Introduction Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. Methods We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. Results 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). Conclusion This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.

Introduction: Graph theory has been applied to study the pathophysiology of multiple sclerosis (MS) since it provides global and focal measures of brain network properties that are affected by MS. Typically, the connection strength and, consequently, the network properties are computed by counting the number of streamlines (NOS) connecting couples of gray matter regions. However, recent studies have shown that this method is not quantitative. Methods: We evaluated diffusion-based microstructural measures extracted from three different models to assess the network properties in a group of 66 MS patients and 64 healthy subjects. Besides, we assessed their correlation with patients' disability and with a biological measure of neuroaxonal damage. Results: Graph metrics extracted from connectomes weighted by intra-axonal microstructural components were the most sensitive to MS pathology and the most related to clinical disability. In contrast, measures of network segregation extracted from the connectomes weighted by maps describing extracellular diffusivity were the most related to serum concentration of neurofilament light chain. Network properties assessed with NOS were neither sensitive to MS pathology nor correlated with clinical and pathological measures of disease impact in MS patients. Conclusion: Using tractometry-derived graph measures in MS patients, we identified a set of metrics based on microstructural components that are highly sensitive to the disease and that provide sensitive correlates of clinical and biological deterioration in MS patients. Impact statement Graph theory has been widely used to study the alterations in the structural connectivity of multiple sclerosis (MS) patients. Usually, brain graphs used for the extraction of network metrics are created by counting the number of streamlines connecting gray matter regions, however, this method is not quantitative. In this study, we used tractometry to average the values of diffusion-based microstructural maps along the reconstructed streamlines. Our results show that network metrics extracted from the connectomes weighted on microstructural maps provide sensitive information to MS pathology, which correlate with clinical and biological measures of disease impact.

Although epigenetic modifications have been intensely investigated over the last decade due to their role in crop adaptation to rapid climate change, it is unclear which epigenetic changes are heritable and therefore transmitted to their progeny. The identification of epigenetic marks that are transmitted to the next generations is of primary importance for their use in breeding and for the development of new cultivars with a broad-spectrum of tolerance/resistance to abiotic and biotic stresses. In this review, we discuss general aspects of plant responses to environmental stresses and provide an overview of recent findings on the role of transgenerational epigenetic modifications in crops. In addition, we take the opportunity to describe the aims of EPI-CATCH, an international COST action consortium composed by researchers from 28 countries. The aim of this COST action launched in 2020 is: (1) to define standardized pipelines and methods used in the study of epigenetic mechanisms in plants, (2) update, share, and exchange findings in epigenetic responses to environmental stresses in plants, (3) develop new concepts and frontiers in plant epigenetics and epigenomics, (4) enhance dissemination, communication, and transfer of knowledge in plant epigenetics and epigenomics.

ABSTRACT Introduction The need to individualize a drug dosage and adjust it to a patient’s physiological and/or pathophysiological status is rarely satisfied in routine clinical practice, primarily because of complexity of the adjustment task. Areas covered The aim of this article is to shed light to basic principles of drug dosage individualization in the most frequent clinical states that affect pharmacokinetics of drugs. The principles are derived from published clinical studies conducted on diverse patient populations, using non-compartmental pharmacokinetic model. Expert opinion Simple, but sufficiently exact, way to calculate appropriate drug dose for a patient is the one based on target average steady-state concentration and non-compartmental pharmacokinetic model. If target steady-state drug concentration and dosage interval are considered fixed, maintenance dose could be adjusted on the basis of expected changes of total drug clearance and bioavailability, while loading dose should be related to changes of volume of distribution and bioavailability. Relative increase or decrease of these pharmacokinetic parameters in regard to normal values in healthy persons is translated to relative (percentual) increase or decrease of maintenance and loading doses recommended in the drug monograph.

Abstract:This paper analyses impact of aircraft noise on community around Podgorica Airport, Montenegro. The airport is located 12 km from the city centre of the Montenegro capital, Podgorica. It served 1.3 million passengers and 7.5 thousand operations in 2019. The noise impact assessment is conducted in IMPACT web-based modelling platform using the distribution of operations by aircraft types, time of the day, and radar tracks for the busiest day (August 15) in 2019. Noise contours are assessed for Lden and Lnight indicators. They were merged with the Global Human Settlement Layer to assess the number of people exposed to different noise levels. In addition, based on the World Health Organization recommended exposure levels related to their health implications, the percentages of the population highly annoyed and highly sleep-disturbed are estimated. Furthermore, facilities of public importance (schools, hospitals, churches, etc.) are assessed against compatibility with the requirements set for the Zones with increased noise protection in national regulations. The results show that the exposure of community around Podgorica Airport to aircraft noise is still not a serious issue. The near vicinity of the airport is industrial zone and the number of people highly annoyed by noise is approximately 3.2% of the total city population. Nevertheless, it is crucial to draw attention to planners to preserve airport neighbourhood from potential inhabiting, to avoid problems that some airports in the region are facing nowadays.

