Photochemical Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Evaluation in Ex Vivo Human Tissue.

PURPOSE: Experimental investigation in human eyelids to confirm that exposing excised tarsal plates to ultraviolet-A radiation can induce a stiffening effect through the riboflavin-photosensitized crosslinking of tarsal collagen. METHODS: Thirteen tarsal plates excised from nonfrozen human cadavers were irradiated with ultraviolet-A rays (365 nm wavelength) at an irradiance of 75 mW/cm2 for 3 minutes, equivalent to a radiation fluence of 13.5 J/cm2, in the presence of a riboflavin derivative as a photosensitizer. The tensile stress (strength) and Young's modulus (stiffness) of both nonirradiated and irradiated specimens were measured with the BioTester 5000 in the uniaxial mode at a strain of 10% and analyzed statistically. Individual specimens excised from 2 cadavers were also examined by routine histopathologic protocols to assess the effect of radiation on the Meibomian glands and collagen organization. RESULTS: The irradiation enhanced both stiffness and strength of the human tarsal specimens, the difference between the test samples and controls being statistically significant (p < 0.0002 for n = 13). Histology indicated no damage to tarsal connective tissue or to Meibomian glands, and revealed a more compact packing of the collagen network located around the glands, which may be beneficial. The existence of collagen compaction was also supported by the reduction of samples' thickness after irradiation (p = 0.0645). CONCLUSIONS: The irradiation of tarsal tissue with ultraviolet-A light of tarsus appears to be a safe and effective method for reducing eyelid laxity in human patients.

miRNA Biology in Chronic Lymphocytic Leukemia.

microRNAs (miRNAs) are a class of small non-coding RNAs that play a crucial regulatory role in fundamental biological processes and have been implicated in various diseases, including cancer. The first evidence of the cancer-related function of miRNAs was discovered in chronic lymphocytic leukemia (CLL) in the early 2000s. Alterations in miRNA expression have since been shown to strongly influence the clinical course, prognosis, and response to treatment in patients with CLL. Therefore, the identification of specific miRNA alterations not only enhances our understanding of the molecular mechanisms underlying CLL but also holds promise for the development of novel diagnostic and therapeutic strategies. This review aims to provide a comprehensive summary of the current knowledge and recent insights into miRNA dysregulation in CLL, emphasizing its pivotal roles in disease progression, including the development of the lethal Richter syndrome, and to provide an update on the latest translational research in this field.

Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

BACKGROUND: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. RESULTS: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). CONCLUSION: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

Epigenetic priming by hypomethylation enhances the immunogenic potential of tolinapant in T-cell lymphoma.

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from peripheral TCL patients treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.

Obesity: a 100 year perspective.

This review has examined the scientific basis for our current understanding of obesity that has developed over the past 100 plus years. Obesity was defined as an excess of body fat. Methods of establishing population and individual changes in levels of excess fat are discussed. Fat cells are important storage site for excess nutrients and their size and number affect the response to insulin and other hormones. Obesity as a reflection of a positive fat balance is influenced by a number of genetic and environmental factors and phenotypes of obesity can be developed from several perspectives, some of which have been elaborated here. Food intake is essential for maintenance of human health and for the storage of fat, both in normal amounts and in obesity in excess amounts. Treatment approaches have taken several forms. There have been numerous diets, behavioral approaches, along with the development of medications.. Bariatric/metabolic surgery provides the standard for successful weight loss and has been shown to have important effects on future health. Because so many people are classified with obesity, the problem has taken on important public health dimensions. In addition to the scientific background, obesity through publications and organizations has developed its own identity. While studying the problem of obesity this reviewer developed several aphorisms about the problem that are elaborated in the final section of this paper.

Decision-Making Confidence of Clinical Competency Committees for Entrustable Professional Activities.

