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Abstract Recovery Colleges (RCs) are learning-based mental health recovery communities, located globally. However, evidence on RC effectiveness outside Western, educated, industrialised, rich, and democratic (WEIRD) countries is limited. This study aimed to evaluate associations between cultural characteristics and RC fidelity, to understand how culture impacts RC operation. Service managers from 169 RCs spanning 28 WEIRD and non-WEIRD countries assessed the fidelity using the RECOLLECT Fidelity Measure, developed based upon key RC operation components. Hofstede’s cultural dimension scores were entered as predictors in linear mixed-effects regression models, controlling for GDP spent on healthcare and Gini coefficient. Higher Individualism and Indulgence, and lower Uncertainty Avoidance were associated with higher fidelity, while Long-Term Orientation was a borderline negative predictor. RC operations were predominantly aligned with WEIRD cultures, highlighting the need to incorporate non-WEIRD cultural perspectives to enhance RCs’ global impact. Findings can inform the refinement and evaluation of mental health recovery interventions worldwide.

Abstract Adaptation transcends scale in both natural and artificial systems, but delineating the causative factors of this phenomenon requires urgent clarification. Herein, we unravel the molecular requirements for adaptation and establish a link to rationalize adaptive behavior on a self-assembled level. These concepts are established by analyzing a model compound exhibiting both light- and pH-responsive units, which enable the combined or independent application of different stimuli. On a molecular level, adaptation arises from coupled stimuli, as the final outcome of the system depends on their sequence of application. However, in a self-assembled state, a single stimulus suffices to induce adaptation as a result of collective molecular behavior and the reversibility of non-covalent interactions. Our findings go beyond state-of-the-art (multi)stimuli-responsive systems and allow us to draw up design guidelines for adaptive behavior both at the molecular and supramolecular levels, which are fundamental criteria for the realization of intelligent matter.

It is an honor to write this tribute to Dr. Paul Christian Pacquing, though I never imagined doing this for him. Given this opportunity to pay my last respects to a dear friend and colleague, I will try my best to recount and share the last 11 years of his life with you. Pax played a myriad of roles. He was a husband, a father, a son, a friend and a physician. Whichever role he played; he was exemplary at it. I first met Pax during pre-residency for the ORL-HNS program at the East Avenue Medical Center. He was cordial to everyone, even to his fellow pre residents, despite us being competitors. During residency, he stood out as Mr. Congeniality. He had an immensely infectious smile, and was literally friends with everyone in the hospital. He always had an amicable demeanor towards his patients. He would call patients like, "Mommy dear! Kumusta ka na?" Sometimes, proceeding to innocently and warmly hug our patients. He had a knack for handling conflicts and toxicities with his laid back nature. He would utter: "Chill. Relax lang tayo pare." Surprisingly, this worked and we would surmount our challenges unscathed most of the time. We had our sleep medicine and surgery fellowship training together in the same year at Chang Gung Medical Center. He excelled even in a foreign land and training institution. As a Fellow, he was sharp, studious and valued the time and experience there. Our mentors acknowledged his brilliance and he finished training with much approval. Back home, he established his practice in Isabela, Cagayan and Manila. However, due to the limited mobility brought about by the pandemic, he opted to stay in his hometown of Isabela and share his medical expertise there. As a physician, he was charitable and compassionate. Sharing a clinic together, our secretary would frequently tell me the incidents where Pax would treat financially-constrained patients for free. He would incessantly discuss his dream of establishing and providing sleep disorder services in the North to cater to his fellow Ilocanos. As a family man, he was affectionate, responsible and thoughtful. He loved his wife and was committed, despite numerous challenges. Our chats never ended without him talking about his daughter, the time they spent together and the dreams he had for her. Even during his last days, he only thought of his daughter and that he was determined to fight on so that he could see her grow up. In March 2023, after attending our annual PSSM convention, he was diagnosed with a rare type of B- lymphoblastic leukemia. This was extremely difficult and sad news to process by everyone close to Pax. How could a fit, sporty and healthy young man have leukemia? He underwent numerous grueling sessions of chemotherapy, but despite this, in a typical Pax manner of managing things, he remained calm, positive and relaxed. Never was there a negative word during the entirety of his treatment. Even in pictures where he was bedridden and attached to IV lines, he was still smiling. On the morning of September 4, 2024, the day prior to the first phase of his bone marrow transplant treatment, he asked for prayers and told me the next time I see him will be during recovery. Four days after, I received news from his wife that he was in critical condition with signs of multiple organ failure. Even prior to intubation, he was seen smiling and waving to his wife and brother and gesturing a thumbs up. Only a brave man would be capable of doing this while feeling the inevitable end nearing. Pax joined our Creator the following day. Paul Christian’s early passing remains a mystery and nagging question to family and friends. Why was this energetic, young and vibrant soul extinguished so early? Perhaps God has a plan. As mere humans, maybe we are not supposed to know the answers to the whys and whens of life and existence. To Pax: "Paalam, kapatid." We will miss you. I know you are smiling down at us from the heavens.

Background: Opportunities to minimize inequities in accessing treatments for tricuspid regurgitation disease should be considered. Objective: The objective of this study was to explore how access to new tricuspid regurgitation technologies change when heart centers are restricted by payer coverage requirements. Methods: This case series study identified U.S. hospitals with a record of performing transcatheter aortic valve replacement, transcatheter edge-to-edge repair, and tricuspid and mitral valve procedures for the calendar year 2021. Population 65+ years of age and Area Deprivation Index (ADI), were identified by zip code. We created 10 scenarios based on low, medium, and high hospital volumes for combinations of transcatheter aortic valve replacement, transcatheter edge-to-edge repair, tricuspid and mitral valve procedures. Distance from a zip code to scenario eligible hospitals was determined; the closest hospital to a zip code was identified as the distance someone with tricuspid regurgitation would have to travel for care. Each scenario was modeled with the dependent variable as the distance to the nearest scenario eligible hospital by ADI, controlling for population size 65+ years of age. Results: A total of 929 U.S. hospitals met our study inclusion. ADI was statistically significant in every scenario—when ADI goes up (more deprivation), distance to the nearest hospital increases. Patients in zip codes with low ADI travel an average of 15 to 52 miles, medium ADI 31 to 67 miles, and high ADI 47 to 95 miles. Conclusions: Patients in higher socioeconomic deprivation areas travel longer distances to hospitals meeting procedure volume requirements. Policymakers and patient advocacy groups should consider this to ensure equitable access to potentially life-saving technologies.

