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The aim of this paper is to relate the condition for cost subadditivity to aggregative efficiency. In particular, we verify that subadditivity of the cost function occurs when aggregate cost efficiency is not less than the cost efficiency of the average production unit. This provides a simple way of examining the potential of merging two or more firms and of making inference about the extent of industry concentration. It also provides a simple nonparametric test for subadditivity of the cost function.

To provide a descriptive insight into the different types of research questions/objectives and associated methodologies of overviews of reviews, supplemented by representative examples from the health care literature.We searched in methodological articles for information on types and methodologies used in overviews and we explored the typology of reviews to identify similar types in literature of overviews. We categorized the types of overviews based on the research question/objective and the methodological approach used. Indicative examples for each category were selected from a sample of 2,121 overviews that were retrieved between 2000 and 2022 from MEDLINE, Scopus, and Cochrane Database of Systematic Reviews.Based on type of research question, overviews were classified as overviews of reviews of interventions, associations, prediction, diagnostic accuracy, prevalence/incidence, experiences/views, economic evaluation, and measurement properties. Based on the methodological approach, we identified a variety of methods (systematic, living, rapid, scoping, evidence mapping, framework, and methodological) used in overviews.The proposed classification and examples provide an essential starting point for future theory-building research on typologies and study designs of overviews of reviews. It is important for methodologists to make vigorous effort to create consensus-based methodological and reporting guidelines to cover these diverse types and key methodological challenges.

Increasing evidence has linked the humoral immune response with the development of various cancers. Therefore, there is growing interest in investigating the predictive value of antibodies to assess overall and tissue site-specific cancer risk. Given the large amount of antibody types and the broad scope of the search (i.e. cancer risk), the primary aim of this systematic review was to present an overview of the most researched antibodies (i.e. immunoglobulin (Ig) isotypes (IgG, IgM, IgA, and IgE), tumour and self-antigen-reactive antibodies, infection-related antibodies) in relation to overall and site-specific cancer risk. We identified various antibody types that have been associated with the risk of cancer. While no significant associations were found for IgM serum levels, studies found an inconsistent association among IgE, IgA, and IgG serum levels in relation to cancer risk. When evaluating antibodies against infectious agents, most studies reported a positive link with specific cancers known to be associated with the specific agent recognized by serum antibodies (i.e. helicobacter pylori and gastric cancer, hepatitis B virus and hepatocellular carcinoma, and human papillomavirus and cervical cancer). Several reports identified autoantibodies, as single biomarkers (e.g. anti-p53, anti-MUC1, and anti-CA125) but especially in panels of multiple autoantibodies, to have potential as diagnostic biomarkers for specific cancer types. Overall, there is emerging evidence associating certain antibodies to cancer risk, especially immunoglobulin isotypes, tumour-associated antigen-specific, and self-reactive antibodies. Further experimental studies are necessary to assess the efficacy of specific antibodies as markers for the early diagnosis of cancer.

Stone has been a basic building material of different monuments and structural components such as foundations and masonry. At the same time, dif-ferent types of stones have been used for decorative architectural elements, such as cornices, reliefs, colonnettes, and corbels. The maintenance of stone ele-ments is essential for the continuity of these structures. Many studies have been performed to produce stones with artificial materials. This study aims to present a new approach to artificial stone with self-healing capability. Crystallines have been implied in two different dosages: 0.8 and 1.6% w./w, to achieve this goal. The addition of the crystalline admixtures affected the physical properties, de-creasing the porosity and the capillary absorption, proving the sealing properties of the admixtures. The self-healing efficiency has been tested with the sorption test, recovery of compressive strength, and 3D acoustic microscopy. The crys-talline admixtures accelerate the self-healing, increasing the sealing efficiency by 20% and recovering compressive strength by 15%. The analysis by 3D to-mography provided results that confirm the healing of the crack hasn't occurred only on the surface but extended to a certain depth.

In the current work the endoscopy and retrieval of mortar covered mosaic patterns, such as the Hagia Sophia ones, is presented. In particular, an appropriate instrumentation is developed combining ultra-sonic tomography and an accurate motion planning. The acquisition of high-response tomographic images is performed utilizing transducers in a linear array through the efficient control of their phase characteristics both in transmit and receive modes. Moreover, an accurate mechanical adaptation is designed in order to move the ultrasonic probe with a con-stant velocity. Then, a sequence of tomographic images is recorded and the 3D endoscopic characteristics of the measured object are extracted via the effective reconstruction of the 3D volume. This device is used on a realistic Hagia Sophia mosaic replica that is covered by a thick mor-tar layer. The evaluated results indicate a complete 3D reconstruction of the hidden mosaic in micrometric resolution, while the inner details of individual tesserae are, also, recovered.

