Clinical Performance Research Articles

Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein.

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro, ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo, as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro, ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.

Predictive model for non-malignant portal vein thrombosis associated with cirrhosis based on inflammatory biomarkers

BACKGROUND Portal vein thrombosis (PVT), a complication of liver cirrhosis, is a major public health concern. PVT prediction is the most effective method for PVT diagnosis and treatment. AIM To develop and validate a nomogram and network calculator based on clinical indicators to predict PVT in patients with cirrhosis. METHODS Patients with cirrhosis hospitalized between January 2016 and December 2021 at the First Hospital of Lanzhou University were screened and 643 patients with cirrhosis who met the eligibility criteria were retrieved. Following a 1:1 propensity score matching 572 patients with cirrhosis were screened, and relevant clinical data were collected. PVT risk factors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis. Variance inflation factors and correlation matrix plots were used to analyze multicollinearity among the variables. A nomogram was constructed to predict the probability of PVT based on independent risk factors for PVT, and its predictive performance was verified using a receiver operating characteristic curve (ROC), calibration curves, and decision curve analysis (DCA). Finally, a network calculator was constructed based on the nomograms. RESULTS This study enrolled 286 cirrhosis patients with PVT and 286 without PVT. LASSO analysis revealed 13 variables as strongly associated with PVT occurrence. Multivariate logistic regression analysis revealed nine indicators as independent PVT risk factors, including etiology, ascites, gastroesophageal varices, platelet count, D-dimer, portal vein diameter, portal vein velocity, aspartate transaminase to neutrophil ratio index, and platelet-to-lymphocyte ratio. LASSO and correlation matrix plot results revealed no significant multicollinearity or correlation among the variables. A nomogram was constructed based on the screened independent risk factors. The nomogram had excellent predictive performance, with an area under the ROC curve of 0.821 and 0.829 in the training and testing groups, respectively. Calibration curves and DCA revealed its good clinical performance. Finally, the optimal cutoff value for the total nomogram score was 0.513. The sensitivity and specificity of the optimal cutoff values were 0.822 and 0.706, respectively. CONCLUSION A nomogram for predicting PVT occurrence was successfully developed and validated, and a network calculator was constructed. This can enable clinicians to rapidly and easily identify high PVT risk groups.

High positive predictive value 22q11.2 microdeletion screening by prenatal cell-free DNA testing that incorporates fetal fraction amplification.

22q11.2 deletion syndrome (DS) is a serious condition with a range of features. The small microdeletion causing 22q11.2DS makes it technically challenging to detect using standard prenatal cfDNA screening. Here, we assess 22q11.2 microdeletion clinical performance by a prenatal cfDNA screen that incorporates fetal fraction (FF) amplification. The study cohort consisted of patients who received Prequel (Myriad Genetics, Inc.), a prenatal cfDNA screening that incorporates FF amplification, and met additional eligibility criteria. Pregnancy outcomes were obtained via a routine process for continuous quality improvement. Samples with diagnostic testing results were used to calculate positive predictive value (PPV). 379,428 patients met study eligibility criteria, 76 of whom were screen-positive for a de novo 22q11.2 microdeletion. 22 (29.7%) had diagnostic testing results available, and all 22 cases were confirmed as true positives, for a PPV of 100% (95% CI 84.6%-100%). This performance was based on cases that ranged broadly across FF (5.9%-41.1%, mean 23.0%), body mass index (22.3-44.8, mean 29.9), and gestational age at testing (10.0w-34.6w, median 12.7w). Ultrasound findings in screen-positive pregnancies were consistent with those known to be associated with 22q11.2DS. 22q11.2 microdeletion screening that incorporates FF amplification demonstrated high PPV across both general and high-risk population cohorts.

