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Competing risks data are commonly encountered in randomized clinical trials or observational studies. Ignoring competing risks in survival analysis leads to biased risk estimates and improper conclusions. Often, one of the competing events is of primary interest and the rest competing events are handled as nuisances. These approaches can be inadequate when multiple competing events have important clinical interpretations and thus of equal interest. For example, in COVID‐19 in‐patient treatment trials, the outcomes of COVID‐19 related hospitalization are either death or discharge from hospital, which have completely different clinical implications and are of equal interest, especially during the pandemic. In this paper we develop nonparametric estimation and simultaneous inferential methods for multiple cumulative incidence functions (CIFs) and corresponding restricted mean times. Based on Monte Carlo simulations and a data analysis of COVID‐19 in‐patient treatment clinical trial, we demonstrate that the proposed method provides global insights of the treatment effects across multiple endpoints. [ABSTRACT FROM AUTHOR]

Bacterial cellulose‐based materials have diverse applications as leather‐like materials, wound‐healing materials, and optoelectronic materials etc. Particularly, functionalization by polymer or organic compounds can help improve specific properties to diversify application areas. In this work, we reported a facile approach to functionalize Kombucha‐derived bacterial cellulose (BC) by AB‐type "Graft Through" click polymerization reaction. Since by this technique, the polymer was anchored on the surfaces as well as was produced in solution, and it provided the flexibility of detailed characterization on the surface as well as in a solution. Apart from standard spectroscopic characterization techniques, multinuclear solid‐state 13C, 29Si, and 15N NMR spectroscopic studies were undertaken extensively for finding the detailed structural information unambiguously. Thermal analysis, X‐Ray Diffraction analysis, and Small Angle Scattering (SAXS) was undertaken to understand the crystallinity and fibrous properties of the bacterial cellulose materials, while various microscopic analyses were undertaken for morphological studies. Those are particularly helpful in understanding the hydrophobicity of the materials an essential parameter for diversifying the application areas of the materials. [ABSTRACT FROM AUTHOR]

Recent observations, especially in cancer immunotherapy clinical trials with time‐to‐event outcomes, show that the commonly used proportional hazard assumption is often not justifiable, hampering an appropriate analysis of the data by hazard ratios. An attractive alternative advocated is given by the restricted mean survival time (RMST), which does not rely on any model assumption and can always be interpreted intuitively. Since methods for the RMST based on asymptotic theory suffer from inflated type‐I error under small sample sizes, a permutation test was proposed recently leading to more convincing results in simulations. However, classical permutation strategies require an exchangeable data setup between comparison groups which may be limiting in practice. Besides, it is not possible to invert related testing procedures to obtain valid confidence intervals, which can provide more in‐depth information. In this paper, we address these limitations by proposing a studentized permutation test as well as respective permutation‐based confidence intervals. In an extensive simulation study, we demonstrate the advantage of our new method, especially in situations with relatively small sample sizes and unbalanced groups. Finally, we illustrate the application of the proposed method by re‐analyzing data from a recent lung cancer clinical trial. [ABSTRACT FROM AUTHOR]

Prognostic models are useful tools for assessing a patient's risk of experiencing adverse health events. In practice, these models must be validated before implementation to ensure that they are clinically useful. The concordance index (C‐Index) is a popular statistic that is used for model validation, and it is often applied to models with binary or survival outcome variables. In this paper, we summarize existing criticism of the C‐Index and show that many limitations are accentuated when applied to survival outcomes, and to continuous outcomes more generally. We present several examples that show the challenges in achieving high concordance with survival outcomes, and we argue that the C‐Index is often not clinically meaningful in this setting. We derive a relationship between the concordance probability and the coefficient of determination under an ordinary least squares model with normally distributed predictors, which highlights the limitations of the C‐Index for continuous outcomes. Finally, we recommend existing alternatives that more closely align with common uses of survival models. [ABSTRACT FROM AUTHOR]

The C−F bond of acyl fluorides can be cleaved and added across tethered alkenes in the presence of a cationic rhodium(I) tetrafluoroborate catalyst. This 1,2‐carbofluorination reaction offers a powerful method for the synthesis of tertiary alkyl fluoride derivatives with an atom economy of 100 %. Mechanistic studies indicate that the concerted action of a rhodium cation and a tetrafluoroborate anion is key for the success of this catalytic cleavage and formation of C−F bonds in a controlled manner. [ABSTRACT FROM AUTHOR]

The effects of irradiation‐induced defects on the fluorite‐structured dioxide materials were investigated in the literature and explained with complex physical phenomena. An interpretation that can simply explain their effects on the structure has not been put forward so far. However, in a recent atomistic simulation study, a specific defect was found to be directly responsible for the α‐particle irradiated UO2 lattice dilatation, and there was a linear relationship between them. It was also determined that this linear equation has two different slopes at low and high defect concentrations. In this paper, it was found that these phenomenon were not specific to UO2 and applicable to all fluorite‐structured actinide and lanthanide dioxides studied here (CmO2, AmO2, CeO2, UO2, NpO2, PuO2, ThO2). The findings provide clues to the existence of more general law. The results have the potential to lead to significant improvements, such as why different radiation types (α‐particle, α‐decay, fission) swell the lattice at different saturation levels. [ABSTRACT FROM AUTHOR]

