Colossal c-Axis Response and Lack of Rotational Symmetry Breaking within the Kagome Planes of the CsV_{3}Sb_{5} Superconductor.

The kagome materials AV_{3}Sb_{5} (A=K, Rb, Cs) host an intriguing interplay between unconventional superconductivity and charge-density waves. Here, we investigate CsV_{3}Sb_{5} by combining high-resolution thermal-expansion, heat-capacity, and electrical resistance under strain measurements. We directly unveil that the superconducting and charge-ordered states strongly compete, and that this competition is dramatically influenced by tuning the crystallographic c axis. In addition, we report the absence of additional bulk phase transitions within the charge-ordered state, notably associated with rotational symmetry breaking within the kagome planes. This suggests that any breaking of the C_{6} invariance occurs via different stacking of C_{6}-symmetric kagome patterns. Finally, we find that the charge-density-wave phase exhibits an enhanced A_{1g}-symmetric elastoresistance coefficient, whose large increase at low temperature is driven by electronic degrees of freedom.

Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests.

BACKGROUND: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation. METHODS: We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines. RESULTS: The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively. CONCLUSIONS: Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.

No Increased Risk of Aseptic Loosening with Tourniquetless Cemented Total Knee Arthroplasty.

Our study examined whether risk of revision for aseptic loosening following cemented total knee arthroplasty (TKA) is (1) increased with tourniquetless surgery and (2) affected by patient characteristics or surgical factors. Primary cemented TKAs from 2005-2012 with 2-year follow up were analyzed (n = 5,508 with tourniquet; n=101 without). Revision for aseptic loosening was compared between TKA performed with and without a tourniquet. Patient characteristics were recorded. At mean 4.8-year follow up, risk of aseptic loosening was similar between TKA performed with or without a tourniquet (p = 0.3151). Aseptic loosening was more likely in men (p = 0.0018) and patients younger than 50 (p < 0.0001). No difference was observed between cruciate-retaining and posterior-stabilized implants (p = 0.1250). With the numbers available for study, we did not observe an increased risk of aseptic loosening with tourniquetless cemented primary TKA. Patients younger than 50, particularly men, should be counselled on the increased risk of TKA revision for aseptic loosening. (Journal of Surgical Orthopaedic Advances 32(2):111-113, 2023).

Monitoring the Formation of Nickel-Poor and Nickel-Rich Oxide Cathode Materials for Lithium-Ion Batteries with Synchrotron Radiation.

The syntheses of Ni-poor (NCM111, LiNi1/3Co1/3Mn1/3O2) and Ni-rich (NCM811 LiNi0.8Co0.1Mn0.1O2) lithium transition-metal oxides (space group R3̅m) from hydroxide precursors (Ni1/3Co1/3Mn1/3(OH)2, Ni0.8Co0.1Mn0.1(OH)2) are investigated using in situ synchrotron powder diffraction and near-edge X-ray absorption fine structure spectroscopy. The development of the layered structure of these two cathode materials proceeds via two utterly different reaction mechanisms. While the synthesis of NCM811 involves a rock salt-type intermediate phase, NCM111 reveals a layered structure throughout the entire synthesis. Moreover, the necessity and the impact of a preannealing step and a high-temperature holding step are discussed.

Disentangling Lattice and Electronic Instabilities in the Excitonic Insulator Candidate Ta_{2}NiSe_{5} by Nonequilibrium Spectroscopy.

Ta_{2}NiSe_{5} is an excitonic insulator candidate showing the semiconductor or semimetal-to-insulator (SI) transition below T_{c}=326 K. However, since a structural transition accompanies the SI transition, deciphering the role of electronic and lattice degrees of freedom in driving the SI transition has remained controversial. Here, we investigate the photoexcited nonequilibrium state in Ta_{2}NiSe_{5} using pump-probe Raman and photoluminescence spectroscopies. The combined nonequilibrium spectroscopic measurements of the lattice and electronic states reveal the presence of a photoexcited metastable state where the insulating gap is suppressed, but the low-temperature structural distortion is preserved. We conclude that electron correlations play a vital role in the SI transition of Ta_{2}NiSe_{5}.

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

An electronic nematic liquid in BaNi2As2.

Understanding the organizing principles of interacting electrons and the emergence of novel electronic phases is a central endeavor of condensed matter physics. Electronic nematicity, in which the discrete rotational symmetry in the electron fluid is broken while the translational one remains unaffected, is a prominent example of such a phase. It has proven ubiquitous in correlated electron systems, and is of prime importance to understand Fe-based superconductors. Here, we find that fluctuations of such broken symmetry are exceptionally strong over an extended temperature range above phase transitions in [Formula: see text], the nickel homologue to the Fe-based systems. This lends support to a type of electronic nematicity, dynamical in nature, which exhibits a particularly strong coupling to the underlying crystal lattice. Fluctuations between degenerate nematic configurations cause splitting of phonon lines, without lifting degeneracies nor breaking symmetries, akin to spin liquids in magnetic systems.