Electronic medical record redesign to improve patient safety and use of non-medication orders by clinicians

Background: Electronic medical records (EMRs) have become highly customizable. Although customization allows changes for workflow optimization, such changes can result in a less standardized system and create barriers due to individual preferences. Aim: This was a documentation of the efforts of a greenfield academic medical centre in Qatar to improve patient safety, physician operational efficiency and revenue capture by standardizing the design of the non-medication orders and associated revenue of the EMR . Methods: A multi-disciplinary group reviewed and revamped the design and workflow for non-medication orders, including redistributing orders into order catalogues, standardizing their naming, assigning them billing codes, and reviewing other order details. Measurement of project performance followed cross-sectional and prospective cohort designs. Results: The redesign improved clinicians’ satisfaction with the EMR and reduced patient safety incidents and other technical issues. Improvements in the organization’s operations and staff performance were noticeable across multiple areas. The proportion of clinicians finding it difficult to navigate and select orders reduced from 31% to 21%. The proportion of clinicians who believed the orders to be clear and accurate increased from about 16% to 31%. The estimated percentage of clinicians reporting a technical issue with an order during the last month reduced from 52% to 41.94%, and physicians’ dissatisfaction with the overall organization of non-medication orders in the EMR reduced from about 32% to 23%. The average number of technical issues and change requests sent monthly to the technology team for non-medication orders reduced from 30 to 1.4 technical issues and 3.2 change requests. Conclusion: EMR performance improvement projects that consider and address staff input, patient safety and performance metrics can uplift an organization’s clinical and financial performance.

A systemic approach to identifying sequence frameworks that decrease mAb production in a transient Chinese hamster ovary cell expression system.

Monoclonal antibodies (mAbs) are often engineered at the sequence level for improved clinical performance yet are rarely evaluated prior to candidate selection for their "developability" characteristics, namely expression, which can necessitate additional resource investments to improve the manufacturing processes for problematic mAbs. A strong relationship between primary sequence and expression has emerged, with slight differences in amino acid sequence resulting in titers differing by up to an order of magnitude. Previous work on these "difficult-to-express" (DTE) mAbs has shown that these phenotypes are driven by post-translational bottlenecks in antibody folding, assembly, and secretion processes. However, it has been difficult to translate these findings across cell lines and products. This work presents a systematic approach to study the impact of sequence variation on mAb expression at a larger scale and under more industrially relevant conditions. The analysis found 91 mutations that decreased transient expression of an IgG1κ in Chinese hamster ovary (CHO) cells and revealed that mutations at inaccessible residues, especially those leading to decreases in residue hydrophobicity, are not favorable for high expression. This workflow can be used to better understand sequence determinants of mAb expression to improve candidate selection procedures and reduce process development timelines.

Patient-derived PixelPrint phantoms for evaluating clinical imaging performance of a deep learning CT reconstruction algorithm.

Objective
Deep learning reconstruction (DLR) algorithms exhibit object-dependent resolution and noise performance. Thus, traditional geometric CT phantoms cannot fully capture the clinical imaging performance of DLR. This study uses a patient-derived 3D-printed PixelPrint lung phantom to evaluate a commercial DLR algorithm across a wide range of radiation dose levels.

Method
The lung phantom used in this study is based on a patient chest CT scan containing ground glass opacities and was fabricated using PixelPrint 3D-printing technology. The phantom was placed inside two different size extension rings to mimic a small- and medium-sized patient and was scanned on a conventional CT scanner at exposures between 0.5 and 20 mGy. Each scan was reconstructed using filtered back projection (FBP), iterative reconstruction, and DLR at five levels of denoising. Image noise, contrast to noise ratio (CNR), root mean squared error (RMSE), structural similarity index (SSIM), and multi-scale SSIM (MS SSIM) were calculated for each image.

Results
DLR demonstrated superior performance compared to FBP and iterative reconstruction for all measured metrics in both phantom sizes, with better performance for more aggressive denoising levels. DLR was estimated to reduce dose by 25-83% in the small phantom and by 50-83% in the medium phantom without decreasing image quality for any of the metrics measured in this study. These dose reduction estimates are more conservative compared to the estimates obtained when only considering noise and CNR. 

Conclusion
DLR has the capability of producing diagnostic image quality at up to 83% lower radiation dose, which can improve the clinical utility and viability of lower dose CT scans. Furthermore, the PixelPrint phantom used in this study offers an improved testing environment with more realistic tissue structures compared to traditional CT phantoms, allowing for structure-based image quality evaluation beyond noise and contrast-based assessments.

