There is great demand for analytical methods capable of providing high-throughput and rapid screening, especially for anti-doping and clinical point-of-care applications. In this work, automated microfluidic open interface-mass spectrometry (MOI-MS) was used for coupling with high-throughput, automated solid-phase microextraction (SPME) to achieve this objective. The design of the MOI-MS interface provides a continuous and stable electrospray fluid flow to the MS without introducing any bubble, a feature that we exploit to introduce the concept of multi-segment injection for the determination of multiple samples in a single MS run. By eliminating the need to start a new MS run between sample assays, the developed approach provides significantly simplified protocols controlled by programmed software and increased reproducibility. Furthermore, the biocompatible SPME device, which utilizes coating consisting of hydrophilic-lipophilic balanced particles embedded in a polyacrylonitrile (PAN) binder, can be directly used for biological sample analysis, as the PAN acts as both a binder and a matrix-compatible barrier, thus enabling the enrichment of small molecules while eliminating interferences associated with the presence of interfering macromolecules. The above design was employed to develop a fast, quantitative method capable of analyzing drugs of abuse in saliva samples in as little as 75 s per sample. The findings indicate that the developed method provides good analytical performance, with limits of detection ranging between 0.05 and 5 ng/mL for analysis of 16 drugs of abuse, good calibration linear correlation coefficients (R2 ≥ 0.9957), accuracy between 81 and 120%, and excellent precision (RSD% < 13%). Finally, a proof-of-concept experiment was performed to demonstrate the method's suitability for real-time analysis in anti-doping applications.

Purpose The purpose of this paper is to assess the possibility of asymmetric impact of monetary policy on housing permits issued in each state of the USA. Design/methodology/approach The methodology and approach are based on the linear ARDL and nonlinear ARDL approach to error-correction modeling and asymmetric cointegration. Findings The linear models predict that money supply impact housing permits in 28 states in the short run and only nine states in the long run. However, the asymmetric effects are far more pervasive, highlighting the restrictive nature of the linear model. The results from the nonlinear model show at least one lag of positive and/or negative changes in money supply significantly impacts housing permits in nearly all states. Even in the long run, housing permits in 32 states share a long-run relationship with positive and/or negative changes in money supply. The authors also find contractionary monetary policy has a greater influence on housing permits in most states compared to expansionary policy. Originality/value For the first time, the authors use state-level data and asymmetric approach to assess the impact of monetary policy on house permits issued in each state of the USA.

Abstract The amperometric biosensor was created using a flat sheet of the Cu-Zn-Al shape memory alloy, with a shiny surface and uniform thickness below 1 mm. The high biocompatibility and a large specific surface area for enzyme loading are evaluated. In vitro biomedical corrosion testing of samples revealed successful immobilization of catalase, which has undergone quasi-reversible electron transfer from the surface and saline solution. A catalase that had been immobilized retained its basic structure and bioactivity and demonstrated a remarkable electrocatalytic response to hydrogen peroxide reduction. The reduction of hydrogen peroxide on the catalase-modified Cu-25.38Zn-3.3Al alloy was investigated using hydrodynamic amperometry in both the absence and presence of l-cysteine and K2[B3O3F4OH] inhibitors. Catalytic reduction currents have increased as a result of the gradual increase in hydrogen peroxide concentration. The study on enzyme activity inhibition has shown a lower corrosion rate of catalase-modified bioalloy than the initial sample because inhibitor ions occupy all sites of the immobilized enzyme.

Abstract Objectives: Assess the extent to which the clinical trial registration and reporting policies of 25 of the world’s largest public and philanthropic medical research funders meet best practice benchmarks as stipulated by the 2017 WHO Joint Statement, and document changes in the policies and monitoring systems of 19 European funders over the past year. Design, Setting, Participants: Cross-sectional study, based on assessments of each funder’s publicly available documentation plus validation of results by funders. Our cohort includes 25 of the largest medical research funders in Europe, Oceania, South Asia, and Canada. Interventions: Scoring all 25 funders using an 11-item assessment tool based on WHO best practice benchmarks, grouped into three primary categories: trial registries, academic publication, and monitoring, plus validation of results by funders. Main outcome measures: How many of the 11 WHO best practice items each of the 25 funders has put into place, and changes in the performance of 19 previously assessed funders over the preceding year. Results: The 25 funders we assessed had put into place an average of 5/11 (49%) WHO best practices. Only 6/25 funders (24%) took the PI’s past reporting record into account during grant application reviews. Funders’ performance varied widely from 0/11 to 11/11 WHO best practices adopted. Of the 19 funders for which 2021(2) baseline data was available, 10/19 (53%) had strengthened their policies over the preceding year. Conclusions: Most medical research funders need to do more to curb research waste and publication bias by strengthening their clinical trial policies.