The lack of suitable indicators of changes in such as sea‐level and circulation has been a major limit to paleoenvironmental and paleoceanographic investigations in continental shelf regions. This paper presents an environmental magnetic study by comparing two late‐Quaternary sediment cores (DH02 and DH03) from the outer shelf of the East China Sea (ECS). Late and early Marine Isotope Stage (MIS) 3 sediments were deposited in a prodelta under cold coastal currents and an open‐shelf with the Taiwan Warm Current and upwelling. The dominant iron‐bearing minerals of the late and early MIS 3 sediments are authigenic greigite (Fe3S4) and pyrite (FeS2), respectively, which were assumed to be formed nearly syndepositionally. The overlying sediments, however, are magnetically dominated by detrital magnetite. This pattern corresponds well to the temporal changes in sea‐level over this period. The widespread occurrence of greigite in the late MIS 3 sediments can also be used for future stratigraphic division and correlation in the ECS. Additionally, compared to microfossil assemblages, rock magnetic parameters based on greigite may be more sensitive to environmental changes on continental shelves. Furthermore, the inter‐borehole spatial comparisons imply not only a sedimentary hiatus/erosion of at least 30‐m thickness in core DH02, most probably during the Last Glacial Maximum, but also that core DH02 was in a more reductive environment than core DH03 during late MIS 3. The findings highlight the potential of authigenic greigite as an indicator of spatiotemporal changes in paleoenvironmental and paleoceanographic conditions on the continental shelf at orbital or even suborbital timescales. Plain Language Summary: Environmental and oceanographic conditions on continental shelves are vital for sedimentation processes and human settlements, but the reconstruction of their evolution is hindered by the lack of effective indicators. Recent studies have indicated that syndepositional formation of greigite, a precursor to pyrite, is highly likely in shallow‐water environments with rapid sedimentation. Here, two sediment cores meridionally traversing the outer shelf of the East China Sea were investigated. The magnetic mineral assemblage and sedimentary environment exhibited almost identical change patterns, with pyrite, greigite, and magnetite as the major magnetic minerals of the early and late Marine Isotope Stage 3, and Last Glacial Maximum/last deglacial deposits, respectively. This agreeably reflects the temporal fluctuations in sea‐level and ocean circulation. By comparing the two cores, the spatial characteristics of stratigraphy and redox conditions could be determined clearly. This study thus provides a good reference for paleoenvironmental and paleoceanographic research based on authigenic greigite in continental shelf sediments. Key Points: Greigite was further confirmed as the major magnetic mineral of the late Marine Isotope Stage 3 deposits widespread on the outer shelf of the East China SeaSpatiotemporal changes in environmental and oceanographic conditions on the continental shelf are well revealed by greigite‐based parametersAuthigenic greigite can serve as a sensitive indicator for paleoenvironmental and paleoceanographic studies in continental shelf regions [ABSTRACT FROM AUTHOR]

Background: The predictive value of left ventricular (LV) global longitudinal strain (GLS) to predict outcomes in different left ventricular ejection fraction (LVEF) cohorts is not well known. We aimed to assess the role of LV GLS predicting outcomes in HF patients by LVEF. Methods: In the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy (MADIT‐CRT), we studied 1077 patients (59%) with 2D speckle tracking data available, 437 patients with LVEF > 30% and 640 with LVEF ≤ 30%. Baseline LV GLS was stratified in tertiles in both LVEF subgroups. The primary endpoint was ventricular tachycardia/fibrillation (VT/VF) or death; the secondary endpoint was heart failure (HF) or death. Results: In patients with LVEF ≤ 30%, a higher tertile GLS (T3, less contractility) was associated with a higher rate of VT/VF/death (P < 0.001), with similar association in patients with LVEF > 30% (P = 0.057). In patients with LVEF ≤ 30%, a higher tertile GLS was also associated with a higher rate of HF/death. In multivariable models, LV GLS predicted VT/VF or death in the LVEF ≤ 30% subgroup [T1 vs. T2/3 HR = 1.67 (1.16–2.38), P = 0.005], but not in those with LVEF > 30% [T1 vs. T2.3 HR = 1.32 (0.86–2.04), P = 0.21]. LV GLS predicted HF/death in the LVEF ≤ 30% subgroup [T1 vs T2/3 HR = 2.00 (1.30–3.13), P = 0.002], but not in in those with LVEF > 30%. Conclusions: In this MADIT‐CRT sub‐study, LV GLS identified patients at higher risk of VT/VF, HF/death risk independently of conventional clinical parameters in patients with LVEF ≤ 30%, but not in patients with LVEF > 30%. [ABSTRACT FROM AUTHOR]

Anthropogenic stressors can affect the emergence of aquatic insects. These insects link aquatic and adjacent terrestrial food webs, serving as high‐quality subsidy to terrestrial consumers, such as spiders. While previous studies have demonstrated that changes in the emergence biomass and timing may propagate across ecosystem boundaries, the physiological consequences of altered subsidy quality for spiders are largely unknown. We used a model food chain to study the potential effects of subsidy quality: Tetragnatha spp. were exclusively fed with emergent Chironomus riparius cultured in the absence or presence of either copper (Cu), Bacillus thuringiensis var. israelensis (Bti), or a mixture of synthetic pesticides paired with two basal resources (Spirulina vs. TetraMin®) of differing quality in terms of fatty acid (FA) composition. Basal resources shaped the FA profile of chironomids, whereas their effect on the FA profile of spiders decreased, presumably due to the capacity of both chironomids and spiders to modify (dietary) FA. In contrast, aquatic contaminants had negligible effects on prey FA profiles but reduced the content of physiologically important polyunsaturated FAs, such as 20:4n‐6 (arachidonic acid) and 20:5n‐3 (eicosapentaenoic acid), in spiders by approximately 30% in Cu and Bti treatments. This may have contributed to the statistically significant decline (40%–50%) in spider growth. The observed effects in spiders are likely related to prey nutritional quality because biomass consumption by spiders was, because of our experimental design, constant. Analyses of additional parameters that describe the nutritional quality for consumers such as proteins, carbohydrates, and the retention of contaminants may shed further light on the underlying mechanisms. Our results highlight that aquatic contaminants can affect the physiology of riparian spiders, likely by altering subsidy quality, with potential implications for terrestrial food webs. Environ Toxicol Chem 2023;42:1346–1358. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Background: Pediatric chronic kidney disease (CKD) patients are at risk for cognitive deficits with worsening disease progression. Limited, existing cross‐sectional studies suggest that cognitive deficits may improve following kidney transplantation. We sought to assess cognitive performance in relationship to kidney transplantation and kidney‐specific medical variables in a sample of pediatric kidney transplant patients who provided cross‐sectional and longitudinal observations. Methods: A retrospective chart review was conducted in patients who completed pre‐ and/or post‐transplant neurocognitive testing at the University of Iowa from 2015–2021. Cognitive outcomes were investigated with developmentally appropriate, standardized measures. Mixed linear models estimated the impact of transplant status on cognitive function (z‐scores). Subsequent post‐hoc t‐tests on change scores were limited to patients who had provided pre‐ and post‐transplant assessments. Results: Thirty eight patients underwent cognitive assessments: 10 had both pre‐ and post‐transplant cognitive assessments, 11 had pre‐transplant assessments only, and 17 had post‐transplant data only. Post‐transplant status was associated with significantly lower full‐scale IQ and slower processing speed compared to pre‐transplant status (estimate = −0.32, 95% confidence interval [CI] = −0.52: −0.12; estimate = −0.86, CI = −1.17: −0.55, respectively). Post‐hoc analyses confirmed results from the mixed models (FSIQ change score = −0.34, 95% CI = −0.56: −0.12; processing speed change score = −0.98, CI = −1.28: −0.68). Finally, being ≥80 months old at transplant was associated with substantially lower FSIQ compared to being <80 months (estimate = −1.25, 95% CI = −1.94: −0.56). Conclusions: Our results highlight the importance of monitoring cognitive function following pediatric kidney transplant and identify older transplant age as a risk factor for cognitive deficits. [ABSTRACT FROM AUTHOR]

