A Clinical, Pharmacological, and Formulation Evaluation of Melatonin in the Treatment of Ocular Disorders-A Systematic Review.

Melatonin's cytoprotective properties may have therapeutic implications in treating ocular diseases like glaucoma and age-related macular degeneration. Literature data suggest that melatonin could potentially protect ocular tissues by decreasing the production of free radicals and pro-inflammatory mediators. This study aims to summarize the screened articles on melatonin's clinical, pharmacological, and formulation evaluation in treating ocular disorders. The identification of relevant studies on the topic in focus was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. The studies were searched in the following databases and web search engines: Pubmed, Scopus, Science Direct, Web of Science, Reaxys, Google Scholar, Google Patents, Espacenet, and Patentscope. The search time interval was 2013-2023, with the following keywords: melatonin AND ocular OR ophthalmic AND formulation OR insert AND disease. Our key conclusion was that using melatonin-loaded nano-delivery systems enabled the improved permeation of the molecule into intraocular tissues and assured controlled release profiles. Although preclinical studies have demonstrated the efficacy of developed formulations, a considerable gap has been observed in the clinical translation of the results. To overcome this failure, revising the preclinical experimental phase might be useful by selecting endpoints close to clinical ones.

Assessing Residents in the Department of Surgery at a Tertiary Care Centre Using Mini-Clinical Evaluation Exercise (Mini-CEX).

OBJECTIVE: This study aimed to introduce, sensitize, and train our postgraduate students and faculty of the department of general surgery with the use of mini-Clinical Evaluation Exercise (mini­CEX) and to assess the perception of students and faculty towards it. MATERIAL AND METHODS: A cross­sectional observational study was conducted over a period of four months. Ten surgery residents in the department were asked to volunteer to participate and five professors conducted the session. Five sessions of mini­CEX (nine points) were conducted for each resident in different settings of the out­patient department (OPD) and in­patient department (IPD). A total of five skills were tested. Feedback from faculty and residents regarding the perception of mini­CEX was also taken. RESULTS: A statistically significant difference in mean scores of all domains was observed comparing the first and last assessment (p<0.05). Hundred percent of the residents scored superior category (7-9) in the final assessment in all domains, whereas the maximum was in a satisfactory scoring grade in 1st assessment. The time taken for the assessment significantly reduced from 1st assessment to the last assessment in OPD and IPD settings (p=0.001). The mini-CEX assessment tool got 100% feedback from faculty in terms of skill improvement, method, attitude of residents, and ability to identify gaps in knowledge. However, one assessor thought that "time given for assessment" was inadequate and more effort was required than the usual traditional assessment methods. The most identified problem faced by residents was that the "time given during assessment" was less (50%); however, overall residents also found it valid, effective, and helpful in identifying knowledge gaps and improving clinical and communication skills. CONCLUSION: Mini­CEX improves the learning environment in residency and also leads to improvement in medical interviewing skills, physical examination skills, humanistic qualities/professionalism, and counseling skills. So, it can be used for residency training in clinical departments.

Improved Resolution and Image Quality of Musculoskeletal Magnetic Resonance Imaging using Deep Learning-based Denoising Reconstruction: A Prospective Clinical Study.

OBJECTIVE: To prospectively evaluate a deep learning-based denoising reconstruction (DLR) for improved resolution and image quality in musculoskeletal (MSK) magnetic resonance imaging (MRI). METHODS: Images from 137 contrast-weighted sequences in 40 MSK patients were evaluated. Each sequence was performed twice, first with the routine parameters and reconstructed with a routine reconstruction filter (REF), then with higher resolution and reconstructed with DLR, and with three conventional reconstruction filters (NL2, GA43, GA53). The five reconstructions (REF, DLR, NL2, GA43, and GA53) were de-identified, randomized, and blindly reviewed by three MSK radiologists using eight scoring criteria and a forced ranking. Quantitative SNR, CNR, and structure's full width at half maximum (FWHM) for resolution assessment were measured and compared. To account for repeated measures, Generalized Estimating Equations (GEE) with Bonferroni adjustment was used to compare the reader's scores, SNR, CNR, and FWHM between DLR vs. NL2, GA43, GA53, and REF. RESULTS: Compared to the routine REF images, the resolution was improved by 47.61% with DLR from 0.39 ± 0.15 mm2 to 0.20 ± 0.06 mm2 (p < 0.001). Per-sequence average scan time was shortened by 7.93% with DLR from 165.58 ± 21.86 s to 152.45 ± 25.65 s (p < 0.001). Based on the average scores, DLR images were rated significantly higher in all image quality criteria and the forced ranking (p < 0.001). CONCLUSION: This prospective clinical evaluation demonstrated that DLR allows approximately two times finer resolution and improved image quality compared to the standard-of-care images.

