along with cross-linked cytoskeletal chains. The mechanical properties of both the membrane and cytoskeleton were then analyzed through a series of simulated mechanical tests, validated against real-world experiments. The investigation utilized particle-tracking rheology to monitor changes in the mean square displacements of membrane particles over time, facilitating the analysis of the membrane's storage and loss moduli. Additionally, the cytoskeletal network's storage and loss moduli were examined via a double-plate oscillatory shear experiment. The simulation results revealed that both the membrane and cytoskeleton exhibit viscoelastic behavior, as evidenced by the power-law dependency of their storage and loss moduli on frequency. Furthermore, indentation and microinjection simulations were conducted to examine the overall mechanical properties of cells. In the indentation experiments, an increase in the shear modulus of the membrane's WLCs correlated with a higher Young's modulus for the entire cell. Regarding the microinjection experiment, augmenting the microinjection speed resulted in reduced deformation of the cell at the point of membrane rupture and a lower percentage of high strain.

Potential of DPD ((S)-4,5-dihydroxy-2,3-pentanedione) Analogs in Microparticulate Formulation as Vaccine Adjuvants.

The molecule (S)-4,5-dihydroxy-2,3-pentanedione (DPD) is produced by many different species of bacteria and is involved in bacterial communication. DPD is the precursor of signal molecule autoinducer-2 (AI-2) and has high potential to be used as a vaccine adjuvant. Vaccine adjuvants are compounds that enhance the stability and immunogenicity of vaccine antigens, modulate efficacy, and increase the immune response to a particular antigen. Previously, the microparticulate form of (S)-DPD was found to have an adjuvant effect with the gonorrhea vaccine. In this study, we evaluated the immunogenicity and adjuvanticity of several synthetic analogs of the (S)-DPD molecule, including ent-DPD((R)-4,5-dihydroxy-2,3-pentanedione), n-butyl-DPD ((S)-1,2-dihydroxy-3,4-octanedione), isobutyl-DPD ((S)-1,2-dihydroxy-6-methyl-3,4-heptanedione), n-hexyl-DPD ((S)-1,2-dihydroxy-3,4-decanedione), and phenyl-DPD ((S)-3,4-dihydroxy-1-phenyl-1,2-butanedione), in microparticulate formulations. The microparticulate formulations of all analogs of (S)-DPD were found to be noncytotoxic toward dendritic cells. Among these analogs, ent-DPD, n-butyl-DPD, and isobutyl-DPD were found to be immunogenic toward antigens and showed adjuvant efficacy with microparticulate gonorrhea vaccines. It was observed that n-hexyl-DPD and phenyl-DPD did not show any adjuvant effect. This study shows that synthetic analogs of (S)-DPD molecules are capable of eliciting adjuvant effects with vaccines. A future in vivo evaluation will further confirm that these analogs are promising vaccine adjuvants.

Listening and Processing Skills in Young School Children with a History of Developmental Phonological Disorder.

There is a lack of longitudinal studies on the broad-based outcomes in children with Developmental Phonological Disorder (DPD). The aim of this study was to investigate listening and processing skills in a clinical sample of 7-to-10-year-old children diagnosed with DPD in their preschool years and compare these to same-aged typically developing (TD) children. The Evaluation of Children's Listening and Processing Skills (ECLiPS) was completed by parents of 115 children with DPD and by parents of 46 TD children. The total ECLiPS mean score, and the five subscale mean scores, the proportion of children with clinically significant difficulties (≤10th percentile), and the proportion of children with co-occurrence of clinically significant difficulties on more than one subscale, were calculated. Results showed that the ECLiPS mean scores did not differ between the groups. There was no difference between groups regarding language and literacy, but a higher proportion of children with DPD than TD had difficulties in the total score, speech, and auditory processing, environmental and auditory sensitivity, and pragmatic and social skills. In addition, 33.9% of children with DPD had clinically significant difficulties in two or more subscales compared to 10.9% of TD children.