Importance: A competency-based assessment framework using entrustable professional activities (EPAs) was endorsed by the American Board of Surgery following a 2-year feasibility pilot study. Pilot study programs' clinical competency committees (CCCs) rated residents on EPA entrustment semiannually using this newly developed assessment tool, but factors associated with their decision-making are not yet known. Objective: To identify factors associated with variation in decision-making confidence of CCCs in EPA summative entrustment decisions. Design, Setting, and Participants: This cohort study used deidentified data from the EPA Pilot Study, with participating sites at 28 general surgery residency programs, prospectively collected from July 1, 2018, to June 30, 2020. Data were analyzed from September 27, 2022, to February 15, 2023. Exposure: Microassessments of resident entrustment for pilot EPAs (gallbladder disease, inguinal hernia, right lower quadrant pain, trauma, and consultation) collected within the course of routine clinical care across four 6-month study cycles. Summative entrustment ratings were then determined by program CCCs for each study cycle. Main Outcomes and Measures: The primary outcome was CCC decision-making confidence rating (high, moderate, slight, or no confidence) for summative entrustment decisions, with a secondary outcome of number of EPA microassessments received per summative entrustment decision. Bivariate tests and mixed-effects regression modeling were used to evaluate factors associated with CCC confidence. Results: Among 565 residents receiving at least 1 EPA microassessment, 1765 summative entrustment decisions were reported. Overall, 72.5% (1279 of 1765) of summative entrustment decisions were made with moderate or high confidence. Confidence ratings increased with increasing mean number of EPA microassessments, with 1.7 (95% CI, 1.4-2.0) at no confidence, 1.9 (95% CI, 1.7-2.1) at slight confidence, 2.9 (95% CI, 2.6-3.2) at moderate confidence, and 4.1 (95% CI, 3.8-4.4) at high confidence. Increasing number of EPA microassessments was associated with increased likelihood of higher CCC confidence for all except 1 EPA phase after controlling for program effects (odds ratio range: 1.21 [95% CI, 1.07-1.37] for intraoperative EPA-4 to 2.93 [95% CI, 1.64-5.85] for postoperative EPA-2); for preoperative EPA-3, there was no association. Conclusions and Relevance: In this cohort study, the CCC confidence in EPA summative entrustment decisions increased as the number of EPA microassessments increased, and CCCs endorsed moderate to high confidence in most entrustment decisions. These findings provide early validity evidence for this novel assessment framework and may inform program practices as EPAs are implemented nationally.

The potential of virtual triage AI to improve early detection, care acuity alignment, and emergent care referral of life-threatening conditions.

Objective: To evaluate the extent to which patient-users reporting symptoms of five severe/acute conditions requiring emergency care to an AI-based virtual triage (VT) engine had no intention to get such care, and whose acuity perception was misaligned or decoupled from actual risk of life-threatening symptoms. Methods: A dataset of 3,022,882 VT interviews conducted over 16 months was evaluated to quantify and describe patient-users reporting symptoms of five potentially life-threatening conditions whose pre-triage healthcare intention was other than seeking urgent care, including myocardial infarction, stroke, asthma exacerbation, pneumonia, and pulmonary embolism. Results: Healthcare intent data was obtained for 12,101 VT patient-user interviews. Across all five conditions a weighted mean of 38.5% of individuals whose VT indicated a condition requiring emergency care had no pre-triage intent to consult a physician. Furthermore, 61.5% intending to possibly consult a physician had no intent to seek emergency medical care. After adjustment for 13% VT safety over-triage/referral to ED, a weighted mean of 33.5% of patient-users had no intent to seek professional care, and 53.5% had no intent to seek emergency care. Conclusion: AI-based VT may offer a vehicle for early detection and care acuity alignment of severe evolving pathology by engaging patients who believe their symptoms are not serious, and for accelerating care referral and delivery for life-threatening conditions where patient misunderstanding of risk, or indecision, causes care delay. A next step will be clinical confirmation that when decoupling of patient care intent from emergent care need occurs, VT can influence patient behavior to accelerate care engagement and/or emergency care dispatch and treatment to improve clinical outcomes.

Glaucoma and the Human Microbiome.

