Marked Variation Research Articles

Biomechanics Explains Variability of Response of Small Hypertropia to Graded Vertical Rectus Tenotomy

PurposeSmall angle hypertropia in sagging eye syndrome is conveniently treated by graded vertical rectus tenotomy, yet adjustable technique under topical anesthesia has been recommended due to variability of effect. We performed graded tenotomy in an experimental model to elucidate the effect reason for variability of response to this surgical procedure. DesignExperimental study: Methods: 32 fresh bovine rectus musculotendon specimens were prepared including continuity with insertional sclera, and extending for a total 40mm length to the proximal muscle bellies, and trimmed to 16mm width. Specimens were anchored by the clamps at the scleral insertion and muscle belly ends within a physiological chamber. After preconditioning and elongation to 10% strain was imposed by a linear motor, tensile force was allowed to stabilize at a plateau state. Then 25, 50, 75, 90, 100% marginal tenotomies were perormed progressively as remnant forces were measured. ResultsTendon thickness averaged 0.29±0.05mm and width 19.71±2.25mm. On average, remnant force decreased linearly (R2=0.985) from 4.23±1.34, 2.76±0.88, 1.70±0.73, 1.01±0.49, 0.39±0.10, and 0 N, at 0, 25, 50, 75, 90, 100% tenotomy. However, there was marked individual variability in effect among specimens, with coefficient of variation 32, 32, 43, 49, and 27%, respectively ConclusionOn average there is a linear relationship between graded rectus tenotomy and percentage force reduction, but the effect among individual tendons is large, paralleling the reported variation in surgical effect. This explains and implies continued advisability of adjustable technique in this procedure.

Abstract CT059: Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas

Abstract Background: AXL is a cell surface receptor tyrosine kinase widely expressed in solid tumors (ST), including sarcomas. ADCT-601 (Mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate comprising a humanized anti-AXL antibody conjugated via a cleavable linker to SG3199 (pyrrolobenzodiazepine dimer cytotoxin). Mipa demonstrated antitumor activity in pre-clinical mice models of sarcoma, adrenocortical carcinoma and pancreatic cancer, and clinical activity in ST patients (pts) in its first-in-human trial. Here, we report initial clinical data in pts with advanced bone and soft tissue sarcomas treated in dose escalation with Mipa. Objective: To characterize the safety and tolerability of Mipa in pts with sarcoma indications who exhausted standard of care therapy. Method: This is a phase 1b, open-label, dose-escalation, dose expansion study of Mipa (NCT05389462; EudraCT: 2021-00566-18). Pts received Mipa every 3 weeks (Q3W) at escalating dose levels, in a 3+3 dose escalation design. Results: As of 04 December 2023, 18 sarcoma patients (15 [83%], soft tissue sarcoma [STS] and 3 [17%] bone sarcoma), unselected for AXL expression, with a median number of 3 prior lines of therapy (1-10), were enrolled in 4 different dose cohorts: 7.5mg, 11mg, 13mg and 15mg. Reasons for treatment discontinuation were disease progression (10 pts [55.6%]), adverse events (3 pts [16.7%]) and consent withdrawal (2 pts [11.1%]). Treatment emergent adverse events (TEAE) were seen in 17 pts (94.4%). Most common TEAE (all grades and relationship [≥20%]) were palmar-plantar erythrodysesthesia syndrome (7 pts [38.9%]); anemia (6 pts [33.3%]); rash maculopapular (5 pts [27.8%]); cheilitis and constipation (4 pts each [22.2%]). TEAE≥grade 3 were seen in 9 pts (50%). Most common TEAE≥grade 3 (≥10%) were GGT increase (2 pts [11.1%]). Two dose limiting toxicities were seen: cheilitis grade 2 and grade 3 at 15mg and 13mg respectively. Cutaneous reactions, all grades, are more prominent in higher doses. Maximum tolerated dose (MTD) has not been established. In 17 sarcoma pts evaluable per RECISTv1.1, best overall response was partial response (PR) (2 pts [11.8%]), including a confirmed PR; stable disease (SD) (8 pts [47.1%]); progressive disease (7 pts [41.2%]). Tumor reductions was observed at 7.5mg, 11mg and 13mg. By week 12, 6/17 pts (35.3%) did not demonstrate PD . Initial IHC staining showed AXL expression in all sarcoma baseline biopsies tested so far. Initial pharmacokinetic (PK) data indicate exposures with moderate to marked interpatient variability; rapid clearance with no accumulation by Cycle 2. Updated biomarkers and PK data will be presented. Conclusion: The MTD was not established. Due to the incidence of TEAE judged related to Mipa and the preliminary activity observed, 15mg was selected as the highest dose to be tested in a fixed dose Q3W regimen. The study continues to enroll to further optimize Mipa dosing regimen and in dose escalation with gemcitabine. Citation Format: Brian Andrew Van Tine, Christopher T. Chen, Victor Moreno, Elizabeth J. Davis, Maria J. de Miguel, Antoine Italiano, Esma Saada-Bouzid, Mohammed Milhem, Claudia Valverde, Sant P. Chawla, Abdul Rafeh Naqash, Louise Carter, Robin Jones, Ilaria Conti, Joe Boni, Karin Havenith, Yvan LeBruchec, Serafino Pantano, Jean-Yves Blay. Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT059.