From quantitative metrics to clinical success: assessing the utility of deep learning for tumor segmentation in breast surgery.

PURPOSE: Preventing positive margins is essential for ensuring favorable patient outcomes following breast-conserving surgery (BCS). Deep learning has the potential to enable this by automatically contouring the tumor and guiding resection in real time. However, evaluation of such models with respect to pathology outcomes is necessary for their successful translation into clinical practice. METHODS: Sixteen deep learning models based on established architectures in the literature are trained on 7318 ultrasound images from 33 patients. Models are ranked by an expert based on their contours generated from images in our test set. Generated contours from each model are also analyzed using recorded cautery trajectories of five navigated BCS cases to predict margin status. Predicted margins are compared with pathology reports. RESULTS: The best-performing model using both quantitative evaluation and our visual ranking framework achieved a mean Dice score of 0.959. Quantitative metrics are positively associated with expert visual rankings. However, the predictive value of generated contours was limited with a sensitivity of 0.750 and a specificity of 0.433 when tested against pathology reports. CONCLUSION: We present a clinical evaluation of deep learning models trained for intraoperative tumor segmentation in breast-conserving surgery. We demonstrate that automatic contouring is limited in predicting pathology margins despite achieving high performance on quantitative metrics.

[Brief Analysis of Clinical Evaluation Concerns of Personalized Abutments and Abutment Crown Bridge Products].

Objective: The applications of personalized abutments and abutment crown bridge products have increased year by year, but there is no clear requirement for clinical evaluation of the same variety of such products. This study mainly introduces the clinical evaluation concerns of personalized abutments and abutment crown bridge products, in order to provide reference for the declaration and registration of such products. Methods: The clinical evaluation of personalized abutments and crown bridge products are summarized, and the research content of clinical evaluation is clarified. Results: The clinical evaluation requirements that need to be considered by enterprises are introduced. Conclusion: Personalized abutment and abutment crown bridge products can refer to this study when they are launched in China, mainly using in vitro performance comparison tests for equivalence verification.

Clinical and Functional Results Following Posterior Cruciate Ligament Reconstruction in Young Patients.

INTRODUCTION:  Posterior cruciate ligament injuries are uncommon, and their management is controversial. However, surgical reconstruction is necessary in case of symptomatic lesions. The present study aimed to analyse patients' reported outcomes and clinical evaluation after isolated posterior cruciate ligament reconstruction. MATERIALS AND METHODS:  The present study includes 12 patients with posterior cruciate ligament rupture. All patients were treated with arthroscopic surgery using single-bundle hamstring autograft ligament reconstruction. The primary outcome was the International Knee Documentation Committee (IKDC) subjective questionnaire; secondary outcomes included the Lysholm score and stability assessment.  Results: At the time of the surgery, the mean age of the study population was 24 years (range: 18-29), with a body mass index (BMI) of 23.2 kg/m2 (range: 21-25), and the mean time from injury was five months (range: 1-8). The follow-up period was at least 24 months. The mean IKDC score significantly increased from 68.0 preoperatively to 92.6 at the final follow-up. The Lysholm score also increased from 68.8 to 95.8. Knee stability was classified as normal in all patients after surgery. CONCLUSION:  The results of this study indicate that the posterior cruciate ligament reconstruction with single-bundle hamstring autograft is an efficient treatment option for managing symptomatic young patients. All patients presented good functional and clinical results at two years of follow-up. However, further studies with more participants and a longer follow-up are needed to validate these data.