Age-related changes in reading performance in normally sighted Arabic-speaking adults

ABSTRACT Clinical relevance Reading performance is important for evaluating near vision and predicting and prescribing near-vision correction. There is a significant gap in the literature on Arabic reading performance and its associated effects. Background Normative data from control participants serve as the baseline for future studies involving groups with specific characteristics. This study aimed to assess baseline measures of Arabic reading performance. Methods In total, 428 normally sighted adults aged 19–83 years read the Balsam Alabdulkader – Leat chart to measure their reading performance. The participants were divided into five age groups. The outcome measures were the maximum reading speed in standard-length words per minute, critical print size, reading acuity, and reading accessibility index. Results The average reading performance measures were as follows: 171 ± 27 standard-length words per minute for maximum reading speed, 0.01 logarithm of the minimum angle of resolution for critical print size, −0.17 logarithm of the minimum angle of resolution for reading acuity, and 1.02 for the accessibility index. There were significant differences among the age groups, indicating a dependency on age and showing a plateau for the young adult group and a decline with age. The accessibility index had an almost perfect correlation with maximum reading speed and a weak but significant relationship with reading acuity and critical print size. Conclusion Arabic exhibits an age-dependent trend in reading speed. However, owing to differences in orthography, visual demands, and reading strategies, the magnitude of the decrease and increase differs, potentially accounting for the variations between languages, especially when compared to English. This study serves as a foundation for future studies on Arabic reading performance. Future studies should examine the reading performance in patients with low vision, study the effects of common diseases on reading ability, evaluate the effectiveness of reading devices, and assess improvements in vision rehabilitation.

R.I.M.E. and reason: multi-station OSCE enhancement to neutralize grade inflation

ABSTRACT To offset grade inflation, many clerkships combine faculty evaluations with objective assessments including the Medical Examiners Subject Examination (NBME-SE) or Objective Structured Clinical Examination (OSCE), however, standardized methods are not established. Following a curriculum transition removing faculty clinical evaluations from summative grading, final clerkship designations of fail (F), pass (P), and pass-with-distinction (PD) were determined by combined NBME-SE and OSCE performance, with overall PD for the clerkship requiring meeting this threshold in both. At the time, 90% of students achieved PD on the Internal Medicine (IM) OSCE resulting in overall clerkship grades primarily determined by the NBME-SE. The clerkship sought to enhance the OSCE to provide a more thorough objective clinical skills assessment, offset grade inflation, and reduce the NBME-SE primary determination of the final clerkship grade. The single-station 43-point OSCE was enhanced to a three-station 75-point OSCE using the Reporter-Interpreter-Manager-Educator (RIME) framework to align patient encounters with targeted assessments of progressive skills and competencies related to the clerkship rotation. Student performances were evaluated pre- and post-OSCE enhancement. Student surveys provided feedback about the clinical realism of the OSCE and the difficulty. Pre-intervention OSCE scores were more tightly clustered (SD = 5.65%) around a high average performance with scores being highly negatively skewed. Post-intervention OSCE scores were more dispersed (SD = 6.88%) around a lower average with scores being far less skewed resulting in an approximately normal distribution. This lowered the total number of students achieving PD on the OSCE and PD in the clerkship, thus reducing the relative weight of the NMBE-SE in the overall clerkship grade. Student response was positive, indicating the examination was fair and reflective of their clinical experiences. Through structured development, OSCE assessment can provide a realistic and objective measurement of clinical performance as part of the summative evaluation of students.