Fishing effort dynamics around the Galápagos Marine Reserve as depicted by AIS data.

The waters around the Galápagos Marine Reserve (GMR) are important fishing grounds for authorized artisanal vessels fishing within the reserve as well as for national and foreign industrial fleets operating in the wider Ecuadorian Insular Exclusive Economic Zone (IEEZ). Although it was not originally designed for fisheries management, Automatic Identification System (AIS) data provides useful, open access, near real-time and high-resolution information that allows for increased monitoring, particularly around Marine Protected Areas (MPAs) and in Areas Beyond National Jurisdiction. This study uses AIS data provided by Global Fishing Watch to assess the spatial distribution and seasonal dynamics of fishing effort by vessel flag within the GMR and the IEEZ from 2012 to 2021. Based on kernel density estimation analysis, we determinate the core-use areas (50%) and spatial extent (95%) of fishing activities by fleets (Ecuadorian and foreign), gear types and seasons (warm, from December to May; and cold, from June to November). Our results show that the Ecuadorian fleet recorded the most observed fishing hours in the study area, with 32,829 hours in the IEEZ and 20,816 hours within the GMR. The foreign flags with the most observed fishing hours in the IEEZ were Panama (3,245 hours) and Nicaragua (2,468.5 hours), while in the GMR were the 'Unknown flag' (4,991.4 hours) and Panama (133.7 hours). Vessels fished employing different fishing gears, but the waters of the GMR and IEEZ were mostly targeted by tuna purse-seiners and drifting longlines. The spatial distribution of the fishing effort exhibits marked seasonal variability, likely influenced by seasonal migrations of target species such as tunas (e.g., Thunnus albacares, T. obesus and Katsuwonus pelamis), marlins (e.g., Makaira nigricans) and sharks (e.g., Alopias pelagicus). The collection and use of this type of spatial and seasonal information is an essential step to understand the dynamics of fishing activities in national waters and improve fisheries management, particularly in less studied areas and fisheries.

Assessment of the Occupational Radiation Exposure of Anesthesia Staff in Interventional Cardiology.

This research seeks to evaluate the occupational radiation dose, quantified as the whole-body Annual Mean Effective Dose (AMED), received by anesthesia personnel in interventional cardiology. Thermoluminescent dosimetry data was collected over five years (2019-2023) for a total of 175 anesthesia staff. Technologists comprised approximately 72.4% of the participants (55% male and 45% female), while consultants accounted for 27.6% (70% male and 30% female). Statistical tests, including Independent Samples T-Test and One-Way ANOVA, compared AMED across genders, job titles, and years. The study's findings on AMED across all staff from 2019 to 2023 showed marked variability in AMED. There was a significant rise in AMED from 0.72 mSv in 2019 to 0.92 mSv in 2020, then a decline to 0.82 mSv in 2021, with further decreases to 0.67 mSv in 2022 and finally to 0.65 mSv in 2023 (p < 0.001). The average AMED over the five-year span (2019-2023) was 0.76 ± 0.4 mSv. In terms of gender, the overall AMED for males was 0.73 ± 0.36 mSv and for females 0.79 ± 0.45 mSv, showing no significant statistical difference (p = 0.272). Significant differences in exposure were observed between the technologists who experienced a higher overall AMED (0.8 ± 0.43 mSv) compared to consultants (0.63 ± 0.29 mSv, p = 0.008). Despite these variations, AMED values remained lower than the annual occupational dose limit of 20 mSv, indicating generally low radiation exposure for anesthesia staff. This study emphasizes the importance of ongoing monitoring and enhanced protective measures to safeguard the health of medical professionals working with radiation.

