Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose.

Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small-fiber innervation and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new therapies are needed for treatment of this condition affecting 20-30 million Americans. Here, we validated a gene therapy approach using an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) directly to scWAT to improve tissue-specific PN as a proof-of-concept approach. AAVRec2-BDNF intra-adipose delivery improved tissue innervation in obese/diabetic mice with PN, but after longer periods of dietary obesity there was reduced efficacy, revealing a key time window for therapies. AAVRec2-NGF also increased scWAT innervation in obese mice and was more effective than BDNF, likely because Rec2 targeted adipocytes, the tissue's endogenous NGF source. AAVRec2-NGF also worked well even after 25 weeks of dietary obesity, unlike BDNF, which likely needs a vector that targets its physiological cellular source (stromal vascular fraction cells). Given the differing effects of AAVs carrying NGF versus BDNF, a combined therapy may be ideal for PN.

Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

BACKGROUND AND AIMS: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. METHODS: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. RESULTS: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. CONCLUSIONS: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

Device innovation in cardiovascular medicine: a report from the European Society of Cardiology Cardiovascular Round Table.

Research performed in Europe has driven cardiovascular device innovation. This includes, but is not limited to, percutaneous coronary intervention, cardiac imaging, transcatheter heart valve implantation, and device therapy of cardiac arrhythmias and heart failure. An important part of future medical progress involves the evolution of medical technology and the ongoing development of artificial intelligence and machine learning. There is a need to foster an environment conducive to medical technology development and validation so that Europe can continue to play a major role in device innovation while providing high standards of safety. This paper summarizes viewpoints on the topic of device innovation in cardiovascular medicine at the European Society of Cardiology Cardiovascular Round Table, a strategic forum for high-level dialogue to discuss issues related to the future of cardiovascular health in Europe. Devices are developed and improved through an iterative process throughout their lifecycle. Early feasibility studies demonstrate proof of concept and help to optimize the design of a device. If successful, this should ideally be followed by randomized clinical trials comparing novel devices vs. accepted standards of care when available and the collection of post-market real-world evidence through registries. Unfortunately, standardized procedures for feasibility studies across various device categories have not yet been implemented in Europe. Cardiovascular imaging can be used to diagnose and characterize patients for interventions to improve procedural results and to monitor devices long term after implantation. Randomized clinical trials often use cardiac imaging-based inclusion criteria, while less frequently trials randomize patients to compare the diagnostic or prognostic value of different modalities. Applications using machine learning are increasingly important, but specific regulatory standards and pathways remain in development in both Europe and the USA. Standards are also needed for smart devices and digital technologies that support device-driven biomonitoring. Changes in device regulation introduced by the European Union aim to improve clinical evidence, transparency, and safety, but they may impact the speed of innovation, access, and availability. Device development programmes including dialogue on unmet needs and advice on study designs must be driven by a community of physicians, trialists, patients, regulators, payers, and industry to ensure that patients have access to innovative care.

Transitioning from 0.5 to 0.9 mT: Protecting against inadvertent activation of magnet mode in active implants.

The "5 gauss line" is a phrase that is likely to be familiar to everyone working with MRI, but what is its significance, how was it defined, and what changes are currently in progress? This review explores the history of 5 gauss (0.5 mT) as a threshold for protecting against inadvertently putting cardiac pacemakers, implantable cardioverter defibrillators, and other active implantable medical devices into a "magnet mode." Additionally, it describes the background to the recent change of this threshold to 9 gauss (0.9 mT) in the International Standard IEC 60601-2-33 edition 4.0 that defines basic safety requirements for MRI. Practical implications of this change and some ongoing and emerging issues are also discussed.

Noninvasive Monitoring to Detect Dehydration: Are We There Yet?