PURPOSE OF REVIEW: To explore a view of the human microbiome as an interconnected, functional, dynamic system that may be linked to the pathogenesis and progression of glaucoma. METHOD: A literature review was undertaken that included publications from 1966 to 2023. RESULTS: Bacterial lipopolysaccharides (LPS) activate toll-like receptors (TLR) and mediate the human immune response. The LPS-TLR4 pathway is a potential avenue for the ocular, gut, and oral microbiomes to interface and/or influence ocular disease. Studies of gut dysbiosis have shown that alterations on the healthy microbiota can predispose the host to immune-mediated inflammatory and neurodegenerative conditions, while oral and ocular surface dysbiosis have been correlated with glaucoma. While developmental exposure to commensal microflora has shown to be necessary for the autoimmune and neurodegenerative responses to elevated intraocular pressure to take place, commensal bacterial products like short chain fatty acids have regulatory effects protective against glaucoma. SUMMARY: Alterations to human microbiotas have been associated with changes in intestinal permeability, gene regulation, immune cell differentiation, and neural functioning, which may predispose the host to glaucoma. Select microbes have been highlighted for their potential contributions to glaucoma disease progression or protection, raising the potential for microbiota-based treatment modalities. Current topical glaucoma treatments may disrupt the ocular surface microbiota, potentially having ramifications on host health. Further study of the relationships between human microbiome and glaucoma is needed.

Additive toxicity arising from combined use of immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with renal or endometrial carcinoma: Protocol for a rapid systematic review.

The combined use of immune checkpoint inhibitors and tyrosine kinase inhibitors (ICI/TKI) is an effective treatment strategy for some cancers. A better understanding of the potential additive toxicity for ICI/TKI combinations is needed to inform patient and provider treatment decisions. We aim to evaluate the safety of ICI/TKI combinations for individuals with renal cell or endometrial carcinoma. This rapid systematic review (SR) protocol follows PRISMA guidelines. A systematic search will be designed, peer reviewed and executed by experienced information specialists (Cochrane Central, MEDLINE, Embase) to identify published SRs and primary studies published since the most recent SR search. Randomized, quasi- or non-randomized controlled trials and comparative cohort studies are eligible if they compare ICI/TKI combinations to monotherapy or standard of care in participants with renal cell or endometrial carcinoma. The primary outcome is grade ≥ 3 treatment-related adverse-effects. Studies will be screened, selected, extracted and assessed for risk of bias by a single reviewer and checked completely by a second. Where feasible and appropriate, we will pool studies separately by design and indication using meta-analysis and test robustness of effects using prespecified subgroup and sensitivity analyses. Results will be summarized descriptively and presented in tables and figures. (PROSPERO ID: CRD42023416388).•This will be a comprehensive systematic review of the additive toxicity arising from the combined use of ICI/TKIs in patients with renal-cell or endometrial carcinoma.•We will consider treatment-related, treatment-emergent adverse events (Grade 3 or higher).•Identified safety profile may be used to inform patient or provider treatment decisions.

Measurement of Water Uptake and States in Nafion Membranes Using Humidity-Controlled Terahertz Time-Domain Spectroscopy.

Perfluorinated sulfonic acid ionomers are well known for their unique water uptake properties and chemical/mechanical stability. Understanding their performance-stability trade-offs is key to realizing membranes with optimal properties. Terahertz time-domain spectroscopy has been demonstrated to resolve water states inside industrially relevant membranes, producing qualitatively agreeable results to conventional gravimetric analysis and prior demonstrations. Using the proposed humidity-controlled terahertz time-domain spectroscopy, here we quantify this detailed water information inside commercially available Nafion membranes at various humidities for direct comparison against literature values from dynamic vapor sorption, differential scanning calorimetry, and Fourier transform infrared spectroscopy on selected samples. Using this technique therefore opens up opportunities for rapid future parameter space investigation for membrane optimization.

A simplified pneumonia severity index (PSI) for clinical outcome prediction in COVID-19.

BACKGROUND: The Pneumonia Score Index (PSI) was developed to estimate the risk of dying within 30 days of presentation for community-acquired pneumonia patients and is a strong predictor of 30-day mortality after COVID-19. However, three of its required 20 variables (skilled nursing home, altered mental status and pleural effusion) are not discreetly available in the electronic medical record (EMR), resulting in manual chart review for these 3 factors. The goal of this study is to compare a simplified 17-factor version (PSI-17) to the original (denoted PSI-20) in terms of prediction of 30-day mortality in COVID-19. METHODS: In this retrospective cohort study, the hospitalized patients with confirmed SARS-CoV-2 infection between 2/28/20-5/28/20 were identified to compare the predictive performance between PSI-17 and PSI-20. Correlation was assessed between PSI-17 and PSI-20, and logistic regressions were performed for 30-day mortality. The predictive abilities were compared by discrimination, calibration, and overall performance. RESULTS: Based on 1,138 COVID-19 patients, the correlation between PSI-17 and PSI-20 was 0.95. Univariate logistic regression showed that PSI-17 had performance similar to PSI-20, based on AUC, ICI and Brier Score. After adjusting for confounding variables by multivariable logistic regression, PSI-17 and PSI-20 had AUCs (95% CI) of 0.85 (0.83-0.88) and 0.86 (0.84-0.89), respectively, indicating no significant difference in AUC at significance level of 0.05. CONCLUSION: PSI-17 and PSI-20 are equally effective predictors of 30-day mortality in terms of several performance metrics. PSI-17 can be obtained without the manual chart review, which allows for automated risk calculations within an EMR. PSI-17 can be easily obtained and may be a comparable alternative to PSI-20.

