Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

Quantum Gas-Enabled Direct Mapping of Active Current Density in Percolating Networks of Nanowires.

Electrically percolating nanowire networks are among the most promising candidates for next-generation transparent electrodes. Scientific interest in these materials stems from their intrinsic current distribution heterogeneity, leading to phenomena like percolating pathway rerouting and localized self-heating, which can cause irreversible damage. Without an experimental technique to resolve the current distribution and an underpinning nonlinear percolation model, one relies on empirical rules and safety factors to engineer materials. We introduce Bose-Einstein condensate microscopy to address the longstanding problem of imaging active current flow in 2D materials. We report on performance improvement of this technique whereby observation of dynamic redistribution of current pathways becomes feasible. We show how this, combined with existing thermal imaging methods, eliminates the need for assumptions between electrical and thermal properties. This will enable testing and modeling individual junction behavior and hot-spot formation. Investigating both reversible and irreversible mechanisms will contribute to improved performance and reliability of devices.

ManyFold: an efficient and flexible library for training and validating protein folding models.

SUMMARY: ManyFold is a flexible library for protein structure prediction with deep learning that (i) supports models that use both multiple sequence alignments (MSAs) and protein language model (pLM) embedding as inputs, (ii) allows inference of existing models (AlphaFold and OpenFold), (iii) is fully trainable, allowing for both fine-tuning and the training of new models from scratch and (iv) is written in Jax to support efficient batched operation in distributed settings. A proof-of-concept pLM-based model, pLMFold, is trained from scratch to obtain reasonable results with reduced computational overheads in comparison to AlphaFold. AVAILABILITY AND IMPLEMENTATION: The source code for ManyFold, the validation dataset and a small sample of training data are available at https://github.com/instadeepai/manyfold. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Shoulder Adhesive Capsulitis Prior to Total Knee Arthroplasty is Associated With Increased Rates of Postoperative Stiffness Requiring Manipulation Under Anesthesia and Arthroscopic Lysis of Adhesions.

BACKGROUND: Arthrofibrosis following total knee arthroplasty (TKA) and adhesive capsulitis (AC) of the shoulder develop via a similar pathologic process. The purpose of this study was to examine the relationship between these two conditions. METHODS: This was a retrospective cohort study using a large nationwide claims database. Patients who had a history of shoulder AC prior to TKA were compared to TKA patients who did not have AC history comparing rates of postoperative stiffness, manipulation under anesthesia (MUA), arthroscopic lysis of adhesions (LOAs), and revision arthroplasty at postoperative timepoints (3 months, 6 months, 1 year, and 2 years). RESULTS: Within 3 months, 6 months, 1 year, and 2 years of their TKAs, patients who had a history of AC prior to TKA were significantly more likely to experience stiffness (OR [odds ratio] = 1.29, 1.28, 1.32, and 1.36, respectively) and LOAs (OR = 6.78, 3.65, 2.99, and 2.81, respectively). They also showed increased risk of MUA within 6 months, 1 year, and 2 years (OR = 1.15, 1.15, and 1.16, respectively) of their TKAs. Patients having a preoperative diagnosis of AC did not have an increased risk of undergoing revision surgery 1 year or 2 years after their TKAs (P > .05). CONCLUSIONS: Patients diagnosed with AC prior to TKA experience higher rates of postoperative stiffness, resulting in additional interventions such as MUA and LOAs. These findings identify a particularly high-risk patient population that may benefit from additional interventions prior to and following TKA. LEVEL OF EVIDENCE: This is a level III prognostic study.

Postoperative Angiotensin Receptor Blocker Use is Associated With Decreased Rates of Manipulation Under Anesthesia, Arthroscopic Lysis of Adhesions, and Prosthesis-Related Complications in Patients Undergoing Total Knee Arthroplasty.