Development of a validated assessment tool for medical students using simulated patients: an 8-year panel survey

BackgroundThe use of simulated patients (SPs) to assess medical students’ clinical performance is gaining prominence, underscored by patient safety perspective. However, few reports have investigated the validity of such assessment. Here, we examined the validity and reliability of an assessment tool that serves as a standardized tool for SPs to assess medical students’ medical interview.MethodsThis longitudinal survey was conducted at Keio University School of Medicine in Japan from 2014 to 2021. To establish content validity, the simulated patient assessment tool (SPAT) was developed by several medical education specialists from 2008 to 2013. A cohort of 36 SPs assessed the performance of 831 medical students in clinical practice medical interview sessions from April 2014 to December 2021. The assessment’s internal structure was analyzed using descriptive statistics (maximum, minimum, median, mean, and standard deviation) for the SPAT’s 13 item total scores. Structural validity was examined with exploratory factor analysis, and internal consistency with Cronbach’s alpha coefficients. The mean SPAT total scores across different SPs and scenarios were compared using one way analysis of variance (ANOVA). Convergent validity was determined by correlating SPAT with the post-clinical clerkship obstructive structured clinical examination (post-CC OSCE) total scores using Pearson’s correlation coefficient.ResultsOf the 831 assessment sheets, 36 with missing values were excluded, leaving 795 for analysis. Thirty-five SPs, excluding one SP who quit in 2014, completed 795 assessments, for a response rate of 95.6%. Exploratory factor analysis revealed two factors, communication and physician performance. The overall Cronbach’s alpha coefficient was 0.929. Significant differences in SPAT total scores were observed across SPs and scenarios via one-way ANOVA. A moderate correlation (r =.212, p <.05) was found between SPAT and post-CC OSCE total scores, indicating convergent validity.ConclusionsEvidence for the validity of SPAT was examined. These findings may be useful in the standardization of SP assessment of the scenario-based clinical performance of medical students.

Comparative Analysis of Endodontic ISO Size 06, 08, and 10 Stainless Steel K-Files Used for Glide Path Procedures

Small-sized stainless steel hand files are conventionally employed in root canal treatment procedures for canal scouting and for glide path establishment, owing to their superior flexibility and proficiency in navigating confined spaces. Given the diversity of brands available in the market, there exists potential variability in their physical characteristics, thereby influencing clinical performance. Consequently, this study aims to conduct a comparative analysis of the design, metallurgy, and mechanical characteristics among seven stainless steel hand file brands across ISO sizes 06, 08, and 10. A total of 315 new 25 mm length stainless steel hand files with apical sizes of 0.06, 0.08, and 0.10 from seven distinct brands were included in the study. A meticulous inspection of all instruments was undertaken to identify any structural deformations that might render them ineligible for the study. The design inspection involved the random selection of instruments from each group, which were examined under various microscopes, including a dental operating microscope, optical microscope, and scanning electron microscope. Furthermore, two instruments from each group underwent energy-dispersive X-ray spectroscopy analysis for elemental composition documentation. Mechanical tests were conducted to evaluate the instruments’ resistance to lateral deformation (buckling) and their microhardness. Statistical analysis was executed using the nonparametric Mood’s median test, with a predetermined significance level of 0.05. Regarding the instruments design, all files exhibited an active blade length ranging from 16 to 17 mm. However, variations were observed in the number of spirals, tip designs, and sizes, with the API K-File notably larger in sizes 0.06 and 0.08 compared to the other instruments. Despite uniform elements composition, differences in geometric features and mechanical properties were evident. Concerning buckling strength, the API K-File demonstrated superior performance across all tested sizes, while the Dentsply ReadySteel, SybronEndo, and Mani K-Files exhibited lower results (p &lt; 0.05). In microhardness assessments, both the API and Oro K-Files displayed the lowest outcomes, with medians of 531 HVN and 532 HVN, respectively, whereas the SybronEndo K-File exhibited the highest microhardness (657 HVN). Despite similar metallurgical composition, the observed distinctions in geometric features and mechanical properties underscore the impact of the manufacturing process on the characteristics of glide path stainless steel endodontic files. These disparities may ultimately influence their clinical performance.

