Papillary tumor of the pineal region: analysis of DNA methylation profiles and clinical outcomes in 76 cases.

Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR's, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.

Origins of High-Activity Cage-Catalyzed Michael Addition.

Cage catalysis continues to create significant interest, yet catalyst function remains poorly understood. Herein, we report mechanistic insights into coordination-cage-catalyzed Michael addition using kinetic and computational methods. The study has been enabled by the detection of identifiable catalyst intermediates, which allow the evolution of different cage species to be monitored and modeled alongside reactants and products. The investigations show that the overall acceleration results from two distinct effects. First, the cage reaction shows a thousand-fold increase in the rate constant for the turnover-limiting C-C bond-forming step compared to a reference state. Computational modeling and experimental analysis of activation parameters indicate that this stems from a significant reduction in entropy, suggesting substrate coencapsulation. Second, the cage markedly acidifies the bound pronucleophile, shifting this equilibrium by up to 6 orders of magnitude. The combination of these two factors results in accelerations up to 109 relative to bulk-phase reference reactions. We also show that the catalyst can fundamentally alter the reaction mechanism, leading to intermediates and products that are not observable outside of the cage. Collectively, the results show that cage catalysis can proceed with very high activity and unique selectivity by harnessing a series of individually weak noncovalent interactions.

Randomized Trial of the Effectiveness of Videoconferencing-Based Versus Message-Based Psychotherapy on Depression.

OBJECTIVE: The authors compared the engagement, clinical outcomes, and adverse events of text or voice message-based psychotherapy (MBP) versus videoconferencing-based psychotherapy (VCP) among adults with depression. METHODS: The study used a sequential multiple-assignment randomized trial design with data drawn from phase 1 of a two-phase small business innovation research study. In total, 215 adults (ages ≥18 years) with depression received care from Talkspace, a digital mental health care company. Participants were initially randomly assigned to receive either asynchronous MBP or weekly VCP. All therapists provided evidence-based treatments such as cognitive-behavioral therapy. After 6 weeks of treatment, participants whose condition did not show a response on the Patient Health Questionnaire-9 or was rated as having not improved on the Clinical Global Impressions scale were randomly reassigned to receive either weekly VCP plus MBP or monthly VCP plus MBP. Longitudinal mixed-effects models with piecewise linear time trends applied to multiple imputed data sets were used to address missingness of data. RESULTS: Participants who were initially assigned to the MBP condition engaged with their therapists over more weeks than did participants in the VCP condition (7.8 weeks for MBP vs. 4.9 weeks for VCP; p<0.001). No meaningful differences were observed between the two groups in rates of change by 6 or 12 weeks for depression, anxiety, disability, or global ratings of improvement. Neither treatment resulted in any adverse events. CONCLUSIONS: MBP appears to be a viable alternative to VCP for treating adults with depression.

Antimicrobial cetylpyridinium chloride suppresses mast cell function by targeting tyrosine phosphorylation of Syk kinase.

Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, we showed that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca 2+ mobilization, microtubule polymerization, and degranulation. In this study, we extend the findings to human mast cells (LAD2) and present data indicating that CPC's mechanism of action centers on its positively-charged quaternary nitrogen in its pyridinium headgroup. CPC's inhibitory effect is independent of signaling platform receptor architecture. Tyrosine phosphorylation events are a trigger of Ca 2+ mobilization necessary for degranulation. CPC inhibits global tyrosine phosphorylation in Ag-stimulated mast cells. Specifically, CPC inhibits tyrosine phosphorylation of specific key players Syk kinase and LAT, a substrate of Syk. In contrast, CPC does not affect Lyn kinase phosphorylation. Thus, CPC's root mechanism is electrostatic disruption of particular tyrosine phosphorylation events essential for signaling. This work outlines the biochemical mechanisms underlying the effects of CPC on immune signaling and allows the prediction of CPC effects on cell types, like T cells, that share similar signaling elements.

Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial protocol (SMART-PDA).