Screening Tools for Spondyloarthritis in Patients With Psoriasis, Uveitis, and Inflammatory Bowel Disease: A Scoping Review.

Extramusculoskeletal manifestations of spondyloarthritis (SpA) may precede the development of articular features. Patients seen in ophthalmology, dermatology, and gastroenterology clinics with uveitis, psoriasis, or inflammatory bowel disease (IBD) may have undiagnosed SpA. We set out to identify and evaluate screening tools for SpA in patients with psoriasis, uveitis, and IBD and determine factors that influence the performance of these instruments. This scoping review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, and Web of Science were searched from inception to January 2022. We identified 13 screening tools for psoriatic arthritis, 2 SpA screening tools for uveitis, and 3 SpA screening tools for IBD. All screening tools were patient-oriented questionnaires except for the Dublin Uveitis Evaluation Tool, a physician-applied algorithm. The questionnaires varied in length, scoring method, cutoff score, and spectrum of included SpA features. Average completion time was less than five minutes. Across the three patient populations, the sensitivities and specificities of these screening tools were comparable in the primary validation cohorts. Sensitivities and specificities were generally lower in secondary validation studies, with marked variability among cohorts. Our results highlight the heterogeneity and limitations of existing SpA screening tools. Although these tools show promise for use within a specific target population, none are generalizable to all patients with extramusculoskeletal manifestations at risk of SpA. Future studies should explore the utility of a generic patient-oriented SpA screening tool that can be applied to patients with psoriasis, uveitis, or IBD; is easy to use and comprehend; and captures all clinical domains of SpA.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells

Diffuse Large B-cell lymphoma (DLBCL) is a highly aggressive disease with heterogeneous outcomes and marked variability in the response to chemotherapy. DLBCL comprises two major subtypes: germinal centre B-cell-like (GCB) and activated B-cell-like (ABC). Our study highlights the extensive antitumour activity of artesunate (ART) against both major DLBCL subtypes. Transcriptome analysis suggests the potential involvement of ferroptosis in artesunate-induced cell death. Because of low glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with the accumulation of free iron (Fe2+), artesunate induces the excessive production of reactive oxygen species (ROS), ultimately leading to ferroptosis, a form of cell death driven by phospholipid peroxidation. A putative target of artesunate, metallothionein 1G (MT1G), was selected for further analysis. Subsequent studies revealed that inhibiting MT1G expression in vitro significantly impedes the ferroptosis-promoting activity of artesunate by reducing lipid peroxidation and iron accumulation. We also showed that the combination of artesunate and doxorubicin had a marked additive inhibitory effect on GCB and ABC DLBCL cells. In conclusion, artesunate induces ferroptotic death in GCB and ABC DLBCL cells by attenuating the GPX4/GSH antioxidant defence system and increasing intracellular iron levels, indicating its therapeutic potential for relapsed or refractory DLBCL.

Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

The Assessment of SF-36 Survey for Quality-of-Life Measurement after Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Systematic Review.