Two-year clinical and radiographic evaluation of ACTIVA BioACTIVE versus Compomer (Dyract® eXtra) in the restoration of class-2 cavities of primary molars: a non-inferior split-mouth randomised clinical trial

ObjectivesThe trial aimed to compare the clinical performance and radiographic success of ACTIVA BioACTIVE versus Compomer in restoring class-II cavities of primary molars.Materials and methodsA non-inferior split-mouth design was considered. A pre-calculated sample size of 96 molars (48 per group) with class-2 cavities of twenty-one children whose ages ranged from 5 to 10 years were randomly included in the trial. Pre-operative Plaque Index (PI), DMFT/dmft scores and the time required to fill the cavity were recorded. Over 24 months, the teeth were clinically evaluated every six months and radiographically every 12 months by two calibrated and blinded evaluators using the United States public health service (USPHS)-Ryge criteria. The two-sided 95% confidence interval (CI) for the difference in success rate was considered to assess non-inferiority, and the margin was set at -18%. The linear mixed model and Firth’s logistic regression model were used for data analysis (P < 0.05).ResultsAfter 24 months, 86 teeth (43 per group) were evaluated. The mean PI score was 1.1(± 0.9), while DMFT/dmft was 0.35 (± 0.74) and 6.55 (± 2.25) respectively. The clinical and radiographic success rate of Dyract vs. ACTIVA was 95.3% and 88.3% vs. 93% and 86%, respectively. The two-sided 95% CI for the difference in success rate (-2.3%) was − 3.2 to 1.3% and didn’t reach the predetermined margin of -18% which had been anticipated as the non-inferiority margin. Clinically, ACTIVA had a significantly better colour match (P = 0.002) but worse marginal discolouration (P = 0.0143). There were no significant differences regarding other clinical or radiographic criteria (P > 0.05). ACTIVA took significantly less placement time than Dyract, with a mean difference of 2.37 (± 0.63) minutes (P < 0.001).ConclusionThe performance of ACTIVA was not inferior to Dyract and both materials had a comparable high clinical and radiographic performance in children with high-caries experience. ACTIVA had a significantly better colour match but more marginal discolouration. It took significantly less time to be placed in the oral cavity.Trial registrationThe study was registered at ClinicalTrials.gov on 4 May 2018 (#NCT03516838).

Diagnostic Performance of an Automated Blood Pressure Monitor With an Irregular Heartbeat Algorithm Designed to Detect Atrial Fibrillation.

Background: Early detection of atrial fibrillation (AF) remains an unsolved challenge and because the greatest risk factor for AF is hypertension, blood pressure (BP) monitors with AF detectors have been developed. We evaluated the clinical performance of an irregular heartbeat (IHB) algorithm built into an A&D automated BP monitor for AF diagnosis. Methods and Results: Each of the 239 enrolled patients underwent BP measurement 3 times using the A&D UM-212 with the IHB algorithm. Real-time 3-lead ECG was recorded using automated ECG analysis software. Independent of the ECG analysis software results, 2 cardiologists interpreted the ECG and made the final diagnosis. Of the 239 patients, 135 were in sinus rhythm, 31 had AF, and 73 had non-AF arrhythmias. The respective sensitivity, specificity, and accuracy of the IHB algorithm for AF diagnosis were 98.9%, 91.2%, and 92.2% for the per-measurement evaluation, and 96.8%, 95.7%, and 95.8% for the per-patient evaluation (3/3 positive measurements). The respective sensitivity, specificity, and accuracy of the ECG analysis software for AF diagnosis were 91.4%, 97.9%, and 97.1% for the per-measurement evaluation, and 77.4%, 99.5%, and 96.7% for the per-patient evaluation (3/3 positive measurements). Conclusions: The IHB algorithm built into an A&D automated BP monitor had high diagnostic performance for AF in general cardiology patients, especially when multiple measurements were obtained.

Clinical performance and risk factors of all-ceramic screw-retained implant crowns in the posterior region based on a retrospective investigation.