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline‐recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice. [ABSTRACT FROM AUTHOR]

Hip fractures are common in patients of advanced age and are associated with excess mortality. Rapid and accurate prediction of the prognosis using information that can be easily obtained before surgery would be advantageous to clinical management. We performed a population‐based retrospective cohort study using an 8.5‐year Japanese claims database (April 2012–September 2020) to develop and validate a predictive model for long‐term mortality after hip fracture. The study included 43,529 patients (34,499 [79.3%] women) aged ≥65 years with first‐onset hip fracture. During the observation period, 43% of the patients died. Cox regression analysis identified the following prognostic predictors: sex, age, fracture site, nursing care certification, and several comorbidities (any malignancy, renal disease, congestive heart failure, chronic pulmonary disease, liver disease, metastatic solid tumor, and deficiency anemia). We then developed a scoring system called the Shizuoka Hip Fracture Prognostic Score (SHiPS); this system was established by scoring based on each hazard ratio and classifying the degree of mortality risk into four categories based on decision tree analysis. The area under the receiver operating characteristic (ROC) curve (AUC) (95% confidence interval [CI]) of 1‐year, 3‐year, and 5‐year mortality based on the SHiPS was 0.718 (95% CI, 0.706–0.729), 0.736 (95% CI, 0.728–0.745), and 0.758 (95% CI, 0.747–0.769), respectively, indicating good predictive performance of the SHiPS for as long as 5 years after fracture onset. Even when the SHiPS was individually applied to patients with or without surgery after fracture, the prediction performance by the AUC was >0.7. These results indicate that the SHiPS can predict long‐term mortality using preoperative information regardless of whether surgery is performed after hip fracture. [ABSTRACT FROM AUTHOR]

Sympathetic nerve loss in the heart predicts the risk of ventricular arrhythmias after myocardial infarction (MI) in patients. Sympathetic denervation after cardiac ischemia–reperfusion is sustained by matrix components chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. We showed that 4,6‐sulfation of CSPGs was critical for preventing nerve growth into the scar. Promoting early reinnervation with therapeutics reduces arrhythmias during the first 2 weeks after MI, but the longer‐term consequences of restoring innervation are unknown. Therefore, we asked if the beneficial effects of early reinnervation were sustained. We compared cardiac function and arrhythmia susceptibility 40 days after MI in mice treated on Days 3–10 with vehicle or with intracellular sigma peptide to restore innervation. Surprisingly, both groups had normal innervation density in the cardiac scar 40 days after MI, indicating delayed reinnervation of the infarct in vehicle‐treated mice. That coincided with similar cardiac function and arrhythmia susceptibility in the two groups. We investigated the mechanism allowing delayed reinnervation of the cardiac scar. We found that CSPG 4,6‐sulfation, which is elevated early after ischemia–reperfusion, was reduced to control levels allowing reinnervation of the infarct. Thus, remodeling of extracellular matrix weeks after injury leads to remodeling of sympathetic neurons in the heart. [ABSTRACT FROM AUTHOR]

The research interest in azulene‐embedded polycyclic aromatic hydrocarbons (PAHs) has significantly increased recently, but the lack of efficient synthetic strategies impedes the investigation of their structure‐property relationships and further opto‐electronic applications. Here we report a modular synthetic strategy towards diverse azulene‐embedded PAHs by a tandem Suzuki coupling and base‐promoted Knoevenagel‐type condensation with good yields and great structural versatility, including non‐alternant thiophene‐rich PAHs, butterfly‐ or Z‐shaped PAHs bearing two azulene units, and the first example of a two‐azulene‐embedded double [5]helicene. The structural topology, aromaticity and photophysical properties were investigated by NMR, X‐ray crystallography analysis and UV/Vis absorption spectroscopy assisted by DFT calculations. This strategy provides a new platform for rapidly synthesizing unexplored non‐alternant PAHs or even graphene nanoribbons with multiple azulene units. [ABSTRACT FROM AUTHOR]

