Introduction. The beginning of the COVID-19 pandemic led to a lockdown resulting in an 85% reduction in the compulsory immunization of children in 82 countries in May 2020 compared to January and February 2020. The World Health Organization states that during the first four months, for the first time in 28 years, the vaccination coverage of children with the third dose of gout, tetanus, and pertussis vaccines dropped significantly. The objective of the research is to determine the effect of COVID-19 on the implementation of mandatory vaccination of children and youth in the FBiH in 2020 compared to 2019. Subjects and methods: Data for vaccination coverage for children and youth in FBiH were extracted from the official records of the Institute for Public Health of the FBiH, in 2019 and 2020. The percentage of children vaccinated through mandatory vaccination processes was analyzed, expressed as a percentage in primary vaccination and revaccination by FBiH counties in 2020 and 2019 in relation to the planned number of children. Results. The study found a decrease in vaccination with the first doses of vaccine in FBiH, with the exception of the BCG vaccine, which has an increase of 2.3% compared to 2019. In particular, there is a decrease in vaccination with the third dose of the Hepatitis B vaccine and the DTaP-IPV-Hib vaccine third dose. In 2020, in the FBiH, there was a decrease of 26.7% in vaccination with the first dose of MRP vaccine. Conclusion. The research found a significant decline in the vaccination of children and youth for almost all vaccines in all FBiH counties in 2020, which indicates an increased risk for vaccine-preventable diseases.Vaccination improvement activities in the FBiH need to be intensified in order to reduce the risk of vaccine-preventable diseases. © 2022 Hrvatski Lijecnicki Zbor. All rights reserved.

Additive manufacturing (AM) or industrial three-dimensional (3D) printing drives a new spectrum of design and production possibilities; pushing the boundaries both in the application by production of sophisticated products as well as the development of next-generation materials. AM technologies apply a diversity of feedstocks, including plastic, metallic, and ceramic particle powders with distinct size, shape, and surface chemistry. In addition, powders are often reused, which may change the particles’ physicochemical properties and by that alter their toxic potential. The AM production technology commonly relies on a laser or electron beam to selectively melt or sinter particle powders. Large energy input on feedstock powders generates several byproducts, including varying amounts of virgin microparticles, nanoparticles, spatter, and volatile chemicals that are emitted in the working environment; throughout the production and processing phases. The micro and nanoscale size may enable particles to interact with and to cross biological barriers, which could, in turn, give rise to unexpected adverse outcomes, including inflammation, oxidative stress, activation of signaling pathways, genotoxicity, and carcinogenicity. Another important aspect of AM-associated risks is emission/leakage of mono- and oligomers due to polymer breakdown and high temperature transformation of chemicals from polymeric particles, both during production, use, and in vivo, including in target cells. These chemicals are potential inducers of direct toxicity, genotoxicity, and endocrine disruption. Nevertheless, understanding whether AM particle powders and their byproducts may exert adverse effects in humans is largely lacking and urges comprehensive safety assessment across the entire AM lifecycle—spanning from virgin and reused to airborne particles. Therefore, this review will detail: 1) brief overview of the AM feedstock powders, impact of reuse on particle physicochemical properties, main exposure pathways and protective measures in AM industry, 2) role of particle biological identity and key toxicological endpoints in the particle safety assessment, and 3) next-generation toxicology approaches in nanosafety for safety assessment in AM. Altogether, the proposed testing approach will enable a deeper understanding of existing and emerging particle and chemical safety challenges and provide a strategy for the development of cutting-edge methodologies for hazard identification and risk assessment in the AM industry.

Introduction: Although evidence has demonstrated that SARS-COV-2 primarily affects the upper respiratory tract, other systems are also involved such as gastrointestinal and cardiovascular system. At present, there is insufficient data on cardiovascular and immunologic involvement in COVID-19 paediatric patients. Patients and Methods: This study evaluated 70 children previously healthy or with no pre-existing heart disease from Sarajevo with positive post-COVID history. Detailed cardiovascular examination was performed, with parameters of body weight, height, oxygen saturation, pulse, blood pressure, electrocardiogram (ECG), 24hrs Holter ECG, echocardiography. Laboratory tests included values of polymerase chain reaction (PCR) and SARS-COV-2 immunoglobulin G /IgG/ and immunoglobulin M /IgM/, CBC /complete blood count/, creatinine phosphokinase myofibrilae /CPKMB/, creatinine phosphokinase/CPK/, lactate dehydrogenase /LDH/, liver enzymes, D dimer, C reactive protein/CRP/ and urine. Results: Majority of children (64.3%) were asymptomatic. ECG was normal in relation to patients’ age, except in eight patients (intermittent palpitations on exertion): short PR interval, so in 24hrs ECG Holter there was no significant arrhythmias except incomplete right branch block / IRBB/ in 12%, monofocal ventricular ectopicextrasystole /VES/ in 15%. Echocardiogram was normal in all patients with normal ejection fraction of the left ventricle, no pericardial effusion, vegetations or thrombus was detected. Mean diameter of coronary arteries right /RCA/ and left /LCA/ ranged from 1.98 mm to LCA 2.09 mm except in one symptomatic patient a diameter of left coronary artery /LCA/ was enlarged up to 3.8 mm. The concentration levels of COVID-19 IgG showed a statistical significance when compared between younger and older age groups in examined children (p < 0.05;p = 0.043). Conclusion: Cardiovascular evaluation should always be an option in post-COVID patients. Immunological assessment is necessary in post-COVID patients in order to gain a further understanding of patient’s status. © 2022 Hrvatski Lijecnicki Zbor. All rights reserved.