Establishment of Anti-Dog Programmed Cell Death Ligand 1 Monoclonal Antibodies for Immunohistochemistry.

Immune checkpoint blockade therapy has shown successful clinical outcomes in multiple human cancers. In dogs, several types of tumors resemble human tumors in many respects. Therefore, several groups have developed the anti-dog programmed cell death ligand 1 (dPD-L1) monoclonal antibodies (mAbs) and showed efficacy in several canine tumors. To examine the abundance of dPD-L1 in canine tumors, anti-dPD-L1 diagnostic mAbs for immunohistochemistry are required. In this study, we immunized the peptide in the dPD-L1 intracellular domain, and established anti-dPD-L1 mAbs, L1Mab-352 (mouse IgG1, kappa), and L1Mab-354 (mouse IgG1, kappa). In enzyme-linked immunosorbent assay, L1Mab-352 and L1Mab-354 showed high-binding affinity to the dPD-L1 peptide, and the dissociation constants (KD) were determined as 6.9 × 10-10 M and 7.2 × 10-10 M, respectively. Furthermore, L1Mab-352 and L1Mab-354 were applicable for the detection of dPD-L1 in immunohistochemical analysis in paraffin-embedded dPD-L1-overexpressed cells. These results indicated that L1Mab-352 and L1Mab-354 are useful for detecting dPD-L1 in immunohistochemical analysis.

[Lymph node metastatic penile cancer: a challenge in uro-oncology-guideline-conform treatment]. / Das lymphonodulär metastasierte Peniskarzinom: eine uroonkologische Herausforderung ­ die leitlinienorientierte Therapie.

Penile squamous cell carcinoma is a rare, highly aggressive cancer of older men. The metastatic stage has significant therapeutic and prognostic features. Treatment of penile cancer is significantly influenced by the operation, in which an R0 situation must be achieved to ensure a realistic chance of cure. Other local therapeutic procedures such as radiotherapy are often of secondary importance. Neoadjuvant and adjuvant chemotherapy are relevant components of multimodal therapy. Post-therapeutically, patients require lifelong, risk-adapted follow-up care.

Utility of three-dimensional proton density-weighted sequence MRI in knee for the assessment of Anterolateral complex in Anterior cruciate ligament injury.

OBJECTIVES: To assess the proportion and pattern of injury of the anterolateral ligament (ALL) and the Kaplan fibre (KF) complex in knees with anterior cruciate ligament (ACL) injuries on MRI using three-dimensional (3D) proton density (PD) sequences. METHODS: A total of 88 patients having ACL injury were included in this cross-sectional study. 3D PD sequences were used to assess injury of ALL and the KF complex and were graded on a scale of 0 to 3. MR images were evaluated by two radiologists. Interobserver agreement was determined using Cohen Kappa. RESULTS: Femoral, meniscal, and tibial portions of ALL were visualized in 90.9%, 92%, and 94.3% of the study subjects, respectively. Proximal and distal KF were visualized in 92% and 93.2% of patients, respectively. Injury to ALL and KF was seen in 63.6% and 17% of the patients, respectively. Excellent interobserver agreement was noted for the identification and grading of ALL and KF complex injuries. CONCLUSIONS: Oblique reformatted 3DPD MRI reliably detect ALC; however, ALL injury is better characterized than KF injury using this sequence. ADVANCES IN KNOWLEDGE: Given the potential role of anterolateral complex (ALC) in maintaining the rotational stability of the knee, ALC assessment using the 3D PD sequences and their oblique reformatted images should be incorporated as routine review area of the knee MRI, particularly in the setting of ACL tear.

Correlation of 99mTc-DPD bone scintigraphy with histological amyloid load in patients with ATTR cardiac amyloidosis.