The need for hydration monitoring is significant, especially for the very young and elderly populations who are more vulnerable to becoming dehydrated and suffering from the effects that dehydration brings. This need has been among the drivers of considerable effort in the academic and commercial sectors to provide a means for monitoring hydration status, with a special interest in doing so outside the hospital or clinical setting. This review of emerging technologies provides an overview of many technology approaches that, on a theoretical basis, have sensitivity to water and are feasible as a routine measurement. We review the evidence of technical validation and of their use in humans. Finally, we highlight the essential need for these technologies to be rigorously evaluated for their diagnostic potential, as a necessary step to meet the need for hydration monitoring outside of the clinical environment.

Regulating Laboratory Tests: What Framework Would Best Support Safety and Validity?

Policy Points With increasing public attention to cases of inaccurate and misleading laboratory-developed tests, there have been calls for regulatory reform. To protect patients from faulty laboratory tests, we need a framework that balances comprehensive test review with laboratory flexibility. The Verifying Accurate Leading-edge IVCT [In Vitro Clinical Test] Development (VALID) Act would have helped ensure laboratory test safety and validity through a much-needed expansion of Food and Drug Administration (FDA) oversight. However, Congress did not pass the VALID Act in 2022, forcing the FDA to start the regulatory reform process on its own.

Device regulation and surveillance in vascular care: Challenges and opportunities.

Cardiovascular devices are essential for the treatment of cardiovascular diseases including cerebrovascular, coronary, valvular, congenital, peripheral vascular and arrhythmic diseases. The regulation and surveillance of vascular devices in real-world practice, however, presents challenges during each individual product's life cycle. Four examples illustrate recent challenges and questions regarding safety, appropriate use and efficacy arising from FDA approved devices used in real-world practice. We outline potential pathways wherein providers, regulators and payors could potentially provide high-quality cardiovascular care, identify safety signals, ensure equitable device access, and study potential issues with devices in real-world practice.

Safety and efficacy of the OdonAssist inflatable device for assisted vaginal birth: the BESANCON ASSIST study.

BACKGROUND: The first feasibility study of the OdonAssist inflatable device for use in clinically indicated assisted vaginal birth reported a success rate of 48% with no significant safety concerns. Additional studies exploring the device performance in other clinical settings are warranted before definitive conclusions can be drawn about its safety and efficacy in current practice. OBJECTIVE: This study aimed to investigate the safety and efficacy of the OdonAssist before conducting a randomized controlled trial. STUDY DESIGN: This was an open-label, nonrandomized study of 104 women with a clinically indicated assisted vaginal birth using the OdonAssist at the Besancon University Hospital, France. Data, including those of a nested cohort group of women who had an assisted vaginal birth using vacuum or spatulas because a trained OdonAssist device operator was not available at the time of delivery, were collected. The primary outcome measure was the proportion of successful assisted vaginal births using the OdonAssist. Neonatal outcome data were reviewed at days 1 and 28, and maternal outcomes were investigated up to day 90. RESULTS: Between December 2019 and May 2021, 2191 pregnant women were approached, and 83% (1636/1973) of them consented to participate in the study. Among them, 10.7% (176/1636) required an assisted vaginal birth owing to a vertex presentation at +1 and below. The OdonAssist was used in 59% of births (104/176), and 41.1% (72/176) of the participants were included in the nested cohort group. The rate of successful assisted vaginal births using the OdonAssist was 88.5% (92/104). No emergency cesarean deliveries were performed in the OdonAssist group. There were no serious adverse maternal or neonatal reactions related to the use of the device. The rate of third- and fourth-degree perineal tears with the OdonAssist was 3.8% (4/104). The maternal perception ratings of the birth experience with the OdonAssist (collected on days 1, 7, and 28 using a 15-point scale) were high. In addition, the operators reported a positive perception of the device, with ease of use across the different steps of the procedure. One single technique was used for all vertex fetal head positions. CONCLUSION: The OdonAssist is a safe and effective alternative to other current devices for assisted vaginal births. The high acceptance rate (83%) among pregnant women and the high rate of successful assisted vaginal births using the OdonAssist confirm the feasibility of a future randomized controlled trial.

The OdonAssist inflatable device for assisted vaginal birth-the ASSIST II study (United Kingdom).