The vector-boson production cross-section for the Higgs boson decay in the $H \rightarrow WW^{\ast} \rightarrow e\nu\mu\nu$ channel is measured as a function of kinematic observables sensitive to the Higgs boson production and decay properties as well as integrated in a fiducial phase space. The analysis is performed using the proton-proton collision data collected by the ATLAS detector in Run 2 of the LHC at $\sqrt{s}= 13$ $\text{TeV}$ center-of-mass energy corresponding to an integrated luminosity of 139 fb$^{-1}$. The different flavor final state is studied by selecting an electron and a muon originating from a pair of $W$ bosons and compatible with the Higgs boson decay. The data are corrected for the effects of detector inefficiency and resolution, and the measurements are compared with different state-of-the-art theoretical predictions. The differential cross-sections are used to constrain anomalous interactions described by dimension-six operators in an Effective Field Theory.

Background. The arbitrability of administrative contracts contributes to sustainable dispute resolution within the United Nations’ Sustainable Development Goals 16 (SDG 16). However, different regulation of administrative contracts in comparative law affects the arbitrability of the disputes arising out of them. The question arises – is protection deserved if an administrative contract containing an arbitration clause concluded in violation of the administrative law of the governmental body or without a special approval is invalid, unenforceable, or if the company was unaware of such a requirement? This paper analyses the concept of an administrative contract and its arbitrability in Saudi Arabia and comparative law to provide for sustainable solutions. Methods. The analysis of the applicable arbitration and administrative laws and rules is conducted with the normative method to establish the arbitrability of the disputes arising out of administrative contracts and the concept of the administrative contract. The case analysis reveals if the legislative approach causes difficulties in practice. The dogmatic method is applied to link the reasons for legislative and case law development to the current normative solutions in comparative and Saudi law. The conclusions on the existing problems and possible solutions shall be based on the analytical method. Results and Conclusions. Government contracts are of great importance and their exclusion from arbitration contradicts the set goal of sustainable dispute resolution mechanism. Differences in comparative law in terms of the notion of the administrative contract and the arbitrability may diminish the positive effects of arbitration in administrative contracts, as they may endanger equal access to dispute resolution as part of the sustainable development goals, be enforceable, or even cause discrepancies between states that annul the arbitration awards and others that still enforce the awards despite their annulment.

Introduction: The use of the Internet is becoming increasingly important in enabling children and adults to fully participate in society, whether it is learning new skills or connecting with friends and family. Consequently, children's opportunities are increasingly dependent on the Internet. The advance of technological innovations has resulted in more and more ICT devices being available to children, contributing to the deterioration of children and adolescents' health. Methods: The study was designed as an epidemiological, cross-sectional, descriptive-analytical, comparative study. The study was conducted from October 18, 2021, to January 16, 2022, using an online questionnaire accessible through the Microsoft Forms platform. Respondents were able to access the questionnaire via a link or QR code located on the child's consent form for participation in the study, which was previously signed by a parent/guardian. Results: The results of the study showed that school-age children were the most frequent users of smartphones and watches TV, with male respondents spending more time using almost all ICT devices, with the exception of tablets, which were used more frequently by female respondents. The analysis of pain intensity in the use of information and communication technologies revealed that respondents most frequently experienced mild pain, especially in the neck/shoulders and lower extremities. The frequency of eye problems after using ICT devices was found to be occasional, with the most pronounced symptoms being fatigue, tearing, and eyestrain, as well as headaches in one in five respondents. Conclusion: Increasing frequency of ICT device use was associated with higher pain intensity in all anatomic regions. A 1-hour increase in weekly ICT device use also increased the likelihood of pain intensity in all anatomic regions, including eye symptoms and headaches. High exposure to ICT is of concern because it leads to adverse health outcomes for children.

