Ocular manifestations of ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. METHODS: This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. RESULTS: Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). CONCLUSION: Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

Remoteness does not enhance coral reef resilience.

Remote coral reefs are thought to be more resilient to climate change due to their isolation from local stressors like fishing and pollution. We tested this hypothesis by measuring the relationship between local human influence and coral community resilience. Surprisingly, we found no relationship between human influence and resistance to disturbance and some evidence that areas with greater human development may recover from disturbance faster than their more isolated counterparts. Our results suggest remote coral reefs are imperiled by climate change, like so many other geographically isolated ecosystems, and are unlikely to serve as effective biodiversity arks. Only drastic and rapid cuts in greenhouse gas emissions will ensure coral survival. Our results also indicate that some reefs close to large human populations were relatively resilient. Focusing research and conservation resources on these more accessible locations has the potential to provide new insights and maximize conservation outcomes.

Eyelid-Cheek Junction Soft-Tissue Perineurioma: Case Report and Controversies.

Perineurioma is a rare soft-tissue tumor with characteristic histologic and immunohistochemical features. The diagnosis; however, can be met with certain challenges. A 71-year-old woman presented with an enlarging painless mass in the right lower eyelid-cheek junction. The lesion presented as a raised overhanging trunk-shaped mass. An excisional biopsy and local reconstruction were performed. The overall morphology and immunohistochemical findings were most supportive of a cellular soft-tissue perineurioma, with differential diagnoses including dermatofibroma. To the authors' knowledge, this is the first histopathologically reported case of a superficially occurring soft-tissue perineurioma in the eyelid-cheek junction. The authors discuss the presentation, relevant literature, and controversies associated with this diagnosis.

Anisotropic Material Characterization of Human Cervix Tissue Based on Indentation and Inverse Finite Element Analysis.

The cervix is essential to a healthy pregnancy as it must bear the increasing load caused by the growing fetus. Preterm birth is suspected to be caused by the premature softening and mechanical failure of the cervix. The objective of this paper is to measure the anisotropic mechanical properties of human cervical tissue using indentation and video extensometry. The human cervix is a layered structure, where its thick stromal core contains preferentially aligned collagen fibers embedded in a soft ground substance. The fiber composite nature of the tissue provides resistance to the complex three-dimensional loading environment of pregnancy. In this work, we detail an indentation mechanical test to obtain the force and deformation response during loading which closely matches in vivo conditions. We postulate a constitutive material model to describe the equilibrium material behavior to ramp-hold indentation, and we use an inverse finite element method based on genetic algorithm (GA) optimization to determine best-fit material parameters. We report the material properties of human cervical slices taken at different anatomical locations from women of different obstetric backgrounds. In this cohort of patients, the anterior internal os (the area where the cervix meets the uterus) of the cervix is stiffer than the anterior external os (the area closest to the vagina). The anatomic anterior and posterior quadrants of cervical tissue are more anisotropic than the left and right quadrants. There is no significant difference in material properties between samples of different parities (number of pregnancies reaching viable gestation age).

Trends in Surgeon Burnout in the US and Canada: Systematic Review and Meta-Regression Analysis.

BACKGROUND: Burnout among surgeons is increasingly recognized as a crisis. However, little is known about changes in burnout prevalence over time. We evaluated temporal trends in burnout among surgeons and surgical trainees of all specialties in the US and Canada. STUDY DESIGN: We systematically reviewed MEDLINE, Embase, and PsycINFO for studies assessing surgeon burnout from January 1981 through September 2021. Changes in dichotomized Maslach Burnout Inventory scores and mean subscale scores over time were assessed using multivariable random-effects meta-regression. RESULTS: Of 3,575 studies screened, 103 studies representing 63,587 individuals met inclusion criteria. Publication dates ranged from 1996 through 2021. Overall, 41% of surgeons met criteria for burnout. Trainees were more affected than attending surgeons (46% vs 36%, p = 0.012). Prevalence remained stable over the study period (-4.8% per decade, 95% CI -13.2% to 3.5%). Mean scores for emotional exhaustion declined and depersonalization declined over time (-4.1 per decade, 95% CI -7.4 to -0.8 and -1.4 per decade, 95% CI -3.0 to -0.2). Personal accomplishment scores remained unchanged. A high degree of heterogeneity was noted in all analyses despite adjustment for training status, specialty, practice setting, and study quality. CONCLUSIONS: Contrary to popular perceptions, we found no evidence of rising surgeon burnout in published literature. Rather, emotional exhaustion and depersonalization may be decreasing. Nonetheless, burnout levels remain unacceptably high, indicating a need for meaningful interventions across training levels and specialties. Future research should be deliberately designed to support longitudinal integration through prospective meta-regression to facilitate monitoring of trends in surgeon burnout.