INTRODUCTION: Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in extremely preterm infants and is associated with poor clinical outcomes. Uncertainty exists on whether early pharmacotherapeutic treatment of a clinically symptomatic and echocardiography-confirmed haemodynamically significant PDA in extremely preterm infants improves outcomes. Given the wide variation in the approach to PDA treatment in this gestational age (GA) group, a randomised trial design is essential to address the question. Before embarking on a large RCT in this vulnerable population, it is important to establish the feasibility of such a trial. METHODS AND ANALYSIS: Design: a multi-centre, open-labelled, parallel-designed pilot randomised controlled trial. Participants: preterm infants born <26 weeks of gestation with a PDA diagnosed within 72 hours after birth. Intervention (selective early medical treatment (SMART) strategy): selective early pharmacological treatment of a moderate-severe PDA shunt (identified based on pre-defined clinical signs and routine screening echocardiography) within the first 72 postnatal hours with provision for repeat treatment if moderate-severe shunt persists. Comparison (early conservative management strategy): no treatment of PDA in the first postnatal week. Primary outcomes: (1) proportion of eligible infants recruited during the study period; (2) proportion of randomised infants treated outside of protocol-mandated therapy. Sites and sample size: the study is being conducted in seven neonatal intensive care units across Canada and the USA with a target of 100 randomised infants. Analysis: the primary feasibility outcomes will be expressed as proportions. A pre-planned Bayesian analysis will be conducted for secondary clinical outcomes such as mortality, severe intraventricular haemorrhage, procedural PDA closure and chronic lung disease to aid stakeholders including parent representatives decide on the appropriateness of enrolling this vulnerable population in a larger trial if the feasibility of recruitment in the pilot trial is established. ETHICS AND DISSEMINATION: The study has been approved by the IWK Research Ethics Board (#1027298) and six additional participating sites. On the completion of the study, results will be presented at national and international meetings, published in peer-reviewed journals and incorporated into existing systematic reviews. TRIAL REGISTRATION NUMBER: NCT05011149 (WHO Trial Registration Data Set in Appendix A). PROTOCOL VERSION: Ver 7.2 (dated July 19, 2023).

Improved quantitative parameter estimation for prostate T2 relaxometry using convolutional neural networks.

OBJECTIVE: Quantitative parameter mapping conventionally relies on curve fitting techniques to estimate parameters from magnetic resonance image series. This study compares conventional curve fitting techniques to methods using neural networks (NN) for measuring T2 in the prostate. MATERIALS AND METHODS: Large physics-based synthetic datasets simulating T2 mapping acquisitions were generated for training NNs and for quantitative performance comparisons. Four combinations of different NN architectures and training corpora were implemented and compared with four different curve fitting strategies. All methods were compared quantitatively using synthetic data with known ground truth, and further compared on in vivo test data, with and without noise augmentation, to evaluate feasibility and noise robustness. RESULTS: In the evaluation on synthetic data, a convolutional neural network (CNN), trained in a supervised fashion using synthetic data generated from naturalistic images, showed the highest overall accuracy and precision amongst the methods. On in vivo data, this best performing method produced low-noise T2 maps and showed the least deterioration with increasing input noise levels. DISCUSSION: This study showed that a CNN, trained with synthetic data in a supervised manner, may provide superior T2 estimation performance compared to conventional curve fitting, especially in low signal-to-noise regions.

Reliability Theory for Measurements with Variable Test Length, Illustrated with ERN and Pe Collected in the Flanker Task.

In psychophysiology, an interesting question is how to estimate the reliability of event-related potentials collected by means of the Eriksen Flanker Task or similar tests. A special problem presents itself if the data represent neurological reactions that are associated with some responses (in case of the Flanker Task, responding incorrectly on a trial) but not others (like when providing a correct response), inherently resulting in unequal numbers of observations per subject. The general trend in reliability research here is to use generalizability theory and Bayesian estimation. We show that a new approach based on classical test theory and frequentist estimation can do the job as well and in a simpler way, and even provides additional insight to matters that were unsolved in the generalizability method approach. One of our contributions is the definition of a single, overall reliability coefficient for an entire group of subjects with unequal numbers of observations. Both methods have slightly different objectives. We argue in favor of the classical approach but without rejecting the generalizability approach.

Comparing ventriculoatrial and ventriculopleural shunts in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study.