A paradigm shift?-On the ethics of medical large language models.

After a wave of breakthroughs in image-based medical diagnostics and risk prediction models, machine learning (ML) has turned into a normal science. However, prominent researchers are claiming that another paradigm shift in medical ML is imminent-due to most recent staggering successes of large language models-from single-purpose applications toward generalist models, driven by natural language. This article investigates the implications of this paradigm shift for the ethical debate. Focusing on issues like trust, transparency, threats of patient autonomy, responsibility issues in the collaboration of clinicians and ML models, fairness, and privacy, it will be argued that the main problems will be continuous with the current debate. However, due to functioning of large language models, the complexity of all these problems increases. In addition, the article discusses some profound challenges for the clinical evaluation of large language models and threats to the reproducibility and replicability of studies about large language models in medicine due to corporate interests.

Beyond lectures and practical courses: Teaching pharmacology using imaginative pedagogical tools.

Pharmacology has broadened its scope considerably in recent decades. Initially, it was of interest to chemists, doctors and pharmacists. In recent years, however, it has been incorporated into the teaching of biologists, molecular biologists, biotechnologists, chemical engineers and many health professionals, among others. Traditional teaching methods, such as lectures or laboratory work, have been superseded by the use of new pedagogical approaches to enable a better conceptualization and understanding of the discipline. In this article, we present several new methods that have been used in Spanish universities. Firstly, we describe a teaching network that has allowed the sharing of pedagogical innovations in Spanish universities. A European experience to improve prescribing safety is described in detail. The use of popular films and medical TV series in biomedical students shows how these audiovisual resources can be helpful in teaching pharmacology. The use of virtual worlds is detailed to introduce this new approach to teaching. The increasingly important area of the social aspects of pharmacology is also considered in two sections, one devoted to social pharmacology and the other to the use of learning based on social services to improve understanding of this important area. Finally, the use of Objective Structured Clinical Evaluation in pharmacology allows to know how this approach can help to better evaluate clinical pharmacology students. In conclusion, this article allows to know new pedagogical methods resources used in some Spanish universities that may help to improve the teaching of pharmacology.

Assessment of the performance of the plasma separation card for HIV-1 viral load monitoring in South Africa.

Scaling up of newer innovations that address the limitations of the dried blood spot and the logistics of plasma monitoring is needed. We employed a multi-site, cross-sectional assessment of the plasma separation card (PSC) on blood specimens collected from all consenting adults, assenting young and pediatric patients living with HIV from 10 primary healthcare clinics in South Africa. Venous blood for EDTA-plasma samples was collected and analyzed according to the standard of care assay, while collected capillary blood for the PSC samples was analyzed using the Roche COBAS AmpliPrep/Cobas TaqMan (CAP/CTM) HIV-1 Test at the National Reference laboratories. McNemar tests assessed the differences in concordance between the centrifuged plasma and dried plasma spots. The usability of PSC by blood spotting, PSC preparation, and pre-analytical work was assessed by collecting seven-point Likert-scale data from healthcare and laboratory workers. We enrolled 538 patients, mostly adults [n = 515, 95.7% (95% CI: 93.7%-97.1%)] and females [n = 322, 64.2% (95% CI: 60.0%-68.1%)]. Overall, 536 paired samples were collected using both PSC- and EDTA-plasma diagnostics, and 502 paired PSC- and EDTA-plasma samples assessed. Concordance between the paired samples was obtained for 446 samples. Analysis of these 446 paired samples at 1,000 copies per milliliter threshold yielded an overall sensitivity of 87.5% [95% CI: 73.2%-95.8%] and specificity of 99.3% [95% CI: 97.9%-99.8%]. Laboratory staff reported technical difficulties in most tasks. The usability of the PSC by healthcare workers was favorable. For policymakers to consider PSC scale-up for viral load monitoring, technical challenges around using PSC at the clinic and laboratory level need to be addressed. IMPORTANCE: Findings from this manuscript emphasize the reliability of the plasma separation card (PSC), a novel diagnostic method that can be implemented in healthcare facilities in resource-constrained settings. The agreement of the PSC with the standard of care EDTA plasma for viral load monitoring is high. Since the findings showed that these tests were highly specific, we recommend a scale-up of PSC in South Africa for diagnosis of treatment failure.

