Clinical Relevance Research Articles

Strong Correlation Between Femoral Condyle Radius of Curvature and Anterior-Posterior Length

Background: The radius of curvature (ROC) of the femoral condyle is a factor in potential cartilage incongruities following osteochondral allograft (OCA) transplantation. Accurate restoration of the chondral surface may be achievable by using “best-fit” donor-recipient matching based on linear femorotibial dimensions, such as the femoral condyle anterior-posterior length (APL), femoral condyle width (lateral-medial length, LML), femoral hemicondyle width (HCW), and tibial plateau width (TPW), particularly if they correlate well with the ROC. This study aimed to investigate the correlative relationship between femorotibial dimensions and the ROC. Methods: Computed tomography (CT) scans from 49 patients (31 men 28 ± 10 years old and 18 women 27 ± 6 years old) were analyzed. Axial images were used for APL and LML measurements, while coronal images were used for HCW and TPW. True sagittal images of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) were used to calculate their individual ROCs by determining the best-fit circles along the condylar surface. Linear regression models were used to determine the relationship between the femorotibial dimensions and ROC. Measurements were repeated for a randomly selected subset of the data, and intraclass correlation coefficients (ICCs) were calculated to investigate intra- and interobserver reliability. Results: All femorotibial dimensions showed significant correlations with the MFC and LFC ROCs (p < 0.01). The ROC correlations with femorotibial dimensions were found to be in the following descending order: APL (R2 ≥ 0.83), LML (R2 ≥ 0.52), TPW (R2 ≥ 0.36), and HCW (R2 ≥ 0.27). The intra- and interobserver reliabilities for the APL (ICC > 0.98) and ROC (ICC > 0.94) were excellent. Conclusions: The ROC was strongly correlated with the APL of the MFC and LFC. Donor-recipient APL matching in OCA transplantation may provide a level of matching similar to that achievable by direct ROC measurements. Clinical Relevance: Determining the most predictive femorotibial dimension for ROC restoration in the OCA matching process may improve clinical outcomes, particularly for patients with large osteochondral lesions.

An observational study of farmer-reported clinical mastitis in New Zealand dairy ewes

ABSTRACT Aims To describe the incidence, aetiology, treatment, and outcomes of farmer-reported clinical mastitis on New Zealand dairy sheep farms. Methods A prospective cohort study was conducted on 20 spring-lambing New Zealand sheep milking farms over the 2022–2023 season. Clinical mastitis was defined as a change in the appearance of milk and/or signs of inflammation in the gland. Farmers were required to report all cases of clinical mastitis and collect information on affected ewes’ demographics, clinical features, treatments (where applicable), and outcomes. Milk samples from mastitic glands were submitted for microbiological culture and identification by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF). Results Partial or complete clinical mastitis data were available for 236 cases from 221 ewes on 18/20 study farms. Clinical mastitis was diagnosed in 0–6% of ewes at the farm level, with an overall incidence of 1.8 (95% CI = 1.0–3.2)% using the study data, or 2.3 (95% CI = 1.6–3.3)% using the study data and farmer estimates that included unreported cases. Cases occurred mostly in early lactation, with 59% detected during the lambing period (August–October), at a median of 7 (IQR 3, 40) days in milk. The majority of cases featured clots in the milk (59%), swelling (55%), and unevenness (71%) of the glands. Pyrexia (rectal temperature ≥ 40.0°C) was diagnosed in 25% of cases and depression (lethargy, inappetence, or inability to stand) in 26% of cases. Treatment was given to 46% of cases, with tylosin being the most commonly used treatment (50% of treated cases). The most common outcome was immediate drying off to be culled without treatment (32%), followed by still milking and recovered but with lasting problems (25%). Nearly half of all the milk samples submitted were culture negative. Streptococcus uberis (14%), non-aureus staphylococci (12%), and Staphylococcus aureus (11%) were the most common isolates, found on 12, 8 and 8 of the 16 farms with microbiological data, respectively. Conclusions Clinical mastitis affected up to 6% of ewes at the farm level. Systemic signs were observed in one quarter of affected ewes, suggesting a role for supportive treatment. Clinical mastitis can be severe and challenging to fully resolve in New Zealand dairy sheep. Clinical relevance This is the first systematic study of clinical mastitis in New Zealand dairy ewes. It provides baseline information specific to New Zealand conditions for farmers, veterinarians, and other advisors to guide the management of mastitis for the relatively new dairy sheep industry in New Zealand.

Saccharomyces cerevisiae fungemias: how heterogenous is their management?