Background The treatment of severe aortic stenosis has evolved considerably since the introduction of transcatheter aortic valve replacement (TAVR), yet trends in complications for patients undergoing TAVR or surgical aortic valve replacement (SAVR) at a national level have yet to be evaluated. Methods and Results We performed a retrospective cohort study using Medicare data to evaluate temporal trends in complications among beneficiaries, aged ≥65 years, treated with elective isolated transfemoral TAVR or SAVR between 2012 and 2019. The study end point was the occurrence of a major complication (composite outcome) during index and up to 30 days after. Multivariable logistic regression was used to assess odds of complications for TAVR and SAVR, individually over time, and for TAVR versus SAVR, over time. The cohort included 211 212 patients (mean±SD age, 78.6±7.3 years; 45.0% women). Complication rates during index following elective isolated aortic valve replacement decreased from 49% in 2012 to 22% in 2019. These reductions were more pronounced for TAVR (41% to >19%, Δ=22%) than SAVR (51% to >47%, Δ=4%). After risk adjustment, the risk of any complication with TAVR was 47% (P

Background Aortic regurgitation is distinguished by the backflow of blood from the aorta into the left ventricle. American College of Cardiology/American Heart Association guidelines recommend surgical aortic valve replacement (SAVR) for patients with symptomatic aortic regurgitation (sAR). This study estimates the difference in mortality, health care use, and costs between patients with sAR who receive SAVR within 12 months of diagnosis versus those who do not. Methods and Results We used the Optum United Healthcare database to identify 132 317 patients diagnosed with sAR from 2016 to 2021 who had at least 6 months of enrollment before sAR and 12 months of enrollment after. Criteria were no history of aortic stenosis or transcatheter aortic valve replacement and ≥2 visits for heart failure, angina, dyspnea, or syncope. Outcomes were all‐cause mortality, health care use, and annualized cost. Baseline differences in demographics and comorbidities were adjusted with inverse propensity score weighting. We modeled survival and estimated health care use and costs using Cox proportional hazards and general linear models, respectively. Of the 132 317 patients, 400 underwent SAVR within 12 months of diagnosis. They were on average younger, more often men, and with a slightly higher Elixhauser Comorbidity Index score. After inverse propensity score weighting, patients with sAR who had SAVR had lower mortality, fewer inpatient and emergency department visits, fewer hospital days, and lower annualized cost. Conclusions SAVR performed within 12 months of an sAR diagnosis is associated with improved mortality and lower annualized health care use and costs. These clinical and economic benefits should be considered when managing patients with sAR.

# Background Acetabular dysplasia (AD) causes pain, limited function, and development of early hip osteoarthritis. Periacetabular osteotomy (PAO) is a surgical treatment for AD that aims to reposition the acetabulum to reduce pain and improve function. # Purpose To examine pain recovery and physical activity (PA) before and during the six months after PAO. # Study Design Case series, prospective # Methods Individuals with AD scheduled for PAO were enrolled. Pain intensity was evaluated before PAO and at one week and one, three, and six months following PAO. PA levels was evaluated before and six months following PAO using accelerometers (time spent in sedentary behavior, light PA, moderate-to-vigorous PA \[MVPA\], and daily steps) and the International Physical Activity Questionnaire (IPAQ; time spent in walking and in MVPA). Pain improvements was examined over time following PAO using a repeated-measures one-way ANOVA as well as improvements in PA levels before and six months after PAO using paired-sample *t* tests. In addition, time spent in MVPA was qualitatively summarized at each time point (before and six months after PAO) measured by both the accelerometers and IPAQ. # Results Out of 49 screened participants, 28 were enrolled, and 23 individuals (22 females; age=23.1±7.9 years) completed both study visits. Compared to pre-PAO pain, participants reported significant improvements in pain at one month and onward following PAO (*p*\0.05). Qualitatively, participants reported spending more time in MVPA recorded by the IPAQ (pre-PAO=73.3±150.2 mins/day; six-months after PAO=121.2±192.2 mins/day), compared with MVPA recorded by accelerometers (pre-PAO=22.6±25.2 mins/day; six-months after PAO=25.0±21.4 mins/day). # Conclusions Individuals with AD reported significant pain reduction at one month and up to six months after PAO, but PA levels did not change six months after PAO compared to baseline testing. Future studies should consider examining longitudinal pain recovery and PA improvements over longer periods of time with larger samples of individuals with AD undergoing PAO and identifying modifiable factors to minimize pain and increase PA participation. # Level of Evidence III

CMN 8917 is a small, partial skull of a duck-billed dinosaur from the upper Campanian Dinosaur Park Formation in what is now Dinosaur Provincial Park, Alberta. It represents one of the few nestling-sized juvenile hadrosaurines known to date. Support for this phylogenetic placement includes a narial vestibule not enclosed within the premaxillary dorsal and lateral processes, the presence of an anterodorsal maxillary process, and a maxillary dorsal process that is longer anteroposteriorly than dorsoventrally. The skull also possesses tooth traits traditionally associated with lambeosaurines, such as secondary ridges on some maxillary and dentary tooth crowns, and denticulation on some maxillary tooth crowns. The occurrence of these features in a juvenile hadrosaurine suggests that they were modified during ontogeny, calling into question their taxonomic utility for identifying juvenile specimens. The dentary teeth of CMN 8917 are similar to those of many adult hadrosaurids in that they possess a concave occlusal surface with steeper lingual and shallower buccal wear zones. This differs from the occlusal surface morphology present in some other juvenile hadrosaurids, which suggests interspecific differences in dental battery development—possibly reflective of dietary differences—occurred during early ontogeny in some taxa.