Progress and challenges in the clinical evaluation of immune responses to respiratory mucosal vaccines.

INTRODUCTION: Following the coronavirus disease pandemic, respiratory mucosal vaccines that elicit both mucosal and systemic immune responses have garnered increasing attention. However, human physiological characteristics pose significant challenges in the evaluation of mucosal immunity, which directly impedes the development and application of respiratory mucosal vaccines. AREAS COVERED: This study summarizes the characteristics of immune responses in the respiratory mucosa and reviews the current status and challenges in evaluating immune response to respiratory mucosal vaccines. EXPERT OPINION: Secretory Immunoglobulin A (S-IgA) is a major effector molecule at mucosal sites and a commonly used indicator for evaluating respiratory mucosal vaccines. However, the unique physiological structure of the respiratory tract pose significant challenges for the clinical collection and detection of S-IgA. Therefore, it is imperative to develop a sampling method with high collection efficiency and acceptance, a sensitive detection method, reference materials for mucosal antibodies, and to establish a threshold for S-IgA that correlates with clinical protection. Sample collection is even more challenging when evaluating mucosal cell immunity. Therefore, a mucosal cell sampling method with high operability and high tolerance should be established. Targets of the circulatory system capable of reflecting mucosal cellular immunity should also be explored.

The impact of intensive training in preliminary image evaluation (PIE) for radiographers in the emergency department of a regional hospital in New Zealand - A pilot study.

INTRODUCTION: New Zealand has seen an increase in the X-ray examinations in the emergency departments (ED), and the radiology report is generally unavailable immediately. This requires practitioners managing the patient to take the responsibility of detecting any abnormalities in the images and using such information for the management of the patient. There is, therefore, a need for consideration of the contribution that radiographers could make in the accurate management of the patients in ED in New Zealand. The aim of this study was to assess if an intensive preliminary image evaluation (PIE) training course improved radiographer accuracy, sensitivity, and specificity on extremity X-ray examinations in a regional ED in New Zealand. METHOD: A pre-post-intervention design was employed for this study. Seven radiographers working at a regional base hospital in New Zealand undertook image evaluation tests to evaluate their ability to detect and describe abnormalities prior to and following a 2-day intensive PIE training course. The training concentrated on acute extremity abnormalities. Tests were then scored to determine sensitivity, specificity, and accuracy. RESULTS: Following an intensive PIE training course, the post-intervention test mean demonstrated an improved sensitivity by an average of 3.99% (89.01-93.0), specificity improved by an average of 6.13% (79.77-85.90%), and accuracy improved by an average of 3.33% (77.55-80.87%). CONCLUSION: This study demonstrated that an intensive training course in PIE improved the participants' sensitivity, specificity, and accuracy when evaluating acute extremity X-ray examinations in ED at the study site, however further research is required to see if these results also represent clinical ability. IMPLICATION FOR PRACTICE: The NZ healthcare system could benefit by the introduction of a radiographers' PIE system. It is therefore recommended that when introducing PIE into an ED in New Zealand, radiographers should undertake additional training to improve image evaluation sensitivity, specificity, and accuracy prior to participation.

Ruptured sinus of Valsalva aneurysm in a case of Ebstein anomaly: a clinical masquerade of two perfectly balanced lesions.

A combination of a ruptured sinus of Valsalva (RSOV) with Ebstein anomaly is a rare and clinically challenging entity. We describe a case of a 29-year-old female who presented with progressive dyspnoea and epigastric discomfort with symptoms and clinical findings not consistent with any single definitive diagnosis. In the primary echocardiography assessment, she was diagnosed with Ebstein anomaly. On the grounds of several unexplained clinical features and routine review echocardiography by the cardiology team, she was found to have a rare combination of Ebstein anomaly associated with RSOV. A cath study was performed to study the interplay of the hemodynamics of the two lesions, not described before in the literature, and also explain the clinical features not consistent with any one entity. We emphasize the significance of meticulous history-taking and sound clinical evaluation followed by corroboration with the diagnostic modalities for precise diagnosis and timely planned intervention in such rare associations. Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01622-4.