BACKGROUND: Decreasing rates of assisted vaginal birth have been paralleled with increasing rates of cesarean deliveries over the last 40 years. The OdonAssist is a novel device for assisted vaginal birth. Iterative changes to clinical parameters, device design, and technique have been made to improve device efficacy and usability. OBJECTIVE: This study aimed to determine if the feasibility, safety, and efficacy of the OdonAssist device were sufficient to justify conducting a future randomized controlled trial. STUDY DESIGN: An open-label nonrandomized study of 104 participants having a clinically indicated assisted vaginal birth using the OdonAssist was undertaken at Southmead Hospital, Bristol, United Kingdom. Data were also collected from participants who consented to participate in the study but for whom trained OdonAssist operators were not available, providing a nested cohort. The primary clinical outcome was the proportion of births successfully expedited with the OdonAssist. Secondary outcomes included clinical, patient-reported, operator-reported, device and health care utilization. Neonatal outcome data were reviewed at day 28, and maternal outcomes were investigated up to day 90. Given that the number of successful OdonAssist births was ≥61 out of 104, the hypothesis of a poor rate of 50% was rejected in favor of a good rate of ≥65%. RESULTS: Between August 2019 and June 2021, 941 (64%) of the 1471 approached, eligible participants consented to participate. Of these, 104 received the OdonAssist intervention. Birth was assisted in all cephalic vertex fetal positions, at all stations ≥1 cm below the ischial spines (with or without regional analgesia). The OdonAssist was effective in 69 of the 104 (66%) cases, consistent with the hypothesis of a good efficacy rate. There were no serious device-related maternal or neonatal adverse reactions, and there were no serious adverse device effects. Only 4% of neonatal soft tissue bruising in the successful OdonAssist group was considered device-related, as opposed to 20% and 23% in the unsuccessful OdonAssist group and the nested cohort, respectively. Participants reported high birth perception scores. All practitioners found the device use to be straightforward. CONCLUSION: Recruitment to an interventional study of a new device for assisted vaginal birth is feasible; 64% of eligible participants were willing to participate. The success rate of the OdonAssist was comparable to that of the Kiwi OmniCup when introduced in the same unit in 2002, meeting the threshold for a randomized controlled trial to compare the OdonAssist with current standard practice. There were no disadvantages of study participation in terms of maternal and neonatal outcomes. There were potential advantages of using the OdonAssist, particularly reduced neonatal soft tissue injury. The same application technique is used for all fetal positions, with all operators deeming the device straightforward to use. This study provides important data to inform future study design.

Initial interactions with the FDA on developing a validation dataset as a medical device development tool.

Quantifying tumor-infiltrating lymphocytes (TILs) in breast cancer tumors is a challenging task for pathologists. With the advent of whole slide imaging that digitizes glass slides, it is possible to apply computational models to quantify TILs for pathologists. Development of computational models requires significant time, expertise, consensus, and investment. To reduce this burden, we are preparing a dataset for developers to validate their models and a proposal to the Medical Device Development Tool (MDDT) program in the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA). If the FDA qualifies the dataset for its submitted context of use, model developers can use it in a regulatory submission within the qualified context of use without additional documentation. Our dataset aims at reducing the regulatory burden placed on developers of models that estimate the density of TILs and will allow head-to-head comparison of multiple computational models on the same data. In this paper, we discuss the MDDT preparation and submission process, including the feedback we received from our initial interactions with the FDA and propose how a qualified MDDT validation dataset could be a mechanism for open, fair, and consistent measures of computational model performance. Our experiences will help the community understand what the FDA considers relevant and appropriate (from the perspective of the submitter), at the early stages of the MDDT submission process, for validating stromal TIL density estimation models and other potential computational models. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Effectiveness and tolerability of rectal ointment and suppositories containing sucralfate for hemorrhoidal symptoms: a prospective, observational study.