A large data set measuring surface stream turbidity, dissolved oxygen levels, and water temperature was developed by sampling 32 rivers and streams with forested catchments at weekly intervals for between two and three years. This was in response to allegations of possible water quality impairment by forest harvesting (“logging”). Additionally, nine rivers or streams external to the forests were sampled to form a “reference set”; concern was expressed that the water quality of these may be impaired by upstream forest harvesting. An unlogged forested control catchment was selected from the data set and used as a comparator to help reduce seasonal variation. Division of the data into “logged forested catchments” and “unlogged forested catchments” allowed for us to test the null hypothesis. The null hypothesis was that there was no difference between the means of the logged and unlogged sets by a “Student’s t test of difference between means”. The null hypothesis was supported for the three parameters. There was no discernible deterioration in water quality associated with the presence of logging in the stream catchments. It was concluded that logging in this environment was not a determinant of water quality, and that the presence or absence of logging in these catchments did not affect the measured water quality. Spearman rank correlation analysis was unable to detect any statistically significant correlations between the water quality parameters, suggesting they are substantially independent measures of water quality. The monitoring showed that the small upland streams had generally good-to-excellent water quality. The water quality in these was generally better than the “reference set”—this probably reflected agriculture and cultivation in the proximity of their sampling points.

Background To explore how differences in local socioeconomic deprivation impact access to aortic valve procedures and the treatment of aortic valve disease, in comparison to other open and minimally invasive surgical procedures. Methods and Results Procedure volume data were obtained from the Healthcare Cost and Utilization Project from 18 states from 2016 to 2019 and merged with area deprivation index data, an index of zip code‐level socioeconomic distress. We estimate the relationship between local deprivation ranking and differences in volumes of aortic valve replacement, which include transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), versus coronary artery bypass graft surgery and laparoscopic colectomy (LC). All regressions control for state and year fixed effects and an array of zip code‐level characteristics. TAVR procedures have increased over time across all zip codes. The rate of increase is negatively correlated with deprivation ranking, regardless of the higher share of hospitalizations per population in high deprivation areas. Distributional analysis further supports these findings, showing that lower area deprivation index areas account for a disproportionately large share of SAVR, TAVR, and LC procedures in our sample relative to their share of all hospitalizations in our sample. By comparison, the cumulative distribution of coronary artery bypass graft procedures was nearly identical to that of total hospitalizations, suggesting that this procedure is equitably distributed. Regressions show high area deprivation index areas have lower prevalence of SAVR (β=−15.1%, [95% CI, −26.8 to −3.5]), TAVR (β=−9.1%, [95% CI, −18.0 to −0.2]), and LC (β=−19.9%, [95% CI, −35.4 to −4.4]), with no statistical difference in the prevalence of coronary artery bypass graft (β=−2.5%, [95% CI, −12.7 to 7.6]), a widespread and commonly performed procedure. In the population aged ≥80 years, results show high area deprivation index areas have a lower prevalence of TAVR (β=−11.9%, [95% CI, −18.7 to −5.2]) but not SAVR (β=−0.8%, [95% CI, 8.1 to 6.3]), LC (β=−3.5%, [95% CI, −13.4 to −6.4]), or coronary artery bypass graft (β=5.2%, [95% CI, −1.1 to 1.1]). Conclusions People living in high deprivation areas have less access to life‐saving technologies, such as SAVR, and even moreso to device‐intensive minimally invasive procedures such as TAVR and LC.

7Li NMR spectroscopy is known to be very sensitive to translational motion in solids and therefore highly suited for investigating temperature-dependent Li+ dynamics. A number of different NMR methods are available for choosing the dynamical range of the observed Li+ jump frequencies present in inorganic solid-state electrolytes. This includes 7Li spin-alignment echo NMR spectroscopy, static 7Li lineshape analysis, and 7Li spin-lattice relaxometry that can be used to detect Li+ jumps in the Hz, kHz, and MHz range, respectively. We introduce and discuss these NMR techniques with respect to their theoretical description and practical application to investigate the Li+ dynamics at different time scales for the two solid-state electrolytes Li8SiP4 and Li14SiP6. The data evaluation for all methods is discussed in detail, focusing on the determination of Li+ jump frequencies and activation energies for the investigated self-diffusion processes in a given structure.

Background and Objectives: Augmented reality head-mounted display (AR-HMD) is a novel technology that provides surgeons with a real-time CT-guided 3-dimensional recapitulation of a patient’s spinal anatomy. In this case series, we explore the use of AR-HMD alongside more traditional robotic assistance in surgical spine trauma cases to determine their effect on operative costs and perioperative outcomes. Materials and Methods: We retrospectively reviewed trauma patients who underwent pedicle screw placement surgery guided by AR-HMD or robotic-assisted platforms at an academic tertiary care center between 1 January 2021 and 31 December 2022. Outcome distributions were compared using the Mann–Whitney U test. Results: The AR cohort (n = 9) had a mean age of 66 years, BMI of 29.4 kg/m2, Charlson Comorbidity Index (CCI) of 4.1, and Surgical Invasiveness Index (SII) of 8.8. In total, 77 pedicle screws were placed in this cohort. Intra-operatively, there was a mean blood loss of 378 mL, 0.78 units transfused, 398 min spent in the operating room, and a 20-day LOS. The robotic cohort (n = 13) had a mean age of 56 years, BMI of 27.1 kg/m2, CCI of 3.8, and SII of 14.2. In total, 128 pedicle screws were placed in this cohort. Intra-operatively, there was a mean blood loss of 432 mL, 0.46 units transfused units used, 331 min spent in the operating room, and a 10.4-day LOS. No significant difference was found between the two cohorts in any outcome metrics. Conclusions: Although the need to address urgent spinal conditions poses a significant challenge to the implementation of innovative technologies in spine surgery, this study represents an initial effort to show that AR-HMD can yield comparable outcomes to traditional robotic surgical techniques. Moreover, it highlights the potential for AR-HMD to be readily integrated into Level 1 trauma centers without requiring extensive modifications or adjustments.

Background and Objectives: Advances in virtual reality (VR), augmented reality (AR), and mixed reality (MR) technologies have resulted in their increased application across many medical specialties. VR’s main application has been for teaching and preparatory roles, while AR has been mostly used as a surgical adjunct. The objective of this study is to discuss the various applications and prospects for VR, AR, and MR specifically as they relate to spine surgery. Materials and Methods: A systematic review was conducted to examine the current applications of VR, AR, and MR with a focus on spine surgery. A literature search of two electronic databases (PubMed and Scopus) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The study quality was assessed using the MERSQI score for educational research studies, QUACS for cadaveric studies, and the JBI critical appraisal tools for clinical studies. Results: A total of 228 articles were identified in the primary literature review. Following title/abstract screening and full-text review, 46 articles were included in the review. These articles comprised nine studies performed in artificial models, nine cadaveric studies, four clinical case studies, nineteen clinical case series, one clinical case–control study, and four clinical parallel control studies. Teaching applications utilizing holographic overlays are the most intensively studied aspect of AR/VR; the most simulated surgical procedure is pedicle screw placement. Conclusions: VR provides a reproducible and robust medium for surgical training through surgical simulations and for patient education through various platforms. Existing AR/MR platforms enhance the accuracy and precision of spine surgeries and show promise as a surgical adjunct.