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin–angiotensin–aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.

PurposeThe main reason for writing this paper was the systematic determination of the state of internationalization of public higher education for the first time in Bosnia and Herzegovina (B&H). This paper aims to compare the state of internationalization with the results of comparative European and world research in higher education in order to determine the direction of public universities in B&H following globalization and connection with the European Higher Education Area (EHEA), as well as to determine future steps for mandatory inclusion into global higher education flows. Furthermore, the aim was to determine the treatment of mobility and student exchange programs and the ways of recognizing acquired qualifications abroad.Design/methodology/approachThe paper opted for a research study by conducting questionnaires that were divided into questions of elimination, questions of qualification and questions of the main survey. A total of 2,822 final year students were surveyed, as well as 386 representatives of the management of public universities. Within the paper, 25 different SWOT analyses of internationalization were performed by public universities, ministries and state/regional agencies, which was the basis for the SWOT analysis of the internationalization of B&H public higher education. The data were supplemented with a qualitative analysis of the obtained results compared with the International Association of Universities (IAU) and European Association for International Education (EAIE) research, as well as an overview of the most significant achievements in the field of internationalization of higher education.FindingsThe paper provides empirical results on the barriers of students to study abroad, the existence of strategies and indicators for internationalization, the benefits of internationalization, internal and external drivers of internationalization and the potential risks of internationalization. These empirical results for B&H were compared with complementary IAUs and EAIE research and provided the basis for SWOT analysis of internationalization, development of institutional internationalization strategies and indicators, B&H recognition model, new criteria for accreditation with emphasis on internationalization and criteria for assessing internationalization. The paper suggests that virtual mobility and internationalization at home are future logical trends of development internationalization in B&H.Research limitations/implicationsSuggestions for future research related to the examination of identified potential risks to the management of the internationalization of individual institutions, as well as to future comparisons of the new state of internationalization of higher education in B&H with current similar research in Europe and the world. Regarding the limitations in the research, it was possible that a larger number of participants participated in the survey with questionnaires, although the target set at the beginning of the survey was achieved.Practical implicationsMost of the research results are the basis for improving the practical situation in the internationalization of public higher education in B&H. The paper presents a special chapter (undertaken improvement activities) dedicated to the practical implications based on the conducted research and comparison of results. Considering that this is a preliminary work related to the internationalization of higher education, based on the researched results, the context of the internationalization of public higher education in B&H was changed by the activities described in the mentioned chapter. The contribution to these activities was given by the approved project of the European Commission (EC) “strengthening of internationalization in B&H higher education” - STINT. Also, the research results of this paper offered a comparison with the research results of research conducted by IAUs and EAIE.Social implicationsDifferent research groups participated in this research study: students, teachers, administration, representatives of ministries and state/regional agencies. All target groups supported the implementation of the questionnaire, the development of SWOT analyses and various reports, as well as the undertaking of various practical activities. In accordance with the research results, all these target groups were subsequently educated on issues of internationalization and recognition of qualifications. Stronger and better internationalization certainly increases the social impact on future students, higher education funders, as well as other interested stakeholders.Originality/valueThis is a preliminary study whose main goal was to review the state of internationalization and to identify the most important undertaken activities in B&H. For the higher education area in B&H, the research study is new and has undertaken internationalization activities, but on the other side, in other developed European countries, similar studies and activities are not new. For the field of higher education in B&H, this work and research results are important because they will be the basis for future internationalization activities and will also serve as a basis for future activities to be undertaken in this field. The value of this paper is significant for both internal and external stakeholders of higher education.

Summary Stress at the work place was declared by the World Health Organization as a worldwide epidemic. The stress caused by work appears when the balance between one’s own possibilities and the environment demands is disturbed, which leads to a poor mental state. The fact is that the majority of dentists find they are under constant stress, which is caused by the nature of dental work. Literature describes dentistry as an extremely stressful profession. The main stressors include the tendency toward technical perfection, the causation of pain in patients, the lack of patient cooperation during dental treatment, the failure to maintain the given appointments. Adequate education and preparation, even during dental studies, non-neglect of symptoms and difficulties at the work place, adequate and timely response to the identification of the cause and its elimination or balancing, have a key role in solving this great problem in modern dentistry.

