Helping ourselves, helping others: the Young Women's Breast Cancer Study (YWS) - a multisite prospective cohort study to advance the understanding of breast cancer diagnosed in women aged 40 years and younger.

PURPOSE: Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women's Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population. PARTICIPANTS: The YWS enrolled 1302 women newly diagnosed with stages 0-IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints. FINDINGS TO DATE: Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors. FUTURE PLANS: With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer. TRIAL REGISTRATION NUMBER: NCT01468246.

Applying a stigma and time framework to facilitate equitable access to hepatitis C care among women who inject drugs: The ETHOS Engage Study.

BACKGROUND: Women who inject drugs are significantly less likely to initiate hepatitis C virus (HCV) treatment than men. Concerted efforts are needed to minimise gender-based inequalities in care. The study aim was to use a stigma and time framework to investigate how women who inject drugs experienced HCV care in healthcare settings. METHODS: Semi-structured, in-depth interviews were conducted with 34 participants from the ETHOS Engage Cohort (n = 1,443) in Australia. Inclusion criteria were aged ≥18 years, history of injection drug use, and persons who injected in the prior six months or were currently receiving opioid agonist treatment. Drawing on the original qualitative dataset (n = 34), we conducted a secondary analysis focused on women participants' experiences of receiving HCV related care (n = 21/34). Utilising thematic analysis, we applied Earnshaw's theoretical framework, which incorporates time into stigma and health research via three "timescales" - historical context, human development, and status course. RESULTS: Among the 21 women interviewed (mean age 42 years, 5 are Aboriginal, 11 received HCV treatment), the majority were currently receiving opioid agonist treatment and over half injected drugs in the past month. For historical context, most participants were diagnosed with HCV during the interferon era (1990s-2014). Participants had to navigate a sociomedical landscape not only largely bereft of adequate HCV medical knowledge, appropriate support, and adequate treatments, but were also generally assessed as "unsuitable" for treatment based on their perceived personhood as people who inject drugs. For human development, many participants reported encountering overlapping stigmatizing experiences (layered stigma) while receiving their HCV diagnosis in prenatal care and early postpartum. Under status course, participants acutely recognised the intersection of HCV infection, injection drug use, and gender, and reported concerns about being judged more harshly from healthcare providers as a result. CONCLUSION: A stigma and time framework illuminated multiple overlapping stigmatizing experiences for women who inject drugs in HCV care and in turn, can help to inform tools and interventions to counter their impact.

Algorithm-Based Linearly Graded Compositions of GeSn on GaAs (001) via Molecular Beam Epitaxy.

The growth of high-composition GeSn films in the future will likely be guided by algorithms. In this study, we show how a logarithmic-based algorithm can be used to obtain high-quality GeSn compositions up to 16% on GaAs (001) substrates via molecular beam epitaxy. Herein, we use composition targeting and logarithmic Sn cell temperature control to achieve linearly graded pseudomorph Ge1-xSnx compositions up to 10% before partial relaxation of the structure and a continued gradient up to 16% GeSn. In this report, we use X-ray diffraction, simulation, secondary ion mass spectrometry, and atomic force microscopy to analyze and demonstrate some of the possible growths that can be produced with the enclosed algorithm. This methodology of growth is a major step forward in the field of GeSn development and the first ever demonstration of algorithmically driven, linearly graded GeSn films.

The attentive reconstruction of objects facilitates robust object recognition.

Humans are extremely robust in our ability to perceive and recognize objects-we see faces in tea stains and can recognize friends on dark streets. Yet, neurocomputational models of primate object recognition have focused on the initial feed-forward pass of processing through the ventral stream and less on the top-down feedback that likely underlies robust object perception and recognition. Aligned with the generative approach, we propose that the visual system actively facilitates recognition by reconstructing the object hypothesized to be in the image. Top-down attention then uses this reconstruction as a template to bias feedforward processing to align with the most plausible object hypothesis. Building on auto-encoder neural networks, our model makes detailed hypotheses about the appearance and location of the candidate objects in the image by reconstructing a complete object representation from potentially incomplete visual input due to noise and occlusion. The model then leverages the best object reconstruction, measured by reconstruction error, to direct the bottom-up process of selectively routing low-level features, a top-down biasing that captures a core function of attention. We evaluated our model using the MNIST-C (handwritten digits under corruptions) and ImageNet-C (real-world objects under corruptions) datasets. Not only did our model achieve superior performance on these challenging tasks designed to approximate real-world noise and occlusion viewing conditions, but also better accounted for human behavioral reaction times and error patterns than a standard feedforward Convolutional Neural Network. Our model suggests that a complete understanding of object perception and recognition requires integrating top-down and attention feedback, which we propose is an object reconstruction.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

IL-17 signaling in primary sclerosing cholangitis patient-derived organoids.

BACKGROUND: The pathogenesis of primary sclerosing cholangitis (PSC) is unclear, although studies implicate IL-17A as an inflammatory mediator in this disease. However, a direct assessment of IL-17 signaling in PSC cholangiocytes is lacking. In this study, we aimed to investigate and characterize the response of PSC extrahepatic cholangiocyte organoids (ECO) to IL-17A stimulation. METHODS: Cholangiocytes obtained from patients with PSC and without PSC by endoscopic retrograde cholangiography were cultured as ECO. The ECO were treated with vehicle or IL-17A and assessed by transcriptomics, secretome analysis, and genome sequencing. RESULTS: Unsupervised clustering of all integrated single-cell RNA sequencing data identified 8 cholangiocyte clusters that did not differ between PSC and non-PSC ECO. However, PSC ECO cells demonstrated a robust response to IL-17 treatment, as noted by an increased number of differentially expressed genes by transcriptomics and more abundant chemokine and cytokine expression and secretion. After rigorous filtering, genome sequencing identified candidate somatic variants shared among PSC ECO from unrelated individuals. However, no candidate rare variants in genes regulating the IL-17 pathway were identified, but rare variants regulating the MAPK signaling pathway were present in all PSC ECO. CONCLUSIONS: PSC and non-PSC patient-derived ECO respond differently to IL-17 stimulation, implicating this pathway in the pathogenesis of PSC.

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

Outcomes of isolated medial tibial plateau fractures by fracture morphology.

PURPOSE: To identify a cohort of isolated medial tibial plateau fractures treated with surgical fixation and to categorize them by Moore and Wahlquist classifications in order to determine the rate of complications with each fracture morphology and the predictive value of each classification system. We hypothesized there would be high rates of neurovascular injury, compartment syndrome, and complications overall with a higher incidence of neurovascular injury in Moore type III rim avulsion fractures and Wahlquist type C fractures that enter the plateau lateral to the tibial spines. METHODS: Patients who presented to six Level I trauma centers between 2010 and 2021 who underwent surgical fixation for isolated medial tibial plateau fractures were retrospectively reviewed. Data including demographics, radiographs, complications, and functional outcomes were collected. RESULTS: One hundred and fifty isolated medial tibial plateau fractures were included. All patients were classified by the Wahlquist classification of medial tibial plateau fractures, and 139 patients were classifiable by the Moore classification of tibial plateau fracture-dislocations. Nine percent of fractures presented with neurovascular injury: 5 % with isolated vascular injury and 6 % with isolated nerve injury. There were no significant differences in neurovascular injury by fracture type (Wahlquist p = 0.16, Moore p = 0.33). Compartment syndrome developed in two patients (1.3 %). The average final range of motion was 0.8-122° with no difference by Wahlquist or Moore classifications (p = 0.11, p = 0.52). The overall complication rate was 32 % without differences by fracture morphology. The overall rate of return to the operating room (OR) was 25 %. CONCLUSIONS: Isolated medial tibial plateau fractures often represent fracture-dislocations of the knee and should receive a meticulous neurovascular exam on presentation with a high suspicion for neurovascular injury. No specific fracture pattern was found to be predictive of neurovascular injuries, complications, or final knee range of motion. Patients should be counseled pre-operatively regarding high rates of return to the OR after the index surgery.

Metabologenomics reveals strain-level genetic and chemical diversity of Microcystis secondary metabolism.

Microcystis spp. are renowned for producing the hepatotoxin microcystin in freshwater cyanobacterial harmful algal blooms around the world, threatening drinking water supplies and public and environmental health. However, Microcystis genomes also harbor numerous biosynthetic gene clusters (BGCs) encoding the biosynthesis of other secondary metabolites, including many with toxic properties. Most of these BGCs are uncharacterized and currently lack links to biosynthesis products. However, recent field studies show that many of these BGCs are abundant and transcriptionally active in natural communities, suggesting potentially important yet unknown roles in bloom ecology and water quality. Here, we analyzed 21 xenic Microcystis cultures isolated from western Lake Erie to investigate the diversity of the biosynthetic potential of this genus. Through metabologenomic and in silico approaches, we show that these Microcystis strains contain variable BGCs, previously observed in natural populations, and encode distinct metabolomes across cultures. Additionally, we find that the majority of metabolites and gene clusters are uncharacterized, highlighting our limited understanding of the chemical repertoire of Microcystis spp. Due to the complex metabolomes observed in culture, which contain a wealth of diverse congeners as well as unknown metabolites, these results underscore the need to deeply explore and identify secondary metabolites produced by Microcystis beyond microcystins to assess their impacts on human and environmental health.IMPORTANCEThe genus Microcystis forms dense cyanobacterial harmful algal blooms (cyanoHABs) and can produce the toxin microcystin, which has been responsible for drinking water crises around the world. While microcystins are of great concern, Microcystis also produces an abundance of other secondary metabolites that may be of interest due to their potential for toxicity, ecological importance, or pharmaceutical applications. In this study, we combine genomic and metabolomic approaches to study the genes responsible for the biosynthesis of secondary metabolites as well as the chemical diversity of produced metabolites in Microcystis strains from the Western Lake Erie Culture Collection. This unique collection comprises Microcystis strains that were directly isolated from western Lake Erie, which experiences substantial cyanoHAB events annually and has had negative impacts on drinking water, tourism, and industry.

The in vitro dynamics of pseudo-vascular network formation.

BACKGROUND/OBJECTIVES: Pseudo-vascular network formation in vitro is considered a key characteristic of vasculogenic mimicry. While many cancer cell lines form pseudo-vascular networks, little is known about the spatiotemporal dynamics of these formations. METHODS: Here, we present a framework for monitoring and characterising the dynamic formation and dissolution of pseudo-vascular networks in vitro. The framework combines time-resolved optical microscopy with open-source image analysis for network feature extraction and statistical modelling. The framework is demonstrated by comparing diverse cancer cell lines associated with vasculogenic mimicry, then in detecting response to drug compounds proposed to affect formation of vasculogenic mimics. Dynamic datasets collected were analysed morphometrically and a descriptive statistical analysis model was developed in order to measure stability and dissimilarity characteristics of the pseudo-vascular networks formed. RESULTS: Melanoma cells formed the most stable pseudo-vascular networks and were selected to evaluate the response of their pseudo-vascular networks to treatment with axitinib, brucine and tivantinib. Tivantinib has been found to inhibit the formation of the pseudo-vascular networks more effectively, even in dose an order of magnitude less than the two other agents. CONCLUSIONS: Our framework is shown to enable quantitative analysis of both the capacity for network formation, linked vasculogenic mimicry, as well as dynamic responses to treatment.

Utility of methylated DNA markers for the diagnosis of malignant biliary strictures.

BACKGROUND AND AIMS: Early identification of malignant biliary strictures (MBS) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography (ERCP). We aimed to evaluate the use of methylated DNA markers (MDM) from biliary brushings to enhance MBS detection in a prospective cohort. METHODS: Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific Droplet Digital Polymerase Chain Reaction (ddPCR).  Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. RESULTS: Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top four MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescent in situ hybridization (FISH). CONCLUSIONS: The selected methylated DNA markers demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. ​ Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.​.

Evaluation of Whole Genome Sequencing-Based Predictions of Antimicrobial Resistance to TB First Line Agents: A Lesson from 5 Years of Data.

Phenotypic susceptibility testing of the Mycobacterium tuberculosis complex (MTBC) isolate requires culture growth, which can delay rapid detection of resistant cases. Whole genome sequencing (WGS) and data analysis pipelines can assist in predicting resistance to antimicrobials used in the treatment of tuberculosis (TB). This study compared phenotypic susceptibility testing results and WGS-based predictions of antimicrobial resistance (AMR) to four first-line antimicrobials-isoniazid, rifampin, ethambutol, and pyrazinamide-for MTBC isolates tested between the years 2018-2022. For this 5-year retrospective analysis, the WGS sensitivity for predicting resistance for isoniazid, rifampin, ethambutol, and pyrazinamide using Mykrobe was 86.7%, 100.0%, 100.0%, and 47.8%, respectively, and the specificity was 99.4%, 99.5%, 98.7%, and 99.9%, respectively. The predictive values improved slightly using Mykrobe corrections applied using TB Profiler, i.e., the WGS sensitivity for isoniazid, rifampin, ethambutol, and pyrazinamide was 92.31%, 100%, 100%, and 57.78%, respectively, and the specificity was 99.63%. 99.45%, 98.93%, and 99.93%, respectively. The utilization of WGS-based testing addresses concerns regarding test turnaround time and enables analysis for MTBC member identification, antimicrobial resistance prediction, detection of mixed cultures, and strain genotyping, all through a single laboratory test. WGS enables rapid resistance detection compared to traditional phenotypic susceptibility testing methods using the WHO TB mutation catalog, providing an insight into lesser-known mutations, which should be added to prediction databases as high-confidence mutations are recognized. The WGS-based methods can support TB elimination efforts in Canada and globally by ensuring the early start of appropriate treatment, rapidly limiting the spread of TB outbreaks.

Mpox Surveillance Based on Rash Characteristics - 13 Emergency Departments, United States, June-December 2023.

In 2022, a global mpox outbreak occurred, primarily affecting gay and bisexual men who have sex with men (GBMSM). To screen for mpox's reemergence and investigate potentially unsuspected cases among non-GBMSM, prospective surveillance of patients aged ≥3 months with an mpox-compatible rash (vesicular, pustular, ulcerated, or crusted) was conducted at 13 U.S. emergency departments (EDs) during June-December 2023. Demographic, historical, and illness characteristics were collected using questionnaires and electronic health records. Lesions were tested for monkeypox virus using polymerase chain reaction. Among 196 enrolled persons, the median age was 37.5 years (IQR = 21.0-53.5 years); 39 (19.9%) were aged <16 years, and 108 (55.1%) were male. Among all enrollees, 13 (6.6%) were GBMSM. Overall, approximately one half (46.4%) and one quarter (23.5%) of enrolled persons were non-Hispanic White and non-Hispanic Black or African American, respectively, and 38.8% reported Hispanic or Latino (Hispanic) ethnicity. Unstable housing was reported by 21 (10.7%) enrollees, and 24 (12.2%) lacked health insurance. The prevalence of mpox among ED patients evaluated for an mpox-compatible rash was 1.5% (95% CI = 0.3%-4.4%); all persons with a confirmed mpox diagnosis identified as GBMSM and reported being HIV-negative, not being vaccinated against mpox, and having engaged in sex with one or more partners met through smartphone dating applications. No cases were identified among women, children, or unhoused persons. Clinicians should remain vigilant for mpox and educate persons at risk for mpox about modifying behaviors that increase risk and the importance of receiving 2 appropriately spaced doses of JYNNEOS vaccine to prevent mpox.

RNA regulatory mechanisms controlling TGF-ß signaling and EMT in cancer.

Epithelial-mesenchymal transition (EMT) is a major contributor to metastatic progression and is prominently regulated by TGF-ß signalling. Both EMT and TGF-ß pathway components are tightly controlled by non-coding RNAs - including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) - that collectively have major impacts on gene expression and resulting cellular states. While miRNAs are the best characterised regulators of EMT and TGF-ß signaling and the miR-200-ZEB1/2 feedback loop plays a central role, important functions for lncRNAs and circRNAs are also now emerging. This review will summarise our current understanding of the roles of non-coding RNAs in EMT and TGF-ß signaling with a focus on their functions in cancer progression.

Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets.

BACKGROUND: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. PATIENTS/METHODS: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, intact BRAF kinase domain). RESULTS: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 patients spanning multiple histologies were treated with MAPK-directed therapies of which 20 were evaluable for RECIST. Best response was partial response (N=2), stable disease (N=11), and progressive disease (N=7). The median time on therapy was 1 month with MEK plus BRAF inhibitors ([N=11], range 0-18 months) and 8 months for MEK inhibitors ([N=14], range 1-26 months). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), melanoma (N=1)]. Fifteen patients had acquired BRAF fusions. CONCLUSIONS: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy underscoring the importance of post-progression biopsies to optimize treatment at relapse in these patients.

Impact of nutrient deficiency on biological sewage treatment - Perspectives towards urine source segregation.

Human urine contains 9 g/L of nitrogen (N) and 0.7 g/L of phosphorus (P). The recovery of N and P from urine helps close the nutrient loop and increase resource circularity in the sewage treatment sector. Urine contributes an average of 80 % N and 50 % P in sewage, whereby urine source segregation could reduce the burden of nutrient removal in sewage treatment plants (STPs) but result in N and P deficiency and unintended negative consequences. This review examines the potential impacts of N and P deficiency on the removal of organic carbon and nutrients, sludge characteristics and greenhouse gas emissions in activated sludge processes. The details of how these impacts affect the operation of STPs were also included. This review helps foresee operational challenges that established STPs may face when dealing with nutrient-deficient sewage in a future where source separation of urine is the norm. The findings indicate that the requirement of nitrification-denitrification and biological P removal processes could shrink at urine segregation above 80 % and 100 %, respectively. Organic carbon, N and biological P removal processes can be severely affected under full urine segregation. The decrease in solid retention time due to urine segregation increases treatment capacity up to 48 %. Sludge flocculation and settleability would deteriorate due to changes in extracellular polymeric substances and induce various forms of bulking. Beneficially, N deficiency reduces nitrous oxide emissions. These findings emphasise the importance of considering and preparing for impacts caused by urine source segregation-induced nutrient deficiency in sewage treatment processes.

Developmental cascades from early childhood attachment security to adolescent level of personality functioning among high-risk youth.

This study examines associations between early childhood attachment security and adolescent personality functioning in a high-risk sample within a developmental psychopathology framework. Data from 2,268 children (1165 male; 1103 female) and caregivers participating in Future of Families and Child Well-Being Study (FFCWS) were used to examine (1) effects of genetic polymorphisms of the serotonin transporter (5-HTTLPR) and dopamine D4 receptor (DRD4) genes and adverse childhood experiences (ACEs) on attachment security and emotional and behavioral dysregulation in early childhood and (2) longitudinal associations and transactional relationships among attachment security, dysregulation, negative parenting attitudes and behaviors, social competence, and adolescent personality functioning. Results revealed that ACEs predicted attachment security over and above sex or the genetic risk, and gene × environment interactions did not increment prediction. Results of cascade models showed that greater early childhood attachment security predicted higher adolescent level of personality functioning via pathways through intermediary variables. Limitations and future research directions are discussed.

Cellular pathways and molecular events that shape autoantibody production in COVID-19.

A hallmark of COVID-19 is the variety of complications that follow SARS-CoV-2 infection in some patients, and that target multiple organs and tissues. Also remarkable are the associations with several auto-inflammatory disorders and the presence of autoantibodies directed to a vast array of antigens. The processes underlying autoantibody production in COVID-19 have not been completed deciphered. Here, we review mechanisms involved in autoantibody production in COVID-19, multisystem inflammatory syndrome in children, and post-acute sequelae of COVID19. We critically discuss how genomic integrity, loss of B cell tolerance to self, superantigen effects of the virus, and extrafollicular B cell activation could underly autoantibody proaction in COVID-19. We also offer models that may account for the pathogenic roles of autoantibodies in the promotion of inflammatory cascades, thromboembolic phenomena, and endothelial and vascular deregulations.

10-Year Cumulative Incidence and Indications for Revision Total Joint Arthroplasty for Patients Who Have Ehlers-Danlos syndrome.

BACKGROUND: Long-term complications following total joint arthroplasty are not well established for patients who have Ehlers-Danlos syndrome (EDS), a group of connective tissue disorders. This study compared 10-year incidence of revision surgery after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in patients who have and do not have EDS. METHODS: A retrospective cohort analysis was conducted using a national all-payer claims database from 2010 to 2021 to identify patients who underwent primary TKA or THA. Patients who had and did not have EDS were propensity-score matched by age, sex, and a comorbidity index. Kaplan-Meier analyses and Cox proportional hazard models were utilized to determine the cumulative incidence and risks of revision experienced by patients who have and do not have EDS. RESULTS: The EDS patients who underwent TKA had a higher risk of all-cause revision (hazard ratio (HR): 1.50, 95% confidence interval (95% CI): 1.09 to 2.07, P < 0.014) and risk of revision due to instability (HR = 2.49, 95% CI: 1.37 to 4.52, P < 0.003). The EDS patients who underwent THA had a higher risk of all-cause revision (HR = 2.32, 95% CI: 1.47 to 3.65, P < 0.001), revision due to instability (HR = 4.26, 95% CI: 2.17 to 8.36, P < 0.001), and mechanical loosening (HR = 3.63, 95% CI: 2.05 to 6.44, P < 0.001). CONCLUSION: Patients who had EDS were found to have a higher incidence of revision within 10 years of undergoing TKA and THA compared to matched controls, especially for instability. Patients who have EDS should be counseled accordingly. Surgical technique and implant selection should include consideration for increased constraint in TKA and larger femoral heads or dual mobility articulations for THA.