Abstract Purpose To determine factors impacting cumulative dissipated energy (CDE) and postoperative best-corrected visual acuity (BCVA) in phacoemulsification. Design Review of 1102 cases at University of California, San Francisco (UCSF) and at Zhongshan Ophthalmic Center (ZOC), China. Subjects Patients who underwent cataract surgery at UCSF 03/2014–03/2019 and at ZOC 10/2018–05/2019. Methods Patient demographics, medical history, routine ocular examination, and surgical information, including disassembly method, complications, and surgeon training level were recorded. Univariable and multivariable regression models were used to determine factors associated with CDE and good postoperative BCVA (20/40 or better) at 1 month. Outcome measures CDE, postoperative BCVA. Results In multivariable analysis, patient age at time of surgery, diabetes, degree of nuclear sclerosis (NS), white-to-white corneal diameter, disassembly method, preoperative BCVA, surgeon training level, and surgical center were significantly associated with CDE. Log10CDE increased by 0.20–0.31 for patient age ≥ 70 years, by 0.07 if the patient had diabetes, by 0.12–0.41 for NS grade ≥ 2, by 0.48 per 10 mm increase in white-to-white corneal diameter, by 0.34–0.47 for disassembly method other than non-stop chop, by 0.16 per unit increase in preoperative logMAR BCVA, and by > 0.09 when phacoemulsification was performed by residents early in their training. Log10CDE was 0.33 higher at UCSF than ZOC. In multivariable analysis, worse baseline visual acuity and age above 90 years at time of surgery decreased the odds of good BCVA (OR = 0.26 per unit increase in preoperative logMAR BCVA; OR = 0.12 for age > 90); comorbid retinal issues decreased the odds of good postoperative BCVA (OR = 0.13–0.39); greater anterior chamber depth (ACD) or shorter axial length (AL), increased the odds of good postoperative outcome (OR = 2.64 per 1 mm increase ACD, OR = 0.84 per 1 mm increase AL). Conclusions Cataract grade determined by slit lamp exam and, for the first time, older patient age, were noted to be important predictors of high CDE. CDE was not a risk factor for postoperative BCVA measured at postoperative 1 month. When surgery was performed by trainees under supervision, lower training level was associated with higher CDE, but not with worse postoperative BCVA.

ABSTRACT: Graphene quantum dots (GQDs) are zero-dimensional (0D) materials having unique luminescence properties due to quantum confinement and edge effect. Coupled with their large surface area, chemical- and photostabilities, biocompatibility, and low-toxicity, GQDs have enchanted many attentions for fundamental research and applications. In particular, the broad synthesis methods with ease of functionalization and controlled-synthesis as well as large variety of naturally available precursors, have made GQDs to be suitable for the development of advanced, rapid, and versatile optical-based biological and environmental sensors with high sensitivity and selectivity. In this review, we summarize the intrinsic knowledge about GQDs related to what properties make them interesting as nanosensors and further highlight the recent advances in their synthesis methods particularly from naturally available resources. Furthermore, fundamental sensing mechanisms will also be given to provide basic knowledge and a more comprehensive understanding to the readers about GQDs as luminescence-based biological and environmental nanosensors. The current limitations and prospects of GQDs are highlighted as the final conclusion of this review, hoping that the readers from various multidisciplinary natures to contribute their expertise and collaborate not only to improve the currently available GQD-based sensors but also to develop new sensing concepts which have never been realized.

4-nitrophenol (4-NP) is one of the organic pollutants that can come up from pesticides, explosives, dyes, and pharmaceutical industries. Since it can be extremely harmful to humans and other living organisms, it is crucial to have a system that can effectively detect the presence of 4-NP. Here, we report the microplasma synthesis of nitrogen-doped graphene quantum dots (N-GQDs) for fluorescence-based detection of 4-NP. Through Förster resonance energy transfer (FRET) between donor N-GQDs to the acceptor 4-NP, synthesized N-GQDs can be employed for the detection of 4-NP starting from 0.5 to 100 µM with a limit of detection as low as 95.14 nM. 4-NP detection also demonstrates remarkable stability over all pH values and wide temperatures (10–60 °C), indicating the high possibility for robust organic pollution monitoring. Our work provides insight into a simple, fast, and environmentally friendly method for synthesizing N-GQDs at ambient conditions usable for environmental nanosensors.

Abstract Curved graphene nanoribbons (GNRs) with hybrid edge structures have recently attracted increasing attention due to their unique band structures and electronic properties as a result of their nonplanar conformation. This work reports the solution synthesis of a long and curved multi‐edged GNR (cMGNR) with unprecedented cove–armchair–gulf edge structures. The synthesis involves an efficient A2B2‐type Diels–Alder polymerization between a diethynyl‐substituted prefused bichrysene monomer (3b) and a dicyclopenta[e,l]pyrene‐5,11‐dione derivative (6) followed by FeCl3‐mediated Scholl oxidative cyclodehydrogenation of the obtained polyarylenes (P1). Model compounds 1a and 1b are first synthesized to examine the suitability and efficiency of the corresponding polymers for the Scholl reaction. The successful formation of cMGNR from polymer P1 bearing prefused bichrysene units is confirmed by FTIR, Raman, and solid‐state NMR analyses. The cove‐edge structure of the cMGNR imparts the ribbon with a unique nonplanar conformation as revealed by density functional theory (DFT) simulation, which effectively enhances its dispersibility in solution. The cMGNR has a narrow optical bandgap of 1.61 eV, as estimated from the UV–vis absorption spectrum, which is among the family of low‐bandgap solution‐synthesized GNRs. Moreover, the cMGNR exhibits a carrier mobility of ≈2 cm2 V−1 s−1 inferred from contact‐free terahertz spectroscopy.