Clinical data on all-ceramic screw-retained implant crowns (SICs) luted on titanium base abutments (TBAs) over more than 3 years are sparse. This study aimed to evaluate the clinical performance and potential risk factors for these restorations. Analysis took place based on the medical patient-records of three dental offices. Implant survival and prosthetic complications over time were evaluated. The study included SICs in premolar and molar regions made from monolithic lithium disilicate ceramic (M_LiDi) or veneered zirconia (V_ZiO) luted on a TBA documented over an observation time of at least 3 years. Survival and complication rates were calculated and compared by a log-rank test. Cox-Regressions were used to check potential predictors for the survival (p < .05). Six hundred and one crowns out of 371 patients met the inclusion criteria and follow-up period was between 3.0 and 12.9 (mean: 6.4 (SD: 2.1)) years. Over time, six implants had to be removed and 16 restorations had to be refabricated. The estimated survival rates over 10 years were 93.5% for M_LiDi and 95.9% for V_ZiO and did not differ significantly among each other (p = .80). However, V_ZiO showed significantly higher complication rates (p = .003). Material selection, sex, age, and implant diameter did not affect the survival of investigated SICs but crown height influences significantly the survival rate (hazard ratio, HR = 1.26 (95%CI: 1.08, 1.49); p = .043). Screw-retained SICs luted on TBAs that were fabricated from monolithic lithium disilicate ceramic or veneered zirconia showed reliable and similar survival rates. Increasing crown heights reduced survival over the years.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Use of a SimBox, a Video-Augmented, Newborn Resuscitation Simulation for Prehospital Providers to Measure Clinical Performance and Educational Experience

Use of a SimBox, a Video-Augmented, Newborn Resuscitation Simulation for Prehospital Providers to Measure Clinical Performance and Educational Experience

How AI challenges the medical device regulation: patient safety, benefits, and intended uses

Abstract This article examines whether the EU Medical Device Regulation (MDR) adequately addresses the novel risks of AI-based medical devices (AIaMDs), focusing on AI medical imaging tools. It examines two questions: first, does the MDR effectively deal with issues of adaptability, autonomy, bias, opacity, and the need of trustworthiness of AIaMD? Second, does the manufacturer’s translation of the MDR’s requirements close a discrepancy between an AIaMDs’ expected benefit and the actual clinical utility of assessing device safety and effectiveness beyond the narrow performance of algorithms? While the first question has previously received attention in scholarly literature on regulatory and policy tensions on AIaMD generally, and work on future technical standard setting, the second has been comparatively overlooked. We argue that effective regulation of AIaMD requires framing notions of patient safety and benefit within the manufacturer’s articulation of the device’s intended use, as well as reconciling tensions. These tensions are on (i) patient safety and knowledge gaps surrounding fairness, (ii) trustworthiness and device effectiveness, (iii) the assessment of clinical performance, and (iv) performance updates. Future guidance needs to focus on the importance of translated benefits, including nuanced risk framing and looking at how the limitations of AIaMD inform the intended purpose statement in the MDR.

Revolutionizing the Treatment of Idiopathic Pulmonary Fibrosis: From Conventional Therapies to Advanced Drug Delivery Systems.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease that has been well-reported in the medical literature. Its incidence has risen, particularly in light of the recent COVID-19 pandemic. Conventionally, IPF is treated with antifibrotic drugs-pirfenidone and nintedanib-along with other drugs for symptomatic treatments, including corticosteroids, immunosuppressants, and bronchodilators based on individual requirements. Several drugs and biologicals such as fluorofenidone, thymoquinone, amikacin, paclitaxel nifuroxazide, STAT3, and siRNA have recently been evaluated for IPF treatment that reduces collagen formation and cell proliferation in the lung. There has been a great deal of research into various treatment options for pulmonary fibrosis using advanced delivery systems such as liposomal-based nanocarriers, chitosan nanoparticles, PLGA nanoparticles, solid lipid nanocarriers, and other nanoformulations such as metal nanoparticles, nanocrystals, cubosomes, magnetic nanospheres, and polymeric micelles. Several clinical trials are also ongoing for advanced IPF treatments. This article elaborates on the pathophysiology of IPF, its risk factors, and different advanced drug delivery systems for treating IPF. Although extensive preclinical data is available for these delivery systems, the clinical performance and scale-up studies would decide their commercial translation.

PET/CT study of dopamine transporter (DAT) binding with the triple reuptake inhibitor toludesvenlafaxine in rats and humans.

