Cross-Seal IDE Trial: Prospective, Multicenter, Single-Arm Study of the Cross-Seal Suture-Mediated Vascular Closure Device System.

BACKGROUND: An increasing number of interventional procedures require large-sheath technology (>12F) with a favorable outcome with endovascular rather than open surgical access. However, vascular complications are a limitation for the management of these patients. This trial aimed to determine the effectiveness and safety of the Cross-Seal suture-mediated vascular closure device in obtaining hemostasis at the target limb access site following interventional procedures using 8F to 18F procedural sheaths. METHODS: The Cross-Seal IDE trial (Investigational Device Exemption) was a prospective, single-arm, multicenter study in subjects undergoing percutaneous endovascular procedures utilizing 8F to 18F ID procedural sheaths. The primary efficacy end point was time to hemostasis at the target limb access site. The primary safety end point was freedom from major complications of the target limb access site within 30 days post procedure. RESULTS: A total of 147 subjects were enrolled between August 9, 2019, and March 12, 2020. Transcatheter aortic valve replacement was performed in 53.7% (79/147) and percutaneous endovascular abdominal/thoracic aortic aneurysm repair in 46.3% (68/147) of subjects. The mean sheath ID was 15.5±1.8 mm. The primary effectiveness end point of time to hemostasis was 0.4±1.4 minutes. An adjunctive intervention was required in 9.2% (13/142) of subjects, of which 2.1% (3/142) were surgical and 5.6% (8/142) endovascular. Technical success was achieved in 92.3% (131/142) of subjects. Freedom from major complications of the target limb access site was 94.3% (83/88). CONCLUSIONS: In selected patients undergoing percutaneous endovascular procedures utilizing 8F to 18F ID procedural sheath, Cross-Seal suture-mediated vascular closure device achieved favorable effectiveness and safety in the closure of the large-bore arteriotomy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03756558.

Definition and perception of autonomy in vascular surgery training.

INTRODUCTION: There is a lack of data evaluating operative autonomy within vascular surgery. This study aims to determine where discrepancies exist in the definition of autonomy between trainees and attending faculty. METHODS: An IRB approved, anonymous survey was emailed to vascular trainees and attending faculty at all ACGME-approved vascular surgery training programs in the United States. Data was compared using chi-square statistical analysis. RESULTS: One-hundred forty-nine responses from vascular surgery trainees (n=89) and faculty (n=60) were obtained. The most highly ranked pre-operative skill by trainees was Case Planning, at all PGY-levels. Although a majority of trainees believe this skill is expected of them, only 36.1% of attendings responded that they expect all trainee levels to perform this task. Draping/positioning was ranked as the 2nd most important intra-operative task for all PGY-levels by attendings, however only 32.8% of attendings expect trainees to perform this. Exposure of Critical Structures was ranked as the most important intra-operative task by both trainees and attendings at the Chief and Fellow level. However, responses by both trainees and attendings showed that this is expected <70% of the time. When asked about double-scrubbing independently of other tasks, most trainees assessed double-scrubbing as inherently important to autonomy at all levels of training and within all regions. Only 44.3% of attendings responded that they expect all trainees to double scrub. Additionally, most trainees in all regions responded that they spend <25% of cases double-scrubbed. CONCLUSION: These responses show a discrepancy between the skills that both trainees and attendings deem important to autonomy versus what is being expected of trainees in reality.

Improving hybrid image and structure-based deformable image registration for large internal deformations.

Objective.Deformable image registration (DIR) is a widely used technique in radiotherapy. Complex deformations, resulting from large anatomical changes, are a regular challenge. DIR algorithms generally seek a balance between capturing large deformations and preserving a smooth deformation vector field (DVF). We propose a novel structure-based term that can enhance the registration efficacy while ensuring a smooth DVF.Approach.The proposed novel similarity metric for controlling structures was introduced as a new term into a commercially available algorithm. Its performance was compared to the original algorithm using a dataset of 46 patients who received pelvic re-irradiation, many of which exhibited complex deformations.Main results.The mean Dice Similarity Coefficient (DSC) under the improved algorithm was 0.96, 0.94, 0.76, and 0.91 for bladder, rectum, colon, and bone respectively, compared to 0.69, 0.89, 0.62, and 0.88 for the original algorithm. The improvement was more pronounced for complex deformations.Significance.With this work, we have demonstrated that the proposed term is able to improve registration accuracy for complex cases while maintaining realistic deformations.

Uphill battle: Innovation of thiopurine therapy in global inflammatory bowel disease care.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.