BACKGROUND: The cellular mechanisms underlying excess scar tissue formation in arthrofibrosis following total knee arthroplasty (TKA) are well-described. Angiotensin receptor blockers (ARB), particularly losartan, is a commonly prescribed antihypertensive with demonstrated antifibrotic properties. This retrospective study aimed to assess the rates of 1- and 2-year postoperative complications in patients who filled prescriptions for ARBs during the 90 days after TKA. METHODS: Patients undergoing primary TKA were selected from a large national insurance database, and the impact of ARB use after TKA on complications was assessed. Of the 1,299,106 patients who underwent TKA, 82,065 had filled at least a 90-day prescription of losartan, valsartan, or olmesartan immediately following their TKA. The rates of manipulation under anesthesia (MUA), arthroscopic lysis of adhesions (LOA), aseptic loosening, periprosthetic fracture, and revision at 1 and 2 years following TKA were analyzed using multivariable logistic regressions to control for various comorbidities. RESULTS: ARB use was associated with decreased rates of MUA (odds ratio [OR] = 0.94, 95% confidence interval (CI), 0.90 to 0.99), arthroscopy/LOA (OR = 0.86, 95% CI, 0.77 to 0.95), aseptic loosening (OR = 0.71, 95% CI, 0.61 to 0.83), periprosthetic fracture (OR = 0.58, 95% CI, 0.46 to 0.71), and revision (OR = 0.79, 95% CI, 0.74 to 0.85) 2 years after TKA. CONCLUSIONS: ARB use throughout the 90 days after TKA is associated with a decreased risk of MUA, arthroscopy/LOA, aseptic loosening, periprosthetic fracture, and revision, demonstrating the potential protective abilities of ARBs. Prospective studies evaluating the use of ARBs in patients at risk for postoperative stiffness would be beneficial to further elucidate this association.

Increased Risk of Hospital Readmissions and Implant-Related Complications in Patients Who Had a Recent History of Fragility Fracture: A Matched Cohort Analysis.

BACKGROUND: With the increasing utilization of total knee arthroplasty (TKA) in a continually aging US population, the number of patients who have low bone mineral density who undergo TKA may concomitantly increase. This study aimed to assess the rates of short-term complications following TKA in patients who did and did not have a recent history of a prior fragility fracture. METHODS: A matched retrospective cohort study analyzing 48,796 patients was performed using a national database to determine the impact of a preceding fragility fracture on rates of short-term complications following TKA. The rates of complications at 1 and 2 years post-TKA were analyzed using multivariate logistic regressions. RESULTS: Prior fragility fracture was associated with increased rates of 1-year hospital readmissions (hazard ratio = 1.30, 95% CI, 1.22-1.38), periprosthetic fractures (odds ratio [OR] = 2.72, 95% CI, 1.89-3.99), non-infection-related revisions (OR = 1.32, 95% CI, 1.09-1.60), secondary fragility fractures (OR = 4.62, 95% CI, 4.19-5.12), prosthesis dislocations (OR = 1.76, 95% CI, 1.22-2.56), prosthesis instabilities (OR = 1.64, 95% CI, 1.25-2.15), and periprosthetic infections (OR = 1.49, 95% CI, 1.29-1.71), with similar trends in implant-related complications also seen at the 2-year mark. Patients who filled a prescription for osteoporosis pharmacotherapy had clinically similar rates of these complications compared to those who did not. CONCLUSION: Sustaining a fragility fracture prior to TKA is associated with an increased risk of hospital readmission and significant implant-related postoperative complications, potentially increasing the morbidity and mortality of TKA in these patients.

All-Carbon Nanotube Solar Cell Devices Mimic Photosynthesis.

Both solar cells and photosynthetic systems employ a two-step process of light absorption and energy conversion. In photosynthesis, they are performed by distinct proteins. However, conventional solar cells use the same semiconductor for optical absorption and electron-hole separation, leading to inefficiencies. Here, we show that an all-semiconducting single-walled carbon nanotube (s-SWCNTs) device provides an artificial system that models photosynthesis in a tandem geometry. We use distinct chirality s-SWCNTs to separate the site and direction of light absorption from those of power generation. Using different bandgap s-SWCNTs, we implement an energy funnel in dual-gated p-n diodes. The device captures photons from multiple regions of the solar spectrum and funnels photogenerated excitons to the smallest bandgap s-SWCNT layer, where they become free carriers. We demonstrate an increase in the photoresponse by adding more s-SWCNT layers of different bandgaps without a corresponding deleterious increase in the dark leakage current.