Saccharomyces cerevisiae is a yeast used mainly as a probiotic for prevention or treatment of diarrhoea. However, the prevalence of S. cerevisiae fungemia has risen over the past years, notably among patients with predisposing factors. This retrospective study presents 21 cases of S. cerevisiae fungemia at the University Hospital of Liege from 2000 to 2022, their clinical relevance and therapeutic management. Each patient presented one or several risk factors prior to fungemia. The isolated strains presented high minimal inhibitory concentration for fluconazole, while MICs for amphotericin B, voriconazole and echinocandins were low. Some patients received antifungal therapy, while for others only central and peripheral lines were removed and probiotics discontinued. The MICs obtained for voriconazole and echinocandins makes them an alternative treatment to fluconazole and amphotericin B as reported in other studies. Since a S. cerevisiae fungemia can induce the same complications as candidemia, follow-up blood cultures should be collected and metastatic foci should be looked for. This study showed an important discrepancy in the clinical management of infections due to S. cerevisiae and highlights the need for guidelines.

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis

Presoaking Grafts in Vancomycin Does Not Impair Graft-Bone Healing in a Rat Anterior Cruciate Ligament Reconstruction Model

Background: The vancomycin presoaking technique (wherein grafts are treated with a vancomycin solution [VS] for anterior cruciate ligament reconstruction [ACLR]) reduces the infection rate after ACLR. However, the effects of this technique on graft-bone healing have not been fully elucidated. Purpose: To investigate the effects of vancomycin presoaking on graft-bone healing in a rat ACLR model. Study Design: Controlled laboratory study. Methods: Long flexor digitorum longus tendons were obtained from 9 Wistar rats, and each was randomly allocated to the normal saline (NS) or VS groups. The grafts were immersed in sterile saline for 30 minutes in the NS group and in a 5-mg/mL VS in the VS group. The presence of time-zero graft bacterial contamination was confirmed, and the grafts were incubated in Fluidised Thioglycollate Broth for 2 weeks. ACLR was performed on the right knees of 65 male Wistar rats using the flexor digitorum longus tendons. Each graft was similarly treated. Biomechanical testing, micro–computed tomography, and histological evaluations were performed 4 and 12 weeks postoperatively. Results: The VS group showed significantly reduced graft contamination at time zero (P = .02). The mean maximum loads to failure were 13.7 ± 8.2 N and 11.6 ± 4.8 N in the NS and VS groups, respectively, at 4 weeks (P = .95); and 23.2 ± 13.2 N and 30.4 ± 18.0 N in the NS and VS groups, respectively, at 12 weeks (P = .35). Regarding micro–computed tomography, the mean bone tunnel volumes were 3.76 ± 0.48 mm3 and 4.40 ± 0.58 mm3 in the NS and VS groups, respectively, at 4 weeks (P = .41); and 3.51 ± 0.38 mm3 and 3.67 ± 0.35 mm3 in the NS and VS groups, respectively, at 12 weeks (P = .54). Histological semiquantitative examination revealed no clear between-group differences at any time point. Conclusion: Presoaking grafts in vancomycin in a rat ACLR model demonstrated no discernible adverse effects on short- and midterm biomechanical, radiological, and histological investigations. Clinical Relevance: The findings provide guidance for surgeons when considering this technique.

Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes

PURPOSE Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R–based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M–based policy ( P = .001). CONCLUSION These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Relationship between macular perfusion and lesion distribution in diabetic retinopathy.

To assess the relationship between macular vessel density metrics and foveal avascular zone (FAZ) characteristics on optical coherence tomography angiography (OCTA) and lesion distribution in eyes with diabetic retinopathy (DR). Patients with DR who underwent both Optos ultrawidefield (UWF) pseudocolor imaging and macular OCTA (Cirrus Angioplex, 6 × 6 mm) were included in this cross-sectional observational study. The distribution of DR lesions was assessed by comparing each of the peripheral ETDRS extended fields (3-7) against their corresponding ETDRS field, hence eyes were defined as either having predominantly peripheral lesions (PPL) or predominantly central lesions (PCL). En face OCTA images from the superficial and deep capillary plexuses (SCP and DCP) were then analysed using Image J software. Perfusion density (PD), vessel length density (VLD), and fractal dimensions (FD) were calculated following binarization and skeletonization of the images. Out of 344 eyes, 116 (33.72%) eyes had PPL and 228 (66.28%) eyes had PCL. For all DRSS levels, VLD, PD, and FD were not significantly different between eyes with PPL and PCL. The FAZ in eyes with PPL, however, was found to be more circular in shape compared to eyes with PCL (p = 0.037). Although the presence of PPL has been associated with a higher risk for diabetic retinopathy progression, the macular perfusion is similar in eyes with PPL and PCL. The FAZ is more circular in eyes with PPL, but the clinical relevance of this difference remains to be defined.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec

Predictive value of different thresholds of morning cortisol in diagnosing adrenal insufficiency

ObjectiveAdrenal insufficiency (AI) is diagnosed with morning cortisol but ACTH stimulation test is usually needed to confirm the diagnosis. In this study we investigated different morning cortisol thresholds that can safely rule out AI without requiring a confirmatory ACTH stimulation test. DesignRetrospective cohort study. MethodsWe included patients aged 18 and above who underwent the 250 mcg ACTH stimulation test from June 2018 to June 2022. Basal and post-ACTH serum cortisol values at 30 and 60 min were documented. Sensitivity, specificity and logistic regression analysis were employed to assess morning cortisol level's ability to predict AI as confirmed by ACTH stimulation test. Results237 patients were included, 66 diagnosed with AI and 171 had normal ACTH results. Hypertension and type 2 Diabetes correlated with lower AI incidence. Median morning cortisol was 138.0 nmol/L for AI group and 286.0 nmol/L for non-AI patients. A morning cortisol of 285 nmol/L had 90.6 % sensitivity, 50.3 % specificity, and a negative predictive value of 93.3 % for ruling out AI. A threshold of 306 nmol/L increased sensitivity to 95.3 % with 40 % specificity. ConclusionMorning cortisol is an effective diagnostic tool for ruling out AI. Using multiple thresholds based on clinical suspicion and the integration of predictive pre-test probability can reduce the need for excessive ACTH stimulation tests. This study contributes to the growing evidence of utilizing morning serum cortisol in the diagnosis of adrenal insufficiency. Clinical relevance statementDiagnosing Adrenal Insufficiency (AI) can be challenging due to debate regarding the cortisol cut-off value that can exclude AI without additional tests. The confirmatory short synacthen test has certain limitations including financial implications and time restrictions. We investigated the performance of various morning cortisol levels that can diagnose AI without additional testing.

Urinary soluble CD163 is a putative non-invasive biomarker for primary sclerosing cholangitis

Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.

Ultra-low-dose vs. standard-of-care-dose CT of the chest in patients with post-COVID-19 conditions—a prospective intra-patient multi-reader study

Abstract Objectives To conduct an intrapatient comparison of ultra-low-dose computed tomography (ULDCT) and standard-of-care-dose CT (SDCT) of the chest in terms of the diagnostic accuracy of ULDCT and intrareader agreement in patients with post-COVID conditions. Methods We prospectively included 153 consecutive patients with post-COVID-19 conditions. All participants received an SDCT and an additional ULDCT scan of the chest. SDCTs were performed with standard imaging parameters and ULDCTs at a fixed tube voltage of 100 kVp (with tin filtration), 50 ref. mAs (dose modulation active), and iterative reconstruction algorithm level 5 of 5. All CT scans were separately evaluated by four radiologists for the presence of lung changes and their consistency with post-COVID lung abnormalities. Radiation dose parameters and the sensitivity, specificity, and accuracy of ULDCT were calculated. Results Of the 153 included patients (mean age 47.4 ± 15.3 years; 48.4% women), 45 (29.4%) showed post-COVID lung abnormalities. In those 45 patients, the most frequently detected CT patterns were ground-glass opacities (100.0%), reticulations (43.5%), and parenchymal bands (37.0%). The accuracy, sensitivity, and specificity of ULDCT compared to SDCT for the detection of post-COVID lung abnormalities were 92.6, 87.2, and 94.9%, respectively. The median total dose length product (DLP) of ULDCTs was less than one-tenth of the radiation dose of our SDCTs (12.6 mGy*cm [9.9; 15.5] vs. 132.1 mGy*cm [103.9; 160.2]; p < 0.001). Conclusion ULDCT of the chest offers high accuracy in the detection of post-COVID lung abnormalities compared to an SDCT scan at less than one-tenth the radiation dose, corresponding to only twice the dose of a standard chest radiograph in two views. Clinical relevance statement Ultra-low-dose CT of the chest may provide a favorable, radiation-saving alternative to standard-dose CT in the long-term follow-up of the large patient cohort of post-COVID-19 patients.

The Role of Cilia and the Complex Genetics of Congenital Heart Disease

Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.