Glimmers of hope in large carnivore recoveries.

In the face of an accelerating extinction crisis, scientists must draw insights from successful conservation interventions to uncover promising strategies for reversing broader declines. Here, we synthesize cases of recovery from a list of 362 species of large carnivores, ecologically important species that function as terminal consumers in many ecological contexts. Large carnivores represent critical conservation targets that have experienced historical declines as a result of direct exploitation and habitat loss. We examine taxonomic and geographic variation in current extinction risk and recovery indices, identify conservation actions associated with positive outcomes, and reveal anthropogenic threats linked to ongoing declines. We find that fewer than 10% of global large carnivore populations are increasing, and only 12 species (3.3%) have experienced genuine improvement in extinction risk, mostly limited to recoveries among marine mammals. Recovery is associated with species legislation enacted at national and international levels, and with management of direct exploitation. Conversely, ongoing declines are robustly linked to threats that include habitat modification and human conflict. Applying lessons from cases of large carnivore recovery will be crucial for restoring intact ecosystems and maintaining the services they provide to humans.

Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: a randomized, single-blind, two-period crossover study in healthy subjects.

BACKGROUND AND OBJECTIVE: Nilotinib (Tasigna®), a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukaemia in the chronic phase (CML-CP) and the accelerated phase (CML-AP) in patients resistant or intolerant to prior therapy, including imatinib. Nilotinib has shown competitive inhibition of cytochrome P450 enzyme (CYP) 2C9 in vitro, but its effect on CYP2C9 activity in humans is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin, a sensitive CYP2C9 substrate, in healthy subjects. METHODS: Twenty-four subjects (six female, 18 male, aged 21-65 years) were enrolled to receive a single oral dose of warfarin 25 mg with either a single oral dose of nilotinib 800 mg or matching placebo (all administered 30 minutes after consumption of a high-fat meal) in a crossover design. Serial blood samples were collected post-dose for determining serum concentrations of nilotinib and plasma concentrations of S- and R-warfarin. Prothrombin time (PT) and international normalized ratio (INR) values were determined as pharmacodynamic measures of warfarin activity. CYP2C9 genotyping was performed in all subjects using TaqMan® assay. RESULTS: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EMs) and eight as intermediate metabolizers (IMs). There were no CYP2C9 poor metabolizers. Pharmacokinetic parameters of S- and R-warfarin were similar between the two treatments (warfarin + nilotinib vs warfarin alone) in both the EM and the IM groups. The geometric mean ratios (90% CIs) for the maximum concentration in plasma (C(max)) and area under the concentration-time curve from time zero to infinity (AUC(∞)) of S-warfarin in plasma in all subjects were 0.98 (0.95, 1.02) and 1.03 (0.99, 1.07), respectively, and for R-warfarin 1.00 (0.96, 1.04) and 1.02 (0.99, 1.04), respectively. Mean ratios for the maximum observed value and AUC from time zero to the last sampling time for PT were 1.00 (0.96, 1.04) and 1.00 (0.98, 1.02), respectively, and for the maximum observed value for INR and the AUC from time zero to the last sampling time for INR were 1.00 (0.97, 1.03) and 1.00 (0.99, 1.01), respectively. Mean ± SD serum nilotinib C(max) was 1872 ± 560 ng/mL, which is comparable to steady-state C(max) in CML and gastrointestinal stromal tumour patients receiving twice-daily 400 mg doses. Adverse events observed following either treatment were generally consistent with the known safety profiles of both drugs, and no new safety issues were observed. CONCLUSION: The study results demonstrate that nilotinib has no effect on single-dose warfarin pharmacokinetics and pharmacodynamics. This implies that nilotinib is unlikely to inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin and nilotinib may be used concurrently as needed.