Relationship Between Adalimumab Concentrations, Antidrug Antibodies, and Disease Activity in Rheumatoid Arthritis: A Cross-Sectional Observational Study.

OBJECTIVES: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations. METHODS: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses. RESULTS: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein (P < 0.001) and higher weight (P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations (r = -0.04, P < 0.01). CONCLUSION: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control.

A dedicated risk prediction model of 1-year mortality following endovascular aortic aneurysm repair involving the renal-mesenteric arteries.

OBJECTIVE: Treatment goals of prophylactic endovascular aortic repair of complex aneurysms involving the renal-mesenteric arteries (complex endovascular aortic repair [cEVAR]) include achieving both technical success and long-term survival benefit. Mortality within the first year after cEVAR likely indicates treatment failure owing to associated costs and procedural complexity. Notably, no validated clinical decision aid tools exist that reliably predict mortality after cEVAR. The purpose of this study was to derive and validate a preoperative prediction model of 1-year mortality after elective cEVAR. METHODS: All elective cEVARs including fenestrated, branched, and/or chimney procedures for aortic disease extent confined proximally to Ishimaru landing zones 6 to 9 in the Society for Vascular Surgery Vascular Quality Initiative were identified (January 2012 to August 2023). Patients (n = 4053) were randomly divided into training (n = 3039) and validation (n = 1014) datasets. A logistic regression model for 1-year mortality was created and internally validated by bootstrapping the AUC and calibration intercept and slope, and by using the model to predict 1-year mortality in the validation dataset. Independent predictors were assigned an integer score, based on model beta-coefficients, to generate a simplified scoring system to categorize patient risk. RESULTS: The overall crude 1-year mortality rate after elective cEVAR was 11.3% (n = 456/4053). Independent preoperative predictors of 1-year mortality included chronic obstructive pulmonary disease, chronic renal insufficiency (creatinine >1.8 mg/dL or dialysis dependence), hemoglobin <12 g/dL, decreasing body mass index, congestive heart failure, increasing age, American Society of Anesthesiologists class ≥IV, current tobacco use, history of peripheral vascular intervention, and increasing extent of aortic disease. The 1-year mortality rate varied from 4% among the 23% of patients classified as low risk to 23% for the 24% classified as high risk. Performance of the model in validation was comparable with performance in the training data. The internally validated scoring system classified patients roughly into quartiles of risk (low, low/medium, medium/high and high), with 52% of patients categorized as medium/high to high risk, which had corresponding 1-year mortality rates of 11% and 23%, respectively. Aneurysm diameter was below Society for Vascular Surgery recommended treatment thresholds (<5.0 cm in females, <5.5 cm in males) in 17% of patients (n = 679/3961), 41% of whom were categorized as medium/high or high risk. This subgroup had significantly increased in-hospital complication rates (18% vs 12%; P = .02) and 1-year mortality (13% vs 5%; P < .0001) compared with patients in the low- or low/medium-risk groups with guideline-compliant aneurysm diameters (≥5.0 cm in females, ≥5.5 cm in males). CONCLUSIONS: This validated preoperative prediction model for 1-year mortality after cEVAR incorporates physiological, functional, and anatomical variables. This novel and simplified scoring system can effectively discriminate mortality risk and, when applied prospectively, may facilitate improved preoperative decision-making, complex aneurysm care delivery, and resource allocation.

Hitting the Target: Developing High-quality Evidence for Proton Beam Therapy Through Randomised Controlled Trials.

The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.

Four-year review of New Zealand laboratory infliximab and adalimumab concentration results indicating potential for improved dosing.

A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.

Parental sensitivity to toddler's need for autonomy: An empirical study on mother-toddler and father-toddler interactions during feeding and play.

During the second year of life, children's need for autonomy grows, and their behaviors become increasingly complex. Parental sensitivity to children's different cues is important in supporting adaptive psycho-emotional development. The present study assumes that mothers and fathers may respond with varying levels of sensitivity to the child's different cues, with particular attention to requests for greater autonomy. The study also examines the possible role played by interactive contexts (ie., play and feeding) and children's and parents' individual factors. The sample comprised N = 91 families with children aged between 12 and 24 months. Mother-toddler and father-toddler interactions were assessed during feeding and play. Parents completed questionnaires assessing children's temperament, psychopathological risk, and parenting stress. RESULTS: showed that toddlers' demands for autonomy were the most frequent cues in both play and feeding contexts, both with mothers and fathers. Furthermore, parents were more sensitive to toddlers' requests for cooperation than their requests for autonomy, in both interactive contexts. Moreover, mothers and fathers showed higher sensitivity to toddlers' demands for greater autonomy in the play context rather than in the feeding context. Mothers were more sensitive than fathers to toddlers' cues of resistance to parents' actions and to toddlers' requests for cooperation. Results showed differences and specificities in mother-toddler and father-toddler interactions in the two interactive contexts, showing associations between child negative emotionality, parental psychopathological risk and parenting stress, and maternal and paternal sensitivity to toddlers' demands for greater autonomy during play and feeding, respectively. These results confirm the initial hypotheses regarding parental sensitivity and its differential expression according to child cues. Implications are discussed.