Background Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. Methods We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. Results Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses. Conclusions sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.

Models have evolved from mere pictures supporting human understanding and communication to sophisticated knowledge structures processable by machines and establish value through their processing capabilities. This entails an inevitable need for computer-understandable modeling languages and causes formalization to be a crucial part in the lifecycle of engineering a modeling method. An appropriate formalism must be a means for providing a structural definition to enable a theoretical investigation of conceptual modeling languages and a unique, unambiguous way of specifying the syntax and semantics of an arbitrary modeling language. For this purpose, it must be generic and open to capturing any domain and any functionality. This paper provides a pervasive description of the formalism MetaMorph based on logic and model theory—an approach fulfilling the requirements above for modeling method engineering. The evaluation of the formalism is presented following three streams of work: First, two evaluative case studies illustrate the applicability of MetaMorph formalism concept by concept on the modeling language ProVis from the domain of stochastic education and the well-known Entity-Relationship language. ProVis as well as ER comprise only a few objects and relation types but with high interconnection and expressive power and are therefore considered interesting specimens for formalization. Second, a comprehensive juxtaposition of MetaMorph to three other formalization approaches based on different foundational theories is outlined concept by concept to underpin the formalism design. Third, an empirical evaluation has been performed, assessing the usability and adequacy of the formalism within a classroom assessment. The results allow for conclusions on the completeness, intuitiveness, and complexity as well as on interdependencies with engineers’ skills.

Evaluation of FRalpha expression by tumor cell lines

Table of Patient Characteristics

IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen–specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcϵ receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127–41. ©2017 AACR.

Description of additional experiments and procedures carried out in this study

Demarcation of tumor islets and immune cell infiltrates in rat lung sections

Table of Healthy Volunteer Characteristics

Gating strategy used in the characterization of tumor-infiltrating macrophages by flow cytometry

Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

Background: A tubed anterolateral thigh (ALT) flap has become a reliable option for laryngopharyngeal defects; however, successful reconstruction remains challenging. Prevention of fistulae, resurfacing of the neck and flap monitoring are key issues that surgeons have sought to address through various flap modifications. Here we describe a chimeric design of the tubed ALT flap which tackles these and other challenges. Methods: Fourteen cases requiring ALT flaps were harvested for reconstruction of total laryngopharyngectomy defects between 2017 and 2019. Each flap was raised on at least two perforators of the descending branch of the lateral circumflex femoral artery (dbLCFA) or both the dbLCFA and transverse branch of the lateral circumflex femoral artery (tbLCFA) to create a chimeric flap. The primary cutaneous paddle was tubed to reconstruct the oesophagus, and the secondary component was inset to the neck as a skin-monitoring paddle. A strip of vascularised vastus lateralis was harvested in the primary paddle continuing with the flap and sutured along the neopharynx suture line, an additional layer preventing anastomotic leak. Results: Patients averaged 61.1 years of age. An average of 2.4 perforators were included per flap. All flaps survived. Donor sites were closed primarily in all cases. Barium swallow was performed in 71.4 per cent of cases (10/14). Fistula occurred in 7.1 per cent of patients (1/14). Patients were followed up for an average of 13 months. Conclusion: Our chimeric ALT free flap design provides a reliable pharyngeal reconstruction, and allows for flap monitoring and neck resurfacing when required, with a low rate of clinically significant leaks or fistula.