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Treatment specific survival curves are an important tool to illustrate the treatment effect in studies with time‐to‐event outcomes. In non‐randomized studies, unadjusted estimates can lead to biased depictions due to confounding. Multiple methods to adjust survival curves for confounders exist. However, it is currently unclear which method is the most appropriate in which situation. Our goal is to compare forms of inverse probability of treatment weighting, the G‐Formula, propensity score matching, empirical likelihood estimation and augmented estimators as well as their pseudo‐values based counterparts in different scenarios with a focus on their bias and goodness‐of‐fit. We provide a short review of all methods and illustrate their usage by contrasting the survival of smokers and non‐smokers, using data from the German Epidemiological Trial on Ankle‐Brachial‐Index. Subsequently, we compare the methods using a Monte‐Carlo simulation. We consider scenarios in which correctly or incorrectly specified models for describing the treatment assignment and the time‐to‐event outcome are used with varying sample sizes. The bias and goodness‐of‐fit is determined by taking the entire survival curve into account. When used properly, all methods showed no systematic bias in medium to large samples. Cox regression based methods, however, showed systematic bias in small samples. The goodness‐of‐fit varied greatly between different methods and scenarios. Methods utilizing an outcome model were more efficient than other techniques, while augmented estimators using an additional treatment assignment model were unbiased when either model was correct with a goodness‐of‐fit comparable to other methods. These "doubly‐robust" methods have important advantages in every considered scenario. [ABSTRACT FROM AUTHOR]

In photo‐induced olefin synthesis, the photocatalysts with high triplet energy could cause the isomerization of olefins. This study demonstrates a new quinoxalinone photocatalytic system for highly stereoselective alkenes preparation from alkenyl sulfones and alkyl boronic acids. Our photocatalyst could not convert the thermodynamically favored E‐olefin to Z‐olefin, guaranteeing the high E‐configuration selectivity of the reaction. There is weak interaction between boronic acids and quinoxalinone according to NMR experiments, probably decreasing the oxidation potential of boronic acids. This system can be further extended to the allyl and alkynyl sulfones to give corresponding alkenes and alkynes. [ABSTRACT FROM AUTHOR]

Body condition refers to an array of physiological or nutritious states in animals, but body condition is typically measured using a single metric in animal behavior studies. In this paper, we conducted a three‐day laboratory study to evaluate whether metrics of body condition affected movement of wild‐caught creek chub (Semotilus atromaculatus) at 16 and 22°C. Movement was counted between two circular tanks connected by a straight corridor, which was equipped with a pair of passive integrated transponder antennas. Fish movement was most frequent during periods of darkness in a simulated photoperiod, and more mobile individuals consistently moved more frequently across the 3 days. In general, individuals in better body condition were more mobile than those in poorer condition, and different metrics of body condition affected movement to different degrees. Specifically, per cent weight loss and dry matter content (ratio of wet versus dehydrated weight) were better predictors of movement than weight‐at‐length, which is most typically used as a surrogate of body condition in animals. In addition, body condition and length interacted to affect fish movement, where body condition affected movement of smaller individuals more significantly than that of larger individuals. Body condition effects on activity were similar at 16 and 22°C. This study demonstrates that body condition metrics may not always affect certain behavior in a similar way. Body condition metrics need to be carefully selected when used in the context of animal behavior, and more than a single metric should be tested when feasible. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is known to have a relatively poor outcome with variable prognoses, raising the need for more informative risk stratification. We investigated a set of digital, artificial intelligence (AI)‐based spatial tumour microenvironment (sTME) features and explored their prognostic value in TNBC. After performing tissue classification on digitised haematoxylin and eosin (H&E) slides of TNBC cases, we employed a deep learning‐based algorithm to segment tissue regions into tumour, stroma, and lymphocytes in order to compute quantitative features concerning the spatial relationship of tumour with lymphocytes and stroma. The prognostic value of the digital features was explored using survival analysis with Cox proportional hazard models in a cross‐validation setting on two independent international multi‐centric TNBC cohorts: The Australian Breast Cancer Tissue Bank (AUBC) cohort (n = 318) and The Cancer Genome Atlas Breast Cancer (TCGA) cohort (n = 111). The proposed digital stromal tumour‐infiltrating lymphocytes (Digi‐sTILs) score and the digital tumour‐associated stroma (Digi‐TAS) score were found to carry strong prognostic value for disease‐specific survival, with the Digi‐sTILs and Digi‐TAS scores giving C‐index values of 0.65 (p = 0.0189) and 0.60 (p = 0.0437), respectively, on the TCGA cohort as a validation set. Combining the Digi‐sTILs feature with the patient's positivity status for axillary lymph nodes yielded a C‐index of 0.76 on unseen validation cohorts. We surmise that the proposed digital features could potentially be used for better risk stratification and management of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Early and rapid diagnosis of tumors is essential for clinical treatment or management. In contrast to conventional means, bioimaging has the potential to accurately locate and diagnose tumors at an early stage. Fluorescent probe has been developed as an ideal tool to visualize tumor sites and to detect biological molecules which provides a requirement for noninvasive, real‐time, precise, and specific visualization of structures and complex biochemical processes in vivo. Rencently, the development of synthetic organic chemistry and new materials have facilitated the development of near‐infrared small molecular sensing platforms and nanoimaging platforms. This provides a competitive tool for various fields of bioimaging such as biological structure and function imaging, disease diagnosis, in situ at the in vivo level, and real‐time dynamic imaging. This review systematically focused on the recent progress of small molecular near‐infrared fluorescent probes and nano‐fluorescent probes as new biomedical imaging tools in the past 3–5 years, and it covers the application of tumor biomarker sensing, tumor microenvironment imaging, and tumor vascular imaging, intraoperative guidance and as an integrated platform for diagnosis, aiming to provide guidance for researchers to design and develop future biomedical diagnostic tools. [ABSTRACT FROM AUTHOR]