The Relationship Between Entrepreneurial Intention and Action: The Effects of Fear of Failure and Role Model.

The purpose of the study was to examine the moderating effect of business role model and fear of failure on the relationship between entrepreneurial intention and behavior. The participants were sampled from 1865 college students who graduated from universities in China from 2012 to 2018. The experimental instrument was comprised of four scales concerning entrepreneurial intention, entrepreneurial behavior, fear of failure, and business role model. The data were analyzed using hierarchical regression. The results showed that: (1) Entrepreneurial intention was positively influenced the entrepreneurial behavior; (2) Fear of failure weakened the relationship between entrepreneurial intention and action; (3) The moderating effect of business role model on entrepreneurial intention and behavior was confirmed. We concluded that entrepreneurial intention was positively related to the entrepreneurial behavior, fear of failure hindered college students from taking entrepreneurial behavior, and business role model will enhance their entrepreneurial intention. The paper suggest that some measures should be taken to overcome college students' fear of failure, and to improve the education system of entrepreneurship in order to cultivate talents with creativity.

Long non-coding RNA LINC00641 suppresses non-small-cell lung cancer by sponging miR-424-5p to upregulate PLSCR4.

Non-small cell lung cancer (NSCLC) , as the most prevalent type of lung carcinoma with high severity, is of urgent necessity to be investigated for novel therapeutic strategies. Long non-coding RNAs (lncRNAs) are notable for their participation in cancer regulation, and lncRNA long intergenic non-protein coding RNA 641 (LINC00641) has been found to have an inhibitory influence on bladder cancer, but its role in NSCLC has not yet been studied. In this research, we launched an investigation into the biological functions and the underlying molecular mechanisms of LINC00641 in NSCLC. At first, downregulation of LINC00641 was identified in NSCLC cells. Functionally, LINC00641 suppressed cell proliferation and induced cell apoptosis in NSCLC, indicating that LINC00641 exerted tumor-suppressive role in NSCLC. Through mechanism investigation, we determined that LINC00641 acted as a competing endogenous RNA (ceRNA) in NSCLC by sponging miR-424-5p to upregulate phospholipid scramblase (PLSCR4) expression. Further rescue assays indicated that miR-424-5p and PLSCR4 could reverse LINC00641-mediated cellular processes. Taken together, it is demonstrated in our study that LINC00641 can function as a tumor suppressor in NSCLC via a ceRNA network.

Farmers' Work-Life Quality and Entrepreneurship Will in China.

New-generation farmers have become a vital force for entrepreneurship in their hometowns. To better promote farmers to start businesses, it's important to know about their quality of work life. Based on a survey of the quality of work life and entrepreneurship will of farmers from three cities and eight counties in Shandong province of China, this paper analyzed the effects of farmers' quality of work life on their entrepreneurship will in their hometowns using a Logistic regression model. Our findings show that farmers have a relatively low cognition level of their quality of work life, and their interpersonal relationship, work characteristics, material security, and family demands have significant effects on their entrepreneurship will. According to the findings, this paper proposed some suggestions for promoting farmers' entrepreneurship will in their hometowns from the perspectives of organizational management, extrinsic entrepreneurship stimulus, and internal demand.

Differential Outcomes and Biologic Markers of Radiation-Associated vs. Sporadic Osteosarcoma: A Single-Institution Experience.