Farm-level risk factors and treatment protocols for lameness in New Zealand dairy cattle

ABSTRACT Aims To identify farm-level risk factors for dairy cow lameness, and to describe lameness treatment protocols used on New Zealand dairy farms. Methods One hundred and nineteen farms from eight veterinary clinics within the major dairying regions of New Zealand were randomly enrolled into a cross-sectional lameness prevalence study. Each farmer completed a questionnaire on lameness risk factors and lameness treatment and management. Trained observers lameness scored cattle on two occasions, between October–December (spring, coinciding with peak lactation for most farms) and between January–March (summer, late lactation for most farms). A four-point (0–3) scoring system was used to assess lameness, with animals with a lameness score (LS) ≥2 defined as lame. At each visit, all lactating animals were scored including animals that had previously been identified lame by the farmer. Associations between the farmer-reported risk factors and lameness were determined using mixed logistic regression models in a Bayesian framework, with farm and score event as random effects. Results A lameness prevalence of 3.5% (2,113/59,631) was reported at the first LS event, and 3.3% (1,861/55,929) at the second LS event. There was a median prevalence of 2.8% (min 0, max 17.0%) from the 119 farms. Most farmers (90/117; 77%) relied on informal identification by farm staff to identify lame animals. On 65% (75/116) of farms, there was no external provider of lame cow treatments, with the farmer carrying out all lame cow treatments. Most farmers had no formal training (69/112; 62%). Animals from farms that used concrete stand-off pads during periods of inclement weather had 1.45 times the odds of lameness compared to animals on farms that did not use concrete stand-off pads (95% equal-tailed credible interval 1.07–1.88). Animals from farms that reported peak lameness incidence from January to June or all year-round, had 0.64 times odds of lameness compared to animals from farms that reported peak lameness incidence from July to December (95% equal-tailed credible interval 0.47–0.88). Conclusions Lameness prevalence was low amongst the enrolled farms. Use of concrete stand-off pads and timing of peak lameness incidence were associated with odds of lameness. Clinical relevance Veterinarians should be encouraging farmers to have formal lameness identification protocols and lameness management plans in place. There is ample opportunity to provide training to farmers for lame cow treatment. Management of cows on stand-off pads should consider the likely impact on lameness.

Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients.

Neutrophil diversity is associated with T-cell immunity and clinical relevance in patients with thyroid cancer

Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I–II), and healthy controls (n = 10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T-cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T-cell-related pathways, such as T-cell receptor signaling pathway and T-cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor-infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer.

Hepatocyte Intrinsic Innate Antiviral Immunity against Hepatitis Delta Virus Infection: The Voices of Bona Fide Human Hepatocytes.

The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.

Molecular mechanisms and clinical relevance of endothelial cell cross-talk in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer in adults and stands out as one of the most vascularized and immune-infiltrated solid tumors. Overproduction of vascular endothelial growth factor A promotes uncontrolled growth of abnormal vessels and immunosuppression, and the tumor microenvironment (TME) has a prominent role in disease progression, drug targeting and drug response, and for patient outcome. Studies of experimental models, large-scale omics approaches, and patient prognosis and therapy prediction, using gene expression signatures and tissue biomarker analysis, have been reviewed for enhanced understanding of the endothelium in ccRCC and the interplay with the surrounding TME. Preclinical and clinical studies have discovered molecular mechanisms of endothelial cross-talk of relevance for disease progression, patient prognosis, and therapy prediction. There is, however, a lack of representative ccRCC experimental models. Omics approaches have identified clinically relevant subsets of angiogenic and immune-infiltrated tumors with distinct molecular signatures and distinct endothelial cell and immune cell populations in patients. Recent genetically engineered ccRCC mouse models together with emerging evidence from single cell RNA sequencing data open up for future validation studies, including multiplex imaging of ccRCC patient cohorts. These studies are of importance for therapy benefit and personalized treatment of ccRCC patients.

Development and external validation of a multimodal integrated feature neural network (MIFNN) for the diagnosis of malignancy in small pulmonary nodules (≤10 mm)