Meniscal Repair with ArthroZheal® an Autologous Bioactive Fibrin Scaffold. A New Technique and Treatment Option.

Injuries of the meniscus often lead to changes in joint biomechanics, which affect the load distribution and contact stresses. The menisci consist of a peripheral vascular region (red zone) and an inner avascular region (white zone). The blood supply plays an important role in the healing of meniscal tears. Surgical treatment of such lesions includes meniscectomy/meniscoplasty and repair, depending on the type of injury, where "meniscoplasty" refers to the treatment modality that occurs under coblation. The application of Autologous Bioactive Matrix (ABM) has been shown to promote healing in such lesions. In addition, a special type of PRF (ArthroZheal®, Vivostat A/S, Allerød, Denmark) has been demonstrated to have healing effects in extracellular matrix synthesis and cell proliferation, as well as regenerative and remodeling effects. This autologous product can be applied directly at the meniscal repair site. We performed a prospective study on meniscus repair with ArthroZheal® alone (plus meniscoplasty) and ArthroZheal® together with an all-inside suturing technique using the STAR AccurFix Meniscal Repair Device system (STAR Sports Medicine, Beijing, China), depending on the type and the site of the lesion. One hundred twenty knees (110 patients) were identified through the use of clinical examination and MRI scan. The study took place between January 2023 and August 2023. Two groups were created: GROUP A was treated only with ArthroZheal®(plus meniscoplasty) and GROUP B was treated with a combination of ArthroZheal® and an all-inside suturing technique (STAR AccurFix). Pre- and postoperative grading was performed with the International Knee Documentation Committee (IKDC) score and the Tegner Activity Level Scale (Tegner Score). The results with both treatment methods were excellent and meniscus restoration has been documented on MRIs conducted 6 months post-op. In 15 patients, 2nd-look arthroscopy was performed through a nanoscope on an outpatient basis, and showed meniscal healing and remodeling. Tegner scores and IKDC scores in both groups showed significant improvement. Meniscal repair should be performed at all costs to maintain meniscal integrity and prevent long-term degenerative changes. New treatment methods include orthobiologics and all-inside suturing techniques. The main idea is to apply an autologous biological scaffold which is able to carry cells into the meniscal lesion and to allow their differentiation, proliferation, and extracellular matrix synthesis to produce a meniscal-like tissue. Our results suggest that the application of autologous ABM (ArthroZheal®) for the treatment of such lesions by means of dry arthroscopy results in better MRI, pain management and functional results at 3 months post-op, and these improvements can persist for up to 6 months.

Inherited metabolic disorders in Cyprus.

Selective screening for inherited metabolic disorders (IMD) began in Cyprus in 1990. Over the last thirty-three years 7388 patients were investigated for IMD and 200 diagnoses were made (diagnostic yield 2.7%). The existence of a single laboratory of Biochemical Genetics for the whole island facilitated the creation of a national registry for IMD. The minimal prevalence of IMD in Cyprus is 53.3 cases per 100,000 live births. The most common group are disorders of amino acid metabolism (41.0%), followed by disorders of carbohydrate metabolism (16.5%), disorders of complex molecule degradation (16.5%), mitochondrial disorders (10.5%) and disorders of vitamin and co-factor metabolism (5.5%). Hyperphenylalaninaemia is the most common IMD (14.0%) followed by galactosaemia (7.0%), glutaric aciduria type I (5.5%) and MSUD (4.0%). Some disorders were found to have a relatively high incidence in specific communities, for example Sandhoff disease among the Cypriot Maronites and GM1 gangliosidosis in one particular area of the island. Other disorders were found to have a relatively higher overall incidence, compared to other Caucasian populations, for example galactosaemia, glutaric aciduria type I and MSUD, while fatty acid oxidation defects, Gaucher disease and classic PKU were found to have a relatively lower incidence. Molecular characterization of selected disorders revealed many novel genetic variants, specific to the Cypriot population.