Evidence-Based Medicine for Mandible Fracture Repair: Current Controversies and Future Opportunities.

Mandibular fractures are among the most common facial fractures resulting from trauma. The nature of the injury, involved facial structures, presence of associated injuries, the dental status of the patient, comorbid conditions, and psychosocial context all must be considered by the surgeon when planning the optimal treatment for these patients. While consensus exists for many aspects of the management of mandibular trauma, some elements remain controversial. Three such topics-antibiotic therapy, treatment of subcondylar fractures, and management of the third molar-remain particularly controversial, with significant heterogeneity in practice patterns and without widely accepted evidence-based guidelines to standardize care. The goals of this work are to (1) review the historical perspective underlying these controversies, (2) summarize recent evidence shaping the current debate, and (3) highlight opportunities for continued efforts to identify best practices.

Plasma IL13Rα2 as a novel liquid biopsy biomarker for glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. METHODS: In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. RESULTS: IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). CONCLUSION: These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy.

The curvature argument.

Dasgupta (2015) has recently put forward a novel argument, which he calls the 'curvature argument', that aims to show that Galilean spacetime is not an ideal setting for our classical theory of motion. This paper examines the curvature argument and argues that it is not sound. The discussion yields a remark about the conditions under which a 'symmetry argument' demonstrates that a particular spacetime is a non-ideal setting for our theory of motion.

Fully reconfigurable coherent optical vector-matrix multiplication.

Optics is a promising platform in which to help realize the next generation of fast, parallel, and energy-efficient computation. We demonstrate a reconfigurable free-space optical multiplier that is capable of over 3000 computations in parallel, using spatial light modulators with a pixel resolution of only 340×340. This enables vector-matrix multiplication and parallel vector-vector multiplication with vector size of up to 56. Our design is, to the best of our knowledge, the first to simultaneously support optical implementation of reconfigurable, large-sized, and real-valued linear algebraic operations. Such an optical multiplier can serve as a building block of special-purpose optical processors such as optical neural networks and optical Ising machines.

Polarization Oscillations in Birefringent Emitter-Cavity Systems.

We present the effects of resonator birefringence on the cavity-enhanced interfacing of quantum states of light and matter, including the first observation of single photons with a time-dependent polarization state that evolves within their coherence time. A theoretical model is introduced and experimentally verified by the modified polarization of temporally long single photons emitted from a ^{87}Rb atom coupled to a high-finesse optical cavity by a vacuum-stimulated Raman adiabatic passage process. Further theoretical investigation shows how a change in cavity birefringence can both impact the atom-cavity coupling and engender starkly different polarization behavior in the emitted photons. With polarization a key resource for encoding quantum states of light and modern micron-scale cavities particularly prone to birefringence, the consideration of these effects is vital to the faithful realization of efficient and coherent emitter-photon interfaces for distributed quantum networking and communications.

Incorporating social dimensions in planning, managing and evaluating environmental projects.

Most conservation research aims to inform management of environmental challenges, but scientific evidence is used inconsistently in environmental programmes and practice. We used semi-structured retrospective interviews to ask 12 environmental scientists and 14 practitioners (land managers, park rangers, project managers and planners from natural resource management agencies) about factors that facilitated and hindered the use of scientific input during 15 environmental projects. We used the common factors from interviews to develop a process model describing how scientific input informs programmes and practice. The model emphasised the social dimensions of environmental projects which are often overlooked when these projects are planned, managed and evaluated. It highlighted the pivotal role of relationships in achieving outcomes which include creating practical, useful products and tools, and robust, credible and trusted evidence. By clarifying the process of how scientific knowledge informs environmental programmes and practice, the model enabled us to provide guidance about how to undertake transdisciplinary work and suggest indicators to track progress. Although derived from environmental projects, the guidance is likely to apply to other fields, particularly where different disciplines work together.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Brain metastasis from squamous cell carcinoma of the head and neck: a review of the literature in the genomic era.

