Background: Oral ruxolitinib is FDA-approved for the treatment of acute and chronic graft-versus-host disease (cGvHD), and ruxolitinib cream has been approved for the treatment of atopic dermatitis and vitiligo. Topical corticosteroids are the mainstay of skin-directed therapy for cutaneous cGvHD but are associated with significant side effects, and may incompletely treat cutaneous cGvHD thereby prompting the use of systemic therapies. Methods: We conducted a single-center, phase 2 prospective, randomized, double-blind trial evaluating the efficacy and safety of ruxolitinib 1.5% cream in patients ≥12 years old with cutaneous nonsclerotic (lichen planus-like, poikilodermatous) and superficially sclerotic (lichen sclerosus, morphea-like) cGvHD with ≥2% of body surface area (BSA) affected. Patients were eligible if systemic therapy, when applicable, was stable for ≥4 weeks and concurrent topical therapy (including phototherapy) was not used. Patients were randomly assigned (1:1) to receive ruxolitinib 1.5% cream to the left or right side of face/body with placebo vehicle cream to contralateral side twice daily for 28 days. The primary endpoint was efficacy at Day 28, as measured by BSA of the GvHD rash on the side of face/body treated with ruxolitinib cream vs contralateral side treated with vehicle. Secondary endpoints included Physician's Global Assessment (PGA), and Composite Assessment of Index Lesion Severity (CAILS) at Days 14 and 28. For the exploratory endpoint, skin samples were noninvasively collected using the SmartSticker™ and RNA-sequencing was used to investigate gene expression differences between 1) ruxolitinib and vehicle treatments, and 2) responders (PGA 0-4) and nonresponders (PGA 5-6) at Day 28. Results: Between 6/28/19 - 9/08/22, 24 patients (median age 47.5 years (range 18-78 years; 11 [46%] male) underwent randomization; Day 14 and Day 28 assessments were completed by 22 and 23 patients, respectively. Most patients had a history of acute leukemia (N=16 [67%]) or non-Hodgkin lymphoma (N=4 [16%]). Median time from transplant to enrollment was 455 days (IQR 357-1020), and from cGvHD onset to enrollment 132 days (IQR 19-384). Most patients had cutaneous nonsclerotic cGvHD (N=21, 87%) with lichen planus-like (N=11), papulosquamous (N=7), and maculopapular rash/erythema features (N=3). Three patients had lichen sclerosus-like cGvHD. Patients were heavily pretreated and had a median of 2 prior systemic treatments. Most patients had failed ≥2 topical therapies: 88% failed topical steroids, 42% topical calcineurin inhibitors, and 29% phototherapy. BSA of cGvHD on the treatment side compared to the vehicle side was significantly improved from Day 1 (14.4 vs 14.5% on treatment/vehicle; p=0.12) to Day 14 (7.7 vs 10.4; p=0.002) to Day 28 (6.2 vs 10.4; p=0.003), respectively. Both secondary endpoints were significantly improved with treatment starting on Day 14 and continuing into Day 28 (PGA D1: 5 treatment vs 5 vehicle; D14: 2.7 vs 3.8, p=0.002; D28: 1.9 vs 3.7, p=0.0004. CAILS D1: 15 treatment vs 15.3 vehicle, p=0.12; D14: 6.9 vs 11, p=0.0009; D28: 5.8 vs 10.6, p=0.004). Seven patients experienced 16 treatment-emergent AEs, the most commonly observed was orofacial dermatitis attributed to protective mask use (n=2). One grade 1 headache was possibly attributed to therapy. RNA sequencing from 22 ruxolitinib- and vehicle- treated patient pairs at Day 28 identified 324 differentially expressed genes (DEGs, fold change (FC)> 2; adjp=0.05) with primary pathway differences in translocation of ZAP-70 to immunological synapse, PD-1 signaling, and Th17 cell differentiation ( Figure 1). Additionally, 288 DEGs (FC>2; p=0.05) were identified between responders (n = 17) and nonresponders (n = 5) at Day 28 ( Figure 2) with pathway differences in IL-12 signaling. Responders had upregulated expression of LCP1 and SOD2, while nonresponders had upregulation in CA1 and SNRPA1. Conclusions: This is the first study to characterize the effect of topical JAK1/2 blockade on cutaneous cGVHD. Ruxolitinib 1.5% cream was safe and effective compared to placebo in treating cutaneous nonsclerotic and superficially sclerotic GvHD. Responders to ruxolitinib cream had genomic signature differences in IL-12 signaling from nonresponders. These encouraging results support a larger clinical trial to further evaluate the efficacy and safety of topical ruxolitinib in patients with cutaneous cGvHD.