Abstract Payers and manufacturers can disagree on the appropriate level of evidence that is required for new medical devices, resulting in high societal costs due to decisions taken with sub‐optimal information. A cost‐effectiveness model of a hypothetical total artificial heart was built using data from the literature and the (simulated) results of a pivotal study. The expected value of perfect information (EVPI) was calculated from both the payer and manufacturer perspectives, using net monetary benefit and the company's return on investment respectively. A function was also defined, linking effectiveness to market shares. Additional constraints such as a minimum clinical difference or maximum budget impact were introduced into the company's decisions to simulate additional barriers to adoption. The difference in the EVPI between manufacturers and payers varied greatly depending on the underlying decision rules and constraints. The manufacturer's EVPI depends on the probability of being reimbursed, the uncertainty on the (cost‐)effectiveness of the technology, as well as other parameters relating to initial investments, operating costs and market dynamics. The use of Value of information for both perspectives can outline potential misalignments and can be particularly useful to inform early dialogs between manufacturers and payers, or negotiations on conditional reimbursement schemes.

The development of autologous chimeric antigen receptor T (CAR-T) cell therapies has revolutionized cancer treatment. Nevertheless, the delivery of CAR-T cell therapy faces challenges, including high costs, lengthy production times, and manufacturing failures. To overcome this, attempts have been made to develop allogeneic CAR-T cells using donor-derived conventional CD4+ or CD8+ T cells (Tconvs), but severe graft-versus-host disease (GvHD) and host immune rejection have made this challenging. CD3+CD4−CD8− double-negative T cells (DNTs) are a rare subset of mature T cells shown to fulfill the requirements of an off-the-shelf cellular therapy, including scalability, cryopreservability, donor-independent anticancer function, resistance to rejection, and no observed off-tumor toxicity including GvHD. To overcome the challenges faced with CAR-Tconvs, we evaluated the feasibility, safety, and efficacy of using healthy donor–derived allogeneic DNTs as a CAR-T cell therapy platform. We successfully transduced DNTs with a second-generation anti–CD19-CAR (CAR19) without hampering their endogenous characteristics or off-the-shelf properties. CAR19-DNTs induced antigen-specific cytotoxicity against B cell acute lymphoblastic leukemia (B-ALL). In addition, CAR19-DNTs showed effective infiltration and tumor control against lung cancer genetically modified to express CD19 in xenograft models. CAR19-DNT efficacy was comparable with that of CAR19-Tconvs. However, unlike CAR19-Tconvs, CAR19-DNTs did not cause alloreactivity or xenogeneic GvHD-related mortality in xenograft models. These studies demonstrate the potential of using allogeneic DNTs as a platform for CAR technology to provide a safe, effective, and patient-accessible CAR-T cell treatment option. Description Allogeneic CAR-DNTs with minimal genetic modification show potent anti-tumor activity without off-tumor toxicities. A CAR that drives killing but not toxicity Chimeric antigen receptor (CAR)–T cell therapies are FDA-approved for treating blood cancers but are often limited by toxicities, and difficult and expensive production. Thus, developing more streamlined CAR-T cell therapies is crucial. Here, Vasic et al. used mouse and human double-negative (DN) T cells as a CAR-T cell therapy, showing robust efficacy in mouse models of blood and lung cancers. They found that the DN CAR-T cells were just as effective as conventional CAR-T cells but induced no toxicity. The double-negative CAR-T cells could be produced from mixed donors, were not rejected from hosts, and could be frozen for long periods of time. Thus, DN CAR-T cells are an attractive “off-the-shelf” CAR-T cell therapy option.

A search for the charged-lepton-flavor-violating process $Z\rightarrow e\mu$ is presented, using 139 fb$^{-1}$ of $\sqrt{s}=13$ TeV $pp$ collision data collected by the ATLAS experiment at the LHC. An excess in the $e\mu$ invariant mass spectrum near the $Z$ boson mass would be a striking signature of new physics. No excess is observed, and an upper limit $B(Z\rightarrow e\mu)<2.62 \times 10^{-7}$ is placed on the branching fraction at 95% confidence level, which is the most stringent limit to date.