Background: Radiation-associated osteosarcoma (RAO) is a rare, life-threatening complication from radiation. Many physicians presume RAO has a worse prognosis than sporadic osteosarcoma (SO), although limited objective data exist. We conducted a retrospective study comparing these entities. Methods: We identified adults treated at our institution with osteosarcoma (1990-2016) and categorized tumors as SO or RAO based on location within a prior radiation field. We extracted data on demographics, treatment and primary malignancy and examined available tumor samples for MTA-1 and ezrin using immunohistochemistry (IHC). Results: Of 159 identified patients, 28 had RAO, diagnosed at a median interval from radiation of 11.5 years (1.5-28 years). Median follow-up was 2.8 years (0.1-19.6 years). Median progression free survival (PFS) and overall survival (OS) were not significantly different in the small population of patients with metastases, SO (n = 20) vs. RAO (n = 6): PFS 10.3 months vs. 4.8 months (p = 0.45) and OS 15.6 months vs. 6.1 months (p = 0.96), respectively. For the larger group with localized disease, median relapse-free survival (RFS) and OS were significantly different, NR vs. 12.2 months (p < 0.001) and NR vs. 27.6 months (p = 0.001) in SO (n = 111) vs. RAO (n = 22), respectively. On IHC, there were significant differences in distribution of high, intermediate or low MTA-1 (p = 0.015) and ezrin (p = 0.002) between RAO and SO tumors. Conclusions: Patients with metastases at diagnosis fared poorly irrespective of prior radiation. RAO patients with localized disease had worse outcomes without detectable differences in therapy rendered or treatment effect in resected specimens. Higher expression of MTA-1 in RAO patients may suggest an underlying difference in tumor biology to explain differences in outcomes.

Ophthalmology referrals from optometry: a comparative study (the R.O.C.S study).

OBJECTIVE: To characterize emergency optometrist referrals triaged at a tertiary ophthalmology care centre by physical examination findings and provisional diagnosis accuracy. DESIGN: Prospective case review. PARTICIPANTS: Consecutive patients referred to a tertiary eye care clinic for an after-hours ocular consult. METHODS: Variables extracted from the patient charts included date of referral, age, sex, eye(s) under examination, referral visual acuity (VA), referral intraocular pressure (IOP), the referring optometrist's provisional diagnosis, VA at the time of the ophthalmologist consultation, IOP at the time of the ophthalmologist consultation, number of days between referral and ophthalmic consultation, and the ophthalmologist's diagnosis. Optometrist VA measures were correlated against ophthalmologist measures for left eye, right eye, diseased eye, and nondiseased eye. The independent t test was used to compare IOP measures between clinicians, and the absolute frequency of agreement between localization of eye pathology was reported. RESULTS: After categorizing disease by anatomic location, absolute agreement between optometrist provisional diagnosis and ophthalmologist diagnosis was 60.0%. Strong correlations were found between optometrist and ophthalmologist VA measurements. IOP measurements were reported less frequently by optometrists. In cases in which referral IOP was documented, no significant difference was observed between clinician measures. CONCLUSIONS: VA and IOP measurements by optometrists are reliable, although IOP measurements were included less frequently in optometrist referrals. Optometrist referrals correctly localized eye pathology in 60.0% of cases. Two cases of retinal tear and 2 cases of retinal detachment, for which a precise reason for referral is ideal, were referred for other reasons.

Patient satisfaction with wait times at an emergency ophthalmology on-call service.

OBJECTIVE: To assess patient satisfaction with emergency ophthalmology care and determine the effect provision of anticipated appointment wait time has on scores. DESIGN: Single-centre, randomized control trial. PARTICIPANTS: Fifty patients triaged at the Hamilton Regional Eye Institute (HREI) from November 2015 to July 2016. METHODS: Fifty patients triaged for next-day appointments at the HREI were randomly assigned to receive standard-of-care preappointment information or standard-of-care information in addition to an estimated appointment wait time. Patient satisfaction with care was assessed postvisit using the modified Judgements of Hospital Quality Questionnaire (JHQQ). In determining how informing patients of typical wait times influenced satisfaction, the Mann-Whitney U test was performed. As secondary study outcomes, we sought to determine patient satisfaction with the intervention material using the Fisher exact test and the effect that wait time, age, sex, education, mobility, and number of health care providers seen had on satisfaction scores using logistic regression analysis. RESULTS: The median JHQQ response was "very good" (4/5) and between "very good" and "excellent" (4.5/5) in the intervention and control arms, respectively. There was no difference in patient satisfaction between the cohorts (Mann-Whitney U = 297.00, p = 0.964). Logistic regression analysis demonstrated that wait times influenced patient satisfaction (OR = 0.919, 95% CI 0.864-0.978, p = 0.008). Of the intervention arm patients, 92.0% (N = 23) found the preappointment information useful, whereas only 12.5% (N = 3) of the control cohort patients noted the same (p < 0.001). CONCLUSION: Provision of anticipated wait time information to patients in an emergency on-call ophthalmology clinic did not influence satisfaction with care as captured by the JHQQ.