Abstract Dual‐graphite batteries (DGBs), being an all‐graphite‐electrode variation of dual‐ion batteries (DIBs), have attracted great attention in recent years as a possible low‐cost technology for stationary energy storage due to the utilization of inexpensive graphite as a positive electrode (cathode) material. However, DGBs suffer from a low specific energy limited by the capacity of both electrode materials. In this work, a composite of black phosphorus with carbon (BP‐C) is introduced as negative electrode (anode) material for DIB full‐cells for the first time. The electrochemical behavior of the graphite || BP‐C DIB cells is then discussed in the context of DGBs and DIBs using alloying anodes. Mechanistic studies confirm the staging behavior for anion storage in the graphite positive electrode and the formation of lithiated phosphorus alloys in the negative electrode. BP‐C containing full‐cells demonstrate promising electrochemical performance with specific energies of up to 319 Wh kg–1 (related to masses of both electrode active materials) or 155 Wh kg–1 (related to masses of electrode active materials and active salt), and high Coulombic efficiency. This work provides highly relevant insights for the development of advanced high‐energy and safe DIBs incorporating BP‐C and other high‐capacity alloying materials in their anodes.

Recently, a new strong optimization algorithm called marine predators algorithm (MPA) has been proposed for tackling the single-objective optimization problems and could dramatically fulfill good outcomes in comparison to the other compared algorithms. Those dramatic outcomes, in addition to our recently-proposed strategies for helping meta-heuristic algorithms in fulfilling better outcomes for the multi-objective optimization problems, motivate us to make a comprehensive study to see the performance of MPA alone and with those strategies for those optimization problems. Specifically, This paper proposes four variants of the marine predators’ algorithm (MPA) for solving multi-objective optimization problems. The first version, called the multi-objective marine predators’ algorithm (MMPA) is based on the behavior of marine predators in finding their prey. In the second version, a novel strategy called dominance strategy-based exploration-exploitation (DSEE) recently-proposed is effectively incorporated with MMPA to relate the exploration and exploitation phase of MPA to the dominance of the solutions—this version is called M-MMPA. DSEE counts the number of dominated solutions for each solution—the solutions with high dominance undergo an exploitation phase; the others with small dominance undergo the exploration phase. The third version integrates M-MMPA with a novel strategy called Gaussian-based mutation, which uses the Gaussian distribution-based exploration and exploitation strategy to search for the optimal solution. The fourth version uses the Nelder-Mead simplex method with M-MMPA (M-MMPA-NMM) at the start of the optimization process to construct a front of the non-dominated solutions that will help M-MMPA to find more good solutions. The effectiveness of the four versions is validated on a large set of theoretical and practical problems. For all the cases, the proposed algorithm and its variants are shown to be superior to a number of well-known multi-objective optimization algorithms.

Background The aim of this study was to identify patients vulnerable for anxiety and/or depression following aortic valve replacement (AVR) and to evaluate factors that may mitigate this risk. Methods and Results This is a retrospective cohort study conducted using a claims database; 18 990 patients (1/2013–12/2018) ≥55 years of age with 6 months of pre‐AVR data were identified. Anxiety and/or depression risk was compared at 3 months, 6 months, and 1 year following transcatheter aortic valve replacement or surgical AVR (SAVR) after risk adjustment using logistic regression and Cox proportional hazards models. Separate models were estimated for patients with and without surgical complications and discharge location. Patients with SAVR experienced a higher relative risk of anxiety and/or depression at 3 months (12.4% versus 8.8%; adjusted hazard ratio [HR] 1.39 [95% CI, 1.19–1.63]) and 6 months (15.6% versus 13.0%; adjusted HR, 1.24 [95% CI, 1.08–1.42]), with this difference narrowing by 12 months (20.1% versus 19.3%; adjusted HR, 1.14 [95% CI, 1.01–1.29]) after AVR. This association was most pronounced among patients discharged to home, with patients with SAVR having a higher relative risk of anxiety and/or depression. In patients who experienced operative complications, there was no difference between SAVR and transcatheter aortic valve replacement. However, among patients without operative complications, patients with SAVR had an increased risk of postoperative anxiety and/or depression at 3 months (adjusted HR, 1.47 [95% CI, 1.23–1.75]) and 6 months (adjusted HR 1.26 [95% CI, 1.08–1.46]), but not at 12 months. Conclusions There is an associated reduction in the risk of new‐onset anxiety and/or depression among patients undergoing transcatheter aortic valve replacement (versus SAVR), particularly in the first 3 and 6 months following treatment.

Abstract Introduction This study is part of the registrational program for intravenously administered (IV) tramadol in the USA and compared the analgesic benefit and tolerability of two doses of IV tramadol (50 mg and 25 mg) to placebo in adult patients undergoing bunionectomy, an orthopedic surgical model. Methods This was a phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate IV tramadol in the management of postoperative pain following bunionectomy. Eligible patients were randomized (1:1:1 ratio) to IV tramadol 50 mg, 25 mg, or placebo. Primary endpoint was summary of pain intensity differences over 48 h (SPID48). Key secondary endpoints included SPID24, total consumption of rescue analgesia, and patient global assessment of efficacy (PGA). Safety assessments included treatment emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Assessment of the dose–response was an important objective of the study. Results The study established a dose response, with IV tramadol 50 mg demonstrating statistically significant benefit (p

Abstract Background and Objective Oral tramadol, an atypical opioid approved in the United States (US) since 1995 and a Schedule IV controlled substance, has less abuse liability compared to Schedule II conventional opioids. Intravenous (IV) tramadol is not available in the US, but has the potential to fill a gap between non-opioid medications and conventional opioids for treatment of acute pain. This study evaluates IV tramadol in the management of postoperative pain compared to placebo and standard-of-care active control. Methods A phase 3, multicenter, double-blind, three-arm, randomized, placebo- and active-controlled, multiple-dose, parallel-group study was conducted to evaluate the efficacy and safety of 50 mg IV tramadol versus placebo and 4 mg IV morphine over 48 h in patients with postoperative pain following abdominoplasty surgery. Results IV tramadol was statistically superior (p