Abstract Ova Studija nastaje u vremenu potrebe za rekonstrukcijom, adaptacijom, popravkom i unapređenjem inženjerskog naselja (Bungalovi) Mješovitog Holdinga “ERS” MP a.d. Trebinje ZP “ Hidroelektrane na Drini” a.d. Višegrad, u naselje koje će biti na mapi turističke ponude Višegrada. Turizam Višegrada je u ekspanziji, raste tražnja za turističkom ponudom. Geografski položaj Višegrada, ćuprija na Drini koja je vezana za nobelovca Ivu Andrića, zatim od nedavno Andrićgrad, kao i blizina Zlatibora, doprinose da Višegrad bude veoma interesantna turistička destinacija. Cilj inoviranog naselja jeste profit, koji će ovo preduzeće ostvarivati putem izdavanja bungalova zainteresovanim turistima. Mješoviti Holding “ERS” MP a.d. Trebinje ZP “ Hidroelektrane na Drini”, a.d. Višegrad, uradilo je sve pripreme za adaptaciju istog, tj. naselje se priprema za turističku ponudu. Godina 2023. jeste godina kada se očekuju intezivni radovi na ovom projektu, odnosno godina završetka najvećeg dijela radova. Finansijska sredstva za rekonstrukciju i adaptaciju istih,od strane nadležnih organa ovog preduzeća, odobrena su planom nabavki za 2023. godinu. Ekonomsko finansijska analiza i istraživanje tržišta, kao sastavni dijelovi ove Studije, pokazuju da je racionalno i ekonomski opravdano ulaganje u rekonstrukciju, adaptaciju i popravku bungalova, s ciljem da postanu sastavni dio turističke ponude Višegrada. Na osnovu Studije može se zaključiti da bi bilo neopravdano da naselje služi samo za izdavanje, znajući da je većina gostiju zainteresovana za usluge SPA centra. Zato ova Studija predviđa izgradnju i SPA centra, sa korištenjem termalne vode koja se nalazi u neposrednoj blizini, što zasigurno može biti komparativna prednost ovog naselja.

Metals and topological insulators have in common that they cannot be described by exponentially localized wave-functions. Here we establish a relationship between these two seemingly unrelated observations. The connection is explicit in the low-lying states of the spectral localizer of trivial metals, an operator that measures the obstruction to finding localized eigenstates. The low-lying spectrum of the spectral localizer of metals is determined by the zero-mode solutions of Dirac fermions with a varying mass parameter. We use this observation, valid in any dimension, to determine the difference between the localizer spectrum of trivial and topological metals, and conjecture the spectrum of the localizer for fractional quantum Hall edges. Because the localizer is a local real-space operator, it may be used as a tool to differentiate between non-crystalline topological and trivial metals, and to characterize strongly correlated systems, for which local topological markers are scarce.

In many areas of oncology, we lack sensitive tumor-burden monitoring to guide critical decision making. While circulating tumor DNA (ctDNA) promises to enable disease monitoring, this approach is limited by the sparsity of ctDNA in the plasma. To overcome this challenge, error-corrected deep targeted sequencing has been proposed. Nonetheless, this framework is limited by the low number of genomic equivalents (GEs, ~103/mL of plasma), imposing a ceiling on effective sequencing depth. We have previously shown that genome-wide mutational integration through plasma whole genome sequencing (WGS) can sever the dependency between available GEs and assay sensitivity (Zviran et al, 2020). In this approach, tumor-informed mutational profiles are applied to plasma WGS, allowing detection of tumor fractions as low as 10−5. However, the higher cost of WGS limits practical depth of coverage (20-30X) and may limit broad adoption. Lower costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (1USD/Gb, Almogy et al, 2022) to plasma from 7 patients with metastatic cancer at ~115x coverage depth. Read depth profiling and error rates were comparable between matched Ultima and standard platform datasets. Integration of deep learning architectures for signal to noise enrichment (Widman et al, biorxiv, 2022) with deeper WGS coverage enabled ctDNA detection at the parts per million range. We reasoned that lower sequencing cost can be harnessed for duplex error-corrected WGS. Proof-of-concept experiments in mouse PDX samples showed ~1,500x decrease in errors. Applied to the plasma of stage IV melanoma patients (n=5), we obtained error rates ~10−7. We used this approach to tackle the challenging context of cancer monitoring in early-stage melanoma without matched tumor sequencing. While in uncorrected WGS, de novo mutation calling yielded limited ability to detect melanoma specific mutations, duplex-corrected WGS allowed us to harness melanoma mutational signatures for disease monitoring without matched tumor profiling. Analytic validation of our assay showed sensitive and specific cancer detection when the concentration of ctDNA was at 10−4 concentrations. Applied to a cohort of stage III melanoma patients with negative ctDNA detection using previously described methods, we detected ctDNA in all cases (n=4), demonstrating enhanced sensitivity using duplex WGS. These data demonstrate the exciting potential of low cost WGS for ultra-sensitive ctDNA cancer monitoring. In the tumor-informed setting, deeper sequencing increased sensitivity for mutational profile detection. Moreover, the application of duplex error-correction at genome scale allowed for sensitive cancer monitoring without matched tumor profiles. We envision that the era of low-cost sequencing will empower ultra-sensitive cancer monitoring via WGS, with transformative impact on cancer care. Citation Format: Alexandre P. Cheng, Adam J. Widman, Anushri Arora, Itai Rusinek, William F. Hooper, Rebecca Murray, Daniel Halmos, Theophile Langanay, Giorgio Inghirami, Soren Germer, Melissa Marton, Adrienne Helland, Rob Furatero, Jaime McClintock, Lara Winterkorn, Zoe Steinsnyder, Yohyoh Wang, Srinivas Rajagopalan, Asrar I. Alimohamed, Murtaza S. Malbari, Ashish Saxena, Margaret K. Callahan, Dennie T. Frederick, Lavinia Spain, Ariel Jaimovich, Doron Lipson, Samra Turajlic, Michael C. Zody, Nasser K. Altorki, Jedd D. Wolchok, Michael A. Postow, Nicolas Robine, Genevieve Boland, Dan A. Landau. Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5709.