Objectives. Current lung cancer screening protocols primarily evaluate pulmonary nodules, yet often neglect the malignancy risk associated with small nodules (≤10 mm). This study endeavors to optimize the management of pulmonary nodules in this population by devising and externally validating a Multimodal Integrated Feature Neural Network (MIFNN). We hypothesize that the fusion of deep learning algorithms with morphological nodule features will significantly enhance diagnostic accuracy. Materials and Methods. Data were retrospectively collected from the Lung Nodule Analysis 2016 (LUNA16) dataset and four local centers in Beijing, China. The study includes patients with small pulmonary nodules (≤10 mm). We developed a neural network, termed MIFNN, that synergistically combines computed tomography (CT) images and morphological characteristics of pulmonary nodules. The network is designed to acquire clinically relevant deep learning features, thereby elevating the diagnostic accuracy of existing models. Importantly, the network’s simple architecture and use of standard screening variables enable seamless integration into standard lung cancer screening protocols. Results. In summary, the study analyzed a total of 382 small pulmonary nodules (85 malignant) from the LUNA16 dataset and 101 small pulmonary nodules (33 malignant) obtained from four specialized centers in Beijing, China, for model training and external validation. Both internal and external validation metrics indicate that the MIFNN significantly surpasses extant state-of-the-art models, achieving an internal area under the curve (AUC) of 0.890 (95% CI: 0.848–0.932) and an external AUC of 0.843 (95% CI: 0.784–0.891). Conclusion. The MIFNN model significantly enhances the diagnostic accuracy of small pulmonary nodules, outperforming existing benchmarks by Zhang et al with a 6.34% improvement for nodules less than 10 mm. Leveraging advanced integration techniques for imaging and clinical data, MIFNN increases the efficiency of lung cancer screenings and optimizes nodule management, potentially reducing false positives and unnecessary biopsies. Clinical relevance statement. The MIFNN enhances lung cancer screening efficiency and patient management for small pulmonary nodules, while seamlessly integrating into existing workflows due to its reliance on standard screening variables.

Structural and Dynamic Features of Acinetobacter baumannii OXA-66 β-Lactamase Explain Its Stability and Evolution of Novel Variants

OXA-66 is a member of the OXA-51 subfamily of class D β-lactamases native to the Acinetobacter genus that includes Acinetobacter baumannii, one of the ESKAPE pathogens and a major cause of drug-resistant nosocomial infections. Although both wild type OXA-66 and OXA-51 have low catalytic activity, they are ubiquitous in the Acinetobacter genomes. OXA-51 is also remarkably thermostable. In addition, newly emerging, single and double amino acid variants show increased activity against carbapenems, indicating that the OXA-51 subfamily is growing and gaining clinical significance. In this study, we used molecular dynamics simulations, X-ray crystallography, and thermal denaturation data to examine and compare the dynamics of OXA-66 wt and its gain-of-function variants: I129L (OXA-83), L167V (OXA-82), P130Q (OXA-109), P130A, and W222L (OXA-234). Our data indicate that OXA-66 wt also has a high melting temperature, and its remarkable stability is due to an extensive and rigid hydrophobic bridge formed by a number of residues around the active site and harbored by the three loops, P, Ω, and β5-β6. Compared to the WT enzyme, the mutants exhibit higher flexibility only in the loop regions, and are more stable than other robust carbapenemases, such as OXA-23 and OXA-24/40. All the mutants show increased rotational flexibility of residues I129 and W222, which allows carbapenems to bind. Overall, our data support the hypothesis that structural features in OXA-51 and OXA-66 promote evolution of multiple highly stable variants with increased clinical relevance in A. baumannii.

Critical appraisal of Australian and New Zealand paediatric vision screening clinical practice guidelines using the AGREE II tool

ABSTRACT Clinical Relevance Vision disorders in children impact health-related quality of life, with early detection and intervention improving outcomes and educational performance. Eye health professionals should be aware of paediatric vision screening guidelines and their development to understand the components of local programmes and the differences in sensitivity and specificity between protocols. Background High-quality clinical practice guidelines (CPGs) for vision screening enable the early detection of common vision disorders; however, they require rigorous development to ensure optimal accuracy in detecting vision disorders, enabling timely interventions. This study evaluated the quality of available vision screening CPGs on vision screening of children in Australia and New Zealand. Methods A systematic search of academic databases, guideline databases, professional associations and Google search engines was conducted to identify relevant paediatric vision screening CPGs. Four independent reviewers used the Appraisal of Guidelines, Research and Evaluation (AGREE II) instrument to assess the quality of individual guidelines and scores were aggregated and reported as the percentage of the total possible score across the six AGREE II domains: scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence. Results Initial 2,999 items were evaluated, with seven guidelines included. AGREE-II quality score agreement ranged from 43.3% to 95.8%. All guidelines scored >60.0% in the scope and purpose, however, most had poor scores of <26.5% in the rigour of development and <3.3% in editorial independence domains. All guidelines recommended screening using measures of habitual distance vision. Conclusion Of the guidelines developed for use in Australia and New Zealand, most guidelines scored poorly when assessed against the AGREE II tool, because of lack of editorial independence and rigour of development. Paediatric vision screening guidelines should prioritise systematic review of literature to inform practice and include statements regarding competing interests.