Many countries are challenged by the medical resources required for COVID-19 detection which necessitates the development of a low-cost, rapid tool to detect and diagnose the virus effectively for a large numbers of tests. Although a chest X-Ray scan is a useful candidate tool the images generated by the scans must be analyzed accurately and quickly if large numbers of tests are to be processed. COVID-19 causes bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities, sometimes with a rounded morphology and a peripheral lung distribution. In this work, we aim to extract rapidly from chest X-Ray images the similar small regions that may contain the identifying features of COVID-19. This paper therefore proposes a hybrid COVID-19 detection model based on an improved marine predators algorithm (IMPA) for X-Ray image segmentation. The ranking-based diversity reduction (RDR) strategy is used to enhance the performance of the IMPA to reach better solutions in fewer iterations. RDR works on finding the particles that couldn't find better solutions within a consecutive number of iterations, and then moving those particles towards the best solutions so far. The performance of IMPA has been validated on nine chest X-Ray images with threshold levels between 10 and 100 and compared with five state-of-art algorithms: equilibrium optimizer (EO), whale optimization algorithm (WOA), sine cosine algorithm (SCA), Harris-hawks algorithm (HHA), and salp swarm algorithms (SSA). The experimental results demonstrate that the proposed hybrid model outperforms all other algorithms for a range of metrics. In addition, the performance of our proposed model was convergent on all numbers of thresholds level in the Structured Similarity Index Metric (SSIM) and Universal Quality Index (UQI) metrics.

The rapid spread of novel coronavirus pneumonia (COVID-19) has led to a dramatically increased mortality rate worldwide. Despite many efforts, the rapid development of an effective vaccine for this novel virus will take considerable time and relies on the identification of drug-target (DT) interactions utilizing commercially available medication to identify potential inhibitors. Motivated by this, we propose a new framework, called DeepH-DTA, for predicting DT binding affinities for heterogeneous drugs. We propose a heterogeneous graph attention (HGAT) model to learn topological information of compound molecules and bidirectional ConvLSTM layers for modeling spatio-sequential information in simplified molecular-input line-entry system (SMILES) sequences of drug data. For protein sequences, we propose a squeezed-excited dense convolutional network for learning hidden representations within amino acid sequences; while utilizing advanced embedding techniques for encoding both kinds of input sequences. The performance of DeepH-DTA is evaluated through extensive experiments against cutting-edge approaches utilising two public datasets (Davis, and KIBA) which comprise eclectic samples of the kinase protein family and the pertinent inhibitors. DeepH-DTA attains the highest Concordance Index (CI) of 0.924 and 0.927 and also achieved a mean square error (MSE) of 0.195 and 0.111 on the Davis and KIBA datasets respectively. Moreover, a study using FDA-approved drugs from the Drug Bank database is performed using DeepH-DTA to predict the affinity scores of drugs against SARS-CoV-2 amino acid sequences, and the results show that that the model can predict some of the SARS-Cov-2 inhibitors that have been recently approved in many clinical studies.

Dual-graphite batteries (DGBs), which are based on anion intercalation into graphite positive electrodes, exhibit great potential for stationary energy storage due to use of more sustainable and low-cost electrode materials and processing routes. Binary-mixed highly concentrated electrolytes (HCEs) appeal highly suitable for the high operating voltages of DGBs, although the lack of sufficient insights into the formation of graphite intercalation compounds (GICs) limits the cell performance in terms of specific capacity and lifetime so far. Herein, anion intercalation from single-salt HCEs (LiPF6 and LiBF4) and an equimolar binary mixture of LiPF6/LiBF4 are studied in graphite || Li metal cells, revealing an improved performance in terms of specific capacity and Coulombic efficiency in the order LiPF6 > LiPF6/LiBF4 > LiBF4. LiBF4-based cells exhibit an increased onset potential for anion intercalation and higher area specific impedance, suggesting an ineffective interphase formation at graphite. X-ray diffraction reveals GIC formation, while a lower stage number is achieved for the LiBF4-based HCE. 19F MAS NMR spectroscopy analysis at various states-of-charge confirms no significant charge transfer between the intercalated anions and the graphite host and suggest preferred intercalation of PF6- compared to BF4- as well as a high translational and/or rotational mobility of the intercalated anions.

Summary: During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca2+ and Zn2+ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn2+-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in metastatic melanoma cells prevents such cell death, overexpression of TRPML1 in normal cells confers ML-SA vulnerability. In the melanoma mouse models, ML-SAs exhibit potent in vivo efficacy of suppressing tumor progression. Hence, targeting maladaptively upregulated lysosome machinery can selectively eradicate metastatic tumor cells in vitro and in vivo.

Graphene quantum dots (GQDs) are a zero-dimensional (0D) carbon-based nanomaterial with a unique quantum confinement effect that have captured the eyes of many researchers. In addition to their luminescence properties, a high biocompatibility and large surface area have enabled GQDs to be used for many applications, and even be integrated with either organic or inorganic materials to produce GQD nanocomposites to enhance the application performances and broaden the application scope. In this review, we aim to highlight the exquisite properties and synthesis methods of GQDs, recent advances in the fabrication of GQD nanocomposites with both organic and inorganic materials, and their corresponding luminescence-based and surface enhanced Raman scattering (SERS)-based biosensing applications. Finally, this review article concludes with a summary of current challenges and prospects.

Research in metal matrix composites (MMCs) indicates that superior mechanical properties may be achieved by embedding reinforcement materials. However, the development of new composite powder for additive manufacturing requires an in-depth understanding of its key characteristics prior to its use in the fabrication process. This paper focuses on the low-energy ball milling (LEBM) of aluminium 2024 alloy (AA2024) reinforced with graphene nanoplatelets (GNPs). The main aim is to investigate the effect of the milling time (from 0.5 to 16 h) on the morphology and flowability of the powder. The study shows that, while short milling times (under 2 h) could not break the Van der WaRals forces between nanoparticles, GNPs were well separated and sufficiently covered the powder surface after 4 h of milling, thanks to the continuously applied impact energy. Longer milling time provides increasingly similar flowability results, confirmed by both the experimental work and discrete element model (DEM) simulations. Moreover, the ball milling process decreases the crystallite size of the milled powder by 24%, leading to a 3% higher microhardness. Lastly, the surface energy of the powder was determined as 1.4 mJ/m2 by DEM, using the angle of repose of the as-received powder from experimental work.