Many domains now leverage the benefits of Machine Learning (ML), which promises solutions that can autonomously learn to solve complex tasks by training over some data. Unfortunately, in cyberthreat detection, high-quality data is hard to come by. Moreover, for some specific applications of ML, such data must be labeled by human operators. Many works "assume" that labeling is tough/challenging/costly in cyberthreat detection, thereby proposing solutions to address such a hurdle. Yet, we found no work that specifically addresses the process of labeling from the viewpoint of ML security practitioners. This is a problem: to this date, it is still mostly unknown how labeling is done in practice---thereby preventing one from pinpointing "what is needed" in the real world. In this paper, we take the first step to build a bridge between academic research and security practice in the context of data labeling. First, we reach out to five subject matter experts and carry out open interviews to identify pain points in their labeling routines. Then, by using our findings as a scaffold, we conduct a user study with 13 practitioners from large security companies and ask detailed questions on subjects such as active learning, costs of labeling, and revision of labels. Finally, we perform proof-of-concept experiments addressing labeling-related aspects in cyberthreat detection that are sometimes overlooked in research. Altogether, our contributions and recommendations serve as a stepping stone to future endeavors aimed at improving the quality and robustness of ML-driven security systems. We release our resources.

This paper emphasizes the significance of waqfs in the development of Mostar. Thanks to that institution, Mostar has become one of the largest cultural and economic centers in Eyalet of Bosnia. Special attention was given to the waqf of Babussaade Agha, Ahmed Agha. His waqfiye, which is an integral part of this work, contains information about new buildings, money and other things endowed by the aforementioned Ahmed Agha. It also includes changes to some of his previous waqfiya’s stipulations. His endowments in Istanbul and Mostar are mentioned in the waqfiye. Because little is known about his waqf in Mostar, this work aims to draw attention to the waqfiya’s text. The content of Ahmed Aga’s waqfiye demonstrates the importance of his waqf for cultural life in Mostar and his role in enlightening local imams and students.

As part of the research, the population of the eight-toothed spruce bark beetle in different types of forests in five protected areas in Bosnia and Herzegovina was analyzed. The study focused on the protected areas of Sarajevo Canton, specifically the secondary forests of fir and spruce, as well as the mixed forests of beech and fir (containing spruce). Pheromone traps were used as the research sample, and they were placed within PA Bijambara, PA Trebević, and PA Skakavac. The objective was to investigate the influence of forest type and climatological factors on the number of captured Ips typographus bark beetles from 2018 to 2021. The average number of captured I. typographus bark beetles during that period ranged from 491.39 to 901.68 individuals in secondary fir and spruce forests, and from 201.88 to 701.54 individuals in beech and fir forests (including spruce).

Introduction: Teachers in Bosnia and Herzegovina had insufficient skills in educational technology but had to lead the introduction of online teaching and adapt all aspects of the educational process to the online environment, which placed a great burden on them. The main objective of this research was to identify the challenges faced by teachers during the lockdown period. The sudden shift to online teaching, lack of preparation, and social isolation resulted in significant changes in job demands, perceived control, and social support in the workplace. Methods: A correlational study was conducted with a sample of 345 employees in the education sector in Bosnia and Herzegovina. Descriptive analysis, multiple regression analysis, and t-tests were performed using SPSS version 20.0. Results: The results indicate that teachers who did not have adequate workspace at home experienced greater workload but remained highly motivated. High job demands and low social support at work are associated with increased stress and decreased psychophysical functioning, while higher social support is associated with higher life satisfaction. In addition, higher job demands and stronger social support were related to greater intrinsic and extrinsic motivation at work. Conclusion: Results show that teachers lacking proper home workspaces reported their work as notably more demanding and stress-inducing, with a reported decline in their overall psychophysical well-being. Moreover, they expressed a reduced sense of control over their work, diminished social support, and lower levels of life satisfaction. These findings provide a valuable foundation for developing recommendations to address crisis situations in education, particularly when teachers transition from physical classrooms to virtual spaces, which is also important for online teaching and learning in typical times.