This study presents a systematic review of the literature on individuals' health-related quality of life (HRQoL) following radical cystectomy for muscle-invasive bladder cancer (MIBC), utilizing the Short Form-36 Health Survey (SF-36) as a primary assessment tool. The review was designed as an exhaustive literature search across three major databases including PubMed, Scopus, and Embase up to December 2023, using the PRISMA guidelines. The selection process refined 2281 identified articles down to 11 studies meeting our inclusion criteria. These studies encompassed a diverse demographic and clinical profile of 774 participants, with follow-up durations ranging from 3 to 130 months, thereby offering insights into both short-term and long-term HRQoL outcomes. The results highlighted significant alterations in individuals' HRQoL across various domains post-radical cystectomy. Notably, the Physical Functioning (PF) and Bodily Pain (BP) domains generally scored higher, indicating a moderate to high perceived physical health status. However, the Role Physical (RP) and Role Emotional (RE) domains showed variability, reflecting the challenges in daily role fulfillment and emotional adjustment post-surgery. A marked variability in physical recovery was observed, with studies reporting significant differences in PF and RP scores between patient groups. The General Health (GH) and Vitality (VT) domains sometimes reflected perceived deteriorations, whereas the Mental Health (MH) scores suggested that many patients maintained or achieved high levels of well-being post-operatively. The conclusions drawn from this systematic review underscore the profound and multi-faceted impact of radical cystectomy on HRQoL, varying widely between studies, being influenced by geographic factors, surgical methods, and the time of evaluation. The findings emphasize the necessity for holistic patient care approaches that address both physical and emotional rehabilitation, aiming to improve HRQoL outcomes.

How Long Does Contouring Really Take? Results of the Royal College of Radiologists Contouring Surveys

AimsThe success and safety of modern radiotherapy relies on accurate contouring. Understanding the time taken to complete radiotherapy contours is critical to informing workforce planning and, in the context of a workforce shortfall, advocating for investment in technology and multi-professional skills mix. We aimed to quantify the time taken to delineate target volumes for radical radiotherapy. Materials and methodsThe Royal College of Radiologists circulated two electronic surveys via email to all clinical oncology consultants in the UK. The individual case survey requested anonymous data regarding the next five patients contoured for radical radiotherapy. The second survey collected data on respondents' usual practice in radiotherapy contouring. ResultsThe median time to contour one radiotherapy case was 85 minutes (IQR = 50–131 minutes). Marked variability between and within tumour sites was evident: paediatric cancers took the most time (median = 210 minutes, IQR = 87.5 minutes), followed by head and neck and gynaecological cancers (median = 120 minutes, IQR = 71 and 72.5 minutes respectively). Breast cancer contouring required the least time (median = 43 minutes, IQR = 60 minutes). Radiotherapy technique, inclusion of nodes and 4D CT planning were associated with longer contouring times. A non-medical professional was involved in contouring in 65% of cases, but clinical oncology consultants were involved in target volume delineation in 90% of cases, and OARs in 74%. Peer review took place in 46% of cases with 56% of consultants reporting no time for peer review in their job plan. ConclusionContouring for radical radiotherapy is complex and time-consuming, and despite increasing involvement of non-medical professionals, clinical oncology consultants remain the primary practitioners. Peer review practice is variable and time is often a limiting factor. Many factors influence the time required for contouring, and departments should take these factors and the need for peer-review into account when developing job plans.

Time to full enteral feeds in hospitalised preterm and very low birth weight infants in Nigeria and Kenya.

Preterm (born < 37 weeks' gestation) and very low birthweight (VLBW; <1.5kg) infants are at the greatest risk of morbidity and mortality within the first 28 days of life. Establishing full enteral feeds is a vital aspect of their clinical care. Evidence predominantly from high income countries shows that early and rapid advancement of feeds is safe and reduces length of hospital stay and adverse health outcomes. However, there are limited data on feeding practices and factors that influence the attainment of full enteral feeds among these vulnerable infants in sub-Saharan Africa. To identify factors that influence the time to full enteral feeds, defined as tolerance of 120ml/kg/day, in hospitalised preterm and VLBW infants in neonatal units in two sub-Saharan African countries. Demographic and clinical variables were collected for newborns admitted to 7 neonatal units in Nigeria and Kenya over 6-months. Multiple linear regression analysis was conducted to identify factors independently associated with time to full enteral feeds. Of the 2280 newborn infants admitted, 484 were preterm and VLBW. Overall, 222/484 (45.8%) infants died with over half of the deaths (136/222; 61.7%) occurring before the first feed. The median (inter-quartile range) time to first feed was 46 (27, 72) hours of life and time to full enteral feeds (tFEF) was 8 (4.5,12) days with marked variation between neonatal units. Independent predictors of tFEF were time to first feed (unstandardised coefficient B 1.69; 95% CI 1.11 to 2.26; p value <0.001), gestational age (1.77; 0.72 to 2.81; <0.001), the occurrence of respiratory distress (-1.89; -3.50 to -0.79; <0.002) and necrotising enterocolitis (4.31; 1.00 to 7.62; <0.011). The use of standardised feeding guidelines may decrease variations in clinical practice, shorten tFEF and thereby improve preterm and VLBW outcomes.