BACKGROUND: The significance of measuring 99mTc-labelled-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in transthyretin (ATTR) cardiac amyloidosis has not been adequately studied. This single-centre observational study evaluated the correlation between 99mTc-DPD scintigraphy and histological amyloid load in endomyocardial biopsy (EMB). METHODS: Twenty-eight patients with biopsy-proven ATTR amyloidosis and concomitantly available 99mTc-DPD scintigraphy were included. Visual Perugini scoring, and (semi-)quantitative analysis of cardiac 99mTc-DPD uptake by planar whole-body imaging and single photon emission computed tomography (SPECT/CT) using regions of interest (ROI) were performed. From this, heart-to-whole-body ratio (H/WB) and heart-to-contralateral-chest ratio (H/CL) were calculated. The histological amyloid load was quantified using two different staining methods. RESULTS: Increased cardiac tracer uptake was documented in all patients (planar: ROImean 129 ± 37 cps; SPECT/CT: ROImean 369 ± 142 cps). Histological amyloid load (19 ± 13%) significantly correlated with Perugini score (r = 0.69, p < .001) as well as with cardiac 99mTc-DPD uptake (planar: r = 0.64, p < .001; H/WB: r = 0.50, p = .014; SPECT/CT: r = 0.53, p = .008; H/CL: r = 0.43, p = .037) (results are shown for correlations with Congo Red-staining). CONCLUSION: In ATTR, cardiac 99mTc-DPD uptake significantly correlated with histological amyloid load in EMB. Further studies are needed to implement thresholds in cardiac 99mTc-DPD uptake measurements for risk stratification and guidance of therapy.

Diagnostic and prognostic contribution of DPD scintigraphy in transthyretin V30M cardiac amyloidosis.

BACKGROUND: Early diagnosis and prognostic stratification of cardiac transthyretin amyloidosis are crucial. Although 99mTc 3,3-diphosphono-1,2-propanedicarboxylic acid (DPD) scintigraphy is the preferred method for the non-invasive diagnosis, its accuracy appears to be limited in transthyretin amyloidosis protein (ATTR) V30M mutation. Furthermore, its prognostic value in this mutation is unknown. This study investigated the diagnostic value of DPD scintigraphy to detect ATTR cardiomyopathy in V30M mutation and explored its prognostic value regarding mortality. METHODS: A total of 288 ATTR V30M mutation carriers (median age: 46 years; 49% males) without myocardial thickening (defined as septal thickness ≥13mm) attributable to other causes and who underwent DPD scintigraphy were enrolled. ATTR cardiomyopathy was defined by septal thickness ≥13mm and at least one of the criteria: late heart-to-mediastinum (H/M) 123I-metaiodobenzylguanidine (MIBG) uptake ratio <1.60; electrical heart disease or biopsy-documented amyloidosis. RESULTS: ATTR cardiomyopathy was identified in 41 (14.2%) patients and cardiac DPD uptake in 34 (11.8%). During a mean follow-up of 33.6 ± 1.2 months, 16 patients died (5.6%). Mortality was 14 times higher in patients with ATTR cardiomyopathy, 13 times higher in those with DPD uptake and 10 times higher in those with late H/M MIBG <1.60. The combined assessment of septal thickness and cardiac DPD uptake improved risk stratification: patients without septal thickening and without DPD retention had an excellent prognosis while those who presented either or both of them had a significantly worse prognosis, with 5-year mortality rates ranging from 39.9 to 53.3%. CONCLUSIONS: DPD scintigraphy is useful for prognostic stratification of ATTR V30M mutation carriers. Patients without septal thickening and no DPD uptake present the best prognosis compared to those with any signs of cardiac involvement.

Effect of Film Thickness on the Self-Assembly of CBABC Symmetric Pentablock Terpolymer Melts under 1D Confinement: A Dissipative Particle Dynamic Study.