The lack of transparency and explainability hinders the clinical adoption of Machine learning (ML) algorithms. While explainable artificial intelligence (XAI) methods have been proposed, little research has focused on the agreement between these methods and expert clinical knowledge. This study applies current state-of-the-art explainability methods to clinical decision support algorithms developed for Electronic Medical Records (EMR) data to analyse the concordance between these factors and discusses causes for identified discrepancies from a clinical and technical perspective. Important factors for achieving trustworthy XAI solutions for clinical decision support are also discussed.

Graft-vs-host disease (GVHD) is a common complication of allogeneic stem cell transplant (alloSCT) wherein donor T cells target alloantigens on recipient tissues. It is unclear how alloimmune responses are maintained in GVHD despite abundant antigen, which causes T cell anergy, deletion and exhaustion. Previously, we identified alloreactive TCF-1 high T cells arising post-transplant that resemble exhausted progenitors (T EXP) capable of propagating immune responses in other chronic antigen models. Here, we sought to further characterize these cells in the B6→129 MHC-matched GVHD mouse model, in which 129 recipients express the immunodominant H-2K b-restricted minor histocompatibility antigen (miHA) H60. At day +7 post-transplant, alloreactive CD8 + cells specific to H60 (as determined by MHC-I-tetramer staining; Tet H60+) were nearly uniformly PD-1 hiTox hi whereas Tet H60- cells displayed a bimodal distribution into discrete PD-1 hiTox hi and PD-1 loTox lo populations, indicative of more diverse antigen experiences. Among these both Tet H60+ and Tet H60- cells were TCF-1 hi cells. TCF-1 hi Tet H60+ cells were uniformly CD39 loTox hiPD-1 hi, which is a canonical T EXP phenotype. In contrast, among activated Tet H60- cells there were TCF-1 hi cells that were CD39 loTox hiPD-1 hi and Tox loPD-1 lo. At later times in spleen and lymph node, and in GVHD target tissues, these populations of TCF-1 + Tet H60+ and Tet H60- were found. To test if these CD39 loTCF-1 hi T EXP had proliferative advantages in GVHD, we sorted congenic TCF-1 hiCD39 lo and TCF-1 loCD39 hi CD8 + cells from recipient spleens 14-days post-transplant and adoptively transferred them in competition in a 1:1 ratio (of Tet H60+ cells) into newly transplanted recipients. Among Tet H60+ cells in all tissues at day 14 post-transfer, TCF-1 hiCD39 lo-sorted progeny greatly outperformed TCF-1 loCD39 hi-sorted progeny. In line with their role as a source of GVHD effectors, progeny of TCF-1 hiCD39 lo cells were mostly TCF-1 loCD39 hi; however, a fraction remained TCF-1 hi consistent with their being able to undergo self-renewal. Conversely, we observed few if any TCF-1 + progeny of CD39 hi cells. We next tested whether TCF-1 was an important mediator of T cell fitness or whether it was only a marker for functionality. To do so we competed congenic wild-type (WT) and Tcf7 p45-/- (p45 -/-) donor CD8 cells, which lack the N-terminal β-catenin binding domain of TCF-1, in allogeneic (129) and syngeneic (B6) recipients. Strikingly, p45 -/- CD8 cells were greatly outcompeted by WT CD8 cells in 129 recipients in all tissues and at all times post-transplant, among both Tet H60+ and Tet H60- cells. In contrast, in B6 recipients, WT and p45 -/- cells remained evenly matched, suggesting that full-length TCF-1 isoforms are dispensable for lymphopenia-induced T cell expansion. Further, p45 -/- cells were also not disadvantaged when adoptively transferred into B6 mice and acutely challenged with H60 antigen by vaccination. Together these data suggest a model wherein TCF-1 hi progenitor like T cells are seeded in GVHD target organs where they may serve as a key local source for GVHD effectors, and moreover, full-length TCF-1 is itself critical for alloreactive T cell fitness in GVH responses.