Background: Patients presenting to the emergency department (ED) with acute vertigo or dizziness represent a diagnostic challenge. Neuroimaging has variable indications and yield. We aimed to conduct a systematic review and meta‐analysis of the diagnostic test accuracy of neuroimaging for patients presenting with acute vertigo or dizziness. Methods: An electronic search was designed following patient–intervention–control–outcome (PICO) question—(P) adult patients with acute vertigo or dizziness presenting to the ED; (I) neuroimaging including computed tomography (CT), CT angiography (CTA), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and ultrasound (US); (C) MRI/clinical criterion standard; and (O) central causes (stroke, hemorrhage, tumor, others) versus peripheral causes of symptoms. Articles were assessed in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were followed. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess certainty of evidence in pooled estimates. Results: We included studies that reported diagnostic test accuracy. From 6309 titles, 460 articles were retrieved, and 12 were included: noncontrast CT scan—six studies, 771 patients, pooled sensitivity 28.5% (95% confidence interval [CI] 14.4%–48.5%, moderate certainty) and specificity 98.9% (95% CI 93.4%–99.8%, moderate certainty); MRI—five studies, 943 patients, sensitivity 79.8% (95% CI 71.4%–86.2%, high certainty) and specificity 98.8% (95% CI 96.2%–100%, high certainty); CTA—one study, 153 patients, sensitivity 14.3% (95% CI 1.8%–42.8%) and specificity 97.7% (95% CI 93.8%–99.6%), CT had higher sensitivity than CTA (21.4% and 14.3%) for central etiology; MRA—one study, 24 patients, sensitivity 60.0% (95% CI 26.2%–87.8%) and specificity 92.9% (95% CI 66.1%–99.8%); US—three studies, 258 patients, sensitivity ranged from 30% to 53.6%, specificity from 94.9% to 100%. Conclusions: Noncontrast CT has very low sensitivity and MRI will miss approximately one in five patients with stroke if imaging is obtained early after symptom onset. The evidence does not support neuroimaging as the only tool for ruling out stroke and other central causes in patients with acute dizziness or vertigo presenting to the ED. [ABSTRACT FROM AUTHOR]

Lakes are recipients of allochthonous organic matter and nutrients. However, the importance of these subsidies for food webs and how they vary with lake trophic status remains unclear, especially for large lakes.We assessed the source and fate of organic matter and nutrients in seven perialpine lakes across a gradient of trophic status. We measured carbon and nitrogen stable isotopes of amino acids of lake‐residing Atlantic trout, Salmo trutta, to determine the source of primary production (i.e., how carbon is fixed in the ecosystem) and how it is transferred through food webs, respectively. Based on essential amino acid carbon fingerprinting, we estimated the probability of organic carbon originating from autochthonous (algal), allochthonous (terrestrial plant), and recycled (bacterial) sources. In addition, we used amino acid δ15N to track how this primary production is transferred to consumers in general, and by using different trophic amino acids (glutamic acid and alanine), identify the trophic pathways involving either metazoan or protozoans.We found a high likelihood of autochthonous origin of organic carbon (86 ± 9%) in trout that contrasted with allochthonous origins of particulate organic matter and some sediments. We showed that those estimates are good proxies of source reliance. Our results also highlighted the importance of bacterial origin of organic carbon in fish (12%). The likely autochthonous origin of this carbon was supported by trophic markers (Ala δ15N) that suggest the role of protists in transferring recycled organic carbon up the food web. While the sources of nitrogen sustaining food webs varied among lakes, we found a conserved carbon fingerprinting of fish. Overall, this suggests an uncoupling between the source of nutrients and organic carbon in large perialpine lakes.Across a wide range of trophic status (c. 2 orders of magnitude range of phosphorus concentration), several lines of evidence suggested that perialpine lake food webs shared a common reliance on autochthonous and bacterial production.Our study is the first to quantify the dependence on allochthonous organic carbon in lake food webs based on new amino acid stable isotope markers (carbon fingerprinting and Ala δ15N) and shows promise for estimating the source of carbon fixation in ecosystems. Our results support previous suggestions that terrestrial organic carbon is a relatively minor source for aquatic consumers despite contributing to the pool of organic matter, and more importantly, its contribution does not vary substantially with trophic status in perialpine lakes. [ABSTRACT FROM AUTHOR]