BACKGROUND AND AIMS: A high number of topical products are available for the treatment of hemorrhoidal symptoms. Sucralfate-based topical products constitute a new treatment alternative that act as a mechanical barrier to facilitate healing. The aim of this prospective, observational study was to determine patient- and physician-assessed effectiveness and tolerability of rectal ointment and suppositories containing sucralfate for the treatment of hemorrhoidal symptoms in routine clinical practice. METHODS: Adult patients with diagnosed, mild-to-moderate, symptomatic non-bleeding hemorrhoids treated with rectal ointment or suppositories containing sucralfate were enrolled. Patients were administered treatment twice per day for at least 1 week until symptom resolution and/or for a maximum of 4 weeks. The primary endpoint was patient-assessed effectiveness on a modified Symptom Severity Score (mSSS, range 0 to 14). Physician-assessed effectiveness (9 symptoms, 0 to 5 Likert scale), hemorrhoid grade, and patient satisfaction were also determined. RESULTS: Five investigators enrolled 60 patients; mean age was 48.4 ± 16.6 years and 72.4% were female. Pain or pressure sensitivity was reported as the most severe symptom by patients, and pressure sensitivity, discharge, soiling, and prolapse by physicians. Mean patient-assessed mSSS at baseline was 6.6 ± 1.9 and was significantly improved overall and in the ointment and suppository groups individually by -4.6 ± 2.0, -4.4 ± 1.8, and -4.8 ± 2.2, respectively (p < 0.0001). Investigator-assessed mean baseline symptom score was 18.1 ± 3.9 and improved by -7.1 ± 4.5, -6.9 ± 5.4, and -7.3 ± 3.5, respectively (p < 0.0001). Investigator-assessed symptoms of pressure sensitivity, swelling, and discharge were improved to the greatest extent. Hemorrhoid grade was improved in 38% of patients at the end of treatment. Compliance with treatment was 97.4% and patient satisfaction with application and onset of action was high (81.3% and 76.2%, respectively). Both the ointment and suppository were well tolerated. CONCLUSIONS: The effectiveness of topical ointment or suppository containing sucralfate on patient- and investigator-assessed hemorrhoidal symptoms in real-life clinical practice was demonstrated. Patient satisfaction was high and treatments were well tolerated. Larger controlled trials are warranted to confirm the results.

Prospective multicenter study of continuous tonic-clonic seizure monitoring on Apple Watch in epilepsy monitoring units and ambulatory environments.

OBJECTIVE: Evaluate the performance of a custom application developed for tonic-clonic seizure (TCS) monitoring on a consumer-wearable (Apple Watch) device. METHODS: Participants with a history of convulsive epileptic seizures were recruited for either Epilepsy Monitoring Unit (EMU) or ambulatory (AMB) monitoring; participants without epilepsy (normal controls [NC]) were also enrolled in the AMB group. Both EMU and AMB participants wore an Apple Watch with a research app that continuously recorded accelerometer and photoplethysmography (PPG) signals, and ran a fixed-and-frozen tonic-clonic seizure detection algorithm during the testing period. This algorithm had been previously developed and validated using a separate training dataset. All EMU convulsive events were validated by video-electroencephalography (video-EEG); AMB events were validated by caregiver reporting and follow-ups. Device performance was characterized and compared to prior monitoring devices through sensitivity, false alarm rate (FAR; false-alarms per 24 h), precision, and detection delay (latency). RESULTS: The EMU group had 85 participants (4,279 h, 19 TCS from 15 participants) enrolled across four EMUs; the AMB group had 21 participants (13 outpatient, 8 NC, 6,735 h, 10 TCS from 3 participants). All but one AMB participant completed the study. Device performance in the EMU group included a sensitivity of 100 % [95 % confidence interval (CI) 79-100 %]; an FAR of 0.05 [0.02, 0.08] per 24 h; a precision of 68 % [48 %, 83 %]; and a latency of 32.07 s [standard deviation (std) 10.22 s]. The AMB group had a sensitivity of 100 % [66-100 %]; an FAR of 0.13 [0.08, 0.24] per 24 h; a precision of 22 % [11 %, 37 %]; and a latency of 37.38 s [13.24 s]. Notably, a single AMB participant was responsible for 8 of 31 false alarms. The AMB FAR excluding this participant was 0.10 [0.07, 0.14] per 24 h. DISCUSSION: This study demonstrates the practicability of TCS monitoring on a popular consumer wearable (Apple Watch) in daily use for people with epilepsy. The monitoring app had a high sensitivity and a substantially lower FAR than previously reported in both EMU and AMB environments.

