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BACKGROUND: The 2018 American Association of Hip and Knee Surgeons clinical practice guideline (CPG) 'Tranexamic Acid Use in Total Joint Arthroplasty' evaluated the efficacy and safety of tranexamic acid in primary total joint arthroplasty. The following review assessed the statistical fragility of the randomized controlled trial (RCT) outcomes on which the CPG recommendations were based using a fragility analysis. METHODS: All dichotomous outcomes from the randomized controlled trials used to guide the CPG from its associated network and direct meta-analyses were analyzed. Fragility and reverse fragility indices (FI and rFI) and quotients (FQ and rFQ) were calculated for each outcome. Mean indices and quotients were calculated for each guideline question, outcome category, and comparison of tranexamic dose, formulation, and administration timing. RESULTS: This review evaluated 403 dichotomous outcomes on transfusion and complication rates associated with tranexamic acid (TXA) administration. The mean FI of significant outcomes of the CPG was 5.23, and the mean rFI of nonsignificant outcomes was 5.80. Outcomes assessing complication rates had a mean rFI of 6.48. Most outcomes on transfusion in categories comparing TXA to placebo administration had higher mean FIs than rFIs, and all outcomes comparing transfusion risk associated with different TXA formulations and doses had higher mean rFIs than FI or no associated significant outcomes. CONCLUSION: The rFI and FIs calculated for this CPG are comparable to or higher than mean values reported across orthopaedic literature, indicating the relative statistical stability of its included outcomes. As we learn more about fragility analyses and their potential applications, this type of statistical analysis shows promise as a useful tool to incorporate into future guidelines to assess the quality of RCTs and evaluate the strength of recommendations.

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It is shown that under certain conditions the iterative method suggested by the calculus of variations for calculating a cylindrically symmetric orientation distribution function (ODF) for rodlike particles strictly decreases the free energy at each full step. This monotonic behavior has strong implications for convergence of the sequence, or a subsequence, of the calculated ODFs. The result is valid not only for the reference system of hard core particles with indistinguishable ends, but also for free energy functions of similar type. The effect of an applied field is also permitted. Since the behavior of the iteration is intrinsic to the general form of the free energy function it applies to rod mixtures and may extend to a wider class of free energy functions. Outside the conditions that guarantee a monotonically decreasing free energy, we find that the iteration can fail to converge.

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NASA's space life sciences research programs established a decades-long legacy of enhancing our ability to safely explore the cosmos. From Skylab and the Space Shuttle Program to the NASA Balloon Program and the International Space Station National Lab, these programs generated priceless data that continue to paint a vibrant picture of life in space. These data are available to the scientific community in various data repositories, including the NASA Ames Life Sciences Data Archive (ALSDA) and NASA GeneLab. Here we recognize the 30-year anniversary of data access through ALSDA and the 10-year anniversary of GeneLab.

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Genome sequencing for agriculturally important Rosaceous crops has made rapid progress both in completeness and annotation quality. Whole genome sequence and annotation gives breeders, researchers, and growers information about cultivar specific traits such as fruit quality and disease resistance, and informs strategies to enhance postharvest storage. Here we present a haplotype-phased, chromosomal level genome of Malus domestica, 'WA 38', a new apple cultivar released to market in 2017 as Cosmic Crisp®. Using both short and long read sequencing data with a k-mer based approach, chromosomes originating from each parent were assembled and segregated. This is the first pome fruit genome fully phased into parental haplotypes in which chromosomes from each parent are identified and separated into their unique, respective haplomes. The two haplome assemblies, 'Honeycrisp' originated HapA and 'Enterprise' originated HapB, are about 650 Megabases each, and both have a BUSCO score of 98.7% complete. A total of 53,028 and 54,235 genes were annotated from HapA and HapB, respectively. Additionally, we provide genome-scale comparisons to 'Gala', 'Honeycrisp', and other relevant cultivars highlighting major differences in genome structure and gene family circumscription. This assembly and annotation was done in collaboration with the American Campus Tree Genomes project that includes 'WA 38' (Washington State University), 'd'Anjou' pear (Auburn University), and many more. To ensure transparency, reproducibility, and applicability for any genome project, our genome assembly and annotation workflow is recorded in detail and shared under a public GitLab repository. All software is containerized, offering a simple implementation of the workflow.