A novel phenotype-based drug-induced liver injury causality assessment tool (DILI-CAT) allows for signal confirmation in early drug development.

BACKGROUND: Drug-induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice. AIM: We utilised a novel DILI causality assessment tool (DILI-CAT), which uses drug-specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development. METHODS: We conducted a retrospective analysis of liver injury events from four Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials, in which patients were randomised to receive oral ximelagatran or adjusted-dose warfarin. A stepwise process was used with iterative adjustments. The DILI phenotype was characterised by latency, R-value, and AST/ALT ratio. A scoring algorithm was applied to liver events to assess how closely the liver events matched the Interquatile-Range for the working phenotype for each of the three parameters. FINDINGS: Data from 3115 patients included in the SPORTIF trials as above were available. The initial ximelagatran phenotype was developed based on five liver injury cases from the ximelagatran arm and was then validated against an additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there was a statistically significant difference in the total DILI-CAT scores of the two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten ximelagatran cases generated a second, refined ximelagatran phenotype, which was validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again with statistically significant different DILI-CAT ximelagatran vs. warfarin scores (p < 0.001). CONCLUSION: DILI-CAT, a clinically intuitive, data-driven, computer-assisted scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity in clinical drug development.

New insights into the flavoring potential of cricket (Acheta domesticus) and mealworm (Tenebrio molitor) protein hydrolysates and their Maillard products.

Insect proteins have an earthy-like flavor and have not shown great flavor potential for food applications so far. In this study, insect proteins of cricket Acheta domesticus and mealworm Tenebrio molitor larvae were first enzymatically hydrolyzed using two peptidase preparations (Flavourzyme1000L and ProteaseA "Amano"2SD). Xylose was then added to facilitate Maillard reactions (30 min, T = 98 °C, 1% (w/v) xylose). A comprehensive sensory evaluation showed that both the hydrolysis and the Maillard reactions changed the flavor description of the samples significantly to more complex and savory-like taste profiles (27 descriptors for cricket and 39 descriptors for mealworm protein). In addition, 38 odor-active molecules were identified using gas chromatography-olfactometry (1 alcohol, 5 acids, 11 aldehydes, 5 ketones and 16 heterocyclic compounds). The results showed impressively that the flavoring potential of insect proteins was significantly enhanced with respective processing.

Impact of Peptidase Activities on Plant Protein Hydrolysates Regarding Bitter and Umami Taste.

The aim of this study was to investigate six food-grade peptidase preparations, namely, Flavourzyme 1000L, Protease P "Amano" 6SD, DeltazymAPS-M-FG, Promod278, ProteAX-K, and Peptidase R, regarding their use for the hydrolysis of soy, pea, and canola protein. The relationship between the specific peptidase activities and, first, the degree of hydrolysis, second, the free amino acid profiles of the hydrolysates, and, third, the corresponding taste of the hydrolysates was analyzed using a random forest model. The taste attributes bitter and umami were of special interest. The peptidase ProteAX-K was the biocatalyst most suited for the high umami and low bitter taste of the plant-based protein hydrolysates based on the experimental results and the random forest model.

First-time synthesis of a magnetoelectric core-shell composite via conventional solid-state reaction.

In recent years, multiferroics and magnetoelectrics have demonstrated their potential for a variety of applications. However, no magnetoelectric material has been translated to a real application yet. Here, we report for the first time that a magnetoelectric core-shell ceramic, is synthesized via a conventional solid-state reaction, where core-shell grains form during a single sintering step. The core consists of ferrimagnetic CoFe2O4, which is surrounded by a ferroelectric shell consisting of (BiFeO3)x-(Bi1/2K1/2TiO3)1-x. We establish the core-shell nature of these grains by transmission-electron microscopy (TEM) and find an epitaxial crystallographic relation between core and shell, with a lattice mismatch of 6 ± 0.7%. The core-shell grains exhibit exceptional magnetoelectric coupling effects that we attribute to the epitaxial connection between the magnetic and ferroelectric phase, which also leads to magnetic exchange coupling as demonstrated by neutron diffraction. Apparently, ferrimagnetic CoFe2O4 cores undergo a non-centrosymmetric distortion of the crystal structure upon epitaxial strain from the shell, which leads to simultaneous ferrimagnetism and piezoelectricity. We conclude that in situ core-shell ceramics offer a number of advantages over other magnetoelectric composites, such as lower leakage current, higher density and absence of substrate clamping effects. At the same time, the material is predestined for application, since its preparation is cost-effective and only requires a single sintering step. This discovery adds a promising new perspective for the application of magnetoelectric materials.

Next-Generation DILI Biomarkers: Prioritization of Biomarkers for Qualification and Best Practices for Biospecimen Collection in Drug Development.

The diagnosis and management of drug-induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.

Drug-induced liver injury.

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.

Superior Magnetic Performance in FePt L10 Nanomaterials.

The discovery of the high maximum energy product of 59 MGOe for NdFeB magnets is a breakthrough in the development of permanent magnets with a tremendous impact in many fields of technology. This value is still the world record, for 40 years. This work reports on a reliable and robust route to realize nearly perfectly ordered L10 -phase FePt nanoparticles, leading to an unprecedented energy product of 80 MGOe at room temperature. Furthermore, with a 3 nm Au coverage, the magnetic polarization of these nanomagnets can be enhanced by 25% exceeding 1.8 T. This exceptional magnetization and anisotropy is confirmed by using multiple imaging and spectroscopic methods, which reveal highly consistent results. Due to the unprecedented huge energy product, this material can be envisaged as a new advanced basic magnetic component in modern micro and nanosized devices.

Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort.

Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.

Are laboratory parameter (biomarker) values similar to the healthy volunteer reference range in all patient populations?

BACKGROUND: Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. MATERIALS AND METHODS: Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer's, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in Trans-Celerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. RESULTS: Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer's and asthma, had at least one biomarker that was higher than the HVRR. SUMMARY: The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials.

Serum apolipoprotein A1 and haptoglobin, in patients with suspected drug-induced liver injury (DILI) as biomarkers of recovery.

BACKGROUND: There is a clear need for better biomarkers of drug-induced-liver-injury (DILI). AIMS: We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI. METHODS: We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN), and BILI <2x ULN. RESULTS: After adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending) combining the ActiTest components without BILI and ALT (used as references), apolipoprotein-A1, haptoglobin, alpha-2-macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115) and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500). Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4-8 weeks and at 8-12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases. CONCLUSIONS: We identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated.

Preliminary Results of a Novel Algorithmic Method Aiming to Support Initial Causality Assessment of Routine Pharmacovigilance Case Reports for Medication-Induced Liver Injury: The PV-RUCAM.

INTRODUCTION: Data incompleteness in pharmacovigilance (PV) health records limits the use of current causality assessment methods for drug-induced liver injury (DILI). In addition to the inherent complexity of this adverse event, identifying cases of high causal probability is difficult. OBJECTIVE: The aim was to evaluate the performance of an improved, algorithmic and standardised method called the Pharmacovigilance-Roussel Uclaf Causality Assessment Method (PV-RUCAM), to support assessment of suspected DILI. Performance was compared in different settings with regard to applicability and differentiation capacity. METHODS: A PV-RUCAM score was developed based on the seven sections contained in the original RUCAM. The score provides cut-off values for or against DILI causality, and was applied on two datasets of bona fide individual case safety reports (ICSRs) extracted randomly from clinical trial reports and a third dataset of electronic health records from a global PV database. The performance of PV-RUCAM adjudication was compared against two standards: a validated causality assessment method (original RUCAM) and global introspection. RESULTS: The findings showed moderate agreement against standards. The overall error margin of no false negatives was satisfactory, with 100% sensitivity, 91% specificity, a 25% positive predictive value and a 100% negative predictive value. The Spearman's rank correlation coefficient illustrated a statistically significant monotonic association between expert adjudication and PV-RUCAM outputs (R = 0.93). Finally, there was high inter-rater agreement (K w = 0.79) between two PV-RUCAM assessors. CONCLUSION: Within the PV setting of a pharmaceutical company, the PV-RUCAM has the potential to facilitate and improve the assessment done by non-expert PV professionals compared with other methods when incomplete reports must be evaluated for suspected DILI. Prospective validation of the algorithmic tool is necessary prior to implementation for routine use.

Drug-induced liver injury: recent advances in diagnosis and risk assessment.

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.

Strain-Driven Approach to Quantum Criticality in AFe_{2}As_{2} with A=K, Rb, and Cs.

The iron-based superconductors AFe_{2}As_{2} with A=K, Rb, Cs exhibit large Sommerfeld coefficients approaching those of heavy-fermion systems. We have investigated the magnetostriction and thermal expansion of this series to shed light on this unusual behavior. Quantum oscillations of the magnetostriction allow identifying the band-specific quasiparticle masses which by far exceed the band-structure derived masses. The divergence of the Grüneisen ratio derived from thermal expansion indicates that with increasing volume along the series a quantum critical point is approached. The critical fluctuations responsible for the enhancement of the quasiparticle masses appear to weaken the superconducting state.