Background: The association of aspartate aminotransferase to alanine aminotransferase ratio (De Ritis ratio) with clinical outcomes in patients with chronic coronary syndromes (CCS) remains unclear. This study aims to assess the association of De Ritis ratio with adverse cardiovascular events in patients with CCS. Materials and Methods: The study included 5020 patients with CCS undergoing percutaneous coronary intervention. Patients were categorized into groups according to tertiles of the De Ritis ratio: tertile 1 (De Ritis ratio: <.75; n = 1688 patients), tertile 2 (De Ritis ratio:.75–1.08; n = 1666 patients) and tertile 3 (De Ritis ratio: >1.08; n = 1666 patients). The primary endpoint was 3‐year mortality. Results: At 3 years, there were 384 deaths, 176 myocardial infarctions and 61 strokes. In groups with De Ritis in the 1st, 2nd and 3rd tertiles, deaths occurred in 5.0%, 7.5% and 14.5% of the patients, respectively (adjusted hazard ratio = 1.09, 95% confidence interval [1.06–1.12], p <.001); myocardial infarctions occurred in 2.6%, 3.5% and 5.1% of the patients, respectively (p <.001); strokes occurred in 1.0%, 1.2% and 1.9% of the patients, respectively (p =.030); bleeding at 30 days (n = 112) occurred in 1.4%, 1.6% and 3.7% of the patients, respectively (p <.001). The C‐statistic of the Cox proportional hazards model for all‐cause mortality with baseline data without the De Ritis ratio was.815 [.794–.836] and.818 [.797–.838] after the inclusion of the De Ritis ratio (delta C‐statistic =.003; p =.005). Conclusions: In patients with CCS undergoing percutaneous coronary intervention, an elevated De Ritis ratio was associated with long‐term major adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: Frailty assessment is an important marker of the older adult's fitness for cancer treatment independent of age. Pretreatment geriatric assessment (GA) is associated with improved mortality and morbidity outcomes but must occur in a time sensitive manner to be useful for cancer treatment decision making. Unfortunately, time, resources and other constraints make GA difficult to perform in busy oncology clinics. We developed the Cancer and Aging Interdisciplinary Team (CAIT) clinic model to provide timely GA and treatment recommendations independent of patient's physical location. Methods: The interdisciplinary CAIT clinic model was developed utilizing the surge in telemedicine during the COVID‐19 pandemic. The core team consists of the patient's oncologist, geriatrician, registered nurse, pharmacist, and registered dietitian. The clinic's format is flexible, and the various assessments can be asynchronous. Patients choose the service method—in person, remotely, or hybrid. Based on GA outcomes, the geriatrician provides recommendations and arrange interventions. An assessment summary including life expectancy estimates and chemotoxicity risk calculator scores is conveyed to and discussed with the treating oncologist. Physician and patient satisfaction were assessed. Results: Between May 2021 and June 2022, 50 patients from multiple physical locations were evaluated in the CAIT clinic. Sixty‐eight percent was 80 years of age or older (range 67–99). All the evaluations were hybrid. The median days between receiving a referral and having the appointment was 8. GA detected multiple unidentified impairments. About half of the patients (52%) went on to receive chemotherapy (24% standard dose, 28% with dose modifications). The rest received radiation (20%), immune (12%) or hormonal (4%) therapies, 2% underwent surgery, 2% chose alternative medicine, 8% were placed under observation, and 6% enrolled in hospice care. Feedback was extremely positive. Conclusions: The successful development of the CAIT clinic model provides strong support for the potential dissemination across services and institutions. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) and food allergy (FA) share similar type 2 inflammation and commonly co‐occur, but the precise proportion of AD patients with FA and vice versa, as well as the effect of AD disease severity on the strength of this association remains uncertain. The aim of this comprehensive systematic review and meta‐analysis was to determine the prevalence and bidirectional associations of AD with food sensitivity (FS), FA and challenge‐proven food allergy (CPFA). We searched PubMed and EMBASE and three independent reviewers performed title/abstract and full‐text review and data extraction. Overall, 557 articles (n = 225,568 individuals with AD, n = 1,128,322 reference individuals; n = 1,357,793 individuals with FS, FA or CPFA, n = 1,244,596 reference individuals) were included in quantitative analyses. The overall pooled prevalence of FS, FA and CPFA in individuals with AD were 48.4% (95% confidence interval: 43.7–53.2), 32.7% (28.8–36.6) and 40.7% (34.1–47.5) respectively. AD prevalence among individuals with FS, FA and CPFA were 51.2% (46.3–56.2), 45.3% (41.4–49.3) and 54.9% (47.0–62.8) respectively. Children with AD had higher pooled FS (49.8% (44.4–55.1)) and FA (31.4% (26.9–36.1)) prevalences than adults with AD (28.6% (13.4–46.8) and 24.1% (12.1–38.7) respectively). Prevalences of FS and FA numerically increased with AD severity. FS, FA and CPFA are common comorbidities of AD and are closely related. Physicians should be attentive to this relationship to optimize management and treatment strategies in patients. [ABSTRACT FROM AUTHOR]

Competing risks survival data in the presence of partially masked causes are frequently encountered in medical research or clinical trials. When longitudinal biomarkers are also available, it is of great clinical importance to examine associations between the longitudinal biomarkers and the cause‐specific survival outcomes. In this article, we propose a cause‐specific C‐index for joint models of longitudinal and competing risks survival data accounting for masked causes. We also develop a posterior predictive algorithm for computing the out‐of‐sample cause‐specific C‐index using Markov chain Monte Carlo samples from the joint posterior of the in‐sample longitudinal and competing risks survival data. We further construct the Δ$$ \Delta $$C‐index to quantify the strength of association between the longitudinal and cause‐specific survival data, or between the out‐of‐sample longitudinal and survival data. Empirical performance of the proposed assessment criteria is examined through an extensive simulation study. An in‐depth analysis of the real data from large cancer prevention trials is carried out to demonstrate the usefulness of the proposed methodology. [ABSTRACT FROM AUTHOR]

The pattern of the difference between two survival curves we often observe in randomized clinical trials for evaluating immunotherapy is not proportional hazards; the treatment effect typically appears several months after the initiation of the treatment (ie, delayed difference pattern). The commonly used logrank test and hazard ratio estimation approach will be suboptimal concerning testing and estimation for those trials. The long‐term restricted mean survival time (LT‐RMST) approach is a promising alternative for detecting the treatment effect that potentially appears later in the study. A challenge in employing the LT‐RMST approach is that it must specify a lower end of the time window in addition to a truncation time point that the RMST requires. There are several investigations and suggestions regarding the choice of the truncation time point for the RMST. However, little has been investigated to address the choice of the lower end of the time window. In this paper, we propose a flexible LT‐RMST‐based test/estimation approach that does not require users to specify a lower end of the time window. Numerical studies demonstrated that the potential power loss by adopting this flexibility was minimal, compared to the standard LT‐RMST approach using a prespecified lower end of the time window. The proposed method is flexible and can offer higher power than the RMST‐based approach when the delayed treatment effect is expected. Also, it provides a robust estimate of the magnitude of the treatment effect and its confidence interval that corresponds to the test result. [ABSTRACT FROM AUTHOR]