Abstract Background Lateral epicondylalgia (tennis elbow) is a common, debilitating and often treatment-resistant condition. Two treatments thought to address the pathology of lateral epicondylalgia are hypertonic glucose plus lignocaine injections (prolotherapy) and a physiotherapist guided manual therapy/exercise program (physiotherapy). This trial aimed to compare the short- and long-term clinical effectiveness, cost effectiveness, and safety of prolotherapy used singly and in combination with physiotherapy. Methods Using a single-blinded randomised clinical trial design, 120 participants with lateral epicondylalgia of at least 6 weeks’ duration were randomly assigned to prolotherapy (4 sessions, monthly intervals), physiotherapy (weekly for 4 sessions) or combined (prolotherapy+physiotherapy). The Patient-Rated Tennis Elbow Evaluation (PRTEE) and participant global impression of change scores were assessed by blinded evaluators at baseline, 6, 12, 26 and 52 weeks. Success rate was defined as the percentage of participants indicating elbow condition was either ‘much improved’ or ‘completely recovered.’ Analysis was by intention-to-treat. Results Eighty-eight percent completed the 12-month assessment. At 52 weeks, there were substantial, significant improvements compared with baseline status for all outcomes and groups, but no significant differences between groups. The physiotherapy group exhibited greater reductions in PRTEE at 12 weeks than the prolotherapy group (p = 0.014). Conclusion There were no significant differences amongst the Physiotherapy, Prolotherapy and Combined groups in PRTEE and global impression of change measures over the course of the 12-month trial. Trial registration ACTRN12612000993897.

Though solution-processed conjugated polymers with inverted temperature activated transport have been reported, the origin of this behaviour is unclear. Here, the authors realize temperature-independent electron transport above 280 K in a donor-acceptor copolymer through microstructural engineering.

Cinnamomum cebuense (Kosterm.) is widely known as stomachache remedy, but adverse reaction to varying amount of herbal extract has also been reported, thus, requiring toxicity-profiling studies. Here, the toxicity of C. cebuense leaf extract (CCLE) was evaluated using brine shrimp lethality assay (BSLA) and anthelminthic assay under a complete randomized design with equal replications. Results in BSLA revealed an LC50 value of 7.05 μg/ml (p≤0.05) which is considerably medium-toxic based on standard toxicity criterion. Influence on earthworm activity showed significant difference (p≤0.01) among the different concentrations of the extract (100 mg/ml, 75 mg/ml, 50 mg/ml, and 25 mg/ml) following a concentration-dependent response trend. Results suggest strong toxicity against earthworms at 75–100 mg/ml while having a moderate to weak toxicity at 25–50mg/ml. Both assays were able to elucidate toxicity of CCLE which may be due to the presence of cinnamaldehyde, the main phytochemical found in cinnamon leaves. CCLE is toxic at elevated dosages and thus warrants parallel studies using higher-vertebrate models.

Purpose–The study determines and measures the level of awareness of the PSU –Bayambang Campus students towards different e –learning technologies.Method–The researchers employed Quantitative Research Approach. The study determined the profile of the respondents through a demographic questionnaires and the current status of the campus in terms of the ICT Resources and Network Infrastructure. Result–The survey was carried out in order to measure the level of awareness towards different e –learning technologies among students. It was measured in terms of their familiarity to the existing e –learning technologies as well as the known features of these technologies. Although 52.50% of the respondents seem to be familiar to the concepts of e –learning, it is important to take into consideration the extent of their exposure to these technologies and its level of utilization in order to support the learning process.Conclusion –Technology, Support and Users were considered to be important factors that affect the awareness of the students. These technologies can be used to improve the existing learning process if there is enough support for its implementation through policies and provision of the needed resources.Recommendation –In order to improve the awareness of the stakeholders, the researchers recommended that policies on the integration of e –learning technologies must be designed and integrated to the existing learning process. The administration should also provide the needed ICT Resources and Infrastructure in order to support the use of these technologies. They should also provide training for the students and teachers in order to improve their awareness and enable them to use and maximize the benefits of these technologies.Research Implication –The research can serve as a guide for the design of the policies since it provide an overview of the current status of the university in terms of awareness of the students towards these technologies. These technologies can be used to improve the existing learning process of the University and provide a wider avenue for learning and interaction.

This article introduces a dataset comprising a portfolio of six projects each having a baseline consisting of a budget derived from a standardized first-principles, bottom-up estimation technique. The projects utilize a homogeneous set of resources, both consumable and non-consumable, which are inter-related in a highly complex, multi-dimensional manner with appropriate correlation between quantity, productivity rates and cost rates. The dataset also includes detailed time-phased actual costs and progress over the life of each project as well as the time-phased values of revenue claimed for each project. The collection and attribution of 12,139 actual costs and the measurement of progress over a period of just under 109 consecutive weeks is consistent and standardized across all six projects providing a unique differentiator to other datasets. The data is valid for research in portfolio, program, or project (PPP) management or control of multiple resource-constrained projects, where projects are managed collectively, generally in a standardized manner to support a strategic business aim.

Runoff from heavy precipitation events can lead to microbiological contamination of source waters for public drinking water supplies. Philadelphia is a city of interest for a study of waterborne acute gastrointestinal illness (AGI) because of frequent heavy precipitation, extensive impervious landcover, and combined sewer systems that lead to overflows. We conducted a time-series analysis of the association between heavy precipitation and AGI incidence in Philadelphia, served by drinking water from Delaware River and Schuylkill River source waters. AGI cases on each day during the study period (2015-2017) were captured through syndromic surveillance of patients' chief complaint upon presentation at local emergency departments. Daily precipitation was represented by measurements at the Philadelphia International Airport and by modeled precipitation within the watershed boundaries, and we also evaluated stream flowrate as a proxy of precipitation. We estimated the association using distributed lag nonlinear models, assuming a quasi-Poisson distribution of the outcome variable and with adjustment for potential confounding by seasonal and long-term time trends, ambient temperature, day-of-week, and major holidays. We observed an association between heavy precipitation and AGI incidence in Philadelphia that was primarily limited to the spring season, with significant increases in AGI that peaked from 8 to 16 days following a heavy precipitation event. For example, the increase in AGI incidence related to airport precipitation above the 95th percentile (vs no precipitation) during spring reached statistical significance on lag day 7, peaked on day 16 (102% increase, 95% confidence interval: 16%, 252%), and declined while remaining significantly elevated through day 28. Similar associations were observed in analyses of watershed-specific precipitation in relation to AGI cases within the populations served by drinking water from each river. Our results suggest that heavy precipitation events in Philadelphia result in detectable local increases in waterborne AGI.