We investigated the acute effects of different whole-body vibration (WBV) interventions on the jump height of highly trained karate practitioners. Fifteen male karate club athletes (age: 20.0 ± 3.8 years; stature: 177.3 ± 4.7 cm; body mass: 76.9 ± 11.2 kg; % body fat: 9.2 ± 4.3) performed six randomized interventions: [a] static half-squat (SHS); [b] SHS with external loads at 30% of the body weight (SHS + 30%BW); [c] WBV at frequency (f) 25 Hz, and 2 mm amplitude (A) (WBV 25/2); [d] WBV 25/2 with external loads of 30% of the body weight (WBV 25/2 + 30% BW); [e] WBV at f = 50 Hz, and A = 4 mm (WBV 50/4), and [f] WBV 50/4 with external loads of 30% of the body weight (WBV 50/4 + 30% BW). Each intervention was performed for 5 sets at 60 s/set, with a rest interval of 30 s between sets. Countermovement jump (CMJ) data were collected at 2, 4, 6, 8 and 10 min after each preconditioning intervention. Two-way repeated-measures ANOVA revealed a non-significant main effect of intervention [F(5, 10) = 1.44, η2 = 0.42, p = 0.29)] and a significant main effect of the rest interval [F(4, 11) = 3.51, η2 = 0.56, p = 0.04)] on CMJ height. A rest interval of 4 min resulted in significantly higher CMJ values than a rest interval of 2 min (p = 0.031). In conclusion, utilizing a 4-min rest interval irrespective of the intervention schemes may have potential for enhancing jumping performance among highly trained karate athletes.

To date there remains much ambiguity in the literature regarding the immunological interplay between SARS‐CoV‐2 and HIV and the true risk posed to coinfected individuals. There has been little conclusive data regarding the use of CD4 cell count and HIV viral load stratification as predictors of COVID‐19 severity in this cohort.

AIM To evaluate the progression of wound healing of standardized palatal defects in groups using three different collagen-based wound dressings and a control group, in terms of wound closure, pain perception and descriptive histology. MATERIALS AND METHODS Twenty participants were enrolled in this experimental study, in whom four palatal defects were created. The defects (6 mm diameter, 3 mm depth) were randomly assigned to one of four treatment modalities: C (control), MG (Mucograft®), MD (mucoderm®) and FG (Fibro-Gide®). Photographs were taken, and pain assessment was performed before and after treatment and at 5, 7, 9, 12, 14 and 16 days after surgery. All participants wore a palatal splint for a duration of 16 days. RESULTS All groups achieved complete wound closure at 14 days. The percentage of the remaining open wound on day 7 amounted to 49.3% (C; interquartile range [IQR]: 22.6), 70.1% (FG; IQR: 20.7), 56.8% (MD; IQR: 26.3) and 62.2% (MG; IQR: 34.4). Statistically significant differences were found between FG and C (p =.01) and between MD and FG (p =.04). None of the participants rated pain higher than 4 out of 10 during the entire study period. CONCLUSIONS Collagen-based wound dressings provide coverage of open defects, albeit without acceleration of wound closure or reduction of pain. FG (which is not intended for open oral wounds) showed slower wound closure compared to C and MD.

In recent years, imaging has become increasingly important to confirm diagnosis, monitor disease activity, and predict disease course and outcome in children with juvenile idiopathic arthritis (JIA). Over the past few decades, great efforts have been made to improve the quality of diagnostic imaging and to reach a consensus on which methods and scoring systems to use. However, there are still some critical issues, and the diagnosis, course, and management of JIA are closely related to clinical assessment. This review discusses the main indications for conventional radiography (XR), musculoskeletal ultrasound (US), and magnetic resonance imaging (MRI), while trying to maintain a clinical perspective. The diagnostic-therapeutic timing at which one or the other method should be used, depending on the disease/patient phenotype, will be assessed, considering the main advantages and disadvantages of each imaging modality according to the currently available literature. Some brief clinical case scenarios on the most frequently and severely involved joints in JIA are also presented.

Background : Acute abdomen (AA) is a synonym for a condition caused by an acute disease of an intra-abdominal organ that requires urgent surgical intervention. The gynecological-obstetrical etiopathogenesis of AA is based on pathological events on the genital organs due to hemorrhagic, inflammatory, and ischemic/obstructive genesis, and is a significant reason for admission to emergency gynecological departments, and emergency surgery. Methods : A retrospective clinical research was performed from 2005 to 2021, from the surgical protocol of the University Department for Gynecology and Obstetrics, Clinical Hospital “Sveti Duh” in Zagreb. In the examined sixteen-year period, 703 patients (4.06%) had surgery with a diagnosis of AA. Results : The largest number of surgeries due to AA was performed in the age group of 21–45 years (74.40%), i.e., in the reproductive age, followed by 106 patients aged 46–52 years (15.07%), then 46 (6.54%) patients in children and adolescent age up to 20 years of age, then from 53–60 years 23 (3.27%) patients, and in the elderly > 60 years old, with 5 (0.71%) patients. The etiopathogenetic factors of AA were: the most common intra-abdominal hemorrhage in 68.14%, followed by inflammation and the most common complications of pelvic inflammatory disease in 25.60%, ischemic-obstructive causes in 2.56% and other causes in 3.7%. Out of the total number of surgeries, 450 (64.01%) were due to ectopic tubal pregnancy. Out of the total number of surgeries, 549 (78.09%) were performed (completed) by laparoscopy procedures, and by laparotomy and/or relaparotomy in 154 cases (21.90%). Regarding laparoscopy, 93.48% was performed in the age group up to 20 years, 83.56% in the age group of 21–45 years, and 62.26% was performed in the age group of 46–52 years. Regarding laparotomy, 69.57% was performed in patients aged 53–60 years, and 100% in the age group of patients > 60 years. A pathological substrate was found for all operated patients, which they undergo for surgery, and we had no cases in which we did not prove a perioperative or pathohistological reason for AA. There were no patients’ deaths in the current study, which had to undergo for surgery for AA. Conclusions : We emphasize the urgent need for proper and continuous education of hospital teams, as well as extra-hospital emergency teams in recognizing AA symptoms of gynecological genesis based on history, clinical palpation examination, and ultrasound examination as a fundamental triad in the diagnosis of this life-threatening condition that requires only surgical treatment.

Introduction: Basal cell carcinoma is the most common non melanoma skin cancer. It accounts for approximately 80% of all skin cancers. Case report: We presented a 62-year-old patient with a giant, deeply infiltrative, destructive lesion of the head which lasted for 15 years. Microbiological analysis showed contamination, computed tomography (CT) scan showed deep infiltration and bone destruction. The risks of operative treatment were numerous. The treatment was more complicated by infection, infiltrative spreading and the patient's comorbidity. Regardless, we decided on a wide surgical resection with pathohistological evaluation of the resection margins. The patient denied oncological treatment. After 10 years, there were no recurrent tumours. Conclusion: Aggressive surgical treatment is the treatment of choice for giant basal cell carcinoma. In the case of giant locally aggressive and advanced neoplasms, when surgery is not appropriate or not possible, medical treatment becomes oncological.

Abstract The servitization literature has explored the role that product modularity plays in supporting service design and delivery. Importantly, product modularity has the potential to aid manufacturers in providing customised solutions on a larger scale, thereby strengthening firm performance. However, despite the prospective benefits of product modularity, manufacturers also need considerable servitization depth, which comprises service orientation, resources, and delivery systems, to provide services in a cost-effective manner. Taking this into account, the study both theoretically articulates and empirically tests relationships among product modularity, servitization depth, service types, and firm performance, employing a moderated mediation model. Using survey data collected from 204 manufacturers in the UK and German, the findings indicate that product modularity exerts a positive influence on firm performance, with servitization depth acting as a mediating factor. The mediation effect of servitization depth on the correlation between product modularity and firm performance was found to fluctuate based on the service types offered by the manufacturer. This study adds to the existing literature on servitization and the role of product modularity and servitization depth in achieving superior firm performance.