NanoFIRE: A NanoLuciferase and Fluorescent Integrated Reporter Element for Robust and Sensitive Investigation of HIF and Other Signalling Pathways.

The Hypoxia Inducible Factor (HIF) transcription factors are imperative for cell adaption to low oxygen conditions and development; however, they also contribute to ischaemic disease and cancer. To identify novel genetic regulators which target the HIF pathway or small molecules for therapeutic use, cell-based reporter systems are commonly used. Here, we present a new, highly sensitive and versatile reporter system, NanoFIRE: a NanoLuciferase and Fluorescent Integrated Reporter Element. Under the control of a Hypoxic Response Element (HRE-NanoFIRE), this system is a robust sensor of HIF activity within cells and potently responds to both hypoxia and chemical inducers of the HIF pathway in a highly reproducible and sensitive manner, consistently achieving 20 to 150-fold induction across different cell types and a Z' score > 0.5. We demonstrate that the NanoFIRE system is adaptable via substitution of the response element controlling NanoLuciferase and show that it can report on the activity of the transcriptional regulator Factor Inhibiting HIF, and an unrelated transcription factor, the Progesterone Receptor. Furthermore, the lentivirus-mediated stable integration of NanoFIRE highlights the versatility of this system across a wide range of cell types, including primary cells. Together, these findings demonstrate that NanoFIRE is a robust reporter system for the investigation of HIF and other transcription factor-mediated signalling pathways in cells, with applications in high throughput screening for the identification of novel small molecule and genetic regulators.

Similarities and differences in the functional architecture of mother- infant communication in rhesus macaque and British mother-infant dyads.

Similarly to humans, rhesus macaques engage in mother-infant face-to-face interactions. However, no previous studies have described the naturally occurring structure and development of mother-infant interactions in this population and used a comparative-developmental perspective to directly compare them to the ones reported in humans. Here, we investigate the development of infant communication, and maternal responsiveness in the two groups. We video-recorded mother-infant interactions in both groups in naturalistic settings and analysed them with the same micro-analytic coding scheme. Results show that infant social expressiveness and maternal responsiveness are similarly structured in humans and macaques. Both human and macaque mothers use specific mirroring responses to specific infant social behaviours (modified mirroring to communicative signals, enriched mirroring to affiliative gestures). However, important differences were identified in the development of infant social expressiveness, and in forms of maternal responsiveness, with vocal responses and marking behaviours being predominantly human. Results indicate a common functional architecture of mother-infant communication in humans and monkeys, and contribute to theories concerning the evolution of specific traits of human behaviour.

Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study.

PURPOSES: Habitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response. METHODS: In a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations. RESULTS: A total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from - 2.2 ± 0.1 to - 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004). CONCLUSION: The hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

The USMLE® STEP 1 Pass or Fail Era of the Vascular Surgery Residency Application Process: Implications for Structural Bias and Recommendations.

United States Medical Licensing Examination® (USMLE®) STEP 1 score reporting has been changed to a binary pass/fail format since January 26, 2022. The motives behind this change were (1) the questionable validity of using USMLE STEP 1 as a screening tool during the candidate selection process and (2) the negative impact of using standardized examination scores as an initial gatekeeping threshold for the underrepresented in medicine (URiM) candidates applying to graduate medical education programs, given their generally lower mean standardized exams scores compared to non-URiM students. The USMLE administrators justified this change as a tactic to enhance the overall educational experience for all students and to increase the representation of URiM groups. Moreover, they advised the program directors (PDs) to give more attention to other important qualities and components such as the applicant's personality traits, leadership roles and other extracurricular accomplishments, as part of a holistic evaluation strategy. At this early stage, it is unclear how this change will impact Vascular Surgery Integrated residency (VSIR) programs. Several questions are outstanding, most importantly, how VSIR PDs will evaluate applicants absent the variable which heretofore was the primary screening tool. Our previously published survey showed that VSIR PDs will move their attention to other measures such as USMLE STEP 2 Clinical Knowledge (CK) and letters of recommendation during the VSIR selection process. Furthermore, more emphasis on subjective measures such as the applicant's medical school rank and extracurricular student activities is expected. Given the expected higher weight of USMLE STEP 2CK in the selection process than ever, many anticipate that medical students will dedicate more of their limited time to its preparation at the expense of both clinical and nonclinical activities. Potentially leaving less time to explore specialty pathways and to determine whether Vascular Surgeons  is the appropriate career for them. The critical juncture in the VSIR candidate evaluation paradigm presents an opportunity to thoughtfully transform the process via current (Standardized Letter of Recommendation, USMLE STEP 2CK, and clinical research) and future (Emotional Intelligence, Structure Interview and Personality Assessment) measures which constitute a framework to follow in the USMLE STEP 1 pass/fail era.

