Comparing internal and external stabilization for traumatic elbow instability: a systematic review.

Background: Despite surgical reestablishment of the supporting structures, instability may often persist in traumatic elbow injury. In these cases, a temporary internal or external fixator may be indicated to unload the repaired structures and maintain joint concentricity. Aggregate data are needed to characterize the risk of complication between external fixation (ExFix) and the internal joint stabilizer (IJS) when used for traumatic elbow instability. Our objective was to review the literature to compare the complication profile between external fixation and the IJS. Methods: A database query was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Population, Intervention, Comparison and Outcome characteristics for eligibility were the following: for patients over 18 years clinical outcomes were compared between an ExFix or the IJS for acute or chronic elbow instability. The Cochran risk of bias in nonrandomized studies of interventions and grades of recommendation, assessment, development, and evaluation framework were compiled for risk of bias and quality assessment. Results: The rate of recurrent instability was 4.1% in the IJS group (N = 171) and 7.0% in the ExFix group (N = 435), with an odds ratio of 1.93 (95% confidence interval 0.88-4.23). The rate of device failure was 4.4% in the IJS group and 4.1% in the ExFix group. Pin-related complications occurred in 14.6% of ExFix cases. Complications in the IJS group were the following: 1 case of inflammatory reaction, 4 cases of post removal surgical site infection, and 5 symptomatic removals. Discussion: The literature demonstrates a distinct difference in complication profile between external fixation and the IJS when used as treatment for traumatic elbow instability. Although not statistically significant, the higher rate of recurrent instability following external fixation may be clinically important. The high rate of pin-related complications with external fixation is notable.

Phase II Study of Erdafitinib in Patients With Tumors With Fibroblast Growth Factor Receptor Mutations or Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K2.

PURPOSE: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

Phase II Study of Erdafitinib in Patients With Tumors With FGFR Amplifications: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K1.

PURPOSE: Despite fibroblast growth factor receptor (FGFR) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification. METHODS: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety. RESULTS: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1-amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event. CONCLUSION: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

SERS Microsensors for the Study of pH Regulation in Cystic Fibrosis Patient-Derived Airway Cultures.

Acidification of the airway surface liquid in the respiratory system could play a role in the pathology of Cystic Fibrosis, but its low volume and proximity to the airway epithelium make it a challenging biological environment in which to noninvasively collect pH measurements. To address this challenge, we explored surface enhanced Raman scattering microsensors (SERS-MS), with a 4-mercaptobenzoic acid (MBA) pH reporter molecule, as pH sensors for the airway surface liquid of patient-derived in vitro models of the human airway. Using air-liquid interface (ALI) cultures to model the respiratory epithelium, we show that SERS-MS facilitates the optical measurement of trans-epithelial pH gradients between the airway surface liquid and the basolateral culture medium. SERS-MS also enabled the successful quantification of pH changes in the airway surface liquid following stimulation of the Cystic Fibrosis transmembrane conductance regulator (CFTR, the apical ion channel that is dysfunctional in Cystic Fibrosis airways). Finally, the influence of CFTR mutations on baseline airway surface liquid pH was explored by using SERS-MS to measure the pH in ALIs grown from Cystic Fibrosis and non-Cystic Fibrosis donors.

Computational limits to the legibility of the imaged human brain.

Our knowledge of the organisation of the human brain at the population-level is yet to translate into power to predict functional differences at the individual-level, limiting clinical applications and casting doubt on the generalisability of inferred mechanisms. It remains unknown whether the difficulty arises from the absence of individuating biological patterns within the brain, or from limited power to access them with the models and compute at our disposal. Here we comprehensively investigate the resolvability of such patterns with data and compute at unprecedented scale. Across 23 810 unique participants from UK Biobank, we systematically evaluate the predictability of 25 individual biological characteristics, from all available combinations of structural and functional neuroimaging data. Over 4526 GPU*hours of computation, we train, optimize, and evaluate out-of-sample 700 individual predictive models, including fully-connected feed-forward neural networks of demographic, psychological, serological, chronic disease, and functional connectivity characteristics, and both uni- and multi-modal 3D convolutional neural network models of macro- and micro-structural brain imaging. We find a marked discrepancy between the high predictability of sex (balanced accuracy 99.7%), age (mean absolute error 2.048 years, R2 0.859), and weight (mean absolute error 2.609Kg, R2 0.625), for which we set new state-of-the-art performance, and the surprisingly low predictability of other characteristics. Neither structural nor functional imaging predicted an individual's psychology better than the coincidence of common chronic disease (p < 0.05). Serology predicted chronic disease (p < 0.05) and was best predicted by it (p < 0.001), followed by structural neuroimaging (p < 0.05). Our findings suggest either more informative imaging or more powerful models will be needed to decipher individual level characteristics from the human brain. We make our models and code openly available.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations. METHODS: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity. RESULTS: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified (EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus (EGFR D770_N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash. CONCLUSION: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Patient-Reported Adverse Events and Early Treatment Discontinuation Among Patients With Multiple Myeloma.