It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

ObjectivesThe objective of the current cross-sectional study was to examine Achilles tendon transverse stiffness in a group of recreational runners with Achilles tendinopathy, in comparison to an asymptomatic group of runners with similar training history. We also aimed to determine the between-week intra-individual reliability of this measurement technique.DesignCross-sectional cohort study.MethodsA hand-held dynamometer was used to assess the transverse stiffness of the Achilles tendon (AT) in twenty-five recreational runners. In ten people with midportion Achilles tendinopathy (5 men, 5 women), measurements were taken directly over the most symptomatic location. In 15 people who were free of AT symptoms (7 men, 8 women), measurements were taken at an equivalent location on the tendon. Participants returned after one week to determine measurement reliability (intra-class correlation coefficient/ICC and minimum detectable change/MDC95). We also collected information about people's tendon loading activities, tendon thickness (ultrasound mesaurement), and symptoms (Victorian Institute of Sports Assessment-Achilles / VISA-A score).ResultsThe AT transverse stiffness was lower in people with Achilles tendinopathy (777 N/m ± 86) compared to those who were asymptomatic (873 N/m ± 72) (p < 0.05). AT transverse stiffness was negatively correlated with age and tendon thickness, and positively correlated with VISA-A score and waist circumference. Reliability was good, with ICC of 0.81 in people with tendinopathy and 0.80 in healthy controls, and an MDC95 of 118 and 87N/m in these two respective groups.ConclusionsTransverse Achilles tendon stiffness can be reliably measured in people with midportion Achilles tendinopathy, and appears to be lower in people who are older, more symptomatic, and with more extensive tendon thickening. The potential clinical utility of monitoring tendon stiffness in the management of tendon injuries merits further study.

Origins of mammalian DNA replication are poorly characterised because they lack an Identifiable consensus sequence. Here the authors identify RepID, a protein that binds to a subset of G-rich replication origins and facilitates initiation from those origins.

Race plays a significant role in shaping sense of belonging in higher education. However, little research has analyzed religion and belonging at universities. In this study, we test four hypotheses about race, religion, and belonging with survey data from a Christian university in the South. For first-year students, Asians express less belonging than Whites, but no other differences by race or religion appear. Among seniors, Black, Asian, and nonreligious students report lower levels of belonging than White and Christian students, respectively; however, religious minority students, including nonwhite religious minority students, do not report lower levels of belonging.

Modern solid-state NMR techniques offer a wide range of opportunities for the structural characterization of frustrated Lewis pairs (FLPs), their aggregates, and the products of cooperative addition reactions at their two Lewis centers. This information is extremely valuable for materials that elude structural characterization by X-ray diffraction because of their nanocrystalline or amorphous character, (pseudo-)polymorphism, or other types of disordering phenomena inherent in the solid state. Aside from simple chemical shift measurements using single-pulse or cross-polarization/magic-angle spinning NMR detection techniques, the availability of advanced multidimensional and double-resonance NMR methods greatly deepened the informational content of these experiments. In particular, methods quantifying the magnetic dipole−dipole interaction strengths and indirect spin−spin interactions prove useful for the measurement of intermolecular association, connectivity, assessment of FLP−ligand distributions, and the stereochemistry of adducts. The present review illustrates several important solid-state NMR methods with some insightful applications to open questions in FLP chemistry, with a particular focus on supramolecular associates.

We demonstrate that supercycles of previously introduced two-fold symmetry dipolar recoupling schemes may be utilized successfully in homonuclear correlation nuclear magnetic resonance (NMR) spectroscopy for probing proximities among half-integer spin quadrupolar nuclei in network materials undergoing magic-angle-spinning (MAS). These (SR2 2 1 ) M , (SR2 4 1 ) M , and (SR2 8 1 )M recoupling sequences with M = 3 and M = 4 offer comparably efficient magnetization transfers in single-quantum−single-quantum (1Q−1Q) correlation NMR experiments under moderately fast MAS conditions, as demonstrated at 14.1 T and 24 kHz MAS in the contexts of 11 B NMR on a Na 2 O−CaO−B 2 O 3 −SiO 2 glass and 27 Al NMR on the open framework aluminophosphate AlPO-CJ19 [(NH 4 ) 2 Al 4 (PO 4 ) 4 HPO 4 · H 2 O]. Numerically simulated magnetization transfers in spin−3/2 pairs revealed a progressively enhanced tolerance to resonance offsets and rf-amplitude errors of the recoupling pulses along the series (SR2 2 1 ) M < (SR2 4 1 ) M < (SR2 8 1 )M for increasing differences in chemical shifts between the two nuclei. Nonetheless, for scenarios of a relatively minor chemical-shift dispersions ( ≲ 3 kHz), the (SR2 2 1 )M supercycles perform best both experimentally and in simulations.

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Summary: Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival. : Ricketts et al. find distinctive features of each RCC subtype, providing the foundation for development of subtype-specific therapeutic and management strategies. Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes. Keywords: clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, CDKN2A, DNA hypermethylation, immune signature, chromatin remodeling, TCGA, PanCanAtlas

Summary: Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. : Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability. Keywords: fusion, cancer, RNA, translocation, gene fusions

Summary: Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment. : Tumor-infiltrating lymphocytes (TILs) were identified from standard pathology cancer images by a deep-learning-derived “computational stain” developed by Saltz et al. They processed 5,202 digital images from 13 cancer types. Resulting TIL maps were correlated with TCGA molecular data, relating TIL content to survival, tumor subtypes, and immune profiles. Keywords: digital pathology, immuno-oncology, machine learning, lymphocytes, tumor microenvironment, deep learning, tumor-infiltrating lymphocytes, artificial intelligence, bioinformatics, computer vision

Summary: Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility. : Peng et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to characterize tumor subtypes based on the expression of seven metabolic pathways. They find metabolic expression subtypes are associated with patient survivals and suggest the therapeutic and predictive relevance of subtype-related master regulators. Keywords: The Cancer Genome Atlas, tumor subtypes, prognostic markers, somatic drivers, master regulator, therapeutic targets, drug sensitivity, carbohydrate metabolism