OBJECTIVE: When the peritoneal cavity cannot serve as the distal shunt terminus, nonperitoneal shunts, typically terminating in the atrium or pleural space, are used. The comparative effectiveness of these two terminus options has not been evaluated. The authors directly compared shunt survival and complication rates for ventriculoatrial (VA) and ventriculopleural (VPl) shunts in a pediatric cohort. METHODS: The Hydrocephalus Clinical Research Network Core Data Project was used to identify children ≤ 18 years of age who underwent either VA or VPl shunt insertion. The primary outcome was time to shunt failure. Secondary outcomes included distal site complications and frequency of shunt failure at 6, 12, and 24 months. RESULTS: The search criteria yielded 416 children from 14 centers with either a VA (n = 318) or VPl (n = 98) shunt, including those converted from ventriculoperitoneal shunts. Children with VA shunts had a lower median age at insertion (6.1 years vs 12.4 years, p < 0.001). Among those children with VA shunts, a hydrocephalus etiology of intraventricular hemorrhage (IVH) secondary to prematurity comprised a higher proportion (47.0% vs 31.2%) and myelomeningocele comprised a lower proportion (17.8% vs 27.3%) (p = 0.024) compared with those with VPl shunts. At 24 months, there was a higher cumulative number of revisions for VA shunts (48.6% vs 38.9%, p = 0.038). When stratified by patient age at shunt insertion, VA shunts in children < 6 years had the lowest shunt survival rate (p < 0.001, log-rank test). After controlling for age and etiology, multivariable analysis did not find that shunt type (VA vs VPl) was predictive of time to shunt failure. No differences were found in the cumulative frequency of complications (VA 6.0% vs VPl 9.2%, p = 0.257), but there was a higher rate of pneumothorax in the VPl cohort (3.1% vs 0%, p = 0.013). CONCLUSIONS: Shunt survival was similar between VA and VPl shunts, although VA shunts are used more often, particularly in younger patients. Children < 6 years with VA shunts appeared to have the shortest shunt survival, which may be a result of the VA group having more cases of IVH secondary to prematurity; however, when age and etiology were included in a multivariable model, shunt location (atrium vs pleural space) was not associated with time to failure. The baseline differences between children treated with a VA versus a VPl shunt likely explain current practice patterns.

Genomic characterization of highly pathogenic avian influenza A H5N1 virus newly emerged in dairy cattle.

In March 2024, the emergence of highly pathogenic avian influenza (HPAI) A (H5N1) infections in dairy cattle was detected in the United Sates for the first time. We genetically characterize HPAI viruses from dairy cattle showing an abrupt drop in milk production, as well as from two cats, six wild birds, and one skunk. They share nearly identical genome sequences, forming a new genotype B3.13 within the 2.3.4.4b clade. B3.13 viruses underwent two reassortment events since 2023 and exhibit critical mutations in HA, M1, and NS genes but lack critical mutations in PB2 and PB1 genes, which enhance virulence or adaptation to mammals. The PB2 E627 K mutation in a human case associated with cattle underscores the potential for rapid evolution post infection, highlighting the need for continued surveillance to monitor public health threats.

GPCR-Gα13 Involvement in Mitochondrial Function, Oxidative Stress, and Prostate Cancer.

Gα13 and Gα12, encoded by the GNA13 and GNA12 genes, respectively, are members of the G12 family of Gα proteins that, along with their associated Gßγ subunits, mediate signaling from specific G protein-coupled receptors (GPCRs). Advanced prostate cancers have increased expression of GPCRs such as CXC Motif Chemokine Receptor 4 (CXCR4), lysophosphatidic acid receptor (LPAR), and protease activated receptor 1 (PAR-1). These GPCRs signal through either the G12 family, or through Gα13 exclusively, often in addition to other G proteins. The effect of Gα13 can be distinct from that of Gα12, and the role of Gα13 in prostate cancer initiation and progression is largely unexplored. The oncogenic effect of Gα13 on cell migration and invasion in prostate cancer has been characterized, but little is known about other biological processes such as mitochondrial function and oxidative stress. Current knowledge on the link between Gα13 and oxidative stress is based on animal studies in which GPCR-Gα13 signaling decreased superoxide levels, and the overexpression of constitutively active Gα13 promoted antioxidant gene activation. In human samples, mitochondrial superoxide dismutase 2 (SOD2) correlates with prostate cancer risk and prognostic Gleason grade. However, overexpression of SOD2 in prostate cancer cells yielded conflicting results on cell growth and survival under basal versus oxidative stress conditions. Hence, it is necessary to explore the effect of Gα13 on prostate cancer tumorigenesis, as well as the effect of Gα13 on SOD2 in prostate cancer cell growth under oxidative stress conditions.

Stereotactic Body Proton Therapy Versus Conventionally Fractionated Proton Therapy for Early Prostate Cancer: A Randomized, Controlled, Phase 3 Trial.

