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Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

Epidemiologic studies often quantify exposure using biomarkers, which commonly have statistically skewed distributions. Although normality assumption is not required if the biomarker is used as an independent variable in linear regression, it has become common practice to log-transform the biomarker concentrations. This transformation can be motivated by concerns for nonlinear dose-response relationship or outliers; however, such transformation may not always reduce bias. In this study, we evaluated the validity of motivations underlying the decision to log-transform an independent variable using simulations, considering eight scenarios that can give rise to skewed X and normal Y. Our simulation study demonstrates that (1) if the skewness of exposure did not arise from a biasing factor (e.g., measurement error), the analytic approach with the best overall model fit best reflected the underlying outcome generating methods and was least biased, regardless of the skewness of X and (2) all estimates were biased if the skewness of exposure was a consequence of a biasing factor. We additionally illustrate a process to determine whether the transformation of an independent variable is needed using NHANES. Our study and suggestion to divorce the shape of the exposure distribution from the decision to log-transform it may aid researchers in planning for analysis using biomarkers or other skewed independent variables.

Introduction Second-generation antipsychotics (SGA) are associated with misuse potential; however, there are limited data describing the prevalence and characteristics of this misuse. This study was conducted to identify and describe quetiapine and olanzapine misuse among US adults. Methods This cross-sectional survey questionnaire was conducted online using Qualtrics research panel aggregator service to identify a quota-based sample of respondents constructed to mimic the general US population aged 18 to 59 years, with regards to gender, geographic region, ethnicity, income, and education level. Misuse was defined as using quetiapine or olanzapine for treatment outside of medical recommendations, for reasons other than a diagnosed medical condition, or obtaining without a prescription. A logistic regression was used to identify factors associated with SGA misuse, incorporating relevant covariates. Results Among 1843 total respondents, 229 had a history of quetiapine or olanzapine use. Misuse prevalence was estimated to be 6.3% (95% CI: 5.2, 7.5%). Although most respondents (∼70%) using quetiapine or olanzapine reported doing so to treat a diagnosed medical condition, those misusing them most commonly did so because prescribed medications failed to relieve their symptoms. Misuse was commonly reported (∼50%) concomitantly with opioids, benzodiazepines, or alcohol. Factors significantly associated with quetiapine or olanzapine misuse included employment (OR = 4.64), previous substance use disorder treatment (OR = 2.48), and having riskier attitudes toward medication misuse (OR = 1.23). Discussion Misuse of quetiapine and olanzapine, while fairly limited in prevalence, appears to be primarily associated with under-treatment of existing medical conditions.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

Over 14 million colonoscopies are performed annually in the United States. With the growing number of colonoscopies comes corresponding increases in the rates of colectomies performed for benign polyps. These advanced adenomas have the potential, if removed early, to promote decreased rates of colon cancer and improve patient survival. Difficult to resect polyps may be located at colonic flexures, tortuous turns in the colon, the ileocecal valve, or the appendiceal orifice presenting a unique challenge to endoscopic resection. Various advanced endoscopic techniques are now available for the resection of these polyps such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection, but these techniques have a steep learning curve and are technically challenging. For the community colorectal surgeon, relatively simpler options include combined endoscopic and laparoscopic surgery (CELS) and full-thickness laparo-endoscopic colonic excision (FLEX) for either the endoscopic or laparoscopic removal of challenging polyps. The FLEX procedure resembled a nonanatomic wedge resection of the colon with polyp, while CELS resembles a laparoscopically augmented EMR. With the technical success rate for CELS reportedly between 74 and 97%, the postoperative complication rate of less than 5%, and polyp recurrence rates bordering less than 2%, these procedures have the capacity to safely facilitate the complete removal of difficult-to-resect endoscopic polyps. The purpose of this review is to both provide recommendations for CELS and FLEX utilization for the resection of polyps and describe our operative techniques and tips and tools for increasing the efficacy of these procedures.