Air pollution biomonitoring in an urban-industrial setting (Taranto, Italy) using Mediterranean plant species

This study presents the first report on the elemental composition of five Mediterranean plant species (Pinus pinaster, Eucalyptus camaldulensis, Nerium oleander, Olea europaea and Pittosporum heterophyllum) to trace industrial emissions in Taranto, Italy, a mixed-use industrial and urban setting. Potential metal sources include vehicular traffic, steel and cement plants, and a petrochemical refinery. Samples were collected from 29 sites covering the Tamburi-Lido Azzurro neighbourhood and the historical quarter Città Vecchia-Borgo. High concentrations of toxic metals were observed in all samples, with marked inter-species variability. Model based clustering identified two distinct groups, one dominated by pine needles with higher metal concentrations than the other group composed of the other four plant species. The contamination factor (CF) and pollution load index (PLI) indices which use background samples to standardise the level of pollution, were used to remove species effect allowing for direct site comparison. Spatial analysis of CF and PLI data identified pollution hotspots near industrial areas and major roads, with areas of little to no air pollution near green spaces. Statistical analysis of the CFs revealed the contribution of different sources to element emissions. Ni and Cr were primarily emitted from the steel plant and petrochemical refinery, while Fe and Al were associated with road traffic emissions, and geogenic elements Ca, Mg, K, and Na were linked to marine spray and Saharan dust. This study demonstrates that combining multiple plant species with pollution indices can be a cost-effective biomonitoring approach for assessing air pollution and creating a high-density spatial monitoring network.

Service Improvements and Workload Increases: Royal College of Radiologists (RCR) Re-Audit of Curative Intent Radiotherapy for Non-Small Cell Lung Cancer (NSCLC)

AimsThe Royal College of Radiologists (RCR) audit of radical radiotherapy (RR) for patients with non-small cell lung cancer (NSCLC) in 2013 concluded that there was under-treatment compared to international comparators and marked variability between cancer networks. Elderly patients were less likely to receive guideline recommended treatments. Access to technological developments was low. Various national and local interventions have since taken place. This study aims to re-assess national practice. Materials and methodsRadiotherapy departments completed one questionnaire for each patient started on RR for 4 weeks in January 2023. ResultsNinety-three percent of centres returned data on 295 patients. RR has increased 70% since 2013 but patients on average wait 20% longer to start treatment (p = 0.02). Staging investigations were often outside a desirable timeframe (79% of PET/CT scans). Advanced planning techniques are used more frequently: 4-dimensional planning increased from 33% to 90% (P < 0.001), cone beam imaging from 67% to 97% (p < 0.001) and colleague led peer review increased from 41% to 73% (P < 0.001). ConclusionThere have been significant improvements in care. There has been a considerable increase in clinical oncology workload with evidence of stress on the system that requires additional resourcing.

