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.

Spatial constraints in urban areas very often lead to the application of traffic management measures to meet transport demands. Accordingly, it is very important to identify all potential impacts that could lead to reductions in the street network’s capacity. One such impact is weather conditions. The main motivation of this research is to analyze the impacts of rainfall on one of the most important segments of Belgrade’s street network that represents part of a freeway passing the city center. Our focus is on quantifying the impact of rainfall on speed and capacity. This paper proposes a new approach to analyzing the rainfall impact at the traffic lane level that provides additional possibilities to apply traffic management measures on the traffic lane level instead of at the direction level only. Functional dependences and differences in capacity and speed on traffic lanes were found under the influence of different rainfall intensities. Reductions in free-flow speed depend on the rain category and traffic lanes and vary from 4.5% to 11.58%, while reductions in traffic lane capacity range from 2.46% to 12.97%. We demonstrate the importance of considering the impact of rainfall at the traffic lane level, which could be quality input data for defining appropriate traffic management measures to mitigate the negative impacts.

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.

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.

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.

Many sexting studies conducted in the Western cultures have shown that the percentage is higher in less traditional cultures. However, the generalizability of this phenomenon to non-Western cultures has not been extensively researched. The purpose of this study is to examine and explain cross-cultural differences in sexting behavior among subjects from Bosnia and Herzegovina and Croatia. A mixed methods approach was used. The first, qualitative phase included focus groups with two groups of high school students from Bosnia and Herzegovina and Croatia ( N = 57 ), aged 15 to 19. In the second, quantitative phase, questionnaires were sent to 440 young adults with an average age of 21 years ( SD = 3.8 ). From the interviews with the young people, nonconsensual sexting was perceived as less beneficial. Sexting was viewed as a double standard. The quantitative study revealed gender and country differences in attitudes toward sexting and motives for sexting. Positive attitudes toward sexting were found to predict different forms of sexting motives in both samples. In the sample from Bosnia and Herzegovina, age was found to predict sexting with instrumental motives and body image reinforcement motives. Gender, on the other hand, was found to be predictive of instrumental sexting motives in the Croatian sample and body image reinforcement sexting motives in the Bosnia and Herzegovina sample. This study illustrates the value of cross-cultural approaches combined with mixed methods as a design to study sexting behavior.

Decision-making represents a very popular field with many developed approaches. However, still exists the need for the creation of novel integrated models such as well is the case in this paper. The novel integrated Improved Fuzzy Stepwise Weight Assessment Ratio Analysis (IMF SWARA) method, Fuzzy Dombi weighted geometric averaging (FDWGA) operator and PESTEL (P-Political, E-Economic, S-Social, T-Technological, E-Environmental, L-Legal) model has been developed. Five decision-makers (DMs) have evaluated six main elements of the PESTEL analysis and 30 elements more (five for each group). In total, we have created 35 models based on the developed model. Results of PESTEL analysis based on IMF SWARA method and FDWGA shows that legal and economic factors represent the most significant parameters, while last placed belong environmental group. Also, the usefulness of the developed integrated model has been demonstrated.

Choledochal cysts (CCs) are rare congenital anomalies in the form of cystic dilatation of any part of the biliary tree, and they rarely reach the size over 10 cm. We present a case of a 51-year-old female with a one-year history of abdominal pain and palpable mass in the epigastrium and right upper abdomen. Diagnosis of giant CC was made using magnetic resonance cholangiopancreatography. Intraoperatively, a large CC without gallbladder (no previous cholecystectomy was performed) was found under the liver pushing the surrounding structures, extending into the intrapancreatic portion of bile ducts and leading to the destruction of the backside of the pancreas head. Complete excision of CC and biliopancreatic reconstruction was achieved by Roux-en-Y pancreaticojejunostomy and hepaticojejunostomy. This case report describes an extremely rare association between an atypical giant choledochal cyst and gallbladder agenesis.

Abstract Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), range: 13–88 years; 64% male], 85 participants [6.4%; 95% CI (5.1, 7.8)] had one or more P/LP germline variant in a wider range of CSGs than previously recognized. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield, we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

Introduction: With the advent of the COVID-19 pandemic, people’s dietary habits have changed, so the importance of additional supplementation has become a current topic. The aim of this study is to analyze the attitude of female respondents toward dietary supplementation before and during the COVID-19 pandemic.Methods: The research is a cross-sectional study conducted in two different time periods. The sample consisted of two female subsamples who purchased immunity preparations from Verdant Pharmacy before the pandemic (n = 81) and during the pandemic (n = 120). Female respondents in both subsamples were: Of the same age, in the same health condition, residing in the same area (municipality), users of a local pharmacy located near the health center. The research instrument was a non-standardized questionnaire “Assessment of attitudes towards nutritional supplementation,” which consisted of nine questions.Results: During the pandemic COVID-19, the attitude toward the use of preparations to strengthen immunity differs by 7% compared to the pre-pandemic check. The attitude toward the use of preparations to strengthen immunity throughout the year increased by 32.3% (53.3%) during the pandemic, and the attitude toward the choice of preparations to strengthen immunity changed by 13% during the pandemic COVID-19 based on own experience and by 17% based on the recommendation of the pharmacist.Conclusion: The pandemic COVID-19 has contributed to a change in female respondents’ attitudes toward nutritional supplementation to strengthen the immune system during a pandemic. With the help of the media, public health recommendations, and people’s fear of disease, the COVID-19 pandemic led to a change in respondents’ attitudes compared to the pre-pandemic period.