Background Tumor-related hyperintensities in high b-value diffusion-weighted imaging (DWI) are radiologically important in the workup of gliomas. However, the white matter may also appear as hyperintense, which may conflate interpretation. Purpose To investigate whether DWI with spherical b-tensor encoding (STE) can be used to suppress white matter and enhance the conspicuity of glioma hyperintensities unrelated to white matter. Materials and Methods Twenty-five patients with a glioma tumor and at least one pathology-related hyperintensity on DWI underwent conventional MRI at 3 T. The DWI was performed both with linear and spherical tensor encoding (LTE-DWI and STE-DWI). The LTE-DWI here refers to the DWI obtained with conventional diffusion encoding and averaged across diffusion-encoding directions. Retrospectively, the differences in contrast between LTE-DWI and STE-DWI, obtained at a b-value of 2,000 s/mm2, were evaluated by comparing hyperintensities and contralateral normal-appearing white matter (NAWM) both visually and quantitatively in terms of the signal intensity ratio (SIR) and contrast-to-noise ratio efficiency (CNReff). Results The spherical tensor encoding DWI was more effective than LTE-DWI at suppressing signals from white matter and improved conspicuity of pathology-related hyperintensities. The median SIR improved in all cases and on average by 28%. The median (interquartile range) SIR was 1.9 (1.6 – 2.1) for STE and 1.4 (1.3 – 1.7) for LTE, with a significant difference of 0.4 (0.3 –0.5) (p < 10–4, paired U-test). In 40% of the patients, the SIR was above 2 for STE-DWI, but with LTE-DWI, the SIR was below 2 for all patients. The CNReff of STE-DWI was significantly higher than of LTE-DWI: 2.5 (2 – 3.5) vs. 2.3 (1.7 – 3.1), with a significant difference of 0.4 (−0.1 –0.6) (p < 10–3, paired U-test). The STE improved CNReff in 70% of the cases. We illustrate the benefits of STE-DWI in three patients, where STE-DWI may facilitate an improved radiological description of tumor-related hyperintensity, including one case that could have been missed out if only LTE-DWI was inspected. Conclusion The contrast mechanism of high b-value STE-DWI results in a stronger suppression of white matter than conventional LTE-DWI, and may, therefore, be more sensitive and specific for assessment of glioma tumors and DWI-hyperintensities.

Melanoma is a highly aggressive cancer originating from melanocytes. Its etiopathogenesis is strongly related to genetic, epigenetic, and environmental factors. Melanomas encountered in clinical practice are predominantly sporadic, whereas hereditary melanomas account for approximately 10% of the cases. Hereditary melanomas mainly develop due to mutations in the cyclin-dependent kinase 2A (CDKN2A) gene, which encodes two tumor suppressor proteins involved in the cell cycle regulation. CDKN2A, along with CDK4, TERT, and POT1 genes, are high-risk genes for melanoma. Among the genes that carry a moderate risk are MC1R and MITF, whose protein products are involved in melanin synthesis. The environment also contributes to the development of melanoma. Patients at risk of melanoma should be offered genetic counseling to discuss genetic testing options and the importance of skin UV protection, avoidance of sun exposure, and regular preventive dermatological examinations. Although cancer screening cannot prevent the development of the disease, it allows for early diagnosis when the survival rate is the highest.

ABSTRACT To gain insight into the complex microbiome-gut-brain axis in irritable bowel syndrome (IBS), several modalities of biological and clinical data must be combined. We aimed to identify profiles of fecal microbiota and metabolites associated with IBS and to delineate specific phenotypes of IBS that represent potential pathophysiological mechanisms. Fecal metabolites were measured using proton nuclear magnetic resonance (1H-NMR) spectroscopy and gut microbiome using shotgun metagenomic sequencing (MGS) in a combined dataset of 142 IBS patients and 120 healthy controls (HCs) with extensive clinical, biological and phenotype information. Data were analyzed using support vector classification and regression and kernel t-SNE. Microbiome and metabolome profiles could distinguish IBS and HC with an area-under-the-receiver-operator-curve of 77.3% and 79.5%, respectively, but this could be improved by combining microbiota and metabolites to 83.6%. No significant differences in predictive ability of the microbiome–metabolome data were observed between the three classical, stool pattern-based, IBS subtypes. However, unsupervised clustering showed distinct subsets of IBS patients based on fecal microbiome–metabolome data. These clusters could be related plasma levels of serotonin and its metabolite 5-hydroxyindoleacetate, effects of psychological stress on gastrointestinal (GI) symptoms, onset of IBS after stressful events, medical history of previous abdominal surgery, dietary caloric intake and IBS symptom duration. Furthermore, pathways in metabolic reaction networks were integrated with microbiota data, that reflect the host-microbiome interactions in IBS. The identified microbiome–metabolome signatures for IBS, associated with altered serotonin metabolism and unfavorable stress response related to GI symptoms, support the microbiota-gut-brain link in the pathogenesis of IBS.