Purpose: Identifying efficacious measures to characterize dysphonia in complex neurodegenerative diseases is key to optimal assessment and intervention. This study evaluates the validity and sensitivity of acoustic features of phonatory disruption in amyotrophic lateral sclerosis (ALS). Method: Forty-nine individuals with ALS (40–79 years old) were audio-recorded while producing a sustained vowel and continuous speech. Perturbation/noise-based (jitter, shimmer, and harmonics-to-noise ratio) and cepstral/spectral (cepstral peak prominence, low–high spectral ratio, and related features) acoustic measures were extracted. The criterion validity of each measure was assessed using correlations with perceptual voice ratings provided by three speech-language pathologists. Diagnostic accuracy of the acoustic features was evaluated using area-under-the-curve analysis. Results: Perturbation/noise-based and cepstral/spectral features extracted from /a/ were significantly correlated with listener ratings of roughness, breathiness, strain, and overall dysphonia. Fewer and smaller correlations between cepstral/spectral measures and perceptual ratings were observed for the continuous speech task, although post hoc analyses revealed stronger correlations in speakers with less perceptually impaired speech. Area-under-the-curve analyses revealed that multiple acoustic features, particularly from the sustained vowel task, adequately differentiated between individuals with ALS with and without perceptually dysphonic voices. Conclusions: Our findings support using both perturbation/noise-based and cepstral/spectral measures of sustained /a/ to assess phonatory quality in ALS. Results from the continuous speech task suggest that multisubsystem involvement impacts cepstral/spectral analyses in complex motor speech disorders such as ALS. Further investigation of the validity and sensitivity of cepstral/spectral measures during continuous speech in ALS is warranted.

Purpose: The purpose of this study was to investigate comorbidity prevalence and patterns in childhood apraxia of speech (CAS) and their relationship to severity. Method: In this retroactive cross-sectional study, medical records for 375 children with CAS ( M age = 4;9 [years;months], SD = 2;9) were examined for comorbid conditions. The total number of comorbid conditions and the number of communication-related comorbidities were regressed on CAS severity as rated by speech-language pathologists during diagnosis. The relationship between CAS severity and the presence of four common comorbid conditions was also examined using ordinal or multinomial regressions. Results: Overall, 83 children were classified with mild CAS; 35, with moderate CAS; and 257, with severe CAS. Only one child had no comorbidities. The average number of comorbid conditions was 8.4 ( SD = 3.4), and the average number of communication-related comorbidities was 5.6 ( SD = 2.2). Over 95% of children had comorbid expressive language impairment. Children with comorbid intellectual disability (78.1%), receptive language impairment (72.5%), and nonspeech apraxia (37.3%; including limb, nonspeech oromotor, and oculomotor apraxia) were significantly more likely to have severe CAS than children without these comorbidities. However, children with comorbid autism spectrum disorder (33.6%) were no more likely to have severe CAS than children without autism. Conclusions: Comorbidity appears to be the rule, rather than the exception, for children with CAS. Comorbid intellectual disability, receptive language impairment, and nonspeech apraxia confer additional risk for more severe forms of CAS. Findings are limited by being from a convenience sample of participants but inform future models of comorbidity. Supplemental Material: https://doi.org/10.23641/asha.22096622

In this work, we investigate toughening mechanisms in soft polymers reinforced with stiff fibers, particularly focusing on the effect of the strength of the fiber-matrix bond on the toughness. We print polydimethylsiloxane with short milled glass fibers using direct ink writing, an extrusion-based 3D printing method. This process produces composites with aligned fibers. Fibers can be treated with acid prior to printing, which improves the strength of the fiber-matrix bond. This results in higher yield stress and toughness. The higher toughness of the composites can be attributed to intrinsic mechanisms such as matrix deformation and fiber pullout, as well as to extrinsic mechanisms like mechanical dissipation. The intrinsic toughness of the composites is analytically estimated using a micro-mechanical model and experimentally measured by stretching the composites in the direction of fiber alignment. Finally, we demonstrate partial healing of the fiber-matrix bond after initial pre-stretch. Thermal treatment of the damaged composites results in partial recovery of stiffness and toughness.

Novel preventive interventions are needed to address the rising incidence of human papillomavirus (HPV)-mediated oropharyngeal cancer (HPV+ OPC). This pilot study evaluated the feasibility of a stepped, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate HPV+ OPC outcome.This was a cross-sectional, feasibility study. Eligible 45–74 years old adults identified from three clinical research registries were administered a behavioral risk survey (step 1). Participant tobacco use and sexual behavior history were translated into a quantifiable risk of oral oncogenic HPV DNA, according to prior National Health and Nutrition Examination Survey analyses. Females with >2% risk and males with >7% risk were offered biological screening for oral oncogenic HPV DNA (step 2) via an oral rinse and gargle specimen.A total of 292 individuals were contacted, but only 144 (49%) were reached. Among these, 56 individuals (19%) were uninterested and 18 (13%) were ineligible. Seventy individuals began the survey and 66 completed it (step 1), among whom 46 were classified as low-risk. Among the remaining 20 participants classified as high-risk for an oral oncogenic HPV infection, 5% were current smokers and the median participant had performed oral sex on 10 unique partners. During step 2 (biological screening), 45% (9/20) completed testing, all of whom tested negative for oral oncogenic HPV DNA.In this pilot of a stepped, oral oncogenic HPV screening program, enrollment and study completion were suboptimal. These barriers to screening should be characterized and addressed before reevaluating the feasibility of this program.Prevention Relevance:Novel preventive interventions are needed to address the rising incidence of HPV+ OPC. In this feasibility study, we characterized barriers to a two-step, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate outcome for HPV+ OPC.

Female sex has been associated with decreased mortality after blunt trauma, but whether sex influences the outcomes of thoracic endovascular aortic repair (TEVAR) for traumatic blunt thoracic aortic injury (BTAI) is unknown.In this retrospective study of a prospectively maintained database, the Vascular Quality Initiative registry was queried from 2013 to 2020 for patients undergoing TEVAR for BTAI. Univariate Student's t-tests and χOf 806 eligible patients, 211 (26.2%) were female. Female patients were older (47.9 vs 41.8 years, P .0001) and less likely to smoke (38.3% vs 48.2%, P = .044). Most patients presented with grade III BTAI (54.5% female, 53.6% male), followed by grade IV (19.0% female, 19.5% male). Mean Injury Severity Scores (30.9 + 20.3 female, 30.5 + 18.8 male) and regional Abbreviated Injury Score did not vary by sex. Postoperatively, female patients were less likely to die as inpatients (3.8% vs 7.9%, P = .042) and to be discharged home (41.4% vs 52.2%, P = .008). On multivariate logistic regression, female sex (odds ratio [OR]: 0.05, P = .002) was associated with reduced inpatient mortality. Advanced age (OR: 1.06, P .001), postoperative transfusion (OR: 1.05, P = .043), increased Injury Severity Score (OR: 1.03, P = .039), postoperative stroke (OR: 9.09, P = .016), postoperative myocardial infarction (OR: 9.9, P = .017), and left subclavian coverage (OR: 2.7, P = .029) were associated with inpatient death.Female sex is associated with lower odds of inpatient mortality after TEVAR for BTAI, independent of age, injury severity, BTAI grade, and postoperative complications. Further study of the influence of sex on postdischarge outcomes is needed.

In the setting of total hip arthroplasty (THA), pseudoaneurysms are extremely rare and can be difficult to diagnose, as clinical symptoms can mimic symptoms of other more common complications, such as periprosthetic joint infection, hematoma, and nerve damage. We present a case of a 69-year-old male with a history of slipped capital femoral epiphysis 56 years prior and subsequent right THA. The right hip primary arthroplasty was subsequently complicated by multiple dislocations and recurrent prosthetic joint infections. The most recent infection was treated with debridement, antibiotics, and implant retention (DAIR) in 2017. The patient later presented in 2019 with right thigh pain. Upon further analysis, he was diagnosed with Streptococcus bovis positive periprosthetic joint infection. The patient underwent a two-stage revision of the hip using an antibiotic spacer. Two weeks following the second stage, he presented with a sudden onset of uncontrolled atrial fibrillation with rapid ventricular response and a low hemoglobin. The computed tomography scan revealed a large hematoma involving both the anterior and posterior thigh compartments with lab markers that were questionable for infection. An operation to remove the hematoma revealed no purulence, and a large pulsatile pseudoaneurysm on the posterolateral aspect at the mid femur was found. A sharp bone fragment was noted next to the pseudoaneurysm. The pseudoaneurysm was repaired by a vascular surgeon, and the bone fragment was removed. Following this procedure, the patient developed a subsequent periprosthetic joint infection requiring a double DAIR procedure six weeks following the pseudoaneurysm repair and is now on chronic antibiotic suppression. Orthopedic surgeons should be aware of the potential for pseudoaneurysm in the setting of total joint arthroplasty when treating a postsurgical hematoma of sudden onset.

To investigate the characteristics of shoulder and elbow fellowship directors (FDs).FDs for shoulder and elbow fellowship programs in the United States were identified. Demographic, educational, and professional background data were collected from available curricula vitarum, institutional biographies, and the Scopus database. Data collected included age, sex, race/ethnicity, training locations, graduation years, advanced degrees, current institutional information, and personal research H-index.Thirty current orthopaedic shoulder and elbow FDs were identified. The mean Scopus H-index was 25.5. The mean age of FDs was 52.1 years. In total, 29 FDs (96.7%) were male and 1 (3.3%) was female. In addition, 25 of the 30 (83.3%) were White (83.3%), 4 were Asian, and 1 (3.3%) was Hispanic. Two (6.7%) had a military affiliation. Mean time from fellowship training graduation to FD appointment was 13.5 years. Mean number of years as FD was 6.1 years, whereas the number of years tenure with an FD-affiliated institution was 13.0 years. Mean calendar years for completion of orthopaedic residency training and fellowship training were 1998 and 2000, respectively. The residencies that produced the most future FDs were Hospital of the University of Pennsylvania (n = 2) and University of Nebraska Medical Center/Creighton University Health Foundation (n = 2). The fellowship that produced the most future FDs was Columbia University (n = 6). Moderate correlation was found between age and Scopus H-index (r = 0.48;Women and minorities are under-represented in leadership positions in shoulder and elbow surgery. Shoulder and elbow FDs have the highest H-index of any subspecialty reported in the orthopaedic literature. Research productivity is an important qualification when considering the characteristics of shoulder and elbow FDs.Fellowship directors can have a profound influence on current and future orthopaedic surgeons. It is important to identify the traits that characterize current fellowship directors to have a better understanding of who we choose as leaders in our field.

The purpose of this paper was to review best-practice methods of collecting and analyzing speech production data from minimally verbal autistic speakers. Data on speech production data in minimally verbal individuals are valuable for a variety of purposes, including phenotyping, clinical assessment, and treatment monitoring. Both perceptual ("by ear") and acoustic analyses of speech can reveal subtle improvements as a result of therapy that may not be apparent when correct/incorrect judgments are used. Key considerations for collecting and analyzing speech production data from this population are reviewed. The definition of "minimally verbal" that is chosen will vary depending on the specific hypotheses investigated, as will the stimuli to be collected and the task(s) used to elicit them. Perceptual judgments are ecologically valid but subject to known sources of bias; therefore, training and reliability procedures for perceptual analyses are addressed, including guidelines on how to select vocalizations for inclusion or exclusion. Factors to consider when recording and acoustically analyzing speech are also briefly discussed. In summary, the tasks, stimuli, training methods, analysis type(s), and level of detail that yield the most reliable data to answer the question should be selected. It is possible to obtain rich high-quality data even from speakers with very little speech output. This information is useful not only for research but also for clinical decision-making and progress monitoring.

As many as one-third of patients with heart failure secondary to systemic, wild-type transthyretin amyloidosis have an associated distal biceps tendon (DBT) rupture. Our purpose was to identify the prevalence of amyloid deposition in patients undergoing operative repair of acute traumatic DBT ruptures.In this prospective investigation, a consecutive series of patients who underwent repair of an acute traumatic DBT rupture underwent a tendon biopsy to assess for amyloid deposition. All specimens were viewed under gross microscopy by a board-certified pathologist. For initial screening, either Congo red or Thioflavin-T immunohistochemistry analysis was conducted to determine amyloid status. If staining was positive for amyloid deposition using either technique, the tissue sample was sent to an outside facility for specific amyloid protein identification through liquid chromatography-tandem mass spectrometry. Baseline demographics were also recorded for each patient.A total of 30 patients who underwent biopsy and repair of an acute DBT rupture were included. The mean age was 48 years, and all patients were men. Seven (23%) patients had a history of carpal tunnel syndrome, and 1 (3%) patient had evidence of heart failure at the time of surgery. One (3%) patient had evidence of amyloid deposition in the DBT, which was confirmed using liquid chromatography-tandem mass spectrometry.Although one-third of patients with heart failure secondary to cardiac amyloidosis have an associated DBT rupture, younger patients with acute traumatic DBT ruptures do not appear to be uniquely at risk for amyloid deposition at the time of DBT repair. Larger registry studies may be necessary to define the risk of developing cardiac amyloidosis years after sustaining an acute DBT rupture.Prognostic IV.

BACKGROUND: Amniotic membrane tissue has been thought to potentiate healing in many soft tissue conditions. Specifically, recent studies have shown its therapeutic potential for treatment in the setting of spinal pathologies. The purpose of this study is to thoroughly review the existing scientific literature and evidence concerning the clinical use of amniotic membrane–derived biologic agents on postoperative outcomes following spinal surgery. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines using PubMed, Embase, and Cochrane databases up to December 2020 to identify animal and clinical studies examining the therapeutic potential for amniotic membrane tissue in the setting of spinal pathologies (including disc herniation, prevention of epidural fibrosis, and spinal fusion). Studies were broken down into 2 categories: experimental model type and the type of amnion product being analyzed. RESULTS: A total of 12 studies (4 clinical studies and 8 studies utilizing animal models) met inclusion criteria. Additionally, the major types of amnion product were divided into cryopreserved/freeze-dried amniotic membrane, human amniotic fluid, human amniotic membrane, cross-linked amniotic membrane, and amnion-derived epithelial cells. While heterogeneity of study design precludes definitive specific results reporting, most studies showed positive benefits on healing/outcomes with amniotic augmentation. Specifically, amnion products have shown promising effects in reducing epidural adhesions and scar tissue after spine surgery, improving spinal fusion rate and postoperative pain scores, and promoting better functional outcomes after spine surgery. CONCLUSIONS: A review of the limited number of reported studies revealed a wide variety of amniotic membrane preparations, treatment regimens, and indications, which limit definitive conclusions. To date, while there is no definitive clinical proof that amniotic tissues enhance tissue repair or regeneration, the aggregate results demonstrate promising basic science and outcomes potential in spinal surgery. Further study is warranted to determine whether this application is appropriate in the clinical setting. CLINICAL RELEVANCE: This systematic review provides a summary of the existing literature regarding the use of amniotic membrane preparations, treatment regimens, and indications within spinal surgery. With the growing popularity and utilization of biologic agents such as amniotic membrane-derived products in orthopedic and neurologic surgery, this systematic review gives physicians a concise summary on the outcomes and indications associated with amniotic membrane products. LEVEL OF EVIDENCE: 4.

The leaf-like origami structure was inspired by geometric patterns found in nature, exhibiting unique transitions between open and closed shapes. With a bistable energy landscape, leaf-like origami is able to replicate the autonomous grasping of objects observed in biological systems like the Venus flytrap. We show uniform grasping motions of the leaf-like origami, as well as various non-uniform grasping motions which arise from its multi-transformable nature. Grasping motions can be triggered with high tunability due to the structure's bistable energy landscape. We demonstrate the self-adaptive grasping motion by dropping a target object onto our paper prototype, which does not require an external power source to retain the capture of the object. We also explore the non-uniform grasping motions of the leaf-like structure by selectively controlling the creases, which reveals various unique grasping configurations that can be exploited for versatile, autonomous, and self-adaptive robotic operations.

The behavior and remodeling of the residual aneurysm sac after endovascular repair is predictive of long-term outcomes. Although persistent growth is clearly a harbinger of complications, only recently has the relative advantage of sac regression over sac stability been recognized. There is a growing literature examining the prognostic implications of sac regression after standard infrarenal endovascular aortic repair, and various factors associated with increased likelihood of regression have been identified. However, there is a relative paucity of data on sac regression after more complex aneurysm repairs using fenestrated and/or branched technology. In this article, we aim to review sac regression and its importance as a whole, and specifically examine the role of regression after fenestrated and/or branched endovascular aortic repair for more extensive abdominal and thoracoabdominal aneurysms.

Precipitated by the COVID-19 pandemic, many work systems—including those focused on research activities—have transitioned to remote operations and many may remain remote even after in-person operations no longer present a public health risk. The ability to conduct human subjects research remotely presents many benefits but also numerous challenges. This panel gathers experts in the design, adaptation, and performance of remote macroergonomics research. They will describe their remote methodologies, and evaluate past, current, and future work in this area.

Radiation oncology (RO) has seen declines in Medicare reimbursement (MCR). However, there are no recent studies analyzing the contributions of specific billing codes to overall RO reimbursement. We compared total MCR for specific Healthcare Common Procedure Coding System (HCPCS) codes in 2019 with MCR for those codes in 2010 and 2015, corrected for inflation, to see how the same basket of RO services in 2019 would have been reimbursed in 2010 and 2015 (adjusted MCR).The Centers for MedicareMedicaid Services Physician/Supplier Procedure Summary database was used to obtain MCR data for RO HCPCS codes in 2010, 2015, and 2019. For each code, the total allowed charge was divided by the number of submitted claims to calculate the average MCR per claim in 2010, 2015, and 2019. The 2019 billing frequency for each code was then multiplied by the inflation-adjusted average MCR for those codes in 2010 and 2015 to determine what the MCR would have been in 2010 and 2015 using 2019 dollars and utilization rates. Results were compared with actual 2019 MCR to calculate the projected difference.Total inflation-adjusted RO MCR was $2281 million (M), $1991 M, and $1848 M in 2010, 2015, and 2019 respectively. This represents a cut of $433 M (19%) and $143 M (7%) from 2010 and 2015, respectively, to 2019. After utilization adjustment, total reimbursement was $2534 M, $2034 M, and $1848 M for 2010, 2015, and 2019, respectively, representing a cut of $686 M (27%) and $186 M (9%) from 2010 and 2015, respectively, to 2019. Intensity modulated radiation therapy (IMRT) treatment delivery and planning accounted for $917 M (36%), $670 M (33%), and $573 M (31%) of the adjusted MCR in 2010, 2015, and 2019, respectively.Medicare reimbursement decreased substantially from 2010 to 2019. A decline in IMRT treatment reimbursement was the primary driver of MCR decline. When considering further cuts, policymakers should consider these trends and their consequences for health care quality and access.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

Despite disproportionally high prevalence of HIV and depression in persons with disabilities, no data have been published on the incidence and correlates of depression in Medicare beneficiaries with disabilities. We assessed the effect of HIV infection on developing depression in this population.We conducted a retrospective matched cohort study using a 5% sample of Medicare beneficiaries who qualified for disability coverage (1996-2015).Beneficiaries with incident ( n = 2438) and prevalent ( n = 5758) HIV were individually matched with beneficiaries without HIV (HIV-, n = 20 778). Fine-Gray models with death as a competing risk were used to assess the effect of HIV status, age, and cohort period on developing depression by sex strata.Beneficiaries with HIV had a higher risk of developing depression within 5 years ( P 0.0001). Sex differences were observed ( P 0.0001), with higher subdistribution hazard ratios (sHR) in males with HIV compared with controls. The risk decreased with age ( P 0.0001) and increased in recent years ( P 0.0001). There were significant age-HIV ( P = 0.004) and period-HIV ( P = 0.006) interactions among male individuals, but not female individuals. The sHR was also higher within the first year of follow-up among male individuals, especially those with incident HIV.Medicare enrollees with disabilities and HIV had an increased risk of developing depression compared to those without HIV, especially among males and within the first year of HIV diagnosis. The HIV-depression association varied by sex, age, and cohort period. Our findings may help guide screening and comprehensive management of depression among subgroups in this vulnerable population.

Immunosuppressive drugs (IMD) are widely utilized to treat many autoimmune conditions and to prevent rejection in organ transplantation. Cancer has been associated with prolonged use of IMD in transplant patients. However, no detailed, systematic analysis of the risk of cancer has been performed in patients receiving IMD for any condition and duration. We analyzed Medicare data from Texas Medicare beneficiaries, regardless of their age, between 2007 and 2018, from the Texas Cancer Registry. We analyzed the data for the risk of cancer after IMD use associated with demographic characteristics, clinical conditions, and subsequent cancer type. Of 29,196 patients who used IMD for a variety of indications, 5684 developed cancer. The risk of cancer (standardized incidence ratio) was particularly high for liver (9.10), skin (7.95), lymphoma (4.89), and kidney (4.39). Patients receiving IMD had a four fold greater likelihood of developing cancer than the general population. This risk was higher within the first 3 years of IMD utilization and in patients younger than 65 years and minorities. This study shows that patients receiving IMD for any indications have a significantly increased risk of cancer, even with short-term use. Caution is needed for IMD use; in addition, an aggressive neoplastic diagnostic screening is warranted.

We aimed to collect parallel perspectives from pharmacists and pharmacy students on their use, knowledge, attitudes, and perceptions about herbal supplements/natural products. Two cross-sectional descriptive survey questionnaires—one focusing on pharmacists and the other focusing on pharmacy students—were administered from March to June 2021 via Qualtrics. The surveys were sent out to preceptor pharmacists and pharmacy students currently enrolled at a single U.S. school of pharmacy. The questionnaires were composed of five main sections, including (1) demographics; (2) attitudes/perceptions; (3) educational experience; (4) resource availability; and (5) objective knowledge of herbal supplements/natural products. Data analysis primarily utilized descriptive statistics with relevant comparisons across domains. A total of 73 pharmacists and 92 pharmacy students participated, with response rates of 8.8% and 19.3%, respectively. A total of 59.2% of pharmacists and 50% of pharmacy students stated they personally used herbal supplements/natural products. Most respondents (>95% for both groups) considered vitamins/minerals safe, although a lower percentage agreed on this for herbal supplements/natural products (60% and 79.3% for pharmacists and pharmacy students, respectively). Patient inquiries in the pharmacy setting were most seen for vitamin D, zinc, cannabidiol, and omega-3. A total of 34.2% of pharmacists reported having training in herbal supplements/natural products as a required part of their Pharm.D. training, and 89.1% of pharmacy students desired to learn more. The median score on the objective knowledge quiz was 50% for pharmacists and 45% for pharmacy students. Ultimately, herbal supplements/natural products are recognized by pharmacists/pharmacy students as a consistent and embedded part of pharmacy practice, although there is a need to enhance knowledge and skills in this area.

The actomyosin cytoskeleton generates mechanical forces that power important cellular processes, such as cell migration, cell division, and mechanosensing. Actomyosin self-assembles into contractile networks and bundles that underlie force generation and transmission in cells. A central step is the assembly of the myosin II filament from myosin monomers, regulation of which has been extensively studied. However, myosin filaments are almost always found as clusters within the cell cortex. While recent studies characterized cluster nucleation dynamics at the cell periphery, how myosin clusters grow on stress fibers remains poorly characterized. Here, we utilize a U2OS osteosarcoma cell line with endogenously tagged myosin II to measure the myosin cluster size distribution in the lamella of adherent cells. We find that myosin clusters can grow with Rho-kinase (ROCK) activity alone in the absence of myosin motor activity. Time-lapse imaging reveals that myosin clusters grow via increased myosin association to existing clusters, which is potentiated by ROCK-dependent myosin filament assembly. Enabling myosin motor activity allows further myosin cluster growth through myosin association that is dependent on F-actin architecture. Using a toy model, we show that myosin self-affinity is sufficient to recapitulate the experimentally observed myosin cluster size distribution, and that myosin cluster sizes are determined by the pool of myosin available for cluster growth. Together, our findings provide new insights into the regulation of myosin cluster sizes within the lamellar actomyosin cytoskeleton.

BackgroundThere are no licensed vaccines against Plasmodium vivax, the most common cause of malaria outside of Africa.MethodsWe conducted two Phase I/IIa clinical trials to assess the safety, immunogenicity and efficacy of two vaccines targeting region II of P. vivax Duffy-binding protein (PvDBPII). Recombinant viral vaccines (using ChAd63 and MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst a protein/adjuvant formulation (PvDBPII/Matrix-M™) was administered monthly (0, 1, 2 months) or in a delayed dosing regimen (0, 1, 14 months). Delayed regimens were due to trial halts during the COVID-19 pandemic. Volunteers underwent heterologous controlled human malaria infection (CHMI) with blood-stage P. vivax parasites at 2-4 weeks following their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparison of parasite multiplication rate (PMR) in blood post-CHMI, modelled from parasitemia measured by quantitative polymerase-chain-reaction (qPCR).ResultsThirty-two volunteers were enrolled and vaccinated (n=16 for each vaccine). No safety concerns were identified. PvDBPII/Matrix-M™, given in the delayed dosing regimen, elicited the highest antibody responses and reduced the mean PMR following CHMI by 51% (range 36-66%; n=6) compared to unvaccinated controls (n=13). No other vaccine or regimen impacted parasite growth. In vivo growth inhibition of blood-stage P. vivax correlated with functional antibody readouts of vaccine immunogenicity.ConclusionsVaccination of malaria-naïve adults with a delayed booster regimen of PvDBPII/ Matrix-M™ significantly reduces the growth of blood-stage P. vivax.Funded by the European Commission and Wellcome Trust; VAC069, VAC071 and VAC079 ClinicalTrials.gov numbers NCT03797989, NCT04009096 and NCT04201431.

Although personalized automatic speech recognition (ASR) models have recently been designed to recognize even severely impaired speech, model performance may degrade over time for persons with degenerating speech. The aims of this study were to (1) analyze the change of performance of ASR over time in individuals with degrading speech, and (2) explore mitigation strategies to optimize recognition throughout disease progression. Speech was recorded by four individuals with degrading speech due to amyotrophic lateral sclerosis (ALS). Word error rates (WER) across recording sessions were computed for three ASR models: Unadapted Speaker Independent (U-SI), Adapted Speaker Independent (A-SI), and Adapted Speaker Dependent (A-SD or personalized). The performance of all three models degraded significantly over time as speech became more impaired, but the performance of the A-SD model improved markedly when it was updated with recordings from the severe stages of speech progression. Recording additional utterances early in the disease before speech degraded significantly did not improve the performance of A-SD models. Overall, our findings emphasize the importance of continuous recording (and model retraining) when providing personalized models for individuals with progressive speech impairments., Comment: Submitted to ICASSP 2023

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts. Data and metadata are stored on the Open Science Framework website [https://osf.io/mhg94/].

Background For blood-stage malaria vaccine development, the in vitro growth inhibition assay (GIA) has been widely used to evaluate functionality of vaccine-induced antibodies (Ab), and Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage antigen. However, precision, also called “error of assay (EoA)”, in GIA readouts and the source of EoA has not been evaluated systematically. Methods In the Main GIA experiment, 4 different cultures of P. falciparum 3D7 parasites were prepared with red blood cells (RBC) collected from 4 different donors. For each culture, 7 different anti-RH5 Ab (either monoclonal or polyclonal Ab) were tested by GIA at two concentrations on three different days (168 data points). To evaluate sources of EoA in % inhibition in GIA (%GIA), a linear model fit was conducted including donor (source of RBC) and day of GIA as independent variables. In addition, 180 human anti-RH5 polyclonal Ab were tested in a Clinical GIA experiment, where each Ab was tested at multiple concentrations in at least 3 independent GIAs using different RBCs (5,093 data points). The standard deviation (sd) in %GIA and in GIA50 (Ab concentration that gave 50%GIA) readouts, and impact of repeat assays on 95% confidence interval (95%CI) of these readouts was estimated. Results The Main GIA experiment revealed that the RBC donor effect was much larger than the day effect, and an obvious donor effect was also observed in the Clinical GIA experiment. Both %GIA and log-transformed GIA50 data reasonably fit a constant sd model, and sd of %GIA and log-transformed GIA50 measurements were calculated as 7.54 and 0.206, respectively. Taking the average of three repeat assays (using three different RBCs) reduces the 95%CI width in %GIA or in GIA50 measurements by ~ half compared to a single assay. Conclusions The RBC donor effect (donor-to-donor variance on the same day) in GIA was much bigger than the day effect (day-to-day variance using the same donor’s RBC) at least for the RH5 Ab evaluated in this study; thus, future GIA studies should consider the donor effect. In addition, the 95%CI for %GIA and GIA50 shown here help when comparing GIA results from different samples/groups/studies; therefore, this study supports future malaria blood-stage vaccine development.