Squamous cell carcinoma of the head and neck (HNSCC) affects nearly 500,000 individuals globally each year. With the rise of human papillomavirus (HPV) in the general population, clinicians are seeing a concomitant rise in HPV-related HNSCC. Notably, a hallmark of HPV-related HNSCC is a predilection for unique biological and clinical features, which portend a tendency for hematogenous metastasis to distant locations, such as the brain. Despite the classic belief that HNSCC is restricted to local spread via passive lymphatic drainage, brain metastases (BMs) are a rare complication that occurs in less than 1% of all HNSCC cases. Time between initial diagnosis of HNSCC and BM development can vary considerably. Some patients experience more than a decade of disease-free survival, whereas others present with definitive neurological symptoms that precede primary tumor detection. The authors systematically review the current literature on HNSCC BMs and discuss the current understanding of the effect of HPV status on the risk of developing BMs in the modern genomic era.

Knowledge of proprietary and generic drug names among hospital prescribers: time to mandate generic prescribing?

Although medical students are taught clinical pharmacology using generic drug names, prescribing in hospitals often uses brand names. As a result, junior doctors may be prescribing drugs without knowing their nature or mode of action. We carried out a knowledge survey of 81 medical students and doctors at a 650-bed Australian teaching hospital to assess their knowledge of common drugs when given the brand name. We identified 20 commonly prescribed drugs and their brand names based on current hospital inpatients. No participant was able to provide the generic name, class or mode of action for all 20 drugs, with an average of 8.3 of 20 and 6.3 of the 10 most common drug names correctly identified. These data support calls to mandate prescribing using generic rather than brand names of drugs in hospitals.

Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs.

OBJECTIVE: To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesicsDesign. Randomized, double-blind, active- and placebo-controlled, 7-way crossover studySetting. Contract research organizationSubjects. Nondependent recreational users of prescription opioids. METHODS: Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. RESULTS: Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997). CONCLUSION: Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Evaluation of the tamper-resistant properties of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

CONTEXT: Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release. OBJECTIVE: To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets. MATERIALS AND METHODS: IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet. RESULTS: IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol. DISCUSSION: IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets. CONCLUSION: IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.

Safety and Tolerability of Biphasic Immediate-Release/Extended-Release Oxycodone/Acetaminophen Tablets: Analysis of 11 Clinical Trials.

OBJECTIVES: To characterize the safety of immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP). METHODS: Data were assessed from 9 phase 1 trials in healthy volunteers and recreational users of prescription opioids (N = 405), including 5 single-dose and 3 multidose open-label pharmacokinetic studies of IR/ER OC/APAP and active comparators; and 1 randomized, controlled, single-dose human abuse potential (HAP) study comparing IR/ER OC/APAP, IR OC/APAP, and placebo in recreational users of opioids; and 2 phase 3 trials (N = 701) including a 48-hour placebo-controlled safety and efficacy study in patients with moderate to severe postbunionectomy pain with a 14-day open-label safety extension and a long-term (≤ 35 days) open-label safety study in patients with chronic osteoarthritis pain or chronic low back pain. RESULTS: Adverse events (AEs) experienced by ≥ 10% of participants receiving IR/ER OC/APAP in all trials were pruritus, nausea, vomiting, dizziness, headache, and somnolence; these AEs occurred with similar frequency for equianalgesic doses of IR OC/APAP and IR OC but less frequently for IR tramadol HCl/APAP. In the HAP study, crushing IR/ER or IR OC/APAP tablets did not increase frequency of AEs. Constipation was experienced by < 10% of participants receiving IR/ER OC/APAP. No serious (SAE) or severe AEs were reported in phase 1 trials. In phase 3 trials of 8 reported SAEs, only 1 treatment-related SAE (hypersensitivity to placebo) required treatment discontinuation. No clinically meaningful changes in vital signs, oxygen saturation, electrocardiograms, or laboratory values were reported. CONCLUSIONS: Safety and tolerability of IR/ER OC/APAP are similar to other low-dose opioid/APAP analgesics.