Importance: There is substantial interest in capturing cancer treatment tolerability from the patient's perspective using patient-reported outcomes (PROs). Objective: To examine whether a PRO question, item 5 from the Functional Assessment of Cancer Therapy-General General Physical Wellbeing Scale (GP5), was associated with early treatment discontinuation (ETD) due to adverse events. Design, Setting, and Participants: This prospective survey study was conducted from February to April 2023. Among participants in the ECOG-ACRIN E1A11 trial (a phase 3, parallel design trial conducted between 2013 and 2019), patients with newly diagnosed multiple myeloma were randomized to receive bortezomib (VRd) or carfilzomib (KRd) plus lenalidomide and dexamethasone as induction therapy. The GP5 item was administered at baseline (pretreatment) and at 1 month, 2.8 months, and 5.5 months postbaseline. Eligible participants included patients with newly diagnosed multiple myeloma treated at community oncology practices or academic medical centers in the US. Exposures: GP5 response options were "very much," "quite a bit," "somewhat," "a little bit," and "not at all." Responses at each assessment while undergoing treatment (1 month, 2.8 months, and 5.5 months) were categorized as high adverse event bother (ie, "very much," and "quite a bit") and low adverse event bother (ie, "somewhat," "a little bit," or "not at all"). In addition, change from baseline to each assessment while undergoing treatment was calculated and categorized as worsening by 1 response category and 2 or more response categories. Main Outcome and Measure: ETD due to adverse events (yes vs no) was analyzed using logistic regression adjusting for treatment group, performance status, gender, race, and disease stage. Results: Of the 1087 participants in the original trial, 1058 (mean [SD] age 64 [9] years; 531 receiving VrD [50.2%]; 527 receiving KRd [49.8%]) responded to item GP5 and were included in the secondary analysis. A small proportion (142 patients [13.4%]) discontinued treatment early due to AEs. For those with high adverse-effect bother, GP5 while undergoing treatment was associated with ETD at 1 month (adjusted odds ratio [aOR], 2.20; 95% CI, 1.25-3.89), 2.8 months (aOR, 3.41; 95% CI, 2.01-5.80), and 5.5 months (aOR, 4.66; 95% CI, 1.69-12.83). Worsening by 2 or more response categories on the GP5 was associated with ETD at 2.8 months (aOR, 3.02; 95% CI, 1.64-5.54) and 5.5 months (aOR, 5.49; 95% CI, 1.45-20.76). Conclusions and Relevance: In this survey study of the E1A11 trial, worse GP5 response was associated with ETD. These findings suggest that simple assessment of adverse-effect bother while receiving treatment is an efficient way to indicate treatment tolerability and ETD risk.

Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol J.

PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.

Rebooting nuclear medicine specialist education under the COVID-19 pandemic: From plenary lectures to active e-learning.

Despite major reforms of specialist training in the Nordic countries towards concrete learning outcomes and promoting active learning, most specialist courses continue to be based on lectures. We redesigned our mandatory 5-day course in clinical nuclear medicine (NM) that was last held in 2016 towards active learning. Thirty 1-h lectures were replaced with 10 thematic blocks of 3 h each. Each block was taught by a single teacher in a blend of short introductory lectures alternating with small groups of residents reading NM cases from our newly established national case library in diagnostic format. Due to COVID-19, the entire course in 2021 needed to be run on a videoconferencing system rather than in a computer laboratory as had been originally planned. At the end of the course, we conducted the same anonymized survey as in 2016. All 19 course participants responded. 74% fully agreed that the e-course format had been 'good'. One hundred per cent fully agreed that the practical exercises were 'useful' versus 50% in 2016 (p < 0.001). In their free text answers on the merits or downsides of e-learning, 12/12 respondents only mentioned advantages. Our newly established library of anonymized teaching cases within our national health network is an effective tool for organising courses based on active learning. Despite the change towards distance learning enforced by the pandemic, course participants reported the same high levels of satisfaction with active learning in small groups as in the earlier traditional lecture-based course format.

Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study.

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan-Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial.