Toludesvenlafaxine is a recently developed antidepressant that belongs to the triple reuptake inhibitor class. Despite the in vitro evidence that toludesvenlafaxine inhibits the reuptake of serotonin (5-HT), norepinephrine (NE) and dopamine (DA), there is no in vivo evidence that toludesvenlafaxine binds to DAT and increases DA level, a mechanism thought to contribute to its favorable clinical performance. Positron emission tomography/computed tomography (PET/CT) was used to examine the DAT binding capacity in healthy rats and human subjects and microdialysis was used to examine the striatal DA level in rats. [18F]FECNT and [11C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively. In rats, 9mg/kg of toludesvenlafaxine hydrochloride (i.v.) followed by an infusion of 3mg/kg via minipump led to the binding rate to striatum DAT at 3.7 - 32.41% and to hypothalamus DAT at 5.91 - 17.52% during the 45min scanning period. 32mg/kg oral administration with toludesvenlafaxine hydrochloride significantly increased the striatal DA level with the AUC0 - 180min increased by 63.9%. In healthy volunteers, 160mg daily toludesvenlafaxine hydrochloride sustained-release tablets for 4 days led to an average occupancy rates of DAT at 8.04% ± 7.75% and 8.09% ± 7.00%, respectively, in basal ganglion 6h and 10h postdose. These results represent the first to confirm the binding of toludesvenlafaxine to DAT in both rats and humans using PET/CT, and its elevation of brain DA level, which may help understand the unique pharmacological and functional effects of triple reuptake inhibitors such as toludesvenlafaxine. NCT05905120. Registered 14 June 2023. (retrospectively registered).

A Multiplex Recombinase-Aided qPCR Assay for Highly Sensitive and Rapid Detection of khe, blaKPC -2, and blaNDM -1 Genes in Klebsiella pneumoniae.

This study aimed to establish a highly sensitive and rapid single-tube, two-stage, multiplex recombinase-aided qPCR (mRAP) assay to specifically detect the khe, blaKPC-2, and blaNDM-1 genes in Klebsiella pneumoniae. mRAP was carried out in a qPCR instrument within 1 h. The analytical sensitivities of mRAP for khe, blaKPC-2, and blaNDM-1 genes were tested using recombinant plasmids and dilutions of reference strains. A total of 137 clinical isolates and 86 sputum samples were used to validate the clinical performance of mRAP. mRAP achieved the sensitivities of 10, 8, and 14 copies/reaction for khe, blaKPC-2, and blaNDM-1 genes, respectively, superior to qPCR. The Kappa value of qPCR and mRAP for detecting khe, blaKPC-2, and blaNDM-1 genes was 1, 0.855, and 1, respectively (p < 0.05). mRAP is a rapid and highly sensitive assay for potential clinical identification of khe, blaKPC-2, and blaNDM-1 genes in K. pneumoniae.

A DIRECT BONDING TECHNIQUE VERSUS AN INDIRECT BONDING TECHNIQUE - AN IN VIVO ANALYSIS

Objectives: The objectives of this study were to compare the clinical performance of an indirect versus a direct bonding technique in a split mouth study design and to develop a reproducible and cost efficient technique for indirect bonding for clinical use. Methods: This comparative study was conducted on Twelve patients (212 teeth; 106 each in direct and indirect group) who reported to the Department of Dentistry at Ruxmaniben deepchand gardi medical college, Ujjain, Madhya Pradesh. Transbond XT (3M Unitek) adhesive and primer were used to bond the brackets onto the teeth in both the direct and indirect bonding groups using split mouth study design. Transfer trays constructed using Thermal glue matrix applied through hot glue gun for indirect bonding. The clinical performance was assessed for 6 months. Results: In the 1st month was a failure of one lower 2nd premolar bracket from the indirect bonding group (p=1.00). There on in the subsequent months there were no failures for 6 months. The study showed no statistically significant differences in clinical performance in both group (p=NS). Conclusion: The failure rates for both the indirect and direct bonding techniques in this study were the same. Statistically, there was no significant difference between the two groups. The indirect bonding technique used in this study was found to be an effective and efficient means of bonding orthodontic brackets. Transbond XT and thermal glue matrix found to be suitable choice for use in indirect bonding technique for clinical use.