Predictors and Trends of New Permanent Pacemaker Implantation: A Subanalysis of the International Navitor IDE Study.

Background: The Navitor Investigational Device Exemption (IDE) study is a prospective, multicenter, global study assessing the safety and effectiveness of the Navitor valve in a population with severe, symptomatic aortic stenosis who are at high and extreme surgical risk. The impact of pre-existing conduction abnormalities and implantation technique on new permanent pacemaker implantation (PPI) for the Navitor platform is not fully understood. Therefore, the goal of this analysis was to investigate the associations between patient and procedural factors and the 30-day new PPI rate. Methods: A total of 260 patients who underwent implantation of a Navitor valve in the Navitor IDE study were reviewed. Patients with preprocedural permanent pacemakers (n = 28) were excluded. Baseline risk factors were assessed for statistical significance. Multivariable logistic regression analyses were performed to identify independent predictors of new PPI. Results: Mean age of the pacemaker-naïve population was 83.3 ± 5.2 years, 58.6% were female, average Society of Thoracic Surgeons score was 3.8% ± 1.9%, median frailty score was 1 (interquartile range 1, 2), and 17.7% were deemed at extreme surgical risk. Pre-existing first-degree atrioventricular block and right bundle branch block significantly increased the risk of new PPI postimplantation, whereas left bundle branch block did not. Membranous septum length in relation to noncoronary cusp implant depth was a significant predictor of new PPI, with higher rates of new PPI observed when noncoronary cusp implant depth exceeded membranous septum length. Analysis of implant depth alone revealed deeper implants were associated with a higher rate of new PPI, regardless of patient baseline conduction abnormality. Conclusions: The 30-day rate of new PPI in the Navitor IDE study is associated with patient pre-existing baseline conduction disturbances and implantation depth.

Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase.

There is a compelling need to find drugs active against Mycobacterium tuberculosis (Mtb). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in Mtb that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill Mtb and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in Mtb from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.

Identification of epidermal growth factor receptor-tyrosine kinase inhibitor targeting the VP1 pocket of human rhinovirus.

Screening a library of 1,200 preselected kinase inhibitors for anti-human rhinovirus 2 (HRV-2) activity in HeLa cells identified a class of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) as effective virus blockers. These were based on the 4-anilinoquinazoline-7-oxypiperidine scaffold, with the most potent representative AZ5385 inhibiting the virus with EC50 of 0.35 µM. Several structurally related analogs confirmed activity in the low µM range, while interestingly, other TKIs targeting EGFR lacked anti-HRV-2 activity. To further probe this lack of association between antiviral activity and EGFR inhibition, we stained infected cells with antibodies specific for activated EGFR (Y1068) and did not observe a dependency on EGFR-TK activity. Instead, consecutive passages of HRV-2 in HeLa cells in the presence of a compound and subsequent nucleotide sequence analysis of resistant viral variants identified the S181T and T210A alterations in the major capsid VP1 protein, with both residues located in the vicinity of a known hydrophobic pocket on the viral capsid. Further characterization of the antiviral effects of AZ5385 showed a modest virus-inactivating (virucidal) activity, while anti-HRV-2 activity was still evident when the inhibitor was added as late as 10 h post infection. The RNA copy/infectivity ratio of HRV-2 propagated in AZ5385 presence was substantially higher than that of control HRV indicating that the compound preferentially targeted HRV progeny virions during their maturation in infected cells. Besides HRV, the compound showed anti-respiratory syncytial virus activity, which warrants its further studies as a candidate compound against viral respiratory infections.

Meta-analysis of variation in sport and exercise science: Examples of application within resistance training research.

Meta-analysis has become commonplace within sport and exercise science for synthesising and summarising empirical studies. However, most research in the field focuses upon mean effects, particularly the effects of interventions to improve outcomes such as fitness or performance. It is thought that individual responses to interventions vary considerably. Hence, interest has increased in exploring precision or personalised exercise approaches. Not only is the mean often affected by interventions, but variation may also be impacted. Exploration of variation in studies such as randomised controlled trials (RCTs) can yield insight into interindividual heterogeneity in response to interventions and help determine generalisability of effects. Yet, larger samples sizes than those used for typical mean effects are required when probing variation. Thus, in a field with small samples such as sport and exercise science, exploration of variation through a meta-analytic framework is appealing. Despite the value of embracing and exploring variation alongside mean effects in sport and exercise science, it is rarely applied to research synthesis through meta-analysis. We introduce and evaluate different effect size calculations along with models for meta-analysis of variation using relatable examples from resistance training RCTs.

Rates of Detecting Thyroid Nodules Recommended for Biopsy with Ultrasound: Are All Indications Equal?

Background: The use of thyroid ultrasound increases yearly, adding to costs and overdetection of clinically irrelevant nodules. We investigated which indications most commonly prompt referral for thyroid ultrasound and the diagnostic utility by indication. Methods: We performed a retrospective observational cohort study of adults (≥18 years) undergoing an initial dedicated thyroid ultrasound between 2017 and 2019 at a tertiary academic center. Indicated reasons for referral were categorized into suspected palpable nodule (SPN), compressive symptoms (CS), metabolic symptoms (MS), screening due to high-risk factors, follow-up of incidental finding on other imaging, and combination of factors. Percentage of ultrasounds with an identifiable nodule and with a nodule recommended for biopsy was compared by indication. Separate logistic regression models were used to identify factors associated with finding any nodule and a biopsy-recommended nodule. Results: Among the 1739 patients included, the most common indication for thyroid ultrasound was SPN (40%), followed by incidental imaging (28%), CS (13%), combination (11%), MS (6%), and high-risk factors (2%). Overall, 62% of ultrasounds identified a nodule. Ultrasounds performed for incidental findings had the highest rate of nodule identification (94%), compared with 55%, 39%, and 43%, for SPN, CS, and MS, respectively (p < 0.05). Only 27% of ultrasounds identified a biopsy-recommended nodule. Nodules found incidentally had the highest rate of biopsy-recommended nodules at 55%. Rates of biopsy-recommended nodules for SPN, CS, and MS were 21%, 6%, and 10%, respectively. Logistic regression demonstrated that compared with patients referred for an SPN, those with incidental nodules were 10 times more likely to have a nodule found on ultrasound (odds ratio [OR] = 10.6 [CI 7.0-16.0]), while those referred for CS were half as likely to have a nodule (OR = 0.5 [CI 0.4-0.7]). Similar factors were associated with identification of biopsy-recommended nodules. Conclusions: Of all new dedicated thyroid ultrasounds, only a quarter find biopsy-recommended nodules, and nearly 40% do not identify a nodule at all. Notably, only 55% of ultrasounds done for SPN found a nodule. Ultrasound for CS and MS had the lowest rates of detecting nodules. Providing clear guidance on when to order thyroid ultrasounds can help reduce unnecessary health care utilization and potential overtreatment.

Computed tomography defined femoral artery plaque composition predicts vascular complications during transcatheter aortic valve implantation.

OBJECTIVE: Vascular and bleeding complications after transcatheter aortic valve implantation (TAVI) are common and lead to increased morbidity and mortality. Analysis of plaque at the arterial access site may improve prediction of complications. METHODS: We investigated the association between demographic and procedural risk factors for Valve Academic Research Consortium (VARC-3) vascular complications in patients undergoing transfemoral TAVI with use of a vascular closure device (ProGlide® or MANTA®) in this retrospective cohort study. The ability of pre-procedure femoral CT angiography to predict complications was investigated including a novel method of quantifying plaque composition of the common femoral artery using plaque maps created with patient specific X-ray attenuation cut-offs. RESULTS: 23 vascular complications occurred in the 299 patients in the study group (7.7%). There were no demographic risk factors associated with vascular complications and no statistical difference between use of closure device (ProGlide® vs MANTA®) and vascular complications. Vascular complications after TAVI were associated with sheath size (OR 1.36, 95% CI 1.08-1.76, P 0.01) and strongly associated with CT-derived necrotic core volume in the common femoral artery of the procedural side (OR 17.49, 95% CI 1.21-226.60, P 0.03). CONCLUSION: Plaque map analysis of the common femoral artery by CT angiography reveals patients with greater necrotic core are at increased risk of VARC-3 vascular complications. ADVANCES IN KNOWLEDGE: The novel measurement of necrotic core volume in the common femoral artery on the procedural side by CT analysis was associated with post-TAVI vascular complications, which can be used to highlight increased risk.

Effectiveness and Cost of an Enhanced Mailed Fecal Test Outreach Colorectal Cancer Screening Program: Findings from the PROMPT Stepped-Wedge Trial.

BACKGROUND: Mailed fecal immunochemical test (FIT) outreach can improve colorectal cancer screening rates, yet little is known about how to optimize these programs for effectiveness and cost. METHODS: PROMPT was a pragmatic, stepped-wedge, cluster-randomized effectiveness trial of mailed FIT outreach. Participants in the standard condition were mailed a FIT and received live telephone reminders to return it. Participants in the enhanced condition also received a tailored advance notification (text message or live phone call) and two automated phone call reminders. The primary outcome was 6-month FIT completion; secondary outcomes were any colorectal cancer screening completion at 6 months, implementation, and program costs. RESULTS: The study included 27,585 participants (80% ages 50-64, 82% Hispanic/Latino; 68% preferred Spanish). A higher proportion of enhanced participants completed FIT at 6 months than standard participants, both in intention-to-treat [+2.8%, 95% confidence interval (CI; 0.4-5.2)] and per-protocol [limited to individuals who were reached; +16.9%, 95% CI (12.3-20.3)] analyses. Text messages and automated calls were successfully delivered to 91% to 100% of participants. The per-patient cost for standard mailed FIT was $10.84. The enhanced program's text message plus automated call reminder cost an additional $0.66; live phone calls plus an automated call reminder cost an additional $10.82 per patient. CONCLUSIONS: Adding advance notifications and automated calls to a standard mailed FIT program boosted 6-month FIT completion rates at a small additional per-patient cost. IMPACT: Enhancements to mailed FIT outreach can improve colorectal cancer screening participation. Future research might test the addition of educational video messaging for screening-naïve adults.

A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann-Pick Type C1 Disease.

Niemann-Pick disease type C1 (NP-C) is a prematurely lethal genetic lysosomal storage disorder with neurological and visceral pathology resulting from mutations in the NPC1 gene encoding the lysosomal transmembrane protein NPC1. There is currently no cure for NP-C, and the only disease modifying treatment, miglustat, slows disease progression but does not significantly attenuate neurological symptoms. AAV-mediated gene therapy is an attractive option for NP-C, but due to the large size of the human NPC1 gene, there may be packaging and truncation issues during vector manufacturing. One option is to reduce the size of DNA regulatory elements that are essential for gene expression, such as the promoter sequence. Here, we describe a novel small truncated endogenous NPC1 promoter that leads to high gene expression both in vitro and in vivo and compare its efficacy to other commonly used promoters. Following neonatal intracerebroventricular (ICV) injection into the CNS, this novel promoter provided optimal therapeutic efficacy compared to all other promoters including increased survival, improved behavioural phenotypes, and attenuated neuropathology in mouse models of NP-C. Taken together, we propose that this novel promoter can be extremely efficient in designing an optimised AAV9 vector for gene therapy for NP-C.

30-Day Clinical Outcomes of a Self-Expanding Transcatheter Aortic Valve: The International PORTICO NG Study.

BACKGROUND: The self-expanding, intra-annular Navitor (Abbott Structural Heart) valve includes an outer cuff to reduce paravalvular leak (PVL) and large stent cells for future coronary access. OBJECTIVES: The purpose of the PORTICO NG (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis) study is to evaluate the safety and effectiveness of the Navitor valve in patients with symptomatic, severe aortic stenosis who are at high or extreme surgical risk. METHODS: PORTICO NG is a prospective, multicenter, global study with follow-up at 30 days, 1 year, and annually through 5 years. The primary endpoints are all-cause mortality and moderate or greater PVL at 30 days. Valve Academic Research Consortium-2 events and valve performance are assessed by an independent clinical events committee and echocardiographic core laboratory. RESULTS: A total of 260 subjects were treated at 26 clinical sites across Europe, Australia, and the United States between September 2019 and August 2022. The mean age was 83.4 ± 5.4 years, 57.3% were female, and the average Society of Thoracic Surgeons score was 3.9% ± 2.1%. At 30 days, the rate of all-cause mortality was 1.9%, and no subjects had moderate or greater PVL. The rate of disabling stroke was 1.9%, life-threatening bleeding was 3.8%, stage 3 acute kidney injury was 0.8%, major vascular complications were 4.2%, and new permanent pacemaker implantation was 19.0%. Hemodynamic performance included a mean gradient of 7.4 ± 3.5 mm Hg and an effective orifice area of 2.00 ± 0.47 cm2. CONCLUSIONS: The Navitor valve is safe and effective for the treatment of subjects with severe aortic stenosis who are at high or greater risk for surgery, which is supported by low rates of adverse events and PVL. (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis [PORTICO NG]; NCT04011722).

Thirty-day and one-year outcomes of the Navitor transcatheter heart valve in patients with aortic stenosis: the prospective, multicentre, global PORTICO NG Study.

BACKGROUND: The Navitor transcatheter heart valve (THV) is a self-expanding valve, with an intra-annular leaflet position and an outer cuff intended to reduce paravalvular leak (PVL). AIMS: The aim of the PORTICO NG Study is to assess the safety and performance of the Navitor THV in patients with symptomatic, severe aortic stenosis who are at high or extreme surgical risk. METHODS: PORTICO NG is a prospective, multicentre, global, single-arm, investigational study with follow-up at 30 days, 1 year, and annually up to 5 years. The primary endpoints are all-cause mortality and moderate or greater PVL at 30 days. Valve Academic Research Consortium-2 events and valve performance are assessed by an independent clinical events committee and echocardiographic core laboratory. RESULTS: A total of 120 high- or extreme-risk subjects (age 83.5±5.4 years; 58.3% female; Society of Thoracic Surgeons score 4.0±2.0%) were enrolled in the European conformity (CE) mark cohort. Procedural success was high at 97.5%. At 30 days, the rate of all-cause mortality was 0%, and no subjects had moderate or greater PVL. The rate of disabling stroke was 0.8%, life-threatening bleeding was 2.5%, stage 3 acute kidney injury 0%, major vascular complications 0.8%, and new pacemaker implantation 15.0%. At 1 year, the rates of all-cause mortality and disabling stroke were 4.2% and 0.8%, respectively. The rate of moderate PVL was 1.0% at 1 year. Haemodynamic performance with a mean gradient of 7.5±3.2 mmHg and effective orifice area of 1.9±0.4 cm2 was sustained up to 1 year. CONCLUSIONS: The PORTICO NG Study demonstrates low rates of adverse events and PVL up to 1 year in patients at high or extreme surgical risk, confirming the safety and efficacy of the Navitor THV system.