PURPOSE: We aimed to determine if ultra-hypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. MATERIALS AND METHODS: This study was a multicenter, randomized, controlled, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 according to AJCC 7th ed. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Non-inferiority for FFF was determined based on one-sided confidence intervals. Toxicities were compared at different time points using Fisher's Exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual. RESULTS: Between December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR 3.9-5.2). The 2-year FFF was 100% for both groups, with the one-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI: -1.70%-6.96%), favoring the SBRT arm, thus fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. Rates of gastrointestinal (GI) and genitourinary (GU) G2 and G3 toxicities did not differ significantly between groups but the the study was not powered to detect significant toxicity differences. Also, HRQoL metrics did not differ significantly between groups over the study median follow up. CONCLUSIONS: SBPT is non-inferior to CFPT regarding FFF, with similar long-term GU and GI toxicity rates and minimal impact in patient reported HRQoL over time.

GNA13 suppresses proliferation of ER+ breast cancer cells via ERα dependent upregulation of the MYC oncogene.

GNA13 (Gα13) is one of two alpha subunit members of the G12/13 family of heterotrimeric G-proteins which mediate signaling downstream of GPCRs. It is known to be essential for embryonic development and vasculogenesis and has been increasingly shown to be involved in mediating several steps of cancer progression. Recent studies found that Gα13 can function as an oncogene and contributes to progression and metastasis of multiple tumor types, including ovarian, head and neck and prostate cancers. In most cases, Gα12 and Gα13, as closely related α-subunits in the subfamily, have similar cellular roles. However, in recent years their differences in signaling and function have started to emerge. We previously identified that Gα13 drives invasion of Triple Negative Breast Cancer (TNBC) cells in vitro. As a highly heterogenous disease with various well-defined molecular subtypes (ER+ /Her2-, ER+ /Her2+, Her2+, TNBC) and subtype associated outcomes, the function(s) of Gα13 beyond TNBC should be explored. Here, we report the finding that low expression of GNA13 is predictive of poorer survival in breast cancer, which challenges the conventional idea of Gα12/13 being universal oncogenes in solid tumors. Consistently, we found that Gα13 suppresses the proliferation in multiple ER+ breast cancer cell lines (MCF-7, ZR-75-1 and T47D). Loss of GNA13 expression drives cell proliferation, soft-agar colony formation and in vivo tumor formation in an orthotopic xenograft model. To evaluate the mechanism of Gα13 action, we performed RNA-sequencing analysis on these cell lines and found that loss of GNA13 results in the upregulation of MYC signaling pathways in ER+ breast cancer cells. Simultaneous silencing of MYC reversed the proliferative effect from the loss of GNA13, validating the role of MYC in Gα13 regulation of proliferation. Further, we found Gα13 regulates the expression of MYC, at both the transcript and protein level in an ERα dependent manner. Taken together, our study provides the first evidence for a tumor suppressive role for Gα13 in breast cancer cells and demonstrates for the first time the direct involvement of Gα13 in ER-dependent regulation of MYC signaling. With a few exceptions, elevated Gα13 levels are generally considered to be oncogenic, similar to Gα12. This study demonstrates an unexpected tumor suppressive role for Gα13 in ER+ breast cancer via regulation of MYC, suggesting that Gα13 can have subtype-dependent tumor suppressive roles in breast cancer.

Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice.

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

Binding and sensing diverse small molecules using shape-complementary pseudocycles.

We describe an approach for designing high-affinity small molecule-binding proteins poised for downstream sensing. We use deep learning-generated pseudocycles with repeating structural units surrounding central binding pockets with widely varying shapes that depend on the geometry and number of the repeat units. We dock small molecules of interest into the most shape complementary of these pseudocycles, design the interaction surfaces for high binding affinity, and experimentally screen to identify designs with the highest affinity. We obtain binders to four diverse molecules, including the polar and flexible methotrexate and thyroxine. Taking advantage of the modular repeat structure and central binding pockets, we construct chemically induced dimerization systems and low-noise nanopore sensors by splitting designs into domains that reassemble upon ligand addition.

CUT&Tag applied to zebrafish adult tail fins reveals a return of embryonic H3K4me3 patterns during regeneration.

Regenerative potential is governed by a complex process of transcriptional reprogramming, involving chromatin reorganization and dynamics in transcription factor binding patterns throughout the genome. The degree to which chromatin and epigenetic changes contribute to this process remains only partially understood. Here we provide a modified CUT&Tag protocol suitable for improved characterization and interrogation of changes in chromatin modifications during adult fin regeneration in zebrafish. Our protocol generates data that recapitulates results from previously published ChIP-Seq methods, requires far fewer cells as input, and significantly improves signal to noise ratios. We deliver high-resolution enrichment maps for H3K4me3 of uninjured and regenerating fin tissues. During regeneration, we find that H3K4me3 levels increase over gene promoters which become transcriptionally active and genes which lose H3K4me3 become silenced. Interestingly, these reprogramming events recapitulate the H3K4me3 patterns observed in developing fin folds of 24-h old zebrafish embryos. Our results indicate that changes in genomic H3K4me3 patterns during fin regeneration occur in a manner consistent with reactivation of developmental programs, demonstrating CUT&Tag to be an effective tool for profiling chromatin landscapes in regenerating tissues.

Glenoid lateralization in reverse shoulder arthroplasty: metal vs. bone offset in different implant designs.

Background: Higher bone or metal glenoid offset in reverse shoulder arthroplasty (RSA) reduces scapular notching, improves range of motion (ROM), and reduces postoperative instability. This retrospective multicenter study compared two implant designs to evaluate the short-term clinical and radiologic results of bone increased offset RSA (BIO-RSA) and metal increased offset RSA (MIO-RSA) in reverse shoulder. We hypothesized no difference between groups. Methods: This study analyzed n = 62 BIO-RSA and n = 90 MIO-RSA cases with a mean follow-up of 29.7 ± 6.0 months (BIO-RSA, range 24-49 months) and 24.0 ± 1.1 months (MIO-RSA, range 22-28 months). A 145°-onlay humeral stem was utilized in BIO-RSA cases, while a 135°-semi-inlay humeral stem was implanted in all MIO-RSA cases. Preoperative and postoperative radiologic imaging was reviewed to identify signs of scapular notching. Additionally, lateralization was evaluated according to Erickson et al. The constant score, subjective shoulder value, and ROM were evaluated during the baseline and follow-up consultations, and the findings of both groups were subsequently compared. Results: Scapular notching was observed in 7.0% (n = 8) of MIO-RSA cases and 8.1% (n = 5) of BIO-RSA cases (P = .801). MIO-group had a higher lateralization angle (P = .020) and the BIO-group had a higher distalization angle (P = .005). At baseline, mean constant score in the MIO-RSA group was higher than in the BIO-RSA group (P < .001), and it significantly increased to 67.8 ± 12.1P (MIO-RSA) and 69.5 ± 12.3P (BIO-RSA) to a similar level (P = .399). ROM improved in both groups with no significant difference between the two groups at follow-up. Conclusion: BIO-RSA and MIO-RSA in two distinct implant designs provide comparable short-term outcomes with a similar increase in shoulder function with notable variations in the lateralization and distalization angles between both implants. Scapular notching was rarely seen and unaffected by the method of glenoid lateralization. Follow-up investigations of both techniques are necessary to complement and track changes in the long-term outcome.

A stemless anatomic shoulder arthroplasty design provides increased cortical medial calcar bone loading in variable bone densities compared to a short stem implant.

Background: Several studies have reported proximal bone resorption in stemless and press-fit short-stem humeral implants for anatomic total shoulder arthroplasty. The purpose of this biomechanical study was to evaluate implant and cortical bone micromotion of a cortical rim-supported stemless implant compared to a press-fit short stem implant during cyclic loading and static compression testing. Methods: Thirty cadaveric humeri were assigned to 3 groups based on a previously performed density analysis, adopting the metaphyseal and epiphyseal and inferior supporting bone densities for multivariate analyses. Implant fixation was performed in stemless implant in low bone density (SL-L, n = 10) or short stem implant in low bone density (Stem-L, n = 10) and in stemless implant in high bone density (SL-H, n = 10). Cyclic loading with 220 N, 520 N, and 820 N over 1000 cycles at 1.5 Hz was performed with a constant valley load of 25 N. Optical recording allowed for spatial implant tracking and quantification of cortical bone deformations in the medial calcar bone region. Implant micromotion was measured as rotational and translational displacement. Load-to-failure testing was performed at a rate of 1.5 mm/s with ultimate load and stiffness measured. Results: The SL-H group demonstrated significantly reduced implant micromotion compared to both low-density groups (SL-L: P = .014; Stem-L: P = .031). The Stem-L group showed significantly reduced rotational motion and variance in the test results at the 820-N load level compared to the SL-L group (equal variance: P = .012). Implant micromotion and reversible bone deformation were significantly affected by increasing load (P < .001), metaphyseal cancellous (P = .023, P = .013), and inferior supporting bone density (P = .016, P = .023). Absolute cortical bone deformation was significantly increased with stemless implants in lower densities and percentage reversible bone deformation was significantly higher for the SL-H group (21 ± 7%) compared to the Stem-L group (12 ± 6%, P = .017). Conclusion: A cortical rim-supported stemless implant maintained proximally improved dynamic bone loading in variable bone densities compared to a press-fit short stem implant. Biomechanical time-zero implant micromotion in lower bone densities was comparable between short stem and stemless implants at rehabilitation load levels (220 N, 520 N), but with higher cyclic stability and reduced variability for stemmed implantation at daily peak loads (820 N).

Using health belief model constructs to understand the role of perceived disease threat and resilience in responding to COVID-19 among people who use drugs: a cluster analysis.

Introduction: The Health Belief Model (HBM) has been successfully applied to understanding adherence to COVID-19 prevention practices. It has not, however, been used to understand behavior in people who use drugs (PWUD). The aim of this study was to use the HBM to better understand COVID-19 perceptions among PWUD and understand how resiliency affects those perceptions. Materials and methods: A cross-sectional survey was completed from September to December 2021 with PWUD (n = 75) who utilize services at a large harm reduction organization in Philadelphia. Segmentation analysis was done using a k-means clustering approach. Two clusters emerged based on perceived COVID-19 personal impact and resiliency (Less COVID impact/High resilience (NoCOV/HR) and High COVID impact/Low resilience (COV/LR). Differences in responses by cluster to perceptions of COVID-19 and individual pandemic response grouped by HBM constructs were assessed using Student's t-test and chi squares. Results: Significant differences in HBM constructs were seen between clusters. Those in the COV/LR cluster were more likely to think they were susceptible to getting COVID-19 and less likely to believe they knew how to protect themselves. The NoCOV/HR cluster believed they were able to protect themselves from COVID-19 and that they were able to easily understand messages about protecting themselves. Conclusion: Understanding how PWUD conceptualize disease threat and using HBM can better inform interventions to improve future pandemic response. Findings suggest that resilience is key to protecting PWUD from future infectious disease outbreaks. Interventions aimed at increasing resiliency among PWUD may improve preventative behavior and decrease disease burden in this vulnerable population.

Echocardiographic evaluation of left atrial volume and comparative analysis to left atrial to aortic root ratio in premature neonates and infants with patent ductus arteriosus.

PURPOSE: Left atrium to aortic root ratio (LA/Ao) is an echocardiographic marker of hemodynamically significant patent ductus arteriosus (PDA). Since 2-dimensional measurement of the ratio is geometrically limited, left atrial volume (LAV) which has 3-dimensional characteristics was investigated. The aim of this study was to determine a correlation between LA/Ao ratio and LAV as well as holodiastolic flow reversal in preterm neonates with and without a PDA. METHODS: A retrospective evaluation of neonates with and without PDA was performed. Targeted neonatal echocardiography evaluation of LA/Ao and LAV was measured from parasternal long-axis view and the apical 4 and 2-chamber views, respectively. Univariate and linear regression analysis were performed. RESULTS: 200 patients were included of whom 158 (79.0%) had a PDA shunt. The median gestational age at the time of echo was 27.4 weeks (IQR: 25.7-29.4 weeks). The median LA/Ao ratio was 1.51 (IQR: 1.26-1.83) and median LAV indexed to weight was  .91 mL/kg (IQR: .65-1.18 mL/kg). There was a significant correlation between LA/Ao and LAV indexed to weight in the PDA group (r2 = .080, p = .0003). LA/Ao ratio and LAV indexed to weight differed significantly between those with diastolic flow reversal versus no-flow reversal (LA/Ao, p = .003; LAV, p = .001). CONCLUSIONS: This study demonstrated a significant correlation between LA/Ao and LAV in preterm infants with PDA, with greater magnitude of discordance for LAV. The power of LAV versus LA/Ao in monitoring hemodynamically significant PDA requires prospective evaluation.

COVID-19 mRNA Vaccination Responses in Individuals With Sickle Cell Disease: ASH RC Sickle Cell Research Network Study.

Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The ASH Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether mRNA vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received two doses of the Pfizer-BioNTech vaccine and provided baseline blood samples prior to vaccination and 2 months after the initial vaccination for analysis of IgG reactivity against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Six month IgG reactivity against the viral RBD was also available in 37 patients. Post-vaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2-3 days of 1st or 2nd vaccination was reported by 5 (12%) participants including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 (34%) initially seronegative participants converted to seropositive post vaccination. Overall, mRNA vaccination had a good risk benefit-profile in individuals with sickle cell disease.This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with sickle cell disease. NCT05139992.