Linking Porphyry Cu Formation to Tectonic Change in Postsubduction Settings: A Case Study from the Giant Yulong Belt, Eastern Tibet

Abstract Porphyry deposits in magmatic arcs form coincident with changes to steady-state oceanic subduction conditions, such as changes in plate convergence rate and vector or angle of subduction. However, it remains unclear whether such processes also operated during formation of postsubduction porphyry deposits. The Yulong magmatic belt in the eastern Tibetan Plateau consists of middle to late Eocene igneous rocks (~51–35 Ma) that formed during the India-Asia collision, whereas all known porphyry deposits are associated with late Eocene rocks (43–35 Ma). A synthesis of new and published geochemical data shows marked variations from the middle to late Eocene, including increasing whole-rock La/Yb, Sr/Y, and EuN/EuN* values, as well as zircon EuN/EuN* values. These geochemical variations, together with petrographic observations, indicate a transition from plagioclase-dominated to amphibole-dominated fractionation from the middle to late Eocene. Coupled changes of magma compositions and porphyry Cu metallogeny from the middle to late Eocene coincided with, or were slightly preceded by, the onset of regional uplift and crustal thickening, triggered by the India-Asia hard collision and rapid deceleration of the India-Asia convergence rate at ca. 50 to 44 Ma. Crustal thickening may have caused prolonged magma differentiation at greater depths and accumulation of dissolved H2O, both of which contributed to amphibole-dominated fractionation and generation of hydrous melt that are prospective for porphyry Cu mineralization. Our study highlights the importance of tectonic changes in the formation of the Yulong and other postsubduction porphyry Cu belts—a scenario similar to that operated in subduction-related settings such as the Andes.

Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.

Renal cell carcinoma (RCC) is the most common type of cancer in kidney and is often diagnosed in advanced stages. Until now, there is no reliable biomarker to assess tumor prognosis during histopathological diagnosis. The Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression has been suggested as prognostic indicator for RCC, however, its protein profile needs to be clarified. This study investigated the MTHFD2 expression in different RCC cohorts, associating it with tumor characteristics and prognostic factors. Gene expression comparisons between non-neoplastic (NN) and tumor samples, as well as patients' survival analysis, were assessed using KM-Plotter tool. MTHFD2 protein pattern was evaluated in 117 RCC by immunohistochemistry and associations with prognosis, clinical and pathological data were investigated. The tumors exhibited higher MTHFD2 transcript levels than NN, being even higher in the metastatic group. Opposite gene expression patterns were found among clear cell renal cell carcinoma (ccRCC) and pappilary renal cell carcinoma (pRCC) subtypes, showing higher and lower expressions compared to NN samples respectively. Overexpression was associated with shorter overall survival for ccRCC and pRCC subtypes, and shorter recurrence-free survival for pRCC. The immunolabeling profile varied according to tumor subtypes, with lower intensity and expression scores in ccRCC compared to pRCC and to chromophobe renal cell carcinoma (chRCC). MTHFD2 protein expression was associated with larger tumors and higher Fuhrman grades. Although prognostic value of protein immunostaining was not confirmed, patients with higher MTHFD2 tended to have lower survival rates in the pRCC group. The results highlight MTHFD2 different patterns according to RCC histological subtypes, revealing marked variations at both the genetic and protein levels. The mRNA indicated tumor prognosis, and greater expression in the tumor samples. Although MTHFD2 immunolabeling suggests tumor aggressiveness, it needs to be validated in other cohorts as potential prognostic factor.

Types and concentrations of tire wear particles (TWPs) in road dust generated in slow lanes

Drivers commonly navigate their vehicles at moderate speeds in proximity to traffic lights. In this study, road dust samples were collected in the vicinity of traffic lights, as well as at a taxi stand (TS) situated between traffic lights, with considerations given to both forward direction (FD) and backward direction (BD). The characterization of tire wear particles (TWPs) in the road dust was meticulously conducted based on particle size. Notably, tire-road wear particles (TRWPs) were conspicuously absent in samples surpassing 500 μm. Furthermore, TRWPs comprised less than 1% of identified particles in the road dust samples of 212–500 μm, with their origin traceable to heavy vehicles rather than passenger cars. The abundance of TRWPs from heavy vehicles exhibited marked variations, with heightened prevalence in the TS and BD samples as opposed to the FD sample. For the samples smaller than 212 μm, the composition of natural rubber (NR) in TWPs demonstrated a diminishing trend with escalating particle size. Conversely, the composition of styrene-butadiene rubber (SBR) exhibited an upward trajectory independent of the sampling site. The NR composition ratio in TWPs followed the order: TS (17–55%) > FD (17–47%) > BD (13–36%), while the SBR composition ratio exhibited the sequence: BD (62–86%) > FD (48–79%) > TS (24–70%). The TWP concentrations in road dust obtained from the TS (0.35–0.82%) were discernibly lower than those in the FD (0.54–1.77%) and BD (0.61–1.29%) samples. Specifically, the average TWP concentrations in road dust samples, falling within the size range of 20–212 μm, were 0.45%, 1.06%, and 0.91% for the TS, FD, and BD samples, respectively. These concentrations were lower than the corresponding values observed in samples collected from a bus stop.