Optimization-Based Stable Balancing Weights Versus Propensity Score Weighting for Samples With High Covariate Imbalance.

PURPOSE: To compare the performance (covariate balance, effective sample size [ESS]) of stable balancing weights (SBW) versus propensity score weighting (PSW). Two applied cases were used to compare performance: (Case 1) extreme imbalance in baseline covariates between groups and (Case 2) substantial discrepancy in sample size between groups. METHODS: Using the Premier Healthcare Database, we selected patients who (Case 1) underwent a surgical procedure with one of two different bipolar forceps between January 2000 and June 2020, or (Case 2) a neurological procedure using one of two different nonabsorbable surgical sutures between January 2000 and March 2020. Average treatment effects on the treated (ATT) weights were generated based on selected covariates. SBW was implemented using two techniques: (1) "grid search" to find weights of minimum variance at the lowest target absolute standardized mean difference (SMD); (2) finding weights of minimum variance at prespecified SMD tolerance. PSW and SBW methods were compared on postweighting SMDs, the number of imbalanced covariates, and ESS of the ATT-weighted control group. RESULTS: In both studies, improved covariate balance was achieved with both SBW techniques. All methods suffered from postweighting ESS that was lower than the unweighted control group's original sample size; however, SBW methods achieved higher ESS for the control groups. Sensitivity analyses using SBW to apply variable-specific SMD thresholds increased ESS, outperforming PSW. CONCLUSIONS: In this applied example, the optimization-based SBW method provided ample flexibility with respect to prespecification of covariate balance goals and resulted in better postweighting covariate balance and larger ESS as compared with PSW.

Robotic technology in surgery; a classification system of soft tissue surgical robotic devices.

BACKGROUND: The field of robotic-assisted surgery is rapidly growing as many robotic surgical devices are in development and about to enter the market. Currently, there is no universally accepted language for labeling the different robotic systems. To facilitate this communication, we created what is, to our knowledge, the first classification of surgical robotic technologies that organizes and classifies surgical robots used for endoscopy, laparoscopy and thoracoscopy. METHODS: We compiled a list of surgical robots intended to be used for endoscopy, laparoscopy, and/or thoracoscopy by searching United States, European, Hong Kong, Japan, and Korean databases for approved devices. Devices showcased at the 2023 Annual Meeting for the Society of Robotic Surgery were added. We also systematically reviewed the literature for any existing surgical robotic classifications or categorizations. We then created a multidisciplinary committee of 8 surgeons and 2 engineers to construct a proposed classification of the devices included in our search. RESULTS: We identified 40 robotic surgery systems intended to be used for endoscopy, laparoscopy and/or thoracoscopy. The proposed classification organizes robotic devices with regard to architecture, port design, and configuration (modular carts, multi-arm integrated cart, table-attachable or arm-table integration). CONCLUSION: This 3-level classification of robotic surgical devices used for endoscopy, laparoscopy and/or thoracoscopy describes important characteristics of robotic devices systematically.

The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Bayesian spatial cluster signal learning with application to adverse event (AE).