Topological insulators are described by topological invariants that can be computed by integrals over momentum space, but also as traces over local, real-space topological markers. These markers are useful to detect topological insulating phases in disordered crystals, quasicrystals and amorphous systems. Among these markers, only the spectral localizer operator can be used to distinguish topological metals, that show zero-modes of the localizer spectrum. However, it remains unclear whether trivial metals also display zero-modes, and if their localizer spectrum is distinguishable from topological ones. Here, we show that trivial metals generically display zero-modes of the localizer spectrum. The localizer zero-modes are determined by the zero-mode solutions of a Dirac equation with a varying mass parameter. We use this observation, valid in any dimension, to determine the difference between the localizer spectrum of trivial and topological metals, and conjecture the spectrum of the localizer for fractional quantum Hall edges. Because the localizer is a local, real-space operator, it may be used as a tool to differentiate between non-crystalline topological and trivial metals, and characterize strongly correlated systems, for which local topological markers are scarce.

Introduction: SETD2, a histone H3-K36 trimethyltransferase, is necessary for regulation of proper intron splicing. SETD2 is frequently inactivated in kidney cancer. We hypothesized that SETD2 deficiency would cause aberrant translation of retained introns (ATaRI) that could serve as potential immunotherapeutic targets in SETD2-mutant states. Methods and Results: We detected increased presence of retained introns in SETD2-mutant vs WT tumors in two publicly available renal cell carcinoma RNA-seq data sets. We hypothesized that if intronic sequences translated into proteins, accumulation of misfolded proteins would activate the Unfolded Protein Response (UPR). The UPR pathway was strongly transcriptionally enriched as measured by GSEA, as were several immunotherapy-relevant pathways, suggesting that tumors are inflamed, possibly related to the antigenic nature of translated introns. To investigate this further, we generated Setd2-isogenic mouse renal cancer cells using CRISPR in the RENCA cell line. RNAseq followed by GSEA confirmed upregulation of UPR pathway transcriptional signature in the Setd2-null condition, supporting our observation in human tumors. Indicators of UPR activation such as cleavage of ATF6 and increase in ATF4 and Xbp1 levels in Setd2 deficient vs. unedited RENCA cells, as well as nuclear translocation of ATF6 in SETD2-mutant human kidney cancer samples validates these findings. We then measured the presence of ATaRI-derived peptides in Setd2-mutant RENCA cells using mass spectrometry, detecting 47 such peptides. Using publicly available proteomics data from one human data set, we preliminarily identified peptides translated from 151 introns that are retained in SETD2-mutant cases. Applying netMHCpan to both the human and murine data, we found that detectable ATaRI peptides were predicted to generate multiple 10-amino acid-long peptides which strongly bind to the 8 murine MHC or to the 20 most common human HLA receptors. We propose that these presentable peptides might activate an immune response to SETD2-mutant renal cell carcinoma. Conclusions: We identified intron retention which may cause activation of the UPR as a feature of SETD2-mutant kidney cancer. ATaRI peptides are detectable and should be presented to the adaptive immune system. These features may represent a new therapeutic vulnerability for exploitation as a rationale for personalized medicine. Citation Format: Marya T. Kozinova, Alexander Metz, Robert Uzzo, Janusz Franco-Barraza, Michael Slifker, Jessica Peskin, Angel Fernández Sanromán, Samra Turajlic, Edna Cukierman, Phillip Phillip Abbosh. SETD2 loss in renal cell carcinoma generates peptides from aberrantly translated retained introns. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6794.