Effect of ultrasound pretreatment on rennet-induced coagulation properties of goat's milk.

The effects of ultrasound (US) pretreatment on goat milk before rennet-induced coagulation were studied in order to improve the milk coagulation properties. Skimmed goat milk was subjected to US at 800 W for different times (0-20 min) and various parameters were evaluated. The particle sizes in US pretreated goat milk under the transmission electron microscopy were smaller than in untreated samples. For US pretreated samples, the degree of whey protein denaturation, contents of soluble calcium and phosphorus increased by 9.57%, 16.90% and 13.68%, respectively. The gel firmness, coagulum strength, final storage modulus, cohesiveness, water holding capacity and cross-linking of gels demonstrated marked increase. The turbiscan stability index (TSI) also confirmed the improvement of goat milk coagulation properties with increasing duration of US pretreatment, whereas the gelation time was prolonged.

Expression of αB-crystallin and its potential anti-apoptotic role in oral verrucous carcinoma.

αB-crystallin, a member of the small heat shock protein family, acts as a molecular chaperone. αB-crystallin has been found to be overexpressed in a number of cancer tissues, including head and neck cancers. Overexpression of αB-crystallin in cancer tissue may be related to its anti-apoptotic properties; however, its mechanism of action remains unclear. The aim of this study was to investigate the anti-apoptotic role of αB-crystallin in oral verrucous carcinoma (OVC). Since oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity, we selected OSCC as a control group. Immunohistochemical staining was used to evaluate the expression levels. The results showed that the expression of αB-crystallin was detected in OVC, OSCC and normal oral mucosa (NM). The expression in OVC was higher compared to that of NM, but lower compared to OSCC, indicating that OVC was less aggressive than OSCC with respect to malignancy potential. Furthermore, we found that in OVC, the increased expression of αB-crystallin coincided with the decreased expression of activated caspase-3. The results indicated that αB-crystallin may play an anti-apoptotic role via inhibition of the activation of caspase-3 in OVC.

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer.

PURPOSE: Panobinostat is a novel oral pan-deacetylase inhibitor with promising anti-cancer activity. The study aimed to determine the influence of food on the oral bioavailability of panobinostat. METHODS: This multicenter study consisted of a randomized, three-way crossover, food-effect study period (cycle 1) followed by single-agent panobinostat continual treatment phase in patients with advanced cancer. Patients received panobinostat 20 mg twice weekly, and panobinostat pharmacokinetics was investigated on days 1, 8, and 15 with a randomly assigned sequence of three prandial states (fasting, high-fat, and normal breakfast). RESULTS: Thirty-six patients were assessed for the food effect on pharmacokinetics and safety in cycle 1, after which 29 patients continued treatment, receiving single-agent panobinostat. Safety and antitumor activity were assessed during the extension period. Panobinostat systemic exposure was marginally reduced (14-16%) following food [geometric mean ratio (GMR) of the AUC(0-∞)/high-fat breakfast/fasting, 0.84 (90% confidence interval {CI}, 0.74-0.96); normal breakfast/fasting, 0.86 (90% CI, 0.75-1.00)], and interpatient variability (coefficient of variation, 59%) remained essentially unchanged with or without food. Panobinostat C (max) was reduced by 44% (high-fat) and 36% (normal) with median T (max) prolonged by 1-1.5 h following food. Panobinostat was well tolerated, with thrombocytopenia, fatigue, nausea, and vomiting as common adverse events, and demonstrated antitumor activity with one patient with a partial response and six patients with stable disease as best response. CONCLUSIONS: Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor.

PURPOSE: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. METHODS: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. RESULTS: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. CONCLUSIONS: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary.