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IMPORTANCE: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. OBJECTIVE: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. EVIDENCE REVIEW: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. FINDINGS: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. CONCLUSIONS AND RELEVANCE: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Abstract Background Cochlear synaptopathy is a disorder where auditory perceptual impairments, such as speech perception in noise and tinnitus, may not be accurately reflected by audiometric thresholds, even if the audiogram appears normal. It is proposed that the connections between hair cells and the auditory nerve are more susceptible to sound and aging damage than the cochlea’s hair cells. Cochlear synaptopathy can be present in ears with normal audiograms and undamaged hair cells, leading to hidden hearing loss. This study aims to construct electrophysiological and behavioral auditory parameters associated with persons exposed to loudness and having normal audiograms and auditory complaints to identify hidden hearing loss. Results A case–control study was done with forty participants with a documented history of exposure to loud sounds and various auditory complaints, compared to a control group of forty persons who had all been confirmed to have normal audiograms. The chosen behavioral core tests comprised the speech intelligibility in noise test (SPIN), gaps detection in noise (GIN test), and pitch pattern sequence test (PPS). The electrophysiological measures utilized in the study were the auditory brainstem response test (ABR) and electrocochleography (ECochG). The SPIN, PPS, and GIN test results demonstrated statistically significant disparities between the control and case groups. The amplitude ratio of wave I to wave V in ABR and the ratio of EcochG AP to SP demonstrated a statistically significant variance between the two groups. The SPIN test exhibited the highest AUC, signifying its superior diagnostic capability in identifying hidden hearing loss. Conclusion The present study has shown that the SPIN, as a behavioral test, and the EcochG AP amplitude measure, as an electrophysiological test, provide the greatest auditory diagnostic capability for identifying cochlear synaptopathy. Wave I amplitude in the auditory brainstem response (ABR) and the SP/AP ratio in electrocochleography (EcochG) are promising non-behavioral measures of cochlear synaptopathy or hidden hearing loss.

Objectives: This study aims to assess (i) the health-related Quality of Life (QoL) of medical students in Lebanon, (ii) its association with their general characteristics, and (iii) to investigate the combined effects of the predictors affecting the quality of life of students. Methods: An observational cross-sectional study was performed over three months, targeting 401 medical students from six universities. The 36-item Short Form survey was used to quantify the different QoL scores. Results: The physical component (PC) domains had higher scores than the mental component (MC) ones (70.2 vs. 55.9). Students aged 30 years or less had higher scores in all the PC domains than older students (70.9 vs. 59.3; p<0.010) but comparable scores in the MC domains (55.6 vs. 59.8; p>0.050). Single students had a significantly higher role-emotional score (63.5 vs. 49.0; p<0.050), and those studying in public universities had greater general health scores (57.7 vs. 53.7; p<0.050). Younger age significantly increased most of the health-related PC scores, and having chronic diseases decreased all the QoL scores except the mental health score. Conclusion: The QoL of medical students was negatively affected during the pandemic, particularly their mental health. Informed educational and health decisions are required to minimize this impact on their academic performance.

Abstract Cholera is a life-threatening gastrointestinal infection caused by a toxigenic bacterium, Vibrio cholerae. After a lull of almost 30 years, a first case of cholera was detected in Lebanon in October 2022. The outbreak lasted three months, with 8007 suspected cases (671 laboratory-confirmed) and 23 deaths. In this study, we use phenotypic methods and microbial genomics to study 34 clinical and environmental Vibrio cholerae isolates collected throughout this outbreak. All isolates are identified as V. cholerae O1, serotype Ogawa strains from wave 3 of the seventh pandemic El Tor (7PET) lineage. Phylogenomic analysis unexpectedly reveals the presence of two different strains of the seventh pandemic El Tor (7PET) lineage. The dominant strain has a narrow antibiotic resistance profile and is phylogenetically related to South Asian V. cholerae isolates and derived African isolates from the AFR15 sublineage. The second strain is geographically restricted and extensively drug-resistant. It belongs to the AFR13 sublineage and clusters with V. cholerae isolates collected in Yemen. In conclusion, the 2022-2023 Lebanese cholera outbreak is caused by the simultaneous introduction of two different 7PET strains. Genomic surveillance with cross-border collaboration is therefore crucial for the identification of new introductions and routes of circulation of cholera, improving our understanding of cholera epidemiology.

Abstract Background The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. Methods A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). Results In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. Conclusions AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications. Graphical Abstract

The intricate interplay existing between gut microbiota and homeostasis extends to the realm of the brain, where emerging research underscores the significant impact of the microbiota on mood regulation and overall neurological well-being and vice-versa, with inflammation playing a pivotal role in mediating these complex interactions. This comprehensive review explores the complex interplay between inflammation, alterations in gut microbiota, and their impact on major depressive disorder (MDD). It provides a cohesive framework for the puzzle pieces of this triad, emphasizing recent advancements in understanding the gut microbiota and inflammatory states' contribution to the depressive features. Two directions of communication between the gut and the brain in depression are discussed, with inflammation serving as a potential modulator. Therapeutic implications were discussed as well, drawing insights from interventional studies on the effects of probiotics on gut bacterial composition and depressive symptoms. Ultimately, this review will attempt to provide a complete and valuable framework for future research and therapeutic interventions in MDD.

This article offers a new perspective on children and youth’s coerced displacement in the context of the Ottoman Middle East and highlights their potential as a social group to inform studies of children, kinship, and family vis-a-vis the state. Using iltizām contracts, I argue that the Ottoman state prioritized its stability and economic interests and turned a blind eye to promises it made to ensure the “well-being” of young Ottoman subjects. The contracts recorded around the mid-eighteenth century document an institutionalized practice by the state to remove and incarcerate young and minor males associated with the families of multazims, or tax farmers, who generally hailed from the class of provincial notables, or a‘yān, to persuade the latter to render payment of taxes. Although multazims appeared to be indifferent to the fate of their castaway children, evidence suggests that multazims took advantage of geopolitical changes toward the last quarter of the eighteenth century to avoid the incarceration of their children, as the practice completely disappeared at that time. This article also attempts to approach the question of whether this forced displacement of children represents a form of mobility, in comparison to other forms of children’s mobility, like the devširme, and explores what this meant for the expansion, or retraction, of the state power and its governing policies.

Summary: Recent developments in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy (ACT), have encountered challenges such as immune-related adverse events and resistance, especially in solid tumors. To advance the field, a deeper understanding of the molecular mechanisms behind treatment responses and resistance is essential. However, the lack of functionally characterized immune-related gene sets has limited data-driven immunological research. To address this gap, we adopted non-negative matrix factorization on 83 human bulk RNA sequencing (RNA-seq) datasets and constructed 28 immune-specific gene sets. After rigorous immunologist-led manual annotations and orthogonal validations across immunological contexts and functional omics data, we demonstrated that these gene sets can be applied to refine pan-cancer immune subtypes, improve ICB response prediction and functionally annotate spatial transcriptomic data. These functional gene sets, informing diverse immune states, will advance our understanding of immunology and cancer research.

This study aimed to investigate the SARS-CoV-2 infection prevalence among >18-year-old students in the Faculty of Public Health and Faculty of Sciences at the Lebanese University in Tripoli, Northern Lebanon, in June 2023 and to characterize the circulating Omicron subvariants. Out of 357 participants, only 2 (0.56%) tested positive by qPCR, corresponding to 0.61% (2/326) of asymptomatic students. One case tested positive with a qPCR targeting the Omicron BA.2 variant. These findings indicate a low incidence at that time and emphasize the interest of SARS-CoV-2 surveillance among students.

Addiction medicine is a dynamic field that encompasses clinical practice and research in the context of societal, economic, and cultural factors at the local, national, regional, and global levels. This field has evolved profoundly during the past decades in terms of scopes and activities with the contribution of addiction medicine scientists and professionals globally. The dynamic nature of drug addiction at the global level has resulted in a crucial need for developing an international collaborative network of addiction societies, treatment programs and experts to monitor emerging national, regional, and global concerns. This protocol paper presents methodological details of running longitudinal surveys at national, regional, and global levels through the Global Expert Network of the International Society of Addiction Medicine (ISAM-GEN). The initial formation of the network with a recruitment phase and a round of snowball sampling provided 354 experts from 78 countries across the globe. In addition, 43 national/regional addiction societies/associations are also included in the database. The surveys will be developed by global experts in addiction medicine on treatment services, service coverage, co-occurring disorders, treatment standards and barriers, emerging addictions and/or dynamic changes in treatment needs worldwide. Survey participants in categories of (1) addiction societies/associations, (2) addiction treatment programs, (3) addiction experts/clinicians and (4) related stakeholders will respond to these global longitudinal surveys. The results will be analyzed and cross-examined with available data and peer-reviewed for publication.

Summary: Mesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis, encompassing cross-presentation assays and molecular profiling, among other cellular investigations, elucidated A1’s impact on endosomal escape, reactive oxygen species production, and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma, we observe significant therapeutic potency, particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall, this study introduces a strong target for developing an antigen-adaptable vaccination platform, capable of synergizing with immune checkpoint blockers to trigger tumor regression, supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine.

Since March 2020, the COVID-19 pandemic has swiftly propagated, triggering a competitive race among medical firms to forge vaccines that thwart the infection. Lebanon initiated its vaccination campaign on February 14, 2021. Despite numerous studies conducted to elucidate the characteristics of immune responses elicited by vaccination, the topic remains unclear. Here, we aimed to track the progression of anti-spike SARS-CoV-2 antibody titers at two-time points (T1: shortly after the second vaccination dose, T2: six months later) within a cohort of 201 adults who received Pfizer-BioNTech (BNT162b2), AstraZeneca, or Sputnik V vaccines in North Lebanon. Blood specimens were obtained from participants, and antibody titers against SARS-CoV-2 were quantified through the Elecsys-Anti-SARS-CoV-2 S assay (Roche Diagnostics, Switzerland). We used univariate analysis and multivariable logistic regression models to predict determinants influencing the decline in immune response and the occurrence of breakthrough infections among vaccinated patients. Among the 201 participants, 141 exhibited unchanging levels of antibody titers between the two sample collections, 55 displayed waning antibody titers, and only five participants demonstrated heightened antibody levels. Notably, age emerged as the sole variable significantly linked to the waning immune response. Moreover, the BNT162b2 vaccine exhibited significantly higher efficacy concerning the occurrence of breakthrough infections when compared with the AstraZeneca vaccine. Overall, our study reflected the immune status of a sample of vaccinated adults in North Lebanon. Further studies on a larger scale are needed at the national level to follow the immune response after vaccination, especially after the addition of the third vaccination dose.

The purpose of the present study was to examine the effects of easy goals versus difficult goals on acquisition and retention of basketball free throws in children with intellectual disability. Twenty-one children with intellectual disability were randomly assigned to an easy goals or difficult goals group. The participants were required to improve their basketball free throws according to their own scores in the previous exercise session. More difficult goals were set for the difficult goals group than for the easy goals group. The groups exercised the task for nine sessions. Both groups performed pretest, acquisition, and retention tests. Results showed that participants with easy goals improved their performance while the participants with difficult goals failed to improve their performance. These findings indicate that providing children with intellectual disability with easy goals facilitates the process of sport skill learning.

Background: Toxoplasma gondii infects nearly one-third of the world's population. Due to the significant side effects of current treatment options, identifying safe and effective therapies seems crucial. Nanoparticles (NPs) are new promising compounds in treating pathogenic organisms. Currently, no research has investigated the effects of zinc oxide NPs (ZnO-NPs) on Toxoplasma parasite. We aimed to investigate the therapeutic efficacy of ZnO-NPs against tachyzoite forms of T. gondii, RH strain in BALB/c mice. Methods: In an experiment with 35 female BALB/c mice infected with T. gondii tachyzoites, colloidal ZnO-NPs at concentrations of 10, 20, and 50 ppm, as well as a 50 ppm ZnO solution and a control group, were orally administered four hours after inoculation and continued daily until the mices’ death. Survival rates were calculated and tachyzoite counts were evaluated in the peritoneal fluids of infected mice. Results: The administration of ZnO-NPs resulted in the reduction of tachyzoite counts in infected mice compared to both the ZnO-treated and control group (P

Abstract Background and Aims Dual immune checkpoint blockade (ICB) therapy can result in immune-related-adverse events (irAE) such as ICB-hepatitis. An expansion of effector-memory (TEM) CD4 T cells associated with antiviral immunity against herpesviridae was implicated in ICB-hepatitis. Notably, these memory subsets are frequently associated with age. Here, we sought to understand baseline patient, immune and viral biomarkers associated with the development of ICB-hepatitis to identify currently lacking baseline predictors and test if an expansion of TEM or positive serology against herpesviridae can predict ICB-hepatitis. Methods A discovery (n = 39) and validation cohort (n = 67) of patients with advanced melanoma undergoing anti-PD-1&anti-CTLA4 combination therapy (total n = 106) were analyzed for baseline clinical characteristics, occurrence of irAE and oncological outcomes alongside serological status for CMV, EBV and HSV. Immune populations were profiled by high-parametric flow cytometry (n = 29). Results ICB-hepatitis occurred in 59% of patients within 100 days; 35.9% developed severe (CTCAE 3–4) hepatitis. Incidence of ICB-hepatitis was higher in the younger ( = 55y: 27.8%) age group (p = 0.0003), occured earlier in younger patients (p

Abstract Background Dizziness, including vertigo, affects approximately 15% to over 20% of adults each year. A significant proportion of patients with vertigo develop secondary psychiatric disorders throughout their disease. On the other hand, patients with psychiatric disorders frequently report dizziness as a co-occurring symptom of their illness. The purpose of this study was to screen the prevalence of depression and anxiety indices in dizzy patients and their relation to the severity of their dizziness handicap by administering two different questionnaires: The dizziness handicap inventory (DHI) and the Hospital Anxiety and Depression Scale (HADS). Results Psychological assessments revealed that 49% of the study group was normal, 29% had anxiety, 7% had depression, and 15% had both anxiety and depression. Besides, vestibular neuritis was associated with a higher mean anxiety score, whereas Meniere's disease was associated with a higher mean depression score. Conclusion As this study has shown, there was a statistically significant positive correlation between anxiety and depression scores and physical, emotional, functional, and total DHI scores. Screening and treatment of co-morbid mental health disorders are critical for appropriate management of vertigo disability that leads to a higher quality of life and fewer complications.

Nowadays, due to the pollution that businesses and various industries impose to the environment, the adoption of strategies and policies by governments to improve the environmental performance of the supply chain has received more attention. The green supply chain will have many benefits, such as saving energy resources, reducing pollutants, and so on. Government intervention to develop these chains takes various forms, such as subsidies, taxes, licensing, and advertising. In this study, two manufacturers with green and non-green supply chains compete in a competitive market and sell their products through a joint retailer, and the government intervenes as a leader in the Stackelberg game. These chains are designed based on the selection of agent-based pricing and wholesale pricing methods in four different models. In these models, the government advertises for green products in the first and second models and imposes taxes on the producer of non-green products in the third and fourth models, seeking to maximize social welfare and improving the environment. In order to analyze and compare the models, the game theory approach was used. The results show that in general, government intervention improves the environmental situation and social welfare, and in the case of advertising has a better effect on the overall market trend and also on social welfare than the tax imposing strategy.IntroductionToday, with the rapid growth of industries worldwide, the environmental impact and ecological effects of products have become significant concerns. There is a growing awareness of the environmental consequences and associated risks to human health resulting from industrial activities. Consequently, research on green supply chain management has seen a significant increase. As public awareness about environmental issues continues to rise and concerns about the future of our planet intensify, customers are increasingly inclined to purchase environmentally friendly products. This shift in consumer behavior has prompted manufacturers and businesses to reassess their production processes and adapt to changing customer preferences and new government policies. The primary objective of this research is to investigate the role of government intervention in influencing the demand for green and non-green products through factor-oriented green and non-green supply chains. Additionally, the study aims to identify government policies that can facilitate the development and adoption of green products. The findings of this research can be utilized by governments to promote the use of environmentally friendly goods and enhance environmental protection efforts.Materials and methodsThe approach of this research involves modeling and analysis. The research considers multiple models, each consisting of two supply chains with two manufacturers and a common retailer. One manufacturer produces a green product (environmentally friendly), while the other produces a non-green product (not environmentally friendly). Throughout the research, all comparative models adhere to this structure, with the first supply chain focusing on the production of green products and the second supply chain delivering non-green products to customers. All the analyses conducted in this research are mathematically analyzed and utilize game theory to validate the model results and analyze them. Since the model results are mathematically proven, there is no need to collect real-world data. Instead, hypothetical data are used in the examples to illustrate the various aspects of the problem. In this research, all the models are designed based on the Stackelberg game, and the government takes the initiative in determining its objectives.ResultsIn order to compare the models and analyze the results, we first considered a fixed strategy (advertisement or taxation) for the government. This allowed us to investigate the effect of pricing type on profit, demand, and social welfare. We compared the first model with the second model and also compared the third and fourth models together. Furthermore, we compared the advertising strategy models with the taxation strategy models, examining each strategy within the supply chains. The results indicate that the second model generates the highest level of social welfare and benefits for society, while also resulting in the greatest profit for producers and retailers. Following that, the first model exhibits more social welfare compared to the third and fourth models. Additionally, the profit of the green product producer in the first model significantly surpasses that of the non-green product producer. This difference in profitability serves as an incentive for producers to transition to green product production. Although the profit disparity between producers in the third and fourth models is more substantial and encourages the greater promotion of green product production, it leads to lower satisfaction and well-being.ConclusionsThe results demonstrate the high sensitivity of producers' and retailers' profits to the pricing of their products. The product price is influenced by factors such as whether the supply chain is factor-oriented or wholesale, as well as the type of government intervention. When consumers make purchasing decisions, they consider not only the price but also other parameters, such as the environmental friendliness of the product. In other words, the choice of a product is determined by a set of conditions and is not solely dependent on price fluctuations. The pricing method, whether factor-oriented or wholesale, significantly impacts the profitability of supply chain members and has implications for social welfare and environmental improvement. Different types of government intervention, such as cultural initiatives or taxation, can also lead to changes in the results

The tourism industry plays an important role in boosting economic growth, providing job opportunities, and reducing the poverty rates in many countries. For this reason, the factors influencing tourism should be investigated, to ensure continued growth within the industry. Few studies had examined the effect of violent crime on tourist arrivals and price competitiveness in Malaysia. An increasing criminal activity and a rise in prices may discourage tourism arrivals. This paper applies an autoregressive distributed lag (ARDL) model to estimate Malaysia's determinants of tourism arrivals, on the period from 1986 to 2016. Tourism demand is modeled as a function of economic growth, tourism accommodation, prices (proxied by exchange rates and inflation), unemployment, and the crime index to proxy criminal activity in Malaysia. The results showed that inflation can reduce the number of tourists in the long run and in the short run. Similarly, the results also show that a higher exchange rate and violent crime index can reduce the number of tourists visiting Malaysia in the short run. Economic growth can attract more tourists to Malaysia in the long run.These findings are important for the formulation and implementation of policies. The Malaysian government should combat violent crime in the first place to prevent any reduction in tourist arrivals. Increasing government expenditure on national security could lead to a reduction in the violent crime index, thus increasing the number of tourist arrivals in Malaysia.

Abstract Preparing for environmental risks requires estimating the frequencies of extreme events, often from data records that are too short to confirm them directly. This requires fitting a statistical distribution to the data. To improve precision, investigators often pool data from neighboring sites into single samples, referred to as “superstations,” before fitting. We demonstrate that this technique can introduce unexpected biases in typical situations, using wind and rainfall extremes as case studies. When the combined locations have even small differences in the underlying statistics, the regionalization approach gives a fit that may tend toward the highest levels suggested by any of the individual sites. This bias may be large or small compared to the sampling error, for realistic record lengths, depending on the distribution of the quantity analyzed. The results of this analysis indicate that previous analyses could potentially have overestimated the likelihood of extreme events arising from natural weather variability.

Key Clinical Message We report a 20‐year‐old man with neurofibromatosis type 1 presenting with frequent episodes of suprapubic pain. The episodes started 6 months ago, occurred 1 h a day, and were not related to urination. A prostate‐sparing cystectomy with orthotopic diversion was performed. Histopathological assessment of the specimen confirmed bladder plexiform neurofibromatosis.

Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.

In a system, prediction of remaining useful lifetime (RUL) of servicing before reaching to a specified breakdown threshold is a very important practical issue, and research in this field is still regarded as an appreciated research gap. Operational environment of an equipment is not constant and changes regarding to stresses and shocks. These random environmental factors accelerate system deterioration by affecting on the level or rate of degradation path. The present study focuses on providing a practical operational guideline to estimate the RUL of a system with general degradation path after receiving a shock which only affects on the degradation level. Due to exact estimation of the shock arrival times and measuring the magnitudes of future shocks to investigate shock effects on RUL is almost impossible in the real world and laborious in practice, in this research a new procedure based on total defect size monitored in the constant inspection periods and Accelerated Factor (AF) is proposed to analyze RUL of the system. A Micro-Electro-Mechanical system (MEMS) is used as an example and the results show the applicability of the proposed approach.