There is growing interest in understanding geographic patterns of medical device-related adverse events (AEs). A spatial scan method combined with the likelihood ratio test (LRT) for spatial-cluster signal detection over the geographical region is universally used. The spatial scan method used a moving window to scan the entire study region and collected some candidate sub-regions from which the spatial-cluster signal(s) will be found. However, it has some challenges, especially in computation. First, the computational cost increased when the number of sub-regions increased. Second, the computational cost may increase if a large spatial-cluster pattern is present and a flexible-shaped window is used. To reduce the computational cost, we propose a Bayesian nonparametric method that combines the ideas of Markov random field (MRF) to leverage geographical information to find potential signal clusters. Then, the LRT is applied for the detection of spatial cluster signals. The proposed method provides an ability to capture both locally spatially contiguous clusters and globally discontiguous clusters, and is manifested to be effective and tractable using hypothetical Left Ventricular Assist Device (LVAD) data as an illustration.

Taring the scales: Weight-of-evidence framework for biocompatibility evaluations.

ISO 10993-1:2018 describes evaluating the biocompatibility profile of a medical device from a risk-based approach. This standard details the battery of information that should be considered within the assessment of a device, including raw material composition data, manufacturing processes, and endpoint testing. The ISO 10993/18562 series requires worst-case assumptions and exposure scenarios to be used in the evaluation, which may result in an over-estimation of patient safety risk. Currently, biocompatibility assessments evaluate each data set independently, and the consequence of this individualized assessment of exaggerated inputs is potential false alarms regarding patient safety. To evaluate these safety concerns, the ISO standards indicate that professional judgement should be used to estimate patient risk but does not provide guidance on incorporating a holistic review of the data into the risk assessment. Recalibrating these worst-case data to evaluate them in a weight-of-evidence (WoE) approach may provide a more realistic data set to determine actual patient risk. This proposed WoE framework combines understanding data applicability with a method for gauging the strength of data that can provide additional support for the final safety conclusion. Using a WoE framework will allow risk assessors to contextualize the data and utilize it to comprehensively estimate patient safety.

Targeting bacterial growth in biofilm conditions: rational design of novel inhibitors to mitigate clinical and food contamination using QSAR.

Antimicrobial resistance (AMR) is a pressing global issue exacerbated by the abuse of antibiotics and the formation of bacterial biofilms, which cause up to 80% of human bacterial infections. This study presents a computational strategy to address AMR by developing three novel quantitative structure-activity relationship (QSAR) models based on molecular topology to identify potential anti-biofilm and antibacterial agents. The models aim to determine the chemo-topological pattern of Gram (+) antibacterial, Gram (-) antibacterial, and biofilm formation inhibition activity. The models were applied to the virtual screening of a commercial chemical database, resulting in the selection of 58 compounds. Subsequent in vitro assays showed that three of these compounds exhibited the most promising antibacterial activity, with potential applications in enhancing food and medical device safety.

Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions.

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.

New device, 'old' allergens. Allergic contact dermatitis caused by the Dexcom G7 glucose sensor.

BACKGROUND: Allergic contact dermatitis (ACD) has been reported as an adverse effect from the use of several glucose sensors and insulin pumps from different manufacturers. Isobornyl acrylate (IBOA) has been identified as a major culprit sensitizer, but also other acrylates and (modified) colophonium have been reported as causes of ACD. OBJECTIVES: To report the two first cases diagnosed with ACD caused by the Dexcom G7 (DG7) glucose sensor. PATIENTS AND METHODS: Two children with suspected ACD from DG7 were patch tested with our medical device series with an addition of selected test preparations including two variants of modified colophonium - methyl hydrogenated rosinate (MHR) and glyceryl hydrogenated rosinate (GHR). Both patients were also tested with acetone extracts made from different parts of the DG7 sensor. The extracts were analysed by gas chromatography-mass spectrometry (GC-MS). RESULTS: Both patients tested positive to IBOA, hydroabietyl alcohol and GHR. In addition, patient 1 had a positive reaction to MHR and patient 2 had a positive reaction to colophonium. The GC-MS analyses showed the presence of IBOA and colophonium-related substances in the DG7 extracts. CONCLUSIONS: Both patients were diagnosed with contact allergy to well-known medical device-related sensitizers. The presence of IBOA and (modified) colophonium in a newly introduced (on the Swedish market in 2023) glucose sensor is remarkable and indicates an inadequate toxicological assessment of the materials used in the sensor.