The heritability of methylation patterns in tumor cells, as shown in recent studies, suggests that tumor heterogeneity and progression can be interpreted and predicted in the context of methylation changes. To elucidate methylation-based evolution trajectory in tumors, we introduce a novel computational method for methylation phylogeny reconstruction leveraging single cell bisulfite treated whole genome sequencing data (scBS-seq), incorporating additional copy number information inferred independently from matched single cell RNA sequencing (scRNA-seq) data, when available. We validate our method with the scBS-seq data of multi-regionally sampled colorectal cancer cells, and demonstrate that the cell lineages constructed by our method strongly correlate with original sampling regions. Our method consists of three components: (i) noise-minimizing site selection, (ii) likelihood-based sequencing error correction, and (iii) pairwise expected distance calculation for cells, all designed to mitigate the effect of noise and uncertainty due to data sparsity commonly observed in scBS-seq data. In (i), we present an integer linear program-based biclustering formulation to select a set of CpG-sites and cells so that the number of CpG-sites with non-zero coverage in the selected cells is maximized. This procedure filters out cells with read information in too few sites and CpG-sites with read information in too few cells. In (ii), we address the sequencing errors commonly encountered in currently available platforms with a maximum log likelihood approach to correct likely sequencing errors in scBS-seq reads, incorporating CpG-site copy number information in case it can be orthogonally obtained. Given the copy number and read information for a site in a cell, together with the overall sequencing error probability, we compute the log likelihood for all possible underlying allele statuses. If the mixed read statuses at the CpG-site for the cell are more likely due to sequencing error on homozygous alleles as opposed to the presence of alleles mixed methylation statuses, we correct the reads of the minority methylation status to the majority one. In (iii), we introduce a formulation to estimate distances between any pair of cells. As scBS-seq data is typically characterized by shallow read coverage, there is rarely read count evidence for two (or more, depending on CNV status) alleles at a CpG-site. Since allele-specific methylation has been shown to have increased frequency in cancer tissues, given the reads at a CpG-site, it is especially important to consider the possibility of unobserved alleles and their methylation status when determining the CpG-site9s possible methylation zygosities. Our method incorporates copy number information when available, and for each CpG-site in a cell, we compute a probability distribution across all possible methylation zygosities. Then, given specific distance values between pairs of distinct zygosities and the likelihood of each possible zygosity for each shared CpG-site in both cells, we compute the expected total distance between any pair of cells as the mean of expected distances across all shared CpG-sites. We leverage such pairwise distances in methylation phylogeny construction. Citation Format: Xuan C. Li, Yuelin Liu, Farid Rashidi, Salem Malikic, Stephen M. Mount, Eytan Ruppin, Kenneth Aldape, Cenk Sahinalp. Epigenomic tumor evolution modeling with single-cell methylation data profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB020.

This work is motivated by growing evidence that the standard Cyclic Prefix (CP) length, adopted in the Long Term Evolution (LTE) physical layer (PHY) specifications, is oversized in propagation environments ranging from indoor to typical urban. Although this ostensibly seems to be addressed by 5G New Radio (NR) numerology, its scalable CP length reduction is proportionally tracked by the OFDM symbol length, which preserves the relative CP overhead of LTE. Furthermore, some simple means to optimize fixed or introduce adaptive CP length arose from either simulations or models taking into account only the bit-oriented PHY transmission performance. On the contrary, in the novel crosslayer analytical model proposed here, the closed-form expression for the optimal CP length is derived such as to minimize the effective average codeblock length, by also considering the error recovery retransmissions through the layers above PHY—the Medium Access Control (MAC) and the Radio Link Control (RLC), in particular. It turns out that, for given protective coding, the optimal CP length is determined by the appropriate rms delay spread of the channel power delay profile part remaining outside the CP span. The optimal CP length values are found to be significantly lower than the corresponding industry-standard ones, which unveils the potential for improving the net throughput.

Objectives: Food supplements and medicines which are not on the list of prohibited substances of the World Anti-Doping Agency are included in the group of permitted pharmacological agents for athlete’s recovery. The aim of this study was to describe qualitatively and quantitatively food supplements (FS) and over-the-counter drugs use among athletes in the last six month. Methods: This was a cross sectional study. Data on food supplements and the over-the-counter drugs, usage were collected during 2018 by self-administered, anonymous questionnaire. Results: A total of 112 athletes completed the survey. A total of 51.8% (n = 58) athletes reported the use of food supplements. The use of medical supplements was reported by 50.0% (n = 56) of athletes, 26.8% (n = 30) reported using ergogenic supplements, 1.8% (n = 2) using of sports food and 4.5% (n = 5) using other supplements. The use of over-the-counter drugs was reported by 35.7% (n = 40) of athletes. The over-the-counter analgesic drugs were used by 95% (n = 38) of over-the-counter drug users. Concomitant administration two or more over-the-counter drugs was reported by 40% (n = 16) athletes. Doctors and coaches had no advisory role in the use of food supplements or over-the-counter drugs.