Validation of the Mayo Imaging Classification System for Predicting Kidney Outcomes in ADPKD.

The Mayo Imaging Classification was developed to predict the rate of disease progression in patients with autosomal dominant polycystic kidney disease. This study aimed to validate its ability to predict kidney outcomes in a large multicenter autosomal dominant polycystic kidney disease cohort. Included were patients with ≥1 height-adjusted total kidney volume (HtTKV) measurement and ≥3 eGFR values during ≥1-year follow-up. Mayo HtTKV class stability, kidney growth rates, and eGFR decline rates were calculated. The observed eGFR decline was compared with predictions from the Mayo Clinic future eGFR equation. The future eGFR prediction equation was also tested for nonlinear eGFR decline. Kaplan-Meier survival analysis and Cox regression models were used to assess time to kidney failure using Mayo HtTKV class as a predictor variable. We analyzed 618 patients with a mean age of 47±11 years and mean eGFR of 64±25 ml/min per 1.73 m 2 at baseline. Most patients (82%) remained in their baseline Mayo HtTKV class. During a mean follow-up of 5.1±2.2 years, the mean total kidney volume growth rates and eGFR decline were 5.33%±3.90%/yr and -3.31±2.53 ml/min per 1.73 m 2 per year, respectively. Kidney growth and eGFR decline showed considerable overlap between the classes. The observed annual eGFR decline was not significantly different from the predicted values for classes 1A, 1B, 1C, and 1D but significantly slower for class 1E. This was also observed in patients aged younger than 40 years and older than 60 years and those with PKD2 mutations. A polynomial model allowing nonlinear eGFR decline provided more accurate slope predictions. Ninety-seven patients (16%) developed kidney failure during follow-up. The classification predicted the development of kidney failure, although the sensitivity and positive predictive values were limited. The Mayo Imaging Classification demonstrated acceptable stability and generally predicted kidney failure and eGFR decline rate. However, there was marked interindividual variability in the rate of disease progression within each class.

INSL3 Variation in Dogs Following Suppression and Recovery of the HPG Axis.

Insulin-like peptide 3 (INSL3) is a constitutive product of mature, adult-type Leydig cells of the testes and consequently in most mammals is an ideal biomarker with which to monitor pubertal development. A new heterologous time-resolved fluorescence immunoassay was developed and validated to measure circulating INSL3 in the blood of adult male dogs. Compared to other species, INSL3 concentration is low with marked variation between individuals, which appears to be independent of breed, age, or weight. A model system was then used in which a cohort of beagle dogs was subject to a GnRH-agonist implant to suppress the HPG axis and spermatogenesis, followed by implant removal and recovery. Unlike testosterone, INSL3 levels were not fully suppressed in all animals by the GnRH agonist, nor was the recovery of Leydig cell function following implant removal uniform or complete, even after several weeks. In dogs, and dissimilar from other species (including humans), Leydig-cell INSL3 appears to be quite variable between individual dogs and only weakly connected to the physiology of the HPG axis after its suppression by a GnRH-agonist implant and recovery. Consequently, INSL3 may be less useful in this species for the assessment of testis function.

Diagnosis-Specific Thresholds of the Minimal Clinically Important Difference and Patient Acceptable Symptom State for KOOS After Total Knee Arthroplasty.