On the reliability of single-camera markerless systems for overground gait monitoring.

BACKGROUND AND OBJECTIVE: Motion analysis is crucial for effective and timely rehabilitative interventions on people with motor disorders. Conventional marker-based (MB) gait analysis is highly time-consuming and calls for expensive equipment, dedicated facilities and personnel. Markerless (ML) systems may pave the way to less demanding gait monitoring, also in unsupervised environments (i.e., in telemedicine). However,scepticism on clinical usability of relevant outcome measures has hampered its use. ML is normally used to analyse treadmill walking, which is significantly different from the more physiological overground walking. This study aims to provide end-users with instructions on using a single-camera markerless system to obtain reliable motion data from overground walking, while clinicians will be instructed on the reliability of obtained quantities. METHODS: The study compares kinematics obtained from ML systems to those concurrently obtained from marker-based systems, considering different stride counts and subject positioning within the capture volume. RESULTS: The findings suggest that five straight walking trials are sufficient for collecting reliable kinematics with ML systems. Precision on joint kinematics decreased at the boundary of the capture volume. Excellent correlation was found between ML and MB systems for hip and knee angles (0.92

In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6.

Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane X receptor (PXR). The lead indole, FKK6, displayed PXR-dependent protective effects in DSS-induced colitis in mice and in vitro cytokine-treated intestinal organoid cultures. Here, we report on the initial in vitro pharmacological profiling of FKK6. FKK6-PXR interactions were characterized by hydrogen-deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets (G protein-coupled receptors, steroid and nuclear receptors, ion channels, and xenobiotic membrane transporters) revealed high PXR selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. A large fraction of FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 × 10-6 cm.s-1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. The data from human liver microsomes indicated that FKK6 is rapidly metabolized by cytochromes P450 (t1/2 5 min), notably by CYP3A4. Two oxidized FKK6 derivatives, including DC73 (N6-oxide) and DC97 (C19-phenol), were detected, and these metabolites had 5-7 × lower potency as PXR agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its PXR effects are predicted to be predominantly in the intestines. In conclusion, the PXR ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.

Intraoperative Laparoscopic Hyperspectral Imaging during Esophagectomy-A Pilot Study Evaluating Esophagogastric Perfusion at the Anastomotic Sites.

Hyperspectral imaging (HSI) is a non-invasive and contactless technique that enables the real-time acquisition of comprehensive information on tissue within the surgical field. In this pilot study, we investigated whether a new HSI system for minimally-invasive surgery, TIVITA® Mini (HSI-MIS), provides reliable insights into tissue perfusion of the proximal and distal esophagogastric anastomotic sites during 21 laparoscopic/thoracoscopic or robotic Ivor Lewis esophagectomies of patients with cancer to minimize the risk of dreaded anastomotic insufficiency. In this pioneering investigation, physiological tissue parameters were derived from HSI measurements of the proximal site of the anastomosis (esophageal stump) and the distal site of the anastomosis (tip of the gastric conduit) during the thoracic phase of the procedure. Tissue oxygenation (StO2), Near Infrared Perfusion Index (NIR-PI), and Tissue Water Index (TWI) showed similar median values at both anastomotic sites. Significant differences were observed only for NIR-PI (median: 76.5 vs. 63.9; p = 0.012) at the distal site (gastric conduit) compared to our previous study using an HSI system for open surgery. For all 21 patients, reliable and informative measurements were attainable, confirming the feasibility of HSI-MIS to assess anastomotic viability. Further studies on the added benefit of this new technique aiming to reduce anastomotic insufficiency are warranted.

Development of a rapid and ultrasensitive magnetic chemiluminescence immunoassay for the detection of adiponectin and its clinical application.