Objectives: To understand the magnitude of risk of health events, such as cardiovascular diseases (CVD), related to poor oral health, both relative and absolute risk measures should be reported. Our aim was to investigate the extent to which absolute and relative measures of risk are reported in longitudinal studies that assess the association between oral health indicators (OHIs) and CVD. Methods: A systematic search of longitudinal studies investigating the association of any OHI with CVD was carried out using the Embase, Medline and Cochrane library databases. The search covered each database from its inception date to August 2021. Data about reporting relative and absolute risks of the relationship between CVD and OHI from the abstract were extracted. If the relative risk for OHIs and CVD was reported in the abstract, then the underlying absolute risks were searched from the full text, and it was assessed whether it was similarly adjusted for confounding than was the relative risk in the abstract. Results: One hundred‐six articles were included. From these, 85 (80%) studies reported the association of OHIs and CVD with one or more relative risks in the abstract. Of those 85 studies, the underlying absolute risks were accessible or calculable from the abstract or full text of 60 studies. However, of these 60 studies, in only 10 (12%), the underlying absolute risks were similarly adjusted, as were the relative risks in the abstract. The absolute risks of CVD by OHIs were rarely reported without corresponding relative risks in the abstract (n = 2, 2%). Median absolute risk difference in the CVD risk between exposure levels to which the first relative risk in the abstract referred was 1.8% (interquartile range 0.6–4.6, n = 63). Conclusions: Focusing on relative risks over absolute risks was a common practice in literature. Reporting similarly adjusted underlying absolute risks of relative risks was rare in most studies, despite those being helpful for comprehending the magnitude of CVD‐risk increase related to poor oral health. Current reporting practices could lead to an overinterpretation of risk increase of CVD related to poor oral health. [ABSTRACT FROM AUTHOR]

Delayed separation of survival curves is a common occurrence in confirmatory studies in immuno‐oncology. Many novel statistical methods that aim to efficiently capture potential long‐term survival improvements have been proposed in recent years. However, the vast majority do not consider stratification, which is a major limitation considering that most large confirmatory studies currently employ a stratified primary analysis. In this article, we combine recently proposed weighted log‐rank tests that have been designed to work well under a delayed separation of survival curves, with stratification by a baseline variable. The aim is to increase the efficiency of the test when the stratifying variable is highly prognostic for survival. As there are many potential ways to combine the two techniques, we compare several possibilities in an extensive simulation study. We also apply the techniques retrospectively to two recent randomized clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the measurement properties of a set of six items designed to elicit narrative accounts of pediatric inpatient experience. Data Sources: Data came from 163 participants recruited from a probability‐based online panel of U.S. adults. Participants were family members of a child who had an overnight hospital stay in the past 12 months. Study Design: Cross‐sectional survey with follow‐up phone interviews. Data Collection/Extraction Methods: Participants completed an online (n = 129) or phone (n = 34) survey about their child's hospitalization experience. The survey contained closed‐ended items from the Child Hospital Consumer Assessment of Healthcare Providers and Systems (Child HCAHPS) survey, followed by the six narrative items. Approximately 2 weeks after completing the survey, 47 participants additionally completed a one‐hour, semi‐structured phone interview, the results of which served as a "gold standard" for evaluating the fidelity of narrative responses. Qualitative content analysis was used to code narrative and interview responses for domains of patient experience and actionability. Principal Findings: The average narrative was 248 words (SD = 319). Seventy‐nine percent of narratives mentioned a topic included in the Child HCAHPS survey; 89% mentioned a topic not covered by that survey; and 75% included at least one detailed description of an actionable event. Overall, there was 66% correspondence between narrative and interview responses. Correspondence was higher on the phone than in the online condition (75% vs. 59%). Conclusions: Narratives elicited from rigorously designed multi‐item sets can provide detailed, substantive information about pediatric inpatient experiences that hospitals could use to improve child and family experiences during pediatric hospitalization. They add context to closed‐ended survey item responses and provide information about experiences of care important to children and families that are not included in quantitative surveys. [ABSTRACT FROM AUTHOR]

Objective: To conduct a quality improvement evaluation of the Empower Veterans Program (EVP), an interdisciplinary pain rehabilitation/functional restoration program option for functional restoration for high‐impact chronic pain, offered in a large metro‐area Veterans Health Administration (VHA) system. Data Sources: VHA Corporate Data Warehouse electronic medical record data for patients treated by EVP between 2015 and 2019. Evaluation Design: This retrospective design first compared EVP patients considered engaged or not engaged in completing treatment in terms of demographic characteristics and post‐treatment changes in clinical measures related to opioid use and mental health. We then compared mortality risk between matched groups of treated and untreated patients with chronic pain and concurrent opioid prescriptions using propensity score matching and Cox proportional hazards methods. "Treated" in the matched groups was defined as any level of EVP participation (i.e., both engaged and not engaged). Data Collection/Extraction Methods: We first identified 1053 EVP patients with 1 year of pre‐and post‐treatment follow‐time and determined their engagement level. From those with chronic pain and prescription opioids, we matched 237 EVP patients to 375 untreated patients. Principal Findings: Engaged patients (57.4% of treated patients), were somewhat older than the non‐engaged (mean age 57.1 vs. 53.7, Cohen's D = 0.30), and achieved lower mean PHQ9 depression scores in the post‐treatment year (9.2 vs. 10.6, Cohen's D = 0.20). Participation in EVP was associated with a 65% lower mortality risk among Veterans with chronic pain and opioid use when compared to the untreated patients: (HR: 0.35, 95% CI: 0.17, 0.75). Conclusions: EVP was associated with a large reduction in mortality risk for Veterans with both chronic pain and opioid use. This result could inform the decision process in a VA station or region when considering providing or expanding access to an interdisciplinary rehabilitation/functional restoration program for chronic pain. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer‐related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non‐small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late‐stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA‐Seq) with deconvolution of RNA‐Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B‐cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA‐Seq datasets. As previously described by others, pre‐treatment expression of intratumoral 12‐chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre‐treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non‐ICI treatments. [ABSTRACT FROM AUTHOR]

Commonly used prediction models have been primarily constructed without taking physical activity into account. Using the Kailuan physical activity cohorts from Asymptomatic Polyvascular Abnormalities in Community (APAC) study, we developed a 9‐year cardiovascular or cerebrovascular disease (CVD) risk prediction equation. Participants in this study were included from APAC cohort, which included 5440 participants from the Kailuan cohort in China. Cox proportional hazard regression model was applied to construct sex‐specific risk prediction equations for the physical activity cohort (PA equation). Proposed equations were compared with the 10‐year risk prediction model, which is developed for atherosclerotic cardiovascular disease risk in Chinese cohorts (China‐PAR equation). C statistics of PA equations were 0.755 (95% confidence interval, 0.750–0.758) for men and 0.801 (95% confidence interval, 0.790–0.813) for women. The estimated area under the receiver operating characteristic curves in the validation set shows that the PA equations perform as good as the China‐PAR. From calibration among four categories of predicted risks, the predicted risk rates by PA equations were almost identical to the Kaplan–Meier observed rates. Therefore, our developed sex‐specific PA equations have effective performance for predicting CVD for physically active cohorts in the physical activity cohort in Kailuan. [ABSTRACT FROM AUTHOR]

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high‐field 7T MRI. Data were from the Memory Depression and Aging (Medea)‐7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2‐weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = −0.43, 95% CI: −0.72; −0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors. [ABSTRACT FROM AUTHOR]

Germline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer‐ and polyposis‐focused panels, as well as on broader pan‐cancer panels. With up to 1%–2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross‐sectional self‐report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals. [ABSTRACT FROM AUTHOR]

The hazard ratio (HR) has been the most popular measure to quantify the magnitude of treatment effect on time‐to‐event outcomes in clinical research. However, the traditional Cox's HR approach has several drawbacks. One major issue is that there is no clear interpretation when the proportional hazards (PH) assumption does not hold, because the estimated HR is affected by study‐specific censoring time distribution in non‐PH cases. Another major issue is that the lack of a group‐specific absolute hazard value in each group obscures the clinical significance of the magnitude of the treatment effect. Given these, we propose average hazard with survival weight (AH‐SW) as a summary metric of event time distribution and will use difference in AH‐SW (DAH‐SW) or ratio of AH‐SW (RAH‐SW) to quantify the treatment effect magnitude. The AH‐SW is interpreted as a person‐time incidence rate that does not depend on random censoring. It is defined as the ratio of cumulative incidence probability and restricted mean survival time (RMST), which can be estimated non‐parametrically. Numerical studies demonstrate that DAH‐SW and RAH‐SW offer almost identical power to Cox's HR‐based tests under PH scenarios and can be more powerful for delayed‐difference patterns often seen in immunotherapy trials. Like median and RMST differences, the proposed approach is a good model‐free alternative to the HR‐based approach for evaluating the treatment effect magnitude. Such a model‐free measure will increase the likelihood that results from clinical studies are correctly interpreted and generalized to future populations. [ABSTRACT FROM AUTHOR]

m‐Benziporphyrin(1.1.0.0) and m‐pyreniporphyrin(1.1.0.0) were prepared as ring‐contracted carbaporphyrins. While m‐Benziporphyrin(1.1.0.0) was unstable, m‐pyreniporphyrin(1.1.0.0) was fairly stable. Both of their PdII complexes showed distorted coordination structures with extremely short Pd−C bonds. As compared with the reported m‐benziporphyrin PdII complexes, these PdII complexes showed considerably small HOMO‐LUMO gaps, despite their smaller molecular size. PdII metalation of the m‐pyreniporphyrin(1.1.0.0) dimer gave the corresponding PdII complex, which showed similar distorted coordination and a smaller HOMO‐LUMO gap. Finally, PdII metalation of a pyrene‐sharing formal p‐benziporphyrin(1.1.1.1) dimer gave a nonaromatic PdII dimer, which rearranged to an aromatic PdII complex upon treatment with alumina. [ABSTRACT FROM AUTHOR]

How to select the active variables that have significant impact on the event of interest is a very important and meaningful problem in the statistical analysis of ultrahigh‐dimensional data. In many applications, researchers often know that a certain set of covariates are active variables from some previous investigations and experiences. With the knowledge of the important prior knowledge of active variables, we propose a model‐free conditional screening procedure for ultrahigh dimensional survival data based on conditional distance correlation. The proposed procedure can effectively detect the hidden active variables that are jointly important but are weakly correlated with the response. Moreover, it performs well when covariates are strongly correlated with each other. We establish the sure screening property and the ranking consistency of the proposed method and conduct extensive simulation studies, which suggests that the proposed procedure works well for practical situations. Then, we illustrate the new approach through a real dataset from the diffuse large‐B‐cell lymphoma study S1. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma is a lethal form of skin cancer with morbidity and mortality rates highest amongst European, North American and Australasian populations. The developments of targeted therapies (TTs) directed at the oncogene BRAF and its downstream mediator MEK, and immune checkpoint inhibitors (ICI), have revolutionized the treatment of metastatic melanoma, improving patient outcomes. However, both TT and ICI have their limitations. Although TTs are associated with high initial response rates, these are typically short‐lived due to resistance. Conversely, although ICIs provide more durable responses, they have lower initial response rates. Due to these distinct yet complementary response profiles, it has been proposed that sequencing ICI with TT could lead to a high frequency of durable responses whilst circumventing the toxicity associated with combined ICI + TT treatment. However, several questions remain unanswered, including the mechanisms underpinning this synergy and the optimal sequencing strategy. The key to determining this is to uncover the biology of each phase of the therapeutic response. Aims and methods: In this review, we show that melanoma responds to TT and ICI in three phases: early response, minimal residual disease (MRD) and disease progression. We explore the effects of ICI and TT on melanoma cells and the tumour immune microenvironment, with a particular focus on MRD which is predicted to underpin the development of acquired resistance in the third phase of response. Conclusion: In doing so, we provide a new framework which may inform novel therapeutic approaches for melanoma, including optimal sequencing strategies and agents that target MRD, thereby ultimately improving clinical outcomes for patients. [ABSTRACT FROM AUTHOR]