Imaging in the diagnosis and management of fibrosing interstitial lung diseases.

High-resolution computed tomography (HRCT) plays a pivotal role in the diagnosis and management of interstitial lung diseases (ILDs), particularly given the approval of antifibrotic agents for conditions like idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Diagnosing fibrotic pulmonary disorders through HRCT involves a detailed and methodical examination. The identification of specific lung tissue changes, including ground-glass opacities and reticulation, along with signs of fibrosis like honeycombing, traction bronchiectasis and lung volume loss, establishes clear HRCT patterns indicative of various ILDs. The reliability of these patterns in predicting pathological conditions depends largely on the clinical context. For instance, when a usual interstitial pneumonia pattern is present, the predictive value of this diagnosis is so high that a lung biopsy is considered to be redundant. This review intends to delineate the HRCT signs of fibrosis, elucidate the specific radiological patterns of fibrotic lung diseases, and identify the clinical circumstances under which these patterns emerge. Additionally, we introduce and discuss novel imaging techniques that hold promise for the diagnosis, screening and early detection of ILDs.

Estimation of Photon Path Length and Penetration Depth in Articular Cartilage Zonal Architecture over the Therapeutic Window.

OBJECTIVE: The key characteristics of light propagation are the average penetration depth, average maximum penetration depth, and average path length of photons. These parameters depend on tissue optical properties and, thus, on the pathological state of the tissue. Hence, they could provide diagnostic information on tissue integrity. This study investigates these parameters for articular cartilage which has a complex structure. METHODS: We utilize Monte Carlo simulation to simulate photon trajectories in articular cartilage and estimate the average values of the light propagation parameters (penetration depth, maximum penetration depth, maximum lateral spread, and path length) in the spectral band of 400-1400 nm based on the optical properties of articular cartilage zonal layers and bulk tissue. RESULTS: Our findings suggest that photons in the visible band probe a localized small volume of articular cartilage superficial and middle zones, while those in the NIR band penetrate deeper into the tissue and have larger lateral spread. In addition, we demonstrate that a simple model of articular cartilage tissue, based on the optical properties of the bulk tissue, is capable to provide an accurate description of the light-tissue interaction in articular cartilage. CONCLUSION: The results indicate that as the photons in the spectral band of 400-1400 nm can reach the full depth of articular cartilage matrix, they can provide viable information on its pathological state. Therefore, diffuse optical spectroscopy holds significant importance for objectively assessing articular cartilage health. SIGNIFICANCE: In this study, for the first time, we estimate the light propagation parameters in articular cartilage.

Enhancement of soil aggregation and physical properties through fungal amendments under varying moisture conditions.

Soil structure and aggregation are crucial for soil functionality, particularly under drought conditions. Saprobic soil fungi, known for their resilience in low moisture conditions, are recognized for their influence on soil aggregate dynamics. In this study, we explored the potential of fungal amendments to enhance soil aggregation and hydrological properties across different moisture regimes. We used a selection of 29 fungal isolates, recovered from soils treated under drought conditions and varying in colony density and growth rate, for single-strain inoculation into sterilized soil microcosms under either low or high moisture (≤-0.96 and -0.03 MPa, respectively). After 8 weeks, we assessed soil aggregate formation and stability, along with soil properties such as soil water content, water hydrophobicity, sorptivity, total fungal biomass and water potential. Our findings indicate that fungal inoculation altered soil hydrological properties and improved soil aggregation, with effects varying based on the fungal strains and soil moisture levels. We found a positive correlation between fungal biomass and enhanced soil aggregate formation and stabilization, achieved by connecting soil particles via hyphae and modifying soil aggregate sorptivity. The improvement in soil water potential was observed only when the initial moisture level was not critical for fungal activity. Overall, our results highlight the potential of using fungal inoculation to improve the structure of agricultural soil under drought conditions, thereby introducing new possibilities for soil management in the context of climate change.