Adiponectin (ADPN), which serum/plasma adiponectin levels are closely associated with insulin resistance and type 2 diabetes, and lower adiponectin levels predict an increased risk of diabetes, is a strong indicator of diabetes risk in people at high risk of diabetes in different races. Using the unique principle and performance advantages of chemiluminescence immunoassay (CLIA), an ADPN-CLIA method with high sensitivity, high specificity and wide detection range was established based on the principle of two-steps method of sandwich-type, with the magnetic particles (MPs) as the solid phase carrier and acridinium ester (AE) as the chemiluminescence reaction system. The selection of the main raw materials required, the preparation conditions of MPs-coated antibodies, the methods of AE-labeled antibodies, sample requirements and reaction modes were optimized and evaluated. AE labeling experiment was successfully performed with the labeling efficiency of 8.366 and the antibody utilization rate of 96.8%. The chemiluminescent immunoassay for ADPN had a good linear relationship from 0 ng/mL to 250 ng/mL (R2 =0.9993), with the detection limit of 0.05 ng/mL. The coefficient of variation (CV) of intra-assay and inter-assay precision were both less than 5% respectively. The recovery rates for accuracy were from 91.26% to 107.46%. The comparison experiment of 80 clinical serum samples between the developed ADPN-CLIA with the immunoturbidimetry showed that the correlation coefficient was 0.956, and the Bland-Altman analysis showed that the limits of agreement were - 0.364 and 0.433.

The correlation between dermoscopy and clinical and pathological tests in the evaluation of skin photoaging.

BACKGROUND: There are no standards for evaluating skin photoaging. Dermoscopy is a non-invasive detection method that might be useful for evaluating photoaging. OBJECTIVE: To assess the correlation between the dermoscopic evaluation of photoaging and clinical and pathological evaluations. METHODS: The age, clinical evaluation (Fitzpatrick classification, Glogau Photoaging Classification, and Chung's standardized image ruler), histopathology (Masson staining and MMP-1 immunohistochemistry), and dermoscopy (Hu's and Isik's) of 40 donor skin samples were analyzed statistically, and Spearman rank correlation analysis was performed. RESULTS: There was a robust correlation between the total Hu scores and Isik dermoscopy. The correlation of dermoscopy with histopathology was higher than that of clinical evaluation methods. There is a strong correlation between telangiectases and lentigo. Xerosis, superficial wrinkle, diffuse erythema, telangiectases, and reticular pigmentation were significantly correlated with the three clinical evaluation methods. Superficial wrinkles were correlated with Masson, MMP-1, various clinical indicators, and other dermoscopic items. CONCLUSION: There is a good correlation between dermoscopy and clinical and histopathological examination. Dermoscopy might help evaluate skin photoaging.

Digital workflow for monolithic and veneered zirconia and metal-ceramic posterior fixed partial dentures: A five-year prospective randomized clinical trial.

Purpose To evaluate and compare the survival, success rates, and biological and technical complications of three-unit posterior monolithic and veneered zirconia and metal-ceramic (MC) posterior fixed partial dentures (FPDs) fabricated using a digital workflow and computer-aided design and computer-aided manufacturing (CAD/CAM) over a 5-year follow-up.Methods Ninety patients in need of three-unit posterior FPDs were randomized to receive monolithic zirconia (MZ), veneered zirconia (VZ), and MC restorations (n = 30 each). Teeth preparations were scanned using an intraoral scanner, and restorations were milled and cemented with resin cement. Clinical performance and periodontal parameters were assessed at baseline and yearly up to 5 years after insertion. Data analysis was performed using the Kaplan-Meier method, Friedman test, and Wilcoxon signed-rank test with Bonferroni correction and Mann-Whitney U test.Results The 5-year survival rates of the MZ, VZ, and MC FPDs were 87%, 97%, and 100%, respectively (P = 0.04). Most complications were biological in nature. Only one MZ FPD fractured 58 months after placement. All the restorations were assessed as satisfactory at each recall. Differences were found in the gingival index score over time in the VZ and MC groups. The margin index remained stable throughout the follow-up period in both zirconia groups.Conclusions The results of this study suggest that using a digital workflow to fabricate posterior FPDs is an adequate treatment option and that monolithic zirconia could be a viable alternative to metal-ceramic or veneered zirconia. However, further long-term studies are necessary to provide stronger evidence in patients with bruxism.