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Confocal reflectance imaging typically suffers from high background and poor sensitivity. We demonstrate sensitive and low-background reflectance imaging of cells encapsulated in transparent 3D hydrogels. Nanoscale cell morphology is visualized with sensitivity similar to confocal fluorescence, with low laser power, minimal specimen preparation, and reduced toxicity.

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Performing pattern recognition via correlation in the optical domain has potential advantages, including: (i) high-speed operation at the line rate and (ii) tunability and scalability by operating on the optical wave properties. Such pattern recognition might be performed on quadrature-phase-shift-keying (QPSK) data transmitted over an optical network, which generally requires using coherent detection to distinguish the phase levels of the correlator output. To enable simpler detection, we combine optical correlation with optical biasing to experimentally demonstrate tunable and scalable QPSK pattern recognition using direct detection. The pattern is applied by adjusting the relative phases of the local pumps. Delayed QPSK signals, a coherent bias tone, and local pumps undergo nonlinear wave-mixing in a periodically poled lithium niobate (PPLN) waveguide to perform optical correlation and biasing. The biased correlator output is captured using direct detection, where the highest power level corresponds only to the pattern. Multiple QPSK pattern recognitions are achieved error-free over 3072 symbols using power thresholding values of (i) 0.78 at a 5-Gbaud rate and 0.73 at a 10-Gbaud rate for 2-symbol pattern recognition and (ii) 0.81 at a 5-Gbaud rate and 0.79 at a 10-Gbaud rate for 3-symbol pattern recognition.

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Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

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In this paper, we experimentally demonstrate an 8-Gbit/s quadrature-phase-shift-keying (QPSK) coherent underwater wireless optical communication (UWOC) link under scattering conditions at 532 nm. At the transmitter, we generate the 532-nm QPSK signal using second-harmonic generation (SHG), where the 1064-nm signal modulated with four phase levels of an 8-phase-shift-keying (8-PSK) format is phase doubled to produce the 532-nm QPSK signal. To enhance the receiver sensitivity, we utilize a local oscillator (LO) at the receiver from an independent laser source. The received QPSK data beam is mixed with the independent LO for coherent heterodyne detection. Results show that the bit error rates (BERs) of the received QPSK signal can reach below the 7% forward error correction (FEC) limit under turbid water with attenuation lengths (γL) up to 7.4 and 6.1 for 2- and 8-Gbit/s QPSK, respectively. The corresponding receiver sensitivities are -34.0 and -28.4 dBm for 2- and 8-Gbit/s QPSK, respectively.

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Coifman and Gunstad (2024) raise cogent points about childhood and adolescence as a place to begin to help close the mental health treatment gap, note the potential of applications (apps) as a modality of intervention given the pervasiveness of smartphones, and highlight a large-scale intervention study to convey that treatments can be scaled in outcome research. I expand the range of interventions we might consider, pose a best-buy approach to decide how and where to begin to address the treatment gap, and underscore that mental health problems in children, adolescents, and adults are on the rise. We still have no evidence that we can close the treatment gap and that to do so will require a marriage of multiple disciplines, interventions, and agencies to effect change. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