The study investigates the impact of film thickness on the phase behavior of pentablock terpolymers, denoted as C3B3A6B3C3, when subjected to wall confinement by utilizing the dissipative particle dynamics method. Phase diagrams were constructed to elucidate how factors such as block-block interaction strength, film thickness, and wall properties affect the self-assembly structures. In cases where the wall exhibits no preference for any of the blocks, lamellae phases with orientations perpendicular to the wall are observed. The order-disorder transition (ODT) temperature is found to be influenced by the interaction between the polymer and the wall in thin confinement scenarios. When the wall displays a preference for specific blocks, the orientation of lamellae structures undergoes variations. Lamellae tend to align parallel to the wall when the wall favors A or C blocks, and they orient perpendicularly when B blocks are favored. Furthermore, the mechanical properties of the lamellae structures are related to the conformations of the polymer chains. Structures where chains predominantly adopt a loop conformation exhibit enhanced elastic properties. The ratio of looping to bridging conformations can be adjusted by altering the film thickness and wall selectivity.

The Evaluation of Dihydropyrimidine Dehydrogenase Enzyme Level in the Serum of Colorectal Cancer Iraqi Males on Fluoropyrimidine-Based Chemotherapy (Capecitabine).

The cornerstone of systemic chemotherapy for colorectal cancer (CRC) revolves around fluoropyrimidines. This class encompasses 5-fluorouracil (5-FU), which is administered intravenously, along with its oral prodrug counterpart, capecitabine. Central to the metabolism of both 5-FU and capecitabine is the pivotal enzyme dihydropyrimidine dehydrogenase (DPD). Operating at the rate-limiting juncture, DPD assumes a critical role. Notably, a deficiency in DPD significantly elevates the risk quotient for encountering unfavorable outcomes linked to the administration of fluoropyrimidines. This study seeks to assess the significance of DPD enzyme levels in the serum of Iraqi colorectal cancer male patients undergoing fluoropyrimidine-based chemotherapy, specifically with capecitabine. It adopts a case-control design and comprises 80 male participants. Those males are divided into two distinct groups. Group 1 comprises 45 male patients diagnosed with CRC who have experienced relapse subsequent to undergoing chemotherapy based on fluoropyrimidine (capecitabine). Their ages span from 41 to 71 years, and they were treated at the Misan Health Directorate/Misan Center for Tumor Treatment. Group 2 encompasses 35 male patients diagnosed with CRC who underwent fluoropyrimidine-based chemotherapy (capecitabine) without encountering relapse. Their ages range from 40 to 57 years. All participants were provided with comprehensive information regarding the research, and data collection occurred through a structured questionnaire. Subsequent to capecitabine-based treatment, serum samples were collected from CRC patients (stage III). The findings from this research indicate a notable elevation in DPD enzyme activity. Furthermore, a significant reduction in enzyme activity was observed among patients who experienced relapse, in contrast to those who remained non-relapsed. The results indicate that individuals with an insufficiency in DPD are notably more vulnerable to experiencing severe and potentially life-threatening side effects upon exposure to the commonly utilized chemotherapy drug, 5-FU.

Efficacy and Safety of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Compared to Daratumumab, Bortezomib, and Dexamethasone (DVd) in Daratumumab-Naïve Relapsed Multiple Myeloma.

Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments.

Dissipative Particle Dynamics Simulation for the Self-Assembly of Symmetric Pentablock Terpolymers Melts under 1D Confinements.

The phase behavior of CBABC pentablock terpolymers confined in thin films is investigated using the Dissipative Particle Dynamic method. Phase diagrams are constructed and used to reveal how chain length (i-block length), block composition and wall selectivity influence the self-assembly structures. Under neutral walls, four categories of morphologies, i.e., perpendicular lamellae, core-shell types of microstructures, complex networks, and half-domain morphologies, are identified with the change in i-block length. Ordered structures are more common at weak polymer-polymer interaction strengths. For polymers of a consistent chain length, when one of the three components has a relatively smaller length, the morphologies transition is sensitive to block composition. With selective walls, parallel lamellae structures are prevalent. Wall selectivity also impacts chain conformations. While a large portion of chains form loop conformations under A-selective walls, more chains adopt bridge conformation when the wall prefers C-blocks. These findings offer insights for designing nanopatterns using symmetric pentablock terpolymers.

Plastid inheritance revisited: emerging role of organelle DNA degradation in angiosperms.

Plastids are essential organelles in angiosperms and show non-Mendelian inheritance due to their evolution as endosymbionts. In approximately 80% of angiosperms, plastids are thought to be inherited from the maternal parent, whereas other species transmit plastids biparentally. Maternal inheritance can be generally explained by the stochastic segregation of maternal plastids after fertilization because the zygote is overwhelmed by the maternal cytoplasm. In contrast, biparental inheritance shows transmission of organelles from both parents. In some species, maternal inheritance is not absolute and paternal leakage occurs at a very low frequency (~10-5). A key process controlling the inheritance mode lies in the behavior of plastids during male gametophyte (pollen) development, with accumulating evidence indicating that the plastids themselves or their DNAs are eliminated during pollen maturation or at fertilization. Cytological observations in numerous angiosperm species have revealed several critical steps that mutually influence the degree of plastid transmission quantitatively among different species. This review revisits plastid inheritance and focuses on the mechanistic viewpoint. Particularly, we focus on a recent finding demonstrating that both low temperature and plastid DNA degradation mediated by the organelle exonuclease DPD1 influence the degree of paternal leakage significantly in tobacco. Given these findings, we also highlight the emerging role of DPD1 in organelle DNA degradation.

Amyloid Transthyretin Cardiomyopathy in Elderly Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation.

Background The prevalence of calcific aortic stenosis and amyloid transthyretin cardiomyopathy (ATTR-CM) increase with age, and they often coexist. The objective was to determine the prevalence of ATTR-CM in patients with severe aortic stenosis and evaluate differences in presentations and outcomes of patients with concomitant ATTR-CM undergoing transcatheter aortic valve implantation. Methods and Results Prospective screening for ATTR-CM with Technetium99-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy was performed in 315 patients referred with severe aortic stenosis between August 2019 and August 2021. Myocardial Technetium99-3,3-diphosphono-1,2-propanodicarboxylic acid tracer uptake was detected in 34 patients (10.8%), leading to a diagnosis of ATTR-CM in 30 patients (Perugini ≥2: 9.5%). Age (85.7±4.9 versus 82.8±4.5; P=0.001), male sex (82.4% versus 57.7%; P=0.005), and prior carpal tunnel surgery (17.6% versus 4.3%; P=0.007) were associated with coexisting ATTR-CM, as were ECG (discordant QRS voltage to left ventricular wall thickness [42% versus 12%; P<0.001]), echocardiographic (left ventricular ejection fraction 48.8±12.8 versus 58.4±10.8; P<0.001; left ventricular mass index, 144.4±45.8 versus 117.2±34.4g/m2; P<0.001), and hemodynamic parameters (mean aortic valve gradient, 23.4±12.6 versus 35.5±16.6; P<0.001; mean pulmonary artery pressure, 29.5±9.7 versus 25.8±9.5; P=0.037). Periprocedural (cardiovascular death: hazard ratio [HR], 0.71 [95% CI, 0.04-12.53]; stroke: HR, 0.46 [95% CI, 0.03-7.77]; pacemaker implantation: HR, 1.54 [95% CI, 0.69-3.43]) and 1-year clinical outcomes (cardiovascular death: HR, 1.04 [95% CI, 0.37-2.96]; stroke: HR, 0.34 [95% CI, 0.02-5.63]; pacemaker implantation: HR, 1.50 [95% CI, 0.67-3.34]) were similar between groups. Conclusions Coexisting ATTR-CM was observed in every 10th elderly patient with severe aortic stenosis referred for therapy. While patients with coexisting pathologies differ in clinical presentation and echocardiographic and hemodynamic parameters, peri-interventional risk and early clinical outcomes were comparable up to 1 year after transcatheter aortic valve implantation. REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT04061213.

DPD deficiency in an Irish oncology centre: Prevalence and clinical implications.

INTRODUCTION: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. METHODS: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019-April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. RESULTS: In those treated 2020-2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25-86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. DISCUSSION: Other Irish studies estimated prevalence at 11-12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. CONCLUSIONS: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients.