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Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for the computation of the estimator. Simulation studies show that the proposed method performs well in making inference on the causal effect. We apply our method to the Hispanic Community Health Study/Study of Latinos, a community-based prospective cohort study, and estimate the causal effect of several metabolites on phenotypes of interest., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Full-length Bruton's tyrosine kinase (BTK) has been refractory to structural analysis. The nearest full-length structure of BTK to date consists of the autoinhibited SH3-SH2-kinase core. Precisely how the BTK N-terminal domains (the Pleckstrin homology/Tec homology [PHTH] domain and proline-rich regions [PRR] contain linker) contribute to BTK regulation remains unclear. We have produced crystals of full-length BTK for the first time but despite efforts to stabilize the autoinhibited state, the diffraction data still reveal only the SH3-SH2-kinase core with no electron density visible for the PHTH-PRR segment. Cryo-electron microscopy (cryoEM) data of full-length BTK, on the other hand, provide the first view of the PHTH domain within full-length BTK. CryoEM reconstructions support conformational heterogeneity in the PHTH-PRR region wherein the globular PHTH domain adopts a range of states arrayed around the autoinhibited SH3-SH2-kinase core. On the way to activation, disassembly of the SH3-SH2-kinase core opens a new autoinhibitory site on the kinase domain for PHTH domain binding that is ultimately released upon interaction of PHTH with phosphatidylinositol (3,4,5)-trisphosphate. Membrane-induced dimerization activates BTK and we present here a crystal structure of an activation loop swapped BTK kinase domain dimer that likely represents the conformational state leading to trans-autophosphorylation. Together, these data provide the first structural elucidation of full-length BTK and allow a deeper understanding of allosteric control over the BTK kinase domain during distinct stages of activation., Competing Interests: DL, LK, PJ, TW, JE No competing interests declared, AA Senior editor, eLife, (© 2023, Lin et al.)

Gallium oxide (Ga 2 O 3 ) is a promising wide bandgap semiconductor that is viewed as a contender for the next generation of high-power electronics due to its high theoretical breakdown electric field and large Baliga's figure of merit. Here, we report a facile route of synthesizing β -Ga 2 O 3 via direct oxidation conversion using solution-processed two-dimensional (2D) GaS semiconducting nanomaterial. Higher order of crystallinity in x-ray diffraction patterns and full surface coverage formation in scanning electron microscopy images after annealing were achieved. A direct and wide bandgap of 5 eV was calculated, and the synthesized β -Ga 2 O 3 was fabricated as thin film transistors (TFT). The β -Ga 2 O 3 TFT fabricated exhibits remarkable electron mobility (1.28 cm 2 Vs -1 ) and a good current ratio ( I on / I off ) of 2.06 × 10 5 . To further boost the electrical performance and solve the structural imperfections resulting from the exfoliation process of the 2D nanoflakes, we also introduced and doped graphene in β -Ga 2 O 3 TFT devices, increasing the electrical device mobility by ∼8-fold and thereby promoting percolation pathways for the charge transport. We found that electron mobility and conductivity increase directly with the graphene doping concentration. From these results, it can be proved that the β -Ga 2 O 3 networks have excellent carrier transport properties. The facile and convenient synthesis method successfully developed in this paper makes an outstanding contribution to applying 2D oxide materials in different and emerging optoelectronic applications., (© 2024 IOP Publishing Ltd.)

Background: Fas-associated factor 1 (FAF1) is a multidomain protein that interacts with diverse partners to affect numerous cellular processes. Previously, we discovered two Small Ubiquitin-like Modifier (SUMO)-interacting motifs (SIMs) within FAF1 that are crucial for transcriptional modulation of mineralocorticoid receptor. Recently, we identified Sin3A-associated protein 130 (SAP130), a putative sumoylated protein, as a candidate FAF1 interaction partner by yeast two-hybrid screening. However, it remained unclear whether SAP130 sumoylation might occur and functionally interact with FAF1., Results: In this study, we first show that SAP130 can be modified by SUMO1 at Lys residues 794, 878 and 932 both in vitro and in vivo. Mutation of these three SUMO-accepting Lys residues to Ala had no impact on SAP130 association with Sin3A or its nuclear localization, but the mutations abrogated the association of SAP130 with the FAF1. The mutations also potentiated SAP130 trans-repression activity and attenuated SAP130-mediated promotion of cell growth. Additionally, SUMO1-modified SAP130 was less stable than unmodified SAP130. Transient transfection experiments further revealed that FAF1 mitigated the trans-repression and cell proliferation-promoting functions of SAP130, and promoted SAP130 degradation by enhancing its polyubiquitination in a sumoylation-dependent manner., Conclusions: Together, these results demonstrate that sumoylation of SAP130 regulates its biological functions and that FAF1 plays a crucial role in controlling the SUMO-dependent regulation of transcriptional activity and protein stability of SAP130., (© 2023. The Author(s).)

Bruton's Tyrosine Kinase (BTK) is a nonreceptor tyrosine kinase that belongs to the TEC family. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA) leading to an arrest in B-cell development. BTK is also a drug target for B-cell lymphomas that rely on an intact B-cell receptor signaling cascade for survival. All FDA approved drugs for BTK target the ATP binding site of the catalytic kinase domain, leading to potential adverse events due to off-target inhibition. In addition, acquired resistance mutations occur in a subset of patients, rendering available BTK inhibitors ineffective. Therefore, allosteric sites on BTK should be explored for drug development to target BTK more specifically and in combination with active site inhibitors. Virtual screening against nonactive site pockets and in vitro experiments resulted in a series of small molecules that bind to BTK outside of the active site. We characterized these compounds using biochemical and biophysical techniques and narrowed our focus to compound "C2". C2 activates full-length BTK and smaller multidomain BTK fragments but not the isolated kinase domain, consistent with an allosteric mode of action. Kinetic experiments reveal a C2-mediated decrease in K m and an increase in k cat leading to an overall increase in the catalytic efficiency of BTK. C2 is also capable of activating the BTK XLA mutants. These proof-of-principle data reveal that BTK can be targeted allosterically with small molecules, providing an alternative to active site BTK inhibitors.

Full-length BTK has been refractory to structural analysis. The nearest full-length structure of BTK to date consists of the autoinhibited SH3-SH2-kinase core. Precisely how the BTK N-terminal domains (the Pleckstrin homology/Tec homology (PHTH) domain and proline-rich regions (PRR) contain linker) contribute to BTK regulation remains unclear. We have produced crystals of full-length BTK for the first time but despite efforts to stabilize the autoinhibited state, the diffraction data still reveals only the SH3-SH2-kinase core with no electron density visible for the PHTH-PRR segment. CryoEM data of full-length BTK, on the other hand, provide the first view of the PHTH domain within full-length BTK. CryoEM reconstructions support conformational heterogeneity in the PHTH-PRR region wherein the globular PHTH domain adopts a range of states arrayed around the autoinhibited SH3-SH2-kinase core. On the way to activation, disassembly of the SH3-SH2-kinase core opens a new autoinhibitory site on the kinase domain for PHTH domain binding that is ultimately released upon interaction of PHTH with PIP3. Membrane-induced dimerizationactivates BTK and we present here a crystal structure of an activation loop swapped BTK kinase domain dimer that likely represents the conformational state leading to transautophosphorylation. Together, these data provide the first structural elucidation of full-length BTK and allow a deeper understanding of allosteric control over the BTK kinase domain during distinct stages of activation.

Interval-censored multistate data arise in many studies of chronic diseases, where the health status of a subject can be characterized by a finite number of disease states and the transition between any two states is only known to occur over a broad time interval. We relate potentially time-dependent covariates to multistate processes through semiparametric proportional intensity models with random effects. We study nonparametric maximum likelihood estimation under general interval censoring and develop a stable expectation-maximization algorithm. We show that the resulting parameter estimators are consistent and that the finite-dimensional components are asymptotically normal with a covariance matrix that attains the semiparametric efficiency bound and can be consistently estimated through profile likelihood. In addition, we demonstrate through extensive simulation studies that the proposed numerical and inferential procedures perform well in realistic settings. Finally, we provide an application to a major epidemiologic cohort study., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Biometrika Trust. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Data on the protection conferred by COVID-19 vaccination and previous SARS-CoV-2 infection against omicron (B.1.1.529) infection in young children are scarce. We aimed to estimate the time-varying effects of primary and booster COVID-19 vaccination and previous SARS-CoV-2 infection on subsequent omicron infection and severe illness (hospital admission or death) in children younger than 12 years of age., Methods: In this observational cohort study, we obtained individual-level records on vaccination with the BNT162b2 and mRNA-1273 vaccines and clinical outcomes from the North Carolina COVID-19 Surveillance System and the COVID-19 Vaccine Management System for 1 368 721 North Carolina residents aged 11 years or younger from Oct 29, 2021 (Oct 29, 2021 for children aged 5-11 years and June 17, 2022 for children aged 0-4 years), to Jan 6, 2023. We used Cox regression to estimate the time-varying effects of primary and booster vaccination and previous infection on the risks of omicron infection, hospital admission, and death., Findings: For children 5-11 years of age, the effectiveness of primary vaccination against infection, compared with being unvaccinated, was 59·9% (95% CI 58·5-61·2) at 1 month, 33·7% (32·6-34·8) at 4 months, and 14·9% (95% CI 12·3-17·5) at 10 months after the first dose. Compared with primary vaccination only, the effectiveness of a monovalent booster dose after 1 month was 24·4% (14·4-33·2) and that of a bivalent booster dose was 76·7% (45·7-90·0). The effectiveness of omicron infection against reinfection was 79·9% (78·8-80·9) after 3 months and 53·9% (52·3-55·5) after 6 months. For children 0-4 years of age, the effectiveness of primary vaccination against infection, compared with being unvaccinated, was 63·8% (57·0-69·5) at 2 months and 58·1% (48·3-66·1) at 5 months after the first dose, and the effectiveness of omicron infection against reinfection was 77·3% (75·9-78·6) after 3 months and 64·7% (63·3-66·1) after 6 months. For both age groups, vaccination and previous infection had better effectiveness against severe illness as measured by hospital admission or death as a composite endpoint than against infection., Interpretation: The BNT162b2 and mRNA-1273 vaccines were effective against omicron infection and severe outcomes in children younger than 12 years, although the effectiveness decreased over time. Bivalent boosters were more effective than monovalent boosters. Immunity acquired via omicron infection was high and waned gradually over time. These findings can be used to develop effective prevention strategies against COVID-19 in children younger than 12 years., Funding: US National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Formosan sambar deer ( Rusa unicolor swinhoei ) are of great economic significance in Taiwan, resulting in a substantial increase in deer farming to meet the high demand for velvet antlers. Inbreeding depression and reduced genetic variability can lead to the deterioration of captive populations. In this study, 239 Formosan sambar deer were genotyped using 13 microsatellites to analyze their genetic diversity and population genetic structure. Our results indicate a high-resolution power of these microsatellites in individual discrimination and parentage analysis. However, captive populations exhibit a low level of genetic diversity, likely because of inbreeding and bottleneck effects. Both principal coordinate analysis (PCoA) and STRUCTURE analyses revealed two distinct and segregated genetic groups within the captive populations and indicated no clear population genetic structure among the captive populations. Introducing new genetic material from the wild through translocation offers a potential solution for mitigating the impact of inbreeding and enhancing genetic diversity. The comprehensive information obtained from these genetic analyses is crucial for the development of effective breeding strategies aimed at preserving and enhancing Formosan sambar deer populations.

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Importance: Ritonavir-boosted nirmatrelvir and molnupiravir are currently used in the US and in other countries to treat nonhospitalized patients who have mild-to-moderate COVID-19 and who are at high risk for progression to severe disease. The associations of these 2 oral antiviral drugs with hospitalization and death resulting from infection with new SARS-CoV-2 Omicron subvariants, particularly BQ.1.1 and XBB.1.5, are unknown., Objective: To assess the association of nirmatrelvir or molnupiravir use with the risks of hospitalization and death among patients infected with new Omicron subvariants., Design, Setting, and Participants: This was a cohort study of patients who received a diagnosis of COVID-19 at Cleveland Clinic from April 1, 2022, to February 20, 2023 (during which the Omicron variant evolved from BA.2 to BA.4/BA.5, then to BQ.1/BQ.1.1, and finally to XBB/XBB.1.5) and who were at high risk of progressing to severe disease, with follow-up through 90 days after diagnosis. The final date for follow-up data collection was February 27, 2023., Exposures: Treatment with ritonavir-boosted nirmatrelvir or molnupiravir., Main Outcomes and Measures: The primary outcome was time to death. The secondary outcome was time to either hospitalization or death. The association of either nirmatrelvir or molnupiravir use with each outcome was measured by the hazard ratio (HR) adjusted for demographic factors, socioeconomic status, date of COVID-19 diagnosis, coexisting medical conditions, COVID-19 vaccination status, and previous SARS-CoV-2 infection., Results: There were 68 867 patients (29 386 [42.7%] aged ≥65 years; 26 755 [38.9%] male patients; 51 452 [74.7%] non-Hispanic White patients). Thirty of 22 594 patients treated with nirmatrelvir, 27 of 5311 patients treated with molnupiravir, and 588 of 40 962 patients who received no treatment died within 90 days of Omicron infection. The adjusted HRs of death were 0.16 (95% CI, 0.11-0.23) for nirmatrelvir and 0.23 (95% CI, 0.16-0.34) for molnupiravir. The adjusted HRs of hospitalization or death were 0.63 (95% CI, 0.59-0.68) for nirmatrelvir and 0.59 (95% CI, 0.53-0.66) for molnupiravir. The associations of both drugs with both outcomes were observed across subgroups defined by age, race and ethnicity, date of COVID-19 diagnosis, vaccination status, previous infection status, and coexisting conditions., Conclusions and Relevance: These findings suggest that the use of either nirmatrelvir or molnupiravir is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions. Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.

Multivariate interval-censored data arise when there are multiple types of events or clusters of study subjects, such that the event times are potentially correlated and when each event is only known to occur over a particular time interval. We formulate the effects of potentially time-varying covariates on the multivariate event times through marginal proportional hazards models while leaving the dependence structures of the related event times unspecified. We construct the nonparametric pseudolikelihood under the working assumption that all event times are independent, and we provide a simple and stable EM-type algorithm. The resulting nonparametric maximum pseudolikelihood estimators for the regression parameters are shown to be consistent and asymptotically normal, with a limiting covariance matrix that can be consistently estimated by a sandwich estimator under arbitrary dependence structures for the related event times. We evaluate the performance of the proposed methods through extensive simulation studies and present an application to data from the Atherosclerosis Risk in Communities Study.

Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lin, Andreotti. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Endoscopic polypectomy can prevent colorectal cancer. Adequate surgical field visualization is crucial to complete resection. To prevent visual field loss caused by intestinal peristalsis, we investigated the efficacy and safety of topical lidocaine spraying during the endoscopic sigmoid polypectomy (ESP)., Methods: Retrospective analysis was performed on 100 ESP patients admitted from July 2021 to October 2021, among which 50 patients received lidocaine (case group) and other 50 patients received normal saline (control group). Lidocaine or saline was sprayed on the colonic mucosa within 5 cm above and below the polyps before polypectomy. The en-bloc resection rate (EBRR) and complete resection rate (CRR) were primarily evaluated. Secondary outcomes included EBRR for polyps located in the 5-11 o'clock position, sigmoid colon peristalsis frequency, degree of exposure to the surgical field, operative times, and adverse events., Results: There were no significant differences in the basic demographic characteristics between the two groups. EBRR and CRR in the case group were 72.9% and 95.8%, and in the control group were 53.3% and 91.1%, respectively. The EBRR of sigmoid polyps located at the 5-11 o'clock positions was significantly higher in the case group (82.8%) than in the control group (56.7%) (P = 0.03). Sigmoid colonic peristalsis was significantly inhibited after lidocaine spraying (P < 0.01). There was no statistical difference in the operative times and adverse event rates between the two groups., Conclusion: Topical spraying lidocaine around polyps can safely and effectively reduce intestinal peristalsis, thus improving the EBRR of sigmoid polypectomy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sustainable and safe food is an important issue worldwide, and it depends on cost-effective analysis tools with good sensitivity and reality. However, traditional standard chemical methods of food safety detection, such as high-performance liquid chromatography (HPLC), gas chromatography (GC), and tandem mass spectrometry (MS), have the disadvantages of high cost and long testing time. Those disadvantages have prevented people from obtaining sufficient risk information to confirm the safety of their products. In addition, food safety testing, such as the bioassay method, often results in false positives or false negatives due to little rigor preprocessing of samples. So far, food safety analysis currently relies on the enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), HPLC, GC, UV-visible spectrophotometry, and MS, all of which require significant time to train qualified food safety testing laboratory operators. These factors have hindered the development of rapid food safety monitoring systems, especially in remote areas or areas with a relative lack of testing resources. Surface-enhanced Raman spectroscopy (SERS) has emerged as one of the tools of choice for food safety testing that can overcome these dilemmas over the past decades. SERS offers advantages over chromatographic mass spectrometry analysis due to its portability, non-destructive nature, and lower cost implications. However, as it currently stands, Raman spectroscopy is a supplemental tool in chemical analysis, reinforcing and enhancing the completeness and coverage of the food safety analysis system. SERS combines portability with non-destructive and cheaper detection costs to gain an advantage over chromatographic mass spectrometry analysis. SERS has encountered many challenges in moving toward regulatory applications in food safety, such as quantitative accuracy, poor reproducibility, and instability of large molecule detection. As a result, the reality of SERS, as a screening tool for regulatory announcements worldwide, is still uncommon. In this review article, we have compiled the current designs and fabrications of SERS substrates for food safety detection to unify all the requirements and the opportunities to overcome these challenges. This review is expected to improve the interest in the sensing field of SERS and facilitate the SERS applications in food safety detection in the future.

Background and Objectives: Traditional Chinese Medicine (TCM) is a therapeutic system which has been practiced for thousands of years. Although for much of its history the decoction of medicinal herbs was the most common method of consuming the herbal treatments, TCM prescriptions are now primarily prepared using concentrated Chinese herbal extracts (CCHE) in powder or granular form. However, determining the precise dose of each single Chinese herbal constituent within a prescription creates a challenge in clinical practice due to the potential risk of toxicity. To alleviate this, we invented the Chinese Intelligence Prescription System (CIPS) to calculate the exact dose of each single herb within an individual prescription., Methods: In this study, we applied CIPS in a real-world setting to analyze clinical prescriptions collected and prepared at the TCM Pharmacy of China Medical University Hospital (CMUH)., Results: Our investigation revealed that 3% of all prescriptions filled in a 1-month period contained inexact dosages, suggesting that more than 170,000 prescriptions filled in Taiwan in a given month may contain potentially toxic components. We further analyzed the data to determine the excess dosages and outline the possible associated side effects., Conclusions: In conclusion, CIPS offers TCM practitioners the ability to prepare exact Chinese herbal medicine (CHM) prescriptions in order to avoid toxic effects, thereby ensuring patient safety., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Mapping cell type-specific gene expression quantitative trait loci (ct-eQTLs) is a powerful way to investigate the genetic basis of complex traits. A popular method for ct-eQTL mapping is to assess the interaction between the genotype of a genetic locus and the abundance of a specific cell type using a linear model. However, this approach requires transforming RNA-seq count data, which distorts the relation between gene expression and cell type proportions and results in reduced power and/or inflated type I error. To address this issue, we have developed a statistical method called CSeQTL that allows for ct-eQTL mapping using bulk RNA-seq count data while taking advantage of allele-specific expression. We validated the results of CSeQTL through simulations and real data analysis, comparing CSeQTL results to those obtained from purified bulk RNA-seq data or single cell RNA-seq data. Using our ct-eQTL findings, we were able to identify cell types relevant to 21 categories of human traits., (© 2023. The Author(s).)

The SnS/SnS 2 heterostructure was fabricated by the chemical vapor deposition method. The crystal structure properties of SnS 2 and SnS were characterized by X-ray diffraction (XRD) pattern, Raman spectroscopy, and field emission scanning electron microscopy (FESEM). The frequency dependence photoconductivity explores its carrier kinetic decay process. The SnS/SnS 2 heterostructure shows that the ratio of short time constant decay process reaches 0.729 with a time constant of 4.3 × 10 -4 s. The power-dependent photoresponsivity investigates the mechanism of electron-hole pair recombination. The results indicate that the photoresponsivity of the SnS/SnS 2 heterostructure has been increased to 7.31 × 10 -3 A/W, representing a significant enhancement of approximately 7 times that of the individual films. The results show the optical response speed has been improved by using the SnS/SnS 2 heterostructure. These results indicate an application potential of the layered SnS/SnS 2 heterostructure for photodetection. This research provides valuable insights into the preparation of the heterostructure composed of SnS and SnS 2 , and presents an approach for designing high-performance photodetection devices.

Purpose: To evaluate the Oxford Knee Score (OKS), EQ-5D-5L utility index and EQ-5D visual analogue scale (EQ-VAS) for health-related quality of life outcome measurement in patients undergoing elective total knee arthroplasty (TKA) surgery., Methods: In this prospective multi-centre study, the OKS and EQ-5D-5L index scores were collected preoperatively, six weeks (6w) and six months (6 m) following TKA. The OKS, EQ-VAS and EQ-5D-5L index were evaluated for minimally important difference (MID), concurrent validity, predictive validity (Spearman's Rho of predicted and observed values from a generalised linear regression model (GLM)), responsiveness (effect size (ES) and standard response mean (SRM)). The MID for the individual patient was determined utilising two approaches; distribution-based and anchor-based., Results: 533 patients were analysed. The EQ-5D-5L utility index showed good concurrent validity with the OKS (r = 0.72 preoperatively, 0.65 at 6w and 0.69 at 6 m). Predictive validity for the EQ-5D-5L index was lower than OKS when regressed. Responsiveness was large for all fields at 6w for the EQ-5D-5L and OKS (EQ-5D-5L ES 0.87, SRM 0.84; OKS ES 1.35, SRM 1.05) and 6 m (EQ-5D-5L index ES 1.31, SRM 0.95; OKS ES 1.69, SRM 1.59). The EQ-VAS returned poorer results, at 6w an ES of 0.37 (small) and SRM of 0.36 (small). At 6 m, the EQ-VAS had an ES of 0.59 (moderate) and SRM of 0.47 (small). It, however, had similar predictive validity to the OKS, and better than the EQ-5D-5L index. MID determined using anchor approach, was shown that for OKS at 6 weeks it was 8.84 ± 9.28 and at 6 months 13.37 ± 9.89. For the EQ-5D-5L index at 6 weeks MID was 0.23 ± 0.39, and at 6 months 0.26 ± 0.36., Conclusions: The EQ-5D-5L index score and the OKS demonstrate good concurrent validity. The EQ-5D-5L index demonstrated lower predictive validity at 6w, and 6 m than the OKS, and both PROMs had adequate responsiveness. The EQ-VAS had poorer responsiveness but better predictive validity than the EQ-5D-5L index. This article includes MID estimates for the Australian knee arthroplasty population., (© 2023. The Author(s).)

High-dimensional classification is an important statistical problem that has applications in many areas. One widely used classifier is the Linear Discriminant Analysis (LDA). In recent years, many regularized LDA classifiers have been proposed to solve the problem of high-dimensional classification. However, these methods rely on inverting a large matrix or solving large-scale optimization problems to render classification rules-methods that are computationally prohibitive when the dimension is ultra-high. With the emergence of big data, it is increasingly important to develop more efficient algorithms to solve the high-dimensional LDA problem. In this paper, we propose an efficient greedy search algorithm that depends solely on closed-form formulae to learn a high-dimensional LDA rule. We establish theoretical guarantee of its statistical properties in terms of variable selection and error rate consistency; in addition, we provide an explicit interpretation of the extra information brought by an additional feature in a LDA problem under some mild distributional assumptions. We demonstrate that this new algorithm drastically improves computational speed compared with other high-dimensional LDA methods, while maintaining comparable or even better classification performance.

Two-dimensional materials and their heterostructures have thus far been identified as leading candidates for nanoelectronics owing to the near-atom thickness, superior electrostatic control, and adjustable device architecture. These characteristics are indeed advantageous for neuro-inspired computing hardware where precise programming is strongly required. However, its successful demonstration fully utilizing all of the given benefits remains to be further developed. Herein, we present van der Waals (vdW) integrated synaptic transistors with multistacked floating gates, which are reconfigured upon surface oxidation. When compared with a conventional device structure with a single floating gate, our double-floating-gate (DFG) device exhibits better nonvolatile memory performance, including a large memory window (>100 V), high on-off current ratio (∼10 7 ), relatively long retention time (>5000 s), and satisfactory cyclic endurance (>500 cycles), all of which can be attributed to its increased charge-storage capacity and spatial redistribution. This facilitates highly effective modulation of trapped charge density with a large dynamic range. Consequently, the DFG transistor exhibits an improved weight update profile in long-term potentiation/depression synaptic behavior for nearly ideal classification accuracies of up to 96.12% (MNIST) and 81.68% (Fashion-MNIST). Our work adds a powerful option to vdW-bonded device structures for highly efficient neuromorphic computing.

Background: Understanding immunity against Omicron infection and severe outcomes conferred by coronavirus disease 2019 (Covid-19) vaccination, prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and monoclonal antibody therapy will inform intervention strategies., Methods: We considered 295 691 patients tested for SARS-CoV-2 at Cleveland Clinic between 1 October 2021 and 31 January 2022. We used logistic regression to investigate the association of vaccination and prior infection with the risk of SARS-CoV-2 infection and used Cox regression to investigate the association of vaccination, prior infection, and monoclonal antibody therapy with the risks of intensive care unit (ICU) stay and death., Results: Vaccination and prior infection were less effective against Omicron than Delta infection but provided strong protection against ICU admission and death. Boosting greatly increased vaccine effectiveness against Omicron infection and severe outcomes, although effectiveness waned rapidly over time. Monoclonal antibody therapy considerably reduced risks of ICU admission and death. The relatively low mortality of the Omicron variant was due to both reduced lethality of this variant and increased population immunity acquired from booster vaccination and previous infection., Conclusions: Booster vaccination and prior SARS-CoV-2 infection provide strong protection against ICU admission and death from Omicron infection. Monoclonal antibody therapy is also beneficial., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent technological advances have made it possible to measure multiple types of many features in biomedical studies. However, some data types or features may not be measured for all study subjects because of cost or other constraints. We use a latent variable model to characterize the relationships across and within data types and to infer missing values from observed data. We develop a penalized-likelihood approach for variable selection and parameter estimation and devise an efficient expectation-maximization algorithm to implement our approach. We establish the asymptotic properties of the proposed estimators when the number of features increases at a polynomial rate of the sample size. Finally, we demonstrate the usefulness of the proposed methods using extensive simulation studies and provide an application to a motivating multi-platform genomics study.

Introduction: The current opioid epidemic poses patient safety and economic burdens to healthcare systems worldwide. Postoperative prescriptions of opioids contribute, with reported opioid prescription rates following arthroplasty as high as 89%. In this multi-centre prospective study, an opioid sparing protocol was implemented for patients undergoing knee or hip arthroplasty. The primary outcome is to report our patient outcomes in the context of this protocol, and to examine the rate of opioid prescription on discharge from our hospitals following joint arthroplasty surgery. This is possibly associated with the efficacy of the newly implemented Arthroplasty Patient Care Protocol., Methods: Over three years, patients underwent perioperative education with the expectation to be opioid-free after surgery. Intraoperative regional analgesia, early postoperative mobilisation and multimodal analgesia were mandatory. Long-term opioid medication use was monitored and PROMs (Oxford Knee/Hip Score (OKS/OHS), EQ-5D-5 L) were evaluated pre-operatively, and at 6 weeks, 6 months and 1 year postoperatively. Primary and secondary outcomes were opiate use and PROMs at different time points., Results: A total of 1,444 patients participated. Two (0.2%) knee patients used opioids to one year. Zero hip patients used opioids postoperatively at any time point after six weeks (p < 0.0001). The OKS and EQ-5D-5 L both improved for knee patients from 16 (12-22) pre-operatively to 35 (27-43) at 1 year postoperatively, and 70 (60-80) preoperatively to 80 (70-90) at 1 year postoperatively (p < 0.0001). The OHS and EQ-5D-5 L both improved for hip patients from 12 (8-19) preoperatively to 44 (36-47) at 1 year postoperatively, and 65 (50-75) preoperatively to 85 (75-90) at 1 year postoperatively (p < 0.0001). Satisfaction improved between all pre- and postoperative time points for both knee and hip patients (p < 0.0001)., Conclusions: Knee and hip arthroplasty patients receiving a peri-operative education program can effectively and satisfactorily be managed without long-term opioids when coupled with multimodal perioperative management, making this a valuable approach to reduce chronic opioid use., (© 2023. The Author(s).)

Background: The direct anterior approach (DAA) in total hip arthroplasty (THA) may demonstrate better functional recovery compared to the posterior approach (PA)., Methods: In this prospective multi-centre study, patient-related outcome measures (PROMs) and length of stay (LOS) were compared between DAA and PA THA patients. The Oxford Hip Score (OHS), EQ-5D-5L, pain and satisfaction scores were collected at four perioperative stages., Results: 337 DAA and 187 PA THAs were included. The OHS PROM was significantly better in the DAA group at 6 weeks post-operatively (OHS: 33 vs. 30, p = 0.02, EQ-5D-5L: 80 vs. 75, p = 0.03), but there were no differences at 6 months and at 1 year. EQ-5D-5L scores were similar between both groups at all time points. LOS as inpatient was significantly different, in favour of DAA [median 2 days (IQR 2-3) vs. PA 3 (IQR 2-4), p ≤ 0.0001]., Conclusions: Patients undergoing DAA THA have shorter LOS and report better short-term Oxford Hip Score PROMs at 6 weeks, but DAA did not convey long-term benefits over PA THA., (© 2023. The Author(s).)

There is an increasing interest in using multiple types of omics features (e.g., DNA sequences, RNA expressions, methylation, protein expressions, and metabolic profiles) to study how the relationships between phenotypes and genotypes may be mediated by other omics markers. Genotypes and phenotypes are typically available for all subjects in genetic studies, but typically, some omics data will be missing for some subjects, due to limitations such as cost and sample quality. In this article, we propose a powerful approach for mediation analysis that accommodates missing data among multiple mediators and allows for various interaction effects. We formulate the relationships among genetic variants, other omics measurements, and phenotypes through linear regression models. We derive the joint likelihood for models with two mediators, accounting for arbitrary patterns of missing values. Utilizing computationally efficient and stable algorithms, we conduct maximum likelihood estimation. Our methods produce unbiased and statistically efficient estimators. We demonstrate the usefulness of our methods through simulation studies and an application to the Metabolic Syndrome in Men study., (© 2022 Wiley Periodicals LLC.)

We developed a versatile asymmetric strategy to synthesize different classes of sulfoglycolipids (SGLs) from Mycobacterium tuberculosis. The strategy features the use of asymmetrically protected trehaloses, which were acquired from the glycosylation of TMS α-glucosyl acceptors with benzylidene-protected thioglucosyl donors. The positions of the protecting groups at the donors and acceptors can be fine-tuned to obtain different protecting-group patterns, which is crucial for regioselective acylation and sulfation. In addition, a chemoenzymatic strategy was established to prepare the polymethylated fatty acid building blocks. The strategy employs inexpensive lipase as a desymmetrization agent in the preparation of the starting substrate and readily available chiral oxazolidinone as a chirality-controlling agent in the construction of the polymethylated fatty acids. A subsequent investigation on the immunomodulatory properties of each class of SGLs showed how the structures of SGLs impact the host innate immunity response., (© 2022 Wiley-VCH GmbH.)

Introduction: Hip fractures are a common frailty injury affecting a vulnerable geriatric population. It is debated if anesthetic and analgesic techniques are associated with altered risk for outcomes in hip fracture patients. This study aimed to determine the association of anesthesia and regional analgesia with all cause 12-month mortality and even longer-term mortality after hip fracture surgery in Australia and New Zealand., Methods: Data from the Australian and New Zealand Hip Fracture Registry collected from 2016 to 2018, with a minimum follow-up of 12 months, were reviewed. Anesthesia type and use of regional nerve blocks were investigated. The primary outcome was all cause 12-month mortality., Results: 12-month mortality was 30.6% (n=5410) in a total of 17,635 patients. There was no difference in 12-month mortality between patients who received spinal or general anesthesia (p=0.238). The administration of a combination of general and spinal anesthesia for surgery to repair the fracture was an independent predictor of higher 12-month mortality (unadjusted complete case HR=1.17 (95% CI 1.04 to 1.31); p<0.001). Nerve blocks performed in both the emergency department (ED) and the operating theater (OT) were associated with reduced long-term mortality (median follow-up 21 months) with an unimputed unadjusted HR=0.86 (95% CI 0.77 to 0.96; p=0.043)., Conclusion: There was no difference in the association of 12-month mortality between general and spinal anesthesia in patients undergoing hip fracture surgery. However, there was an association with a higher risk of 12-month mortality in patients who received both general and spinal anesthesia for the same surgery. Patients who received a regional nerve block in both the ED and the OT had a lower association of 12-month and longer-term mortality risk. The reasons for these findings remain unknown and should be the subject of further research investigation., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Current literature has indicated that Peyronie's disease (PD) could be initiated by microtrauma and the subsequent inflammation episodes that follow. PD could be sorted into acute or chronic status, and it can differ when selecting the clinical therapeutics. PD would cause pain and penile deformity to diseased men and impair their erectile function. Occasionally, surgical revision of the penis might be needed to correct the penile curvature. We find that there are limited effective options of intra-lesion injections for the PD plaques. By searching the databases and screening the literature with the PRISMA 2020 guideline, we observed that several preclinical studies that applied stem cell therapy in treating PD were fruitful in the acute phase. Although in the chronic phase of PD, erectile parameters were not significantly improved, and therefore, future studies might be better elevated in certain aspects, such as the sites selected for harvesting stem cells or changing the centrifugation forces. In this review, we concluded the contemporary understanding of inflammatory microenvironments in PD, the stem cell therapy in PD, and our perspectives on future studies. We concluded that there may be great potential in stem cell therapy for treating both acute and chronic phases PD., Competing Interests: The authors declare no conflict of interest.

Hypertriglyceridemia (HTG) remains a risk-enhancing factor of atherosclerotic cardiovascular disease. We aimed to report real-world data on the management of patients with type V hyperlipoproteinemia (HLP5), an uncommon phenotype of dyslipidemia characterized by fasting chylomicronemia and severe HTG. Between July 2018 and May 2021, 90 patients with HTG, including 83 patients with type IV hyperlipoproteinemia (HLP4) and 7 patients with HLP5, were identified by plasma apolipoprotein B (apoB) and lipoprotein electrophoresis. Patients with HLP5 were younger, had higher total cholesterol (TC) (264.9 ± 26.7 mg/dL vs. 183.9 ± 26.1 mg/dL; p < 0.01) and higher triglyceride (TG) (1296.7 ± 380.5 mg/dL vs. 247.6 ± 96.1 mg/dL; p < 0.01), and had lower high-density lipoprotein cholesterol (HDL-C) (30.6 ± 4.8 mg/dL vs. 40.5 ± 8.7 mg/dL; p < 0.01) and lower low-density lipoprotein cholesterol (LDL-C) (62.9 ± 16.4 vs. 103.0 ± 21.1 mg/dL; p < 0.01) compared with patients with HLP4. Despite an aggressive use of statin and fenofibrate with greater reductions in TG (-65.9 ± 13.7% vs. -27.9 ± 30.5%; p < 0.01) following 6 months of treatment, patients with HLP5 had persistent HTG (440.1 ± 239.0 mg/dL vs. 173.9 ± 94.8 mg/dL; p < 0.01) and an increase in LDL-C (28.3 ± 57.2% vs. -19.5 ± 32.0%; p < 0.01) compared with patients with HLP4. Our findings highlight that the lack of novel TG-lowering medications and management guidelines remains an unmet medical need in patients with HLP5. Closely monitoring lipid profiles, full assessment of individual’s risk of cardiovascular disease, and emphasis on medication adherence are of clinical importance.

Decision making about vaccination and boosting schedules for coronavirus disease 2019 (COVID-19) hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also detects plateaus in protective effectiveness more reliably than the standard method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines for which rapid and reliable understanding of vaccine effectiveness over time is desired., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Even though the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, have been approved to reduce plasma low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease in high-risk patients, real-world data showing comparisons of the lipid-lowering effects between alirocumab and evolocumab are scarce because of the low prescription rates of PCSK9 inhibitors in clinical practice., Methods: Between Feb 2018 and Sep 2021, 22 patients who received alirocumab and 22 patients who received evolocumab at a tertiary medical center were enrolled. The patients' baseline characteristics, prescribed medications, plasma LDL-C levels, and percentages of reduction in LDL-C were compared between alirocumab users and evolocumab users., Results: The alirocumab users more frequently received ezetimibe treatment (72.7% vs. 40.9%, p = 0.03) and had higher baseline LDL-C (165.6 ± 63.2 mg/dL vs. 130.8 ± 56.3 mg/dL, p = 0.04) compared with the evolocumab users. At 6 months of follow-up, the plasma LDL-C levels in the alirocumab users were similar to those in the evolocumab users (79.3 ± 64.0 mg/dL vs. 63.5 ± 44.1 mg/dL, p = 0.48). Additionally, the percentages of LDL-C reduction following treatment were similar between the alirocumab users and evolocumab users (-47.0% ± 45.0% vs. -49.8 ± 24.9%, p = 0.66)., Conclusions: The LDL-C lowering effects of alirocumab are similar to those of evolocumab in clinical practice.

Importance: Data about the association of COVID-19 vaccination and prior SARS-CoV-2 infection with risk of SARS-CoV-2 infection and severe COVID-19 outcomes may guide prevention strategies., Objective: To estimate the time-varying association of primary and booster COVID-19 vaccination and prior SARS-CoV-2 infection with subsequent SARS-CoV-2 infection, hospitalization, and death., Design, Setting, and Participants: Cohort study of 10.6 million residents in North Carolina from March 2, 2020, through June 3, 2022., Exposures: COVID-19 primary vaccine series and boosters and prior SARS-CoV-2 infection., Main Outcomes and Measures: Rate ratio (RR) of SARS-CoV-2 infection and hazard ratio (HR) of COVID-19-related hospitalization and death., Results: The median age among the 10.6 million participants was 39 years; 51.3% were female, 71.5% were White, and 9.9% were Hispanic. As of June 3, 2022, 67% of participants had been vaccinated. There were 2 771 364 SARS-CoV-2 infections, with a hospitalization rate of 6.3% and mortality rate of 1.4%. The adjusted RR of the primary vaccine series compared with being unvaccinated against infection became 0.53 (95% CI, 0.52-0.53) for BNT162b2, 0.52 (95% CI, 0.51-0.53) for mRNA-1273, and 0.51 (95% CI, 0.50-0.53) for Ad26.COV2.S 10 months after the first dose, but the adjusted HR for hospitalization remained at 0.29 (95% CI, 0.24-0.35) for BNT162b2, 0.27 (95% CI, 0.23-0.32) for mRNA-1273, and 0.35 (95% CI, 0.29-0.42) for Ad26.COV2.S and the adjusted HR of death remained at 0.23 (95% CI, 0.17-0.29) for BNT162b2, 0.15 (95% CI, 0.11-0.20) for mRNA-1273, and 0.24 (95% CI, 0.19-0.31) for Ad26.COV2.S. For the BNT162b2 primary series, boosting in December 2021 with BNT162b2 had the adjusted RR relative to primary series of 0.39 (95% CI, 0.38-0.40) and boosting with mRNA-1273 had the adjusted RR of 0.32 (95% CI, 0.30-0.34) against infection after 1 month and boosting with BNT162b2 had the adjusted RR of 0.84 (95% CI, 0.82-0.86) and boosting with mRNA-1273 had the adjusted RR of 0.60 (95% CI, 0.57-0.62) after 3 months. Among all participants, the adjusted RR of Omicron infection compared with no prior infection was estimated at 0.23 (95% CI, 0.22-0.24) against infection, and the adjusted HRs were 0.10 (95% CI, 0.07-0.14) against hospitalization and 0.11 (95% CI, 0.08-0.15) against death after 4 months., Conclusions and Relevance: Receipt of primary COVID-19 vaccine series compared with being unvaccinated, receipt of boosters compared with primary vaccination, and prior infection compared with no prior infection were all significantly associated with lower risk of SARS-CoV-2 infection (including Omicron) and resulting hospitalization and death. The associated protection waned over time, especially against infection.

There is a growing interest in precision medicine, where a potentially censored survival time is often the most important outcome of interest. To discover optimal treatment regimens for such an outcome, we propose a semiparametric proportional hazards model by incorporating the interaction between treatment and a single index of covariates through an unknown monotone link function. This model is flexible enough to allow non-linear treatment-covariate interactions and yet provides a clinically interpretable linear rule for treatment decision. We propose a sieve maximum likelihood estimation approach, under which the baseline hazard function is estimated nonparametrically and the unknown link function is estimated via monotone quadratic B-splines. We show that the resulting estimators are consistent and asymptotically normal with a covariance matrix that attains the semiparametric efficiency bound. The optimal treatment rule follows naturally as a linear combination of the maximum likelihood estimators of the model parameters. Through extensive simulation studies and an application to an AIDS clinical trial, we demonstrate that the treatment rule derived from the single-index model outperforms the treatment rule under the standard Cox proportional hazards model., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we present the investigation of optical properties on a series of HfS 2-x Se x crystals with different Se compositions x changing from 0 to 2. We used the chemical-vapor transport method to grow these layered ternary compound semiconductors in bulk form. Their lattice constants and crystal properties were characterized by X-ray diffraction, high-resolution transmission electron microscopy, and Raman spectroscopy. We have performed absorption spectroscopies to determine their optical band-gap energies, which started from 2.012 eV with x = 0, and gradually shifts to 1.219 eV for x = 2. Furthermore, we measured the absorption spectroscopies at different temperatures in the range of 20-300 K to identify the temperature dependence of band-gap energies. The band-gap energies of HfS 2-x Se x were determined from the linear extrapolation method. We have noticed that the band-gap energy may be continuously tuned to the required energy by manipulating the ratio of S and Se. The parameters that describe the temperature influence on the band-gap energy are evaluated and discussed.

Background: The PEricapsular Nerve Group (PENG) block is a novel regional analgesia technique that provides improved analgesia in patients undergoing hip surgery while preserving motor function. In this study the PENG block was investigated for analgesia in elective total hip arthroplasty (THA)., Methods: In this multi-centre double-blinded randomized-controlled trial, in addition to spinal anesthesia and local infiltration analgesia (LIA), THA patients received either a PENG block or a sham block. The primary outcome was pain score (numeric rating scale 0-10) 3 h postoperatively (Day 0). Secondary outcomes were postoperative quadriceps muscle strength, postoperative Day 1 pain scores, opiate use, complications, length of hospital stay, and patient-reported outcome measures., Results: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperative Day 0, the PENG group experienced less pain compared to the sham group (PENG: 14 (47%) patients no pain, 14 (47%) mild pain, 2 (6%) moderate/severe pain versus sham: 6 (20%) no pain, 14 (47%) mild pain, 10 (33%) moderate/severe pain; p = 0.03). There was no difference in quadriceps muscle strength between groups on Day 0 (PENG: 23 (77%) intact versus sham: 24 (80%) intact; p = 0.24) and there were no differences in other secondary outcomes., Conclusions: Patients receiving a PENG block for analgesia in elective THA experience less postoperative pain on Day 0 with preservation of quadriceps muscle strength. Despite these short-term benefits, no quality of recovery or longer lasting postoperative effects were detected., (© 2022. The Author(s).)

Cu-based metal-organic frameworks have attracted much attention for electrocatalytic CO 2 reduction, but they are generally instable and difficult to control the product selectivity. We report flexible Cu(I) triazolate frameworks as efficient, stable, and tunable electrocatalysts for CO 2 reduction to C 2 H 4 /CH 4 . By changing the size of ligand side groups, the C 2 H 4 /CH 4 selectivity ratio can be gradually tuned and inversed from 11.8 : 1 to 1 : 2.6, giving C 2 H 4 , CH 4 , and hydrocarbon selectivities up to 51 %, 56 %, and 77 %, respectively. After long-term electrocatalysis, they can retain the structures/morphologies without formation of Cu-based inorganic species. Computational simulations showed that the coordination geometry of Cu(I) changed from triangular to tetrahedral to bind the reaction intermediates, and two adjacent Cu(I) cooperated for C-C coupling to form C 2 H 4 . Importantly, the ligand side groups controlled the catalyst flexibility by the steric hindrance mechanism, and the C 2 H 4 pathway is more sensitive than the CH 4 one., (© 2022 Wiley-VCH GmbH.)

HER2 is an established therapeutic biomarker in advanced or recurrent endometrial serous carcinoma. Current clinical guidelines recommend HER2 testing exclusively in this endometrial carcinoma (EC) subtype; however, the full spectrum of ECs harboring HER2 amplification remains ill-defined. The present study characterizes the clinicopathologic and molecular features of HER2-amplified ECs across all histologic subtypes. Retrospective analysis of our institutional cohort of 2,042 ECs subjected to targeted clinical massively parallel sequencing identified 77 (3.8%) cases with HER2 amplification, a group comprised of serous (n = 29), endometrioid (low-grade, n = 2, high-grade, n = 1) and clear cell (n = 4) carcinomas, carcinosarcomas (n = 18) and high-grade ECs with ambiguous features (HGEC, n = 23). A co-existing TP53 mutation was identified in 94% (72/77) of HER2-amplified ECs. Other recurrent genetic alterations included amplification of CCNE1 (22%) and ERBB3 (10%), FBXW7 mutations or deletions (13%), and mutations in PIK3CA (40%) and PPP2R1A (13%). The HER2 immunohistochemistry score was 2+ or 3+ for all evaluable cases (n = 61). Apart from carcinosarcomas, which often showed lower HER2 expression, particularly in the sarcomatous component, HER2 immunohistochemical staining pattern and intensity were similar across EC subtypes. Intratumor heterogeneity in HER2 expression was common and correlated with genetic heterogeneity as detected by fluorescence in-situ hybridization. These results demonstrate the frequent co-occurrence of HER2 amplification with TP53 mutation and high-grade histology, rather than being specific to serous carcinoma, per se. Overall, these findings suggest that HER2 targeted therapy may be more broadly applicable to all high-grade EC histotypes and consideration should be given to expanding therapeutic eligibility., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Purpose: To evaluate the measurement properties of the Oxford Hip Score (OHS), EQ-5D-5L utility index and EQ-5D-5L visual analogue scale (EQ-VAS) in patients undergoing elective total hip arthroplasty in Australia., Methods: In this prospective multi-centre study, the OHS and EQ-5D-5L were collected preoperatively, six weeks (6w) and six months (6m) postoperatively. The OHS, EQ-VAS and EQ-5D-5L index were evaluated for concurrent validity, predictive validity (Spearman's Rho of predicted and observed values from a generalised linear regression model (GLM)), and responsiveness (effect size (ES) and standard response mean (SRM))., Results: 362 patients were included in this analysis for 6w and 269 for 6m. The EQ-5D-5L index showed good concurrent validity with the OHS (r = 0.71 preoperatively, 0.61 at 6w and 0.59 at 6m). Predictive validity for EQ-5D-5L index was similar to OHS when regressed (GLM). Responsiveness was good at 6w (EQ-5D-5L index ES 1.53, SRM 1.40; OHS ES 2.16, SRM 1.51) and 6m (EQ-5D-5L index ES 1.88, SRM 1.70; OHS ES 3.12, SRM 2.24). The EQ-VAS returned poorer results, at 6w an ES of 0.75 (moderate) and SRM 0.8. At 6m the EQ-VAS had an ES of 0.92 and SRM of 1.00. It, however, had greater predictive validity., Conclusions: The EQ-5D-5L index and the OHS demonstrate strong concurrent validity. The EQ-5D-5L index demonstrated similar predictive validity at 6w and 6m, and both PROMs had adequate responsiveness. The EQ-VAS should be used routinely together with the EQ-5D-5L index. The EQ-5D-5L is suitable to quantify health-related quality of life in Australian hip arthroplasty patients., (© 2022. The Author(s).)

More than a decade of genome-wide association studies (GWASs) have identified genetic risk variants that are significantly associated with complex traits. Emerging evidence suggests that the function of trait-associated variants likely acts in a tissue- or cell-type-specific fashion. Yet, it remains challenging to prioritize trait-relevant tissues or cell types to elucidate disease etiology. Here, we present EPIC (cEll tyPe enrIChment), a statistical framework that relates large-scale GWAS summary statistics to cell-type-specific gene expression measurements from single-cell RNA sequencing (scRNA-seq). We derive powerful gene-level test statistics for common and rare variants, separately and jointly, and adopt generalized least squares to prioritize trait-relevant cell types while accounting for the correlation structures both within and between genes. Using enrichment of loci associated with four lipid traits in the liver and enrichment of loci associated with three neurological disorders in the brain as ground truths, we show that EPIC outperforms existing methods. We apply our framework to multiple scRNA-seq datasets from different platforms and identify cell types underlying type 2 diabetes and schizophrenia. The enrichment is replicated using independent GWAS and scRNA-seq datasets and further validated using PubMed search and existing bulk case-control testing results., Competing Interests: The authors have declared that no competing interests exist.