This article was updated on May 1, 2024 because of a previous error, which was discovered after the preliminary version of the article was posted online. The byline that had read "Ahmed K. Emara, MD 1 *, Ignacio Pasqualini, MD 1 *, Alison K. Klika, MS 1 , Melissa N. Orr, BS 1 , Pedro J. Rullán, MD 1 , Nicolas S. Piuzzi, MD 1 , and the Cleveland Clinic Arthroplasty Group†" now reads "Ahmed K. Emara, MD 1 *, Ignacio Pasqualini, MD 1 *, Yuxuan Jin, MS 1 , Alison K. Klika, MS 1 , Melissa N. Orr, BS 1 , Pedro J. Rullán, MD 1 , Nicolas S. Piuzzi, MD 1 , and the Cleveland Clinic Arthroplasty Group†". Literature-reported minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) thresholds for patient-reported outcome measures demonstrate marked variability. The purpose of this study was to determine the minimal detectable change (MDC), MCID, and PASS thresholds for the Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subdomain, Physical Function Short Form (PS), and Joint Replacement (JR) among patients with osteoarthritis (OA) who underwent primary total knee arthroplasty (TKA). A prospective cohort of 6,778 patients who underwent primary TKA was analyzed. Overall, 1-year follow-up was completed by 5,316 patients for the KOOS Pain, 5,018 patients for the KOOS PS, and 4,033 patients for the KOOS JR. A total of 5,186 patients had an OA diagnosis; this group had an average age of 67.0 years and was 59.9% female and 80.4% White. Diagnosis-specific MDCs and MCIDs were estimated with use of a distribution-based approach. PASS values were estimated with use of an anchor-based approach, which corresponded to a response to a satisfaction question at 1 year postoperatively. The MCID thresholds for the OA group were 7.9 for the KOOS Pain, 8.0 for the KOOS PS, and 6.7 for the KOOS JR. A high percentage of patients achieved the MCID threshold for each outcome measure (KOOS Pain, 95%; KOOS PS, 88%; and KOOS JR, 94%). The MDC 80% to 95% confidence intervals ranged from 9.1 to 14.0 for the KOOS Pain, 9.2 to 14.1 for the KOOS PS, and 7.7 to 11.8 for the KOOS JR. The PASS thresholds for the OA group were 77.7 for the KOOS Pain (achieved by 73% of patients), 70.3 for the KOOS PS (achieved by 68% of patients), and 70.7 for the KOOS JR (achieved by 70% of patients). The present study provided useful MCID, MDC, and PASS thresholds for the KOOS Pain, PS, and JR for patients with OA. The diagnosis-specific metrics established herein can serve as benchmarks for clinically meaningful postoperative improvement. Future research and quality assessments should utilize these OA-specific thresholds when evaluating outcomes following TKA. Doing so will enable more accurate determinations of operative success and improvements in patient-centered care. Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Revealing spatio-temporal variations of soil CO2 flux at Mt. Etna volcano

Over the past two decades, significant advances in the geochemical monitoring of volcanoes have shown how crucial the observation of specific geochemical tracers is for understanding and evaluating eruptive processes. Among these, the monitoring of soil CO2 flux is one of the most important and widely employed geochemical parameters used in volcanic monitoring. At Mt. Etna volcano (Italy) long-term soil CO2 time series (2011–2019) are available from a network of 14 monitoring sites located around the volcano. Although variations in the exhalative regime of soil CO2 flux are recognized as possible proxies for potential emergent eruptive activity, little has yet been explored regarding the significance of the spatial variation of soil CO2 over time. In this paper, we look for possible dependence of CO2 flux on the altitude of the monitoring sites, their distances from the main craters, and their azimuthal positions on the volcano flanks. While for the first two elements there seems to be no evidence of dependence, we found evidence of long-term azimuthal variations in the soil CO2 flux that could depend on the structure of the volcano. In particular, the sites in south-eastern flank behave somehow differently from the ones located in other flanks. At yearly time scale, marked variations affect the CO2 flux at various sites. Such variations can be ascribable to volcano dynamics during the observation period characterized by a sequence of effusive and strombolian activities. Variations within a single eruptive episode also emerge investigating the 2018–19 flank eruption with bi-monthly windows.