StemRad MD, An Exoskeleton-Based Radiation Protection System, Reduces Ergonomic Posture Risk Based on a Prospective Observational Study.

OBJECTIVE: Poor ergonomic posture during interventional procedures might lead to increased physical discomfort and work-related musculoskeletal disorders. Adjunctive equipment such as lead aprons (LAs) has been shown to increase ergonomic posture risk (EPR). The objective of this study was to evaluate the effectiveness of StemRad MD (StemRad Ltd., Tel Aviv, Israel), a weightless exoskeleton-based radiation protective ensemble, in reducing EPR on the operator using wearable inertial measurement unit (IMU) sensors. METHODS: A prospective, observational study was conducted at an academic hospital. Inertial measurement unit sensors were affixed to the upper back of 9 interventionalists to assess ergonomic risk posture during endovascular procedures while wearing a traditional LA or the StemRad MD radiation protection system. Total fluoroscopy time, procedure type, and ergonomic risk postures were recorded and analyzed. RESULTS: Twenty-one cases were performed with StemRad MD and 30 with LAs. Mean procedure time for the StemRad MD procedures was 48.4±23.3 minutes (range: 24-106 min), and for LA procedures, it was 34.66±25.83 minutes (range: 6-100 min) (p=.060). The operators assumed low-risk ergonomic positions in 96.1% of StemRad MD cases and in 62.9% of LA cases (p=.001), and high-risk ergonomic positions in 0% and 6.2%, respectively (p=.80). Mean EPR score for StemRad MD was 1.16, and for the LA, it was 1.49 (p=.001). CONCLUSIONS: StemRad MD significantly reduces the EPR to the torso compared with a LA-based radiation protection system. CLINICAL IMPACT: Poor ergonomic posture during interventional procedures might leas to work-related musculoskeletal disorders for healthcare workers. StemRad MD, a weightless, exoskeleton-based radiation protection system was shown to significantly reduce ergonomic posture risk to the torso compared to conventional lead aprons. This might lead to reduced physical discomfort for procedure-based specialists.

Proteoliposomes reconstituted with human aquaporin-1 reveal novel single-ion-channel properties.

Human aquaporin 1 (hAQP1) forms homotetrameric channels that facilitate fluxes of water and small solutes across cell membranes. In addition to water channel activity, hAQP1 displays non-selective monovalent cation-channel activity gated by intracellular cyclic GMP. Dual water and ion-channel activity of hAQP1, thought to regulate cell shape and volume, could offer a target for novel therapeutics relevant to controlling cancer cell invasiveness. This study probed properties of hAQP1 ion channels using proteoliposomes, which, unlike conventional cell-based systems such as Xenopus laevis oocytes, are relatively free of background ion channels. Histidine-tagged recombinant hAQP1 protein was synthesized and purified from the methylotrophic yeast, Pichia pastoris, and reconstituted into proteoliposomes for biophysical analyses. Osmotic water channel activity confirmed correct folding and channel assembly. Ion-channel activity of hAQP1-Myc-His6 was recorded by patch-clamp electrophysiology with excised patches. In symmetrical potassium, the hAQP1-Myc-His6 channels displayed coordinated gating, a single-channel conductance of approximately 75 pS, and multiple subconductance states. Applicability of this method for structure-function analyses was tested using hAQP1-Myc-His6 D48A/D185A channels modified by site-directed mutations of charged Asp residues estimated to be adjacent to the central ion-conducting pore of the tetramer. No differences in conductance were detected between mutant and wild-type constructs, suggesting the open-state conformation could differ substantially from expectations based on crystal structures. Nonetheless, the method pioneered here for AQP1 demonstrates feasibility for future work defining structure-function relationships, screening pharmacological inhibitors, and testing other classes in the broad family of aquaporins for previously undiscovered ion-conducting capabilities.