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Platelet factor (F)XIII-A is a major cytoplasmic protein (~3% of total) representing ~50% of total circulating FXIII. However, mobilization of FXIII-A during platelet activation is not well defined. To determine mechanisms mediating the retention versus release of platelet FXIII-A, platelets from healthy humans and mice (F13a1-/-, Fga-/-, Plg-/-, Stim1fl/fl, Pf4-Cre and respective controls) were stimulated with thrombin, convulxin+thrombin, or calcium ionophore (A23187), in the absence or presence of inhibitors of transglutaminase activity, mRNA translation, microtubule rearrangement, calpain, and Rho GTPase. Platelet releasates and pellets were separated by (ultra)centrifugation. FXIII-A was detected by immunoblotting and immunofluorescence microscopy. Even following strong dual agonist (convulxin+thrombin) stimulation of human platelets, >80% platelet FXIII-A remained associated with the platelet pellet. In contrast, essentially all tissue factor pathway inhibitor, another cytoplasmic protein in platelets, was released to the supernatant. Pellet-associated FXIII-A was not due to de novo synthesis via platelet F13A1 mRNA. The proportion of platelet FXIII-A retained by, versus released from, activated platelets was partly dependent on STIM1 signaling, microtubule rearrangement, calpain, and RhoA activation, but did not depend on the presence of fibrinogen or plasminogen. Immunofluorescence microscopy confirmed the presence of considerable FXIII-A within the activated platelets. Whereas released FXIII-A was cleaved to FXIII-A* and could be degraded by plasmin, platelet-associated FXIII-A remained uncleaved. Retention of substantial platelet-derived FXIII-A by activated platelets, and its reduced susceptibility to thrombin- and plasmin-mediated proteolysis, suggests platelet FXIII-A is a protected pool with biological role(s) that differs from plasma FXIII.

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While DNA ligase I (LigI) joins most Okazaki fragments, a backup pathway involving poly(ADP-ribose) synthesis, XRCC1 and DNA ligase IIIα (LigIIIα) functions along with the LigI-dependent pathway and is also capable of supporting DNA replication in the absence of LigI. Here we have addressed for the first time the roles of PARP1 and PARP2 in this pathway using isogenic null derivatives of mouse CH12F3 cells. While single and double null mutants of the parental cell line and single mutants of LIG1 null cells were viable, loss of both PARP1 and PARP2 was synthetically lethal with LigI deficiency. Thus, PARP1 and PARP2 have a redundant essential role in LigI-deficient cells. Interestingly, higher levels of PARP2 but not PARP1 associated with newly synthesized DNA in the LIG1 null cells and there was a much higher increase in PARP2 chromatin retention in LIG1 null cells incubated with the PARP inhibitor olaparib with this effect occurring independently of PARP1. Together our results suggest that PARP2 plays a major role in specific cell types that are more dependent upon the backup pathway to complete DNA replication and that PARP2 retention at unligated Okazaki fragments likely contributes to the side effects of current clinical PARP inhibitors.

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Importance: Infants with neonatal opioid withdrawal syndrome (NOWS) cared for with the Eat, Sleep, Console (ESC) care approach receive less pharmacologic treatment and have shorter hospital stays compared to usual care with the Finnegan Neonatal Abstinence Scoring Tool, but the effects of these approaches on feeding and weight are unknown. Objective: To evaluate feeding practices and weight trajectories in infants cared for with ESC vs usual care. Design, Setting, and Participants: ESC-NOW is a cluster randomized trial of infants with NOWS born at 36 weeks' gestation or later at 26 US hospitals from September 2020 to March 2022. Each site transitioned from usual care to ESC (the study intervention) at a randomized time. Feeding was per site practice and not specified by the intervention. Feeding and weight outcomes were assessed at hospital discharge. Intervention: ESC vs usual care. Main Outcomes and Measures: Outcomes include prospectively identified secondary end points related to feeding and weight. z Scores were used for growth to account for corrected gestational age at the time of measurement. All analyses were intention to treat and adjusted for study design. Maternal/infant characteristics were included in adjusted models. Results: The analyses included 1305 infants (702 in usual care and 603 in ESC; mean [SD] gestational age, 38.6 [1.3] weeks; 655 [50.2%] male and 650 [49.8%] female). Baseline demographic characteristics were similar between groups. The proportion of breastfed infants was higher in the ESC group (52.7% vs 41.7%; absolute difference, 11%; 95% CI, 1.0-20.9). A higher proportion of infants cared for with ESC received exclusive breast milk (15.1% vs 6.7%; absolute difference, 8.4%; 95% CI, 0.9-5.8) or any breast milk (38.8% vs 27.4%; absolute difference, 