Posterior scleritis is a relatively uncommon form of scleral inflammation of the posterior segment of the eye. Clinical manifestations include ocular pain, headache, pain with ocular movements, and loss of vision. A rare presentation of the disease is acute angle closure crisis (AACC) with elevated intraocular pressure (IOP) secondary to anterior displacement of the ciliary body. Various systemic diseases have been described to co-exist with posterior scleritis; however, psoriasis has not been associated with posterior scleritis. Here, we present a case of posterior scleritis which initially presented as AACC in a patient with pre-existing psoriasis. A 50-year-old male with a history of psoriasis under treatment presented to the emergency department with intense sudden ocular pain and loss of vision on the left eye as well as headache and nausea. A thorough medical and ocular history was taken, and a detailed examination of the anterior and posterior segment was completed including visual acuity and IOP. Initial diagnosis of AACC was made, and appropriate actions were taken with partial resolution of his symptoms. However, upon further work-up including ultrasound (B-scan) of the left eye a final diagnosis of posterior scleritis was made. The patient was treated with steroids and nonsteroidal anti-inflammatory drugs which dramatically improved his condition. Photographic evidence of initial presentation and post-treatment condition was obtained and presented in this report. Posterior scleritis is a potentially vision-threatening condition which is usually challenging to diagnose. In this report, we highlight the challenges one might come into when dealing with different manifestations of the same disease, increasing awareness. This case of posterior scleritis presenting as AACC in a patient with a history of psoriasis enhances what we already know from the literature as well as provides some new insights in the clinical manifestations of posterior scleritis in the setting of psoriasis without arthritis.

Choosing the Most Preferred Solution (MPS), namely a real or artificial Decision Making Unit (DMU) reflecting the decision maker’s preferences over the desirable structure of inputs and outputs, is of particular importance in Value Efficiency Analysis (VEA). In this paper, we review various MPS choices used in the VEA literature and propose some new, which rely respectively on the relative position of frontier DMUs, the Most Productive Scale Size (MPSS), the Average Production Unit (APU), and common vectors of weights. The suggested MPS choices reflect overall organizational goals such as the pursuit of scale economies and the maximization of structural efficiency, or the need to assess DMUs against common standards because of limited control over the resources allocated to them or autonomy in setting their own priorities. The potential implications of using different MPSs in VEA are illustrated by providing comparative empirical results using a dataset of 526 Greek cotton farms.

LF is a bioactive protein, derived from colostrum and milk that has been found to possess various immunomodulatory, iron chelating, and antimicrobial properties, especially in its apo-form. Recent studies have demonstrated the functionality of LF in attaching to the S proteins of SARS-CoV-2, thereby preventing it from interacting with the ACE-2 receptor. However, the molecular mechanism mediating the process is poorly understood. In this study, molecular docking and MD simulations coupled with free energy calculations were applied to elucidate the key interaction of apo-LF and its N-lobe and C-lobe derivative forms with the RBD of coronavirus S proteins. This has also been extended into evaluating the L452R mutant, which is associated with the delta variant of SARS-CoV-2. The results demonstrate the efficacy of the apo-LF C-lobe in binding to the RBD of both variants, primarily through electrostatic attractions between the acidic residues of the former and the basic residues of each RBD. Furthermore, due to the additional arginine in the L452R variant, the interaction between the C-lobe and the latter is stronger, resulting in a more favourable binding and tightly bound structure. The simulations highlight that the C-lobe, followed by full-length apo-LF can form a multimeric complex with the RBD of SARS-CoV-2, indicating their potential use as novel therapeutics, particularly the cleaved C-lobe of apo-LF to disrupt the S proteins from binding to the host ACE-2 receptor. Communicated by Ramaswamy H. Sarma.

We present a necessary and sufficient condition for a maximal curve, defined over the algebraic closure of a finite field, to be realised as an HKG-cover. We use an approach via pole numbers in a rational point of the curve. For this class of curves, we compute their Weierstrass semigroup as well as the jumps of their higher ramification filtrations at this point, the unique ramification point of the cover.

Data from the SPLUS surveyhave been cross-matched with GALEX, SDSS, GAIA, 2MASS and WISE with the aim to characterize Hα sources. Thestudy was focused on Hα emitters and their link with UV emitters. Machine learning algorithms were also employedfor the separation of Hα emitters in S-PLUS survey of UV and non-UV sources based on GALEX.

This study compares the International Maritime Organization (IMO) Member State Audit Scheme (IMSAS) and ISO/IEC 17000 series as well as ISO 19011. The part that we investigate in this paper is the marine industry audit cycle that the IMO Member State Audit Scheme uses, such as ISM code certification of the vessels over 500 Gross Tonnage (GT) and the IAF peer evaluation of its members’ accreditation bodies. The reasoning for such effort is that both ISM code certification of the vessels over 500 GT and the IAF peer evaluation are long established and more mature assessment practices. The contribution of our study is to create a robust audit cycle for the IMO Member State Audit Scheme, which has not been examined in the literature.

Background We present a case of hypertensive choroidopathy due to malignant hypertension with exudative retinal detachment as a sole finding. We use OCT- angiography for initial diagnosis and report findings from extensive follow up. Case presentation A 51-year-old female with no past medical history, presented to our clinic with painless loss of vision in her left eye. Fundus examination revealed only exudative retinal detachment in her left eye that was confirmed with Optical Coherence Tomography. Fluorescein angiography showed hyperfluorescent spots with leakage in late phases. OCTA manifested a focal dark area in the choriocapillaris slab corresponding to flow signal voids, signifying regions of non-perfusion. Her blood pressure was 220/120 mmHG. Complete blood work -up failed to reveal any other possible etiology. During follow-up period of 9 months blood pressure normalized, patient regained visual function and choriocapillaris perfusion was completely restored. Discussions and conclusions Hypertensive choroidopathy with exudative retinal detachment can be the only sign of malignant hypertension and no pre-existing history of a systemic disease is required in order to become apparent. OCTA reveals areas of non-perfusion at choriocapillaris level, proving that it is an essential tool in the diagnosis and follow up of patients with hypertensive choroidopathy. Finally, we propose that early diagnosis prevents permanent damage of the RPE and leads to complete choroidal remodeling and better visual outcomes.

The ongoing growth of city populations has brought new challenges and increased complexity to everyday city life. In response, numerous cities are making efforts to adopt new information technologies to become more efficient and transform themselves into smart cities. A large body of research has underlined that the success of these smart city initiatives depends on putting citizens at the center of the design process. In contrast to the techno-centric view applied in the past, citizen-centric approaches focus on prioritizing the needs of citizens over technology and aim to involve them directly in the development of smart city services. In this paper, we describe this involvement as citizen development by introducing a model-based architecture that enables citizens to develop smart city services in a low-code fashion. Consequently, we focus on citizen developers, a group of citizens engaged with the technological development of services. Further, the conceptualization of a citizen development architecture is discussed, as well as the ways citizens can interact with it. An important pillar in this approach are citizen workshops, which aim to stimulate innovative ideas and collaboration among stakeholder by using design thinking methodology. Our approach empowers citizens to become active producers within the smart city ecosystem, leading to more inclusive and citizen-centric smart cities.

Background Finding drugs that can interact with a specific target to induce a desired therapeutic outcome is key deliverable in drug discovery for targeted treatment. Therefore, both identifying new drug–target links, as well as delineating the type of drug interaction, are important in drug repurposing studies. Results A computational drug repurposing approach was proposed to predict novel drug–target interactions (DTIs), as well as to predict the type of interaction induced. The methodology is based on mining a heterogeneous graph that integrates drug–drug and protein–protein similarity networks, together with verified drug-disease and protein-disease associations. In order to extract appropriate features, the three-layer heterogeneous graph was mapped to low dimensional vectors using node embedding principles. The DTI prediction problem was formulated as a multi-label, multi-class classification task, aiming to determine drug modes of action. DTIs were defined by concatenating pairs of drug and target vectors extracted from graph embedding, which were used as input to classification via gradient boosted trees, where a model is trained to predict the type of interaction. After validating the prediction ability of DT2Vec+, a comprehensive analysis of all unknown DTIs was conducted to predict the degree and type of interaction. Finally, the model was applied to propose potential approved drugs to target cancer-specific biomarkers. Conclusion DT2Vec+ showed promising results in predicting type of DTI, which was achieved via integrating and mapping triplet drug–target–disease association graphs into low-dimensional dense vectors. To our knowledge, this is the first approach that addresses prediction between drugs and targets across six interaction types.

Interplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes widespread increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism andde novonucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors.

The purpose of this paper is to briefly chart the current course of distance education in humanities and mathematical sciences in Greece in the post-lockdown (due to the COVID-19 pandemic) era. The questions posed examine whether distance education facilitated students in the aforementioned disciplines or not, the students’ views and attitudes towards distance education, and the effects of this type of teaching / learning. In this paper, we describe distance education as an innovative way of teaching / learning, so we also posed questions regarding the potential changes in students’ relationships with their University, their professors, and their fellow students. It should be noted that this paper is a continuation of the research paper on “The Effects of COVID-19 on Education, with a Focus on Distance Education: A Preliminary Study”, published by the reputable Merit Research Journal of Education and Review, Vol. 10(9), pp.130-137, November 2022.

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Supplementary Material and Methods

Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry–based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. Hence, our findings provide more in-depth information regarding the molecular mechanisms underlying cardiac glycoside-induced cytotoxicity. Mol Cancer Ther; 10(11); 2083–93. ©2011 AACR.

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486–501. ©2017 AACR.

Capture the Flag (CTF) challenges are frequently used as cybersecurity learning environments to engage students in cybersecurity education activities and learning, focusing on technical concepts. CTF challenges cover various learning topics. However, they do not always maintain a clear learning outcome. In this paper, we present a systematic approach to study and evaluate CTF challenges, then apply the evaluation methodology in two CTF challenges that relate to the development of secure mobile applications. For this proof of concept, we used the National Initiative for Cybersecurity Education (NICE) which is a cybersecurity educational framework published by the National Institute of Standards and Technology (NIST). Additional information was used for the evaluation process which included threat, vulnerability, and weakness taxonomies proposed by Open Web Application Security Project® (OWASP) and Mitre Corporation (MITRE). The evaluation methodology could be used to assess and determine the learning outcomes of other existing or upcoming CTF challenges, including though not limited to secure mobile application development.

Calciphylaxis is a rare yet potentially fatal condition, resulting from ectopic calcification of the small arterioles of the dermis with resulting necrotic lesions infection, sepsis, and death. In hemodialysis patients, its prevalence ranges between 1 and 4%, while mortality amounts to 30–80%. We present in here a 45-year-old female on chronic dialysis with morbid obesity, who was admitted for painful nodules in the lower abdomen and necrotic lesions at the lower extremities. Severe uremia and uncontrolled secondary hyperparathyroidism were the main characteristics in this patient, and thus, a clinical diagnosis of calciphylaxis was made. Treatment modalities included wound care plus antibiotics and analgesics, daily hemodialysis, and strategies targeting calcification with sodium thiosulfate, cinacalcet, and non-calcium-containing binders. A crucial factor for overcoming the infection-lesion vicious circle is thorough and daily care of the lesions. Nursing attention was focused on the motivation of her self-care, for the prevention of institutionalization and the psychological support of the patient and her family. The most intriguing feature was the fact that she experienced several exacerbations during the follow-up time. During the final relapse, she was prescribed hyperbaric oxygen sessions that actually put the disease under control thereafter. The good outcome for this patient was probably related to the combination of close follow-up along with a multidisciplinary approach.

Aims/hypothesis Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. Methods We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA1c target of Results Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from −17.71 mmol/mol (−1.62%) to −22.35 mmol/mol (−2.06%) vs placebo, −3.22 mmol/mol (−0.29%) to −10.06 mmol/mol (−0.92%) vs GLP-1 RAs, and −7.66 mmol/mol (−0.70%) to −12.02 mmol/mol (−1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. Conclusions/interpretation A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449. Graphical abstract

Lactoferrin is a protein, primarily found in milk that has attracted the interest of the food industries due to its health properties. Nevertheless, the instability of lactoferrin has limited its commercial application. Recent studies have focused on encapsulation to enhance the stability of lactoferrin. However, the molecular insights underlying the changes of structural properties of lactoferrin and the interaction with protectants remain poorly understood. Computational approaches have proven useful in understanding the structural properties of molecules and the key binding with other constituents. In this review, comprehensive information on the structure and function of lactoferrin and the binding with various molecules for food purposes are reviewed, with a special emphasis on the use of molecular dynamics simulations. The results demonstrate the application of modeling and simulations to determine key residues of lactoferrin responsible for its stability and interactions with other biomolecular components under various conditions, which are also associated with its functional benefits. These have also been extended into the potential creation of enhanced lactoferrin for commercial purposes. This review provides valuable strategies in designing novel nutraceuticals for food science practitioners and those who have interests in acquiring familiarity with the application of computational modeling for food and health purposes.

Fruit is constantly challenged by wounding events, inducing accelerated ripening and irreversible metabolic changes. However, cognate mechanisms that regulate this process are little known. To expand our knowledge of ripening metabolism induced by wounding, an artificial-wound global transcriptome investigation combined with metabolite profiling study was conducted in postharvest kiwifruit (Actinidia chinensis var. deliciosa (A. Chev.) A. Chev. 'Hayward'). Wounding treatment promoted fruit ripening, as demonstrated by changes in fruit firmness, ethylene production and respiration activity determined periodically during a ripening period of 8 d at room temperature. Calcium imaging using fluorescent probe Fluo-3 AM revealed spatial dynamics of Ca