PURPOSE: Despite defined grades of 1 to 5 for adverse events (AEs) on the basis of Common Terminology Criteria for Adverse Events criteria, mild (G1) and moderate (G2) AEs are often not reported in phase III trials. This under-reporting may inhibit our ability to understand patient toxicity burden. We analyze the relationship between the grades of AEs experienced with patient side-effect bother and treatment discontinuation. METHODS: We analyzed a phase III Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial with comprehensive AE data. The Likert response Functional Assessment of Cancer Therapy-GP5 item, "I am bothered by side effects of treatment" was used to define side-effect bother. Bayesian mixed models were used to assess the impact of G1 and G2 AE counts on patient side-effect bother and treatment discontinuation. AEs were further analyzed on the basis of symptomatology (symptomatic or asymptomatic). The results are given as odds ratios (ORs) and 95% credible interval (CrI). RESULTS: Each additional G1 and G2 AEs experienced during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (95% CrI, 1.06 to 1.21) and 35% (95% CrI, 1.19 to 1.54), respectively. Furthermore, only AEs defined as symptomatic were associated with increased side-effect bother, with asymptomatic AEs showing no association regardless of grade. Count of G2 AEs increased the odds of treatment discontinuation by 59% (95% CrI, 1.32 to 1.95), with symptomatic G2 AEs showing a stronger association (OR, 1.75; 95% CrI, 1.28 to 2.39) relative to asymptomatic G2 AEs (OR, 1.45; 95% CrI, 1.12 to 1.89). CONCLUSION: Low- and moderate-grade AEs are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic AEs demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting AE capture to grade 3+ misses important contributors to treatment side-effect bother and discontinuation.

Ultrafast mode-locked laser in nanophotonic lithium niobate.

Mode-locked lasers (MLLs) generate ultrashort pulses with peak powers substantially exceeding their average powers. However, integrated MLLs that drive ultrafast nanophotonic circuits have remained elusive because of their typically low peak powers, lack of controllability, and challenges when integrating with nanophotonic platforms. In this work, we demonstrate an electrically pumped actively MLL in nanophotonic lithium niobate based on its hybrid integration with a III-V semiconductor optical amplifier. Our MLL generates [Formula: see text]4.8-ps optical pulses around 1065 nm at a repetition rate of ∼10 GHz, with energies exceeding 2.6 pJ and peak powers beyond 0.5 W. The repetition rate and the carrier-envelope offset frequency of the output can be controlled in a wide range by using the driving frequency and the pump current, providing a route for fully stabilized on-chip frequency combs.

Mechanisms of interesterified fat digestibility in a muffin matrix using a dynamic gastric model.

Industrially generated trans-fats have been linked with cardiovascular disease (CVD) and have thus been replaced by interesterified (IE) fats, in foods. Interesterification rearranges fatty acids on the glycerol backbone of a triacylglycerol molecule. However, the impact of IE fat on health is unknown. We recently reported differences in lipid absorption kinetics between IE and rapeseed oil (RO). Here, we investigated the mechanisms underpinning IE fat digestion kinetics in the same muffins baked using an IE fat, non-IE fat [with the same fatty acid composition] and rapeseed oil (RO) under simulated conditions. IE and non-IE fats were largely solid in the gastric phase and strongly associated within the muffin matrix, whereas RO formed liquid droplets which separated from the matrix. No significant difference in lipolysis rates was detected between IE and non-IE fats. The lipolysis of the RO fat was slower, due to long-chain PUFAs. Interesterification itself did not affect digestibility, but the strong interaction between the hard fats and the muffin matrix resulted in extensive creaming of the matrix in the stomach, leading to delayed gastric emptying compared to the RO sample. The rate and extent of lipolysis were determined by the amount of fat available and the structure of the fat. This demonstrates the importance of the physical behaviour of the fats during digestion and provides a mechanistic understanding of the overall lipid digestion of IE fats, which relates to their physiological response.

Visible-to-mid-IR tunable frequency comb in nanophotonics.

Optical frequency comb is an enabling technology for a multitude of applications from metrology to ranging and communications. The tremendous progress in sources of optical frequency combs has mostly been centered around the near-infrared spectral region, while many applications demand sources in the visible and mid-infrared, which have so far been challenging to achieve, especially in nanophotonics. Here, we report widely tunable frequency comb generation using optical parametric oscillators in lithium niobate nanophotonics. We demonstrate sub-picosecond frequency combs tunable beyond an octave extending from 1.5 up to 3.3 µm with femtojoule-level thresholds on a single chip. We utilize the up-conversion of the infrared combs to generate visible frequency combs reaching 620 nm on the same chip. The ultra-broadband tunability and visible-to-mid-infrared spectral coverage of our source highlight a practical and universal path for the realization of efficient frequency comb sources in nanophotonics, overcoming their spectral sparsity.

Understanding and addressing the needs of people with cystic fibrosis in the era of CFTR modulator therapy.

Cystic fibrosis is a multiorgan disease caused by impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR). Since the introduction of the CFTR modulator combination elexacaftor-tezacaftor-ivacaftor (ETI), which acts directly on mutant CFTR to enhance its activity, most people with cystic fibrosis (pwCF) have seen pronounced reductions in symptoms, and studies project marked increases in life expectancy for pwCF who are eligible for ETI. However, modulator therapy has not cured cystic fibrosis and the success of CFTR modulators has resulted in immediate questions about the new state of cystic fibrosis disease and clinical challenges in the care of pwCF. In this Series paper, we summarise key questions about cystic fibrosis disease in the era of modulator therapy, highlighting state-of-the-art research and clinical practices, knowledge gaps, new challenges faced by pwCF and the potential for future health-care challenges, and the pressing need for additional therapies to treat the underlying genetic or molecular causes of cystic fibrosis.

Brain tumour genetic network signatures of survival.

Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterized by distinct combinations of genetic and epigenetic alterations, resulting in complex interactions across multiple molecular pathways. Predicting disease evolution and prescribing individually optimal treatment requires statistical models complex enough to capture the intricate (epi)genetic structure underpinning oncogenesis. Here, we formalize this task as the inference of distinct patterns of connectivity within hierarchical latent representations of genetic networks. Evaluating multi-institutional clinical, genetic and outcome data from 4023 glioma patients over 14 years, across 12 countries, we employ Bayesian generative stochastic block modelling to reveal a hierarchical network structure of tumour genetics spanning molecularly confirmed glioblastoma, IDH-wildtype; oligodendroglioma, IDH-mutant and 1p/19q codeleted; and astrocytoma, IDH-mutant. Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours and show that generative network models reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.

Scaphoid fracture and nonunion: new directions.

The scaphoid is the largest of the carpal bones, articulating with both proximal and distal carpal rows. If scaphoid fractures are not appropriately diagnosed and treated, there is a risk of nonunion, osteonecrosis and degenerative arthritis. Operative management of the scaphoid fracture is primarily determined by the fracture location and amount of displacement. There is increased momentum for dual screw fixation constructs, intended to provide greater stability and reduce the risk of nonunion. Our current practice is to utilize two screws without graft as a first-line treatment for scaphoid nonunion with or without humpback deformity and cyst formation. This review will discuss the management of acute scaphoid fractures and the treatment of nonunion.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.

Octave-spanning tunable infrared parametric oscillators in nanophotonics.

Widely tunable coherent sources are desirable in nanophotonics for a multitude of applications ranging from communications to sensing. The mid-infrared spectral region (wavelengths beyond 2 µm) is particularly important for applications relying on molecular spectroscopy. Among tunable sources, optical parametric oscillators typically offer some of the broadest tuning ranges; however, their implementations in nanophotonics have been limited to narrow tuning ranges in the infrared or to visible wavelengths. Here, we surpass these limits in dispersion-engineered periodically poled lithium niobate nanophotonics and demonstrate ultrawidely tunable optical parametric oscillators. Using 100 ns pulses near 1 µm, we generate output wavelengths tunable from 1.53 µm to 3.25 µm in a single chip with output powers as high as tens of milliwatts. Our results represent the first octave-spanning tunable source in nanophotonics extending into the mid-infrared, which can be useful for numerous integrated photonic applications.

Linking the distal humerus columns in articular fracture fixation.

INTRODUCTION: Concerning rates of nonunion in articular distal humerus fractures indicate an unsolved problem. The fixation principles of O'Driscoll describe linking the fractured articular segment to the distal humerus columns with compression screws which creates a stable fixed angle construct. A novel device has been introduced which utilizes an interlocking beam through the articular segment to connect the distal aspect of the medial and lateral plates, creating a linked construct. We sought to evaluate the stability of this linked construct using an articular model of distal humerus fracture. MATERIALS AND METHODS: Ten matched pair specimens of 65 years of age or older were randomized to the use (LB group) or non-use (NLB group) of an interlocking beam to link the medial and lateral locking plates in fixation of an AO Type C3 fracture model. Outside of the linking beam, fixation between the matched pairs was consistent using 2.7 mm locking screws distally with fixed trajectories and +/- 2 mm lengths. RESULTS: Mean stiffness was 273 Newtons/mm in the LB group and 225 Newtons/mm in the NLB group (p = 0.001). Mean maximum displacement was 0.28 in the LB group and 0.93 mm in the NLB group (p = 0.006). Mean load to failure was 277 pounds in the LB group and 280 pounds in the NLB group (p = 0.94). DISCUSSION: Our results indicate that an interlocking beam which links the medial and lateral plates provides greater stability compared to a similar construct without an interlocking beam. We attribute this finding to the beam's double supported design which resists cantilever bending and provides robust compression of the fractured fragments.