What Are the Relative Associations of Surgeon Performance and Prosthesis Quality With THA Revision Rates?

BACKGROUND: Many factors, including some related to the patient, implant selection, and the surgeon's skill and expertise, likely contribute to the risk of THA revision. However, surgeon factors have not been extensively analyzed in national joint replacement registries, and there is limited insight into their potential as a confounding variable for revision outcomes; for example, if surgeons with higher revision rates choose more successful prostheses, would this alone reduce their revision rate? QUESTIONS/PURPOSES: This study used Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) data for patients receiving primary THA for a diagnosis of osteoarthritis to answer the following questions: (1) Will the difference in revision rates among surgeons change or disappear when only procedures performed with the best prostheses or prostheses that have been identified as having higher revision rates are considered? (2) Is the benefit associated with using the best-performing prostheses different among surgeons with different revision rates? (3) Do the reasons for revision differ between surgeons with higher rates of revision compared with surgeons with lower rates of revision? METHODS: All primary THA procedures performed and recorded in the AOANJRR for osteoarthritis from September 1, 1999, to December 31, 2022, were considered for inclusion. Each THA prosthesis used was categorized per the AOANJRR as superior-performing, middle-performing, or identified as having a higher rate of revision by the AOANJRR benchmarking process. Surgeons who had performed at least 50 procedures and had a recorded 2-year cumulative percent revision (CPR) were included. After applying these restrictions, the study consisted of 302,066 procedures performed by 476 known surgeons. For the primary outcome measure of all-cause revision, we examined the variation in all-cause revision rates across individual surgeons when different classes of devices were used to assess whether differences between surgeons persisted when accounting for prosthesis selection. For the purposes of descriptively comparing reasons for revision between surgeons with higher-than-average or lower-than-average risk of revision, surgeons were classified into quartiles and outcomes compared when these surgeons used the same class of prosthesis. RESULTS: The difference in rates of revision among surgeons remained even after accounting for the effects of the prosthesis used. For any given surgeon, identified prostheses were associated with higher revision rates compared with both superior-performing prostheses (HR 1.73 [95% CI 1.57 to 1.92]; p < 0.01) and medium-performing prostheses (HR 1.31 [95% CI 1.20 to 1.43]; p < 0.01). All surgeons demonstrated a lower revision rate when using a superior-performing prosthesis, but the difference was greatest for surgeons with the highest rates of revision. Surgeons with the lowest rates of revision had a 19-year CPR of 3.9% (95% CI 3.0% to 5.0%) when using a superior-performing prosthesis compared with 5.4% (95% CI 4.0% to 7.3%) for procedures in which an identified prosthesis was used. Surgeons with the highest rates of revision had a 19-year CPR of 10.9% (95% CI 8.6% to 13.8%) when using a superior-performing prosthesis, and this increased to 20.4% (95% CI 18.0% to 23.1%) for procedures in which an identified prosthesis was used. The reasons for revision differ between surgeons, with causes of revision likely preventable and not related to the prosthesis choice being apparent for surgeons with high revision rates. CONCLUSION: The choice of implant and the surgeon performing the index procedure both affected the risk of revision as well as the reasons for revision. Surgeons could improve the survivorship of the arthroplasties they perform by choosing implants identified by registries as having lower revision rates. Acceptance of the fact that surgeons have different revision rates is needed, and detailed analysis is required to explain why surgeons with high revision rates have increased rates of likely preventable revisions, and outside of prosthesis choice, how revision rates can be lowered. The influence of training, fellowship completion, ongoing education, patient selection, indications for surgery, and factors underlying prosthesis decision-making should be assessed. The surgeon performing THA is an important confounder that should be considered in future registry analyses. LEVEL OF EVIDENCE: Level III, therapeutic study.

The role of polycystic kidney disease-like homologs in planarian nervous system regeneration and function.

Planarians are an excellent model for investigating molecular mechanisms necessary for regenerating a functional nervous system. Numerous studies have led to the generation of extensive genomic resources, especially whole-animal single-cell RNA-seq resources. These have facilitated in silico predictions of neuronal subtypes, many of which have been anatomically mapped by in situ hybridization. However, our knowledge of the function of dozens of neuronal subtypes remains poorly understood. Previous investigations identified that polycystic kidney disease (pkd)-like genes in planarians are strongly expressed in sensory neurons and have roles in mechanosensation. Here, we examine the expression and function of all the pkd genes found in the Schmidtea mediterranea genome and map their expression in the asexual and hermaphroditic strains. Using custom behavioral assays, we test the function of pkd genes in response to mechanical stimulation and in food detection. Our work provides insight into the physiological function of sensory neuron populations and protocols for creating inexpensive automated setups for acquiring and analyzing mechanosensory stimulation in planarians.

In vivo Mapping of the Mouse Galnt3-specific O-Glycoproteome.

The UDP-N-acetylgalactosamine polypeptide:N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes initiates O-linked glycosylation by catalyzing the addition of the first GalNAc sugar to serine or threonine on proteins destined to be membrane-bound or secreted. Defects in individual isoforms of the GalNAc-T family can lead to certain congenital disorders of glycosylation (CDG). The GALNT3-CDG, is caused by mutations in GALNT3, resulting in hyperphosphatemic familial tumoral calcinosis (HFTC) due to impaired glycosylation of the phosphate-regulating hormone FGF23 within osteocytes of the bone. Patients with hyperphosphatemia present altered bone density, abnormal tooth structure and calcified masses throughout the body. It is therefore important to identify all potential substrates of GalNAc-T3 throughout the body to understand the complex disease phenotypes. Here, we compared the Galnt3-/- mouse model, which partially phenocopies GALNT3-CDG, with wild-type mice and employed a multi-component approach utilizing chemoenzymatic conditions, a product-dependent method constructed using EThcD triggered scans in a mass spectrometry workflow, quantitative O-glycoproteomics, and global proteomics to identify 663 Galnt3-specific O-glycosites from 269 glycoproteins across multiple tissues. Consistent with the mouse and human phenotypes, functional networks of glycoproteins that contain GalNAc-T3-specific O-glycosites involved in skeletal morphology, mineral level maintenance and hemostasis were identified. This library of in vivo GalNAc-T3-specific substrate proteins and O-glycosites will serve as a valuable resource to understand the functional implications of O-glycosylation and to unravel the underlying causes of complex human GALNT3-CDG phenotypes.

Quantifying error in effect size estimates in attention, executive function, and implicit learning.

Accurate quantification of effect sizes has the power to motivate theory and reduce misinvestment of scientific resources by informing power calculations during study planning. However, a combination of publication bias and small sample sizes (∼N = 25) hampers certainty in current effect size estimates. We sought to determine the extent to which sample sizes may produce errors in effect size estimates for four commonly used paradigms assessing attention, executive function, and implicit learning (attentional blink, multitasking, contextual cueing, and serial response task). We combined a large data set with a bootstrapping approach to simulate 1,000 experiments across a range of N (13-313). Beyond quantifying the effect size and statistical power that can be anticipated for each study design, we demonstrate that experiments with lower N may double or triple information loss. We also show that basing power calculations on effect sizes from similar studies yields a problematically imprecise estimate between 40% and 67% of the time, given commonly used sample sizes. Last, we show that skewness of intersubject behavioral effects may serve as a predictor of an erroneous estimate. We conclude with practical recommendations for researchers and demonstrate how our simulation approach can yield theoretical insights that are not readily achieved by other methods such as identifying the information gained from rejecting the null hypothesis and quantifying the contribution of individual variation to error in effect size estimates. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma.

Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.

Multi-scale signaling and tumor evolution in high-grade gliomas.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

Social ecological system framework as a decision-making tool for risk mitigation: A superfund site case study.

Several studies have reported vapor intrusion (VI) occurring when volatile organic compound (VOC) vapors are transported through subsurface piping systems into building spaces (e.g. conduit VI). Site-specific risk assessment and risk management practices are complicated and evolving for conduit VI, especially at large hazardous waste sites, like Superfund sites, where many stakeholders are involved and have varied interests. Here, we propose a social ecological system (SES) framework as a decision-making tool to inform risk mitigation decisions. We demonstrate the SES framework using field data associated with a Superfund site near San Francisco, California. We evaluate sewer invert elevation and groundwater elevation data, as well as pre- and post- mitigation VOC concentration data within a sewer system. Unexpectedly, the sewer located above the groundwater table was determined to be a potential source of conduit VI risks. The SES framework describes how typical stakeholders associated with the site can affect and be affected by mitigation activities. It informs decisions about mitigation implementation and long-term operation efficacy by considering stakeholder roles and interests. Ultimately, gas siphons were selected as the mitigation technology for the example site. To date, approximately 6 gas siphons have been installed to mitigate conduit VI risks throughout the community. Collectively, our findings advance risk management decisions and highlight key considerations for risk mitigation approaches at hazardous waste sites, including Superfund sites, especially where VI risks are a concern.

Development of a Clinical Pathway for Bariatric Surgery as an Integral Part of a Comprehensive Treatment for Adolescents with Severe Obesity in the Netherlands.

INTRODUCTION: In the Netherlands, bariatric surgery in adolescents is currently only allowed in the context of scientific research. Besides this, there was no clinical pathway for bariatric surgery in adolescents. In this paper, the development of a comprehensive clinical pathway for bariatric surgery in adolescents with severe obesity in the Netherlands is described. METHODS: The clinical pathway for bariatric surgery in adolescents consists of an eligibility assessment as well as comprehensive peri- and postoperative care. Regarding the eligibility assessment, the adolescents need to be identified by their attending pediatricians and afterwards be evaluated by specialized pediatric obesity units. If the provided treatment is considered to be insufficiently effective, the adolescent will anonymously be evaluated by a national board. This is an additional diligence procedure specifically established for bariatric surgery in adolescents. The national board consists of independent experts regarding adolescent bariatric surgery and evaluates whether the adolescents meet the criteria defined by the national professional associations. The final step is an assessment by a multidisciplinary team for adolescent bariatric surgery. The various disciplines (pediatrician, bariatric surgeon, psychologist, dietician) evaluate whether an adolescent is eligible for bariatric surgery. In this decision-making process, it is crucial to assess whether the adolescent is expected to adhere to postoperative behavioral changes and follow-up. When an adolescent is deemed eligible for bariatric surgery, he or she will receive preoperative counseling by a bariatric surgeon to decide on the type of bariatric procedure (Roux-en-Y gastric bypass or sleeve gastrectomy). Postoperative care consists of intensive guidance by the multidisciplinary team for adolescent bariatric surgery. In this guidance, several regular appointments are included and additional care will be provided based on the needs of the adolescent and his or her family. Furthermore, the multidisciplinary lifestyle intervention, in which the adolescents participated before bariatric surgery, continues in coordination with the multidisciplinary team for adolescent bariatric surgery, and this ensures long-term counseling and follow-up. CONCLUSION: The implementation of bariatric surgery as an integral part of a comprehensive treatment for adolescents with severe obesity requires the development of a clinical pathway with a variety of disciplines.

Stimulating prefrontal cortex facilitates training transfer by increasing representational overlap.

A recent hypothesis characterizes difficulties in multitasking as being the price humans pay for our ability to generalize learning across tasks. The mitigation of these costs through training has been associated with reduced overlap of constituent task representations within frontal, parietal, and subcortical regions. Transcranial direct current stimulation, which can modulate functional brain activity, has shown promise in generalizing performance gains when combined with multitasking training. However, the relationship between combined transcranial direct current stimulation and training protocols with task-associated representational overlap in the brain remains unexplored. Here, we paired prefrontal cortex transcranial direct current stimulation with multitasking training in 178 individuals and collected functional magnetic resonance imaging data pre- and post-training. We found that 1 mA transcranial direct current stimulation applied to the prefrontal cortex paired with multitasking training enhanced training transfer to spatial attention, as assessed via a visual search task. Using machine learning to assess the overlap of neural activity related to the training task in task-relevant brain regions, we found that visual search gains were predicted by changes in classification accuracy in frontal, parietal, and cerebellar regions for participants that received left prefrontal cortex stimulation. These findings demonstrate that prefrontal cortex transcranial direct current stimulation may interact with training-related changes to task representations, facilitating the generalization of learning.

Uncertainty-modulated attentional capture: Outcome variance increases attentional priority.

Our prior experiences shape the way that we prioritize information from the environment for further processing, analysis, and action. We show in three experiments that this process of attentional prioritization is critically modulated by the degree of uncertainty in these previous experiences. Participants completed a visual search task in which they made a saccade to a target to earn a monetary reward. The color of a color-singleton distractor in the search array signaled the reward outcome(s) that were available, with different degrees of variance (uncertainty). Participants were never required to look at the colored distractor, and doing so would slow their response to the target. Nevertheless, across all experiments, participants were more likely to look at distractors associated with high outcome variance versus low outcome variance. This pattern was observed when all distractors had equal expected value (Experiment 1), when the difference in variance was opposed by a difference in expected value (i.e., the high-variance distractor had a low expected value, and vice versa: Experiment 2), and when high- and low-variance distractors were paired with the maximum-value outcome on an equal proportion of trials (Experiment 3). Our findings demonstrate that experience of prediction error plays a fundamental role in guiding "attentional exploration," wherein priority is driven by the potential for a stimulus to reduce future uncertainty through a process of learning, as opposed to maximizing current information gain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Analysis of spontaneous cytomegalovirus clearance after low level reactivation using a pre-emptive treatment threshold of 4,000 IU/mL in allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) can be a serious complication after allogeneic hematopoietic cell transplant (HCT). CMV viral load is routinely monitored, and pre-emptive therapy is initiated to prevent CMV viremia from developing into CMV organ disease based on institutional thresholds. There is no established universal threshold for pre-emptive therapy and many centers utilize different strategies. METHODS: Allogeneic HCT recipients at WVU Medicine from 2009 to 2021 were routinely initiated on pre-emptive CMV treatment for a PCR viral threshold above 4000 IU/mL. Adult patients with quantifiable values below this threshold, were analyzed to evaluate the rate of spontaneous clearance without initiation of CMV-directed therapy, during their first episode of CMV reactivation. This study excluded any patients that received letermovir prophylaxis. RESULTS: Sixty patients were included in the analysis. The spontaneous clearance rate was 60 %. The risk factors that were associated with a lower spontaneous clearance rate were reactivation within thirty days after transplant (p = 0.031), presence of graft-versus-host-disease (p = 0.031), and CMV PCR values of 2500-4000 IU/mL (p = 0.02). Although these patients had lower rates of spontaneous clearance, they still spontaneously cleared in 42 %, 42 %, and 43 % of the cases, respectively. CONCLUSION: Delaying pre-emptive treatment until a CMV PCR value of 4000 IU/mL is reached appears appropriate and decreases unnecessary treatment toxicity and resistance.

No Difference in Revision Rates or Patient-Reported Outcome Measures Between Surgical Approaches for Total Hip Arthroplasty Performed for Femoral Neck Fracture: An Analysis of 5,025 Primary Total Hip Arthroplasties From the New Zealand Joint Registry.

BACKGROUND: Total hip arthroplasty (THA) for femoral neck fracture (FNF) can be performed through different surgical approaches. This study compared the revision rates and patient-reported outcome measures by surgical approach. METHODS: Data from the New Zealand Joint Registry were analyzed for patients undergoing primary THA for FNF from January 2000 to December 2021. A total of 5,025 THAs were performed for FNF; the lateral approach was used in 2,499 (49.7%), the posterior in 2,255 (44.9%), and the anterior in 271 (4.3%). The primary outcome measure was the all-cause revision rate. Secondary outcome measures included revision rates for: dislocation, aseptic femoral component loosening, periprosthetic fracture, and infection. Oxford Hip Scores (OHS) were also collected. Age, sex, body mass index, American Society of Anesthesiologists score, femoral head size, dual mobility use, femoral fixation, and surgeon experience were assessed as potential confounding variables. RESULTS: There was no difference in the revision rates between lateral and posterior (P = .156), lateral and anterior (P = .680), or posterior and anterior (P = .714) approaches. There was no difference in the reasons for revision between the lateral and posterior approaches or 6-month OHS (P = .712). There was insufficient data to compare the anterior approach. CONCLUSIONS: There is no difference in the overall revision rates, reasons for revision, or OHS between the lateral and posterior surgical approaches for THA performed for FNF. Insufficient data on the anterior approach is available for an accurate comparison. LEVEL OF EVIDENCE: Level III.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

Electrographic screening for infantile epileptic spasms syndrome in a single sleep-wake cycle.

OBJECTIVE: Infantile epileptic spasms syndrome (IESS) is a common and urgent diagnosis with seizure and nonseizure mimics. Evaluation with prolonged video-electroencephalography (EEG) can be time-consuming and costly. This study investigated the use of EEG review of a single sleep-wake cycle to exclude IESS. METHODS: We retrospectively reviewed video-EEG studies to rule out IESS in children between the ages of 2 months and 2 years in the period from January 2019 through June 2020. EEG studies were reviewed from the start of the recording through the first sleep-wake cycle and scored as "normal," "consistent with IESS," or "abnormal but not diagnostic of IESS." Scores were compared to the clinical report created by analysis of the entire video-EEG. RESULTS: Inclusion criteria were met in 238 EEG studies. The mean patient age was 7.6 months. The median duration of the full study was 908 min, compared to 107.5 min for the first sleep-wake cycle only. The median difference in recording time was 801 min, p-value < .01. Scored outcomes were similar. Sixty-eight percent of EEG studies were scored as "normal" on first sleep-wake cycle review as compared to 63% on full study review, 13% scored as "consistent with IESS" compared to 16% and 19% scored as "abnormal but not diagnostic of IESS" compared to 21%. Sensitivity and specificity of the first sleep-wake cycle review for studies "consistent with IESS" was 84% and 100%, respectively. No cases of IESS were scored as normal on first sleep-wake cycle review. SIGNIFICANCE: A single sleep-wake cycle captured on EEG can triage studies when IESS is suspected. A normal first sleep-wake cycle did not miss cases of IESS and could result in reduced EEG recording time. Because most of these cases presented to an emergency department, a normal first sleep-wake cycle may help providers determine the acuity, or necessity, of further testing.

A compendium of multi-omics data illuminating host responses to lethal human virus infections.

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.

Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.

Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed. Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US. Design, Setting, and Participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023. Main Outcomes and Measures: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation. Results: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001). Conclusions and Relevance: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.

Associations of Anxiety, Insomnia, and Physical Activity during the COVID-19 Pandemic.

PURPOSE: Anxiety, insomnia, and physical activity (PA) are interrelated, but the bi-directional relationships between these three variables are not well understood. Less is known of these relationships in settings of disrupted daily activities and acute stress. This study aimed to characterize and examine relationships between insomnia, anxiety, and PA throughout the first year of the COVID-19 pandemic, when many lifestyle behaviors were disrupted. METHODS: Participants comprised a convenience sample of 204 adults (55.4% female; 43.85 ± 15.85 years old) who completed the Generalized Anxiety Disorder Questionnaire (GAD-7), Insomnia Severity Index (ISI), and the International Physical Activity Questionnaire (IPAQ) at three time points through the first year of the COVID-19 pandemic. A cross-lagged panel model was used to evaluate these variables' concurrent, autoregressive, and cross-lagged relationships across time. Follow-up dynamic panel modeling using maximum likelihood and structural equation modeling was employed. RESULTS: Approximately 64% of participants reported their work/occupation as affected by the pandemic. At baseline, associations between anxiety and insomnia were observed (ß-coefficient: 15.87; p < 0.001). Insomnia was a positive future predictor of anxiety (ISI time point 2: 7.9 ± 5.6 points; GAD-7 at time point 3: 4.1 ± 4.2 points; ß-coefficient: 0.16; p < 0.01). No associations were observed between PA and anxiety or insomnia (all p > 0.05). CONCLUSIONS: Insomnia and anxiety were interrelated, and effects were cross-lagged. These data can inform future work focused on improving anxiety in settings of acute stress and disruptions to daily life, such as changes in occupational structure and stability. Specifically, targeting sleep parameters may be of interest to elicit downstream positive health behaviors.

Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition.

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system.

How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision-making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast-acting, suggesting they can be used in clinically unstable patients as "bridge therapy," and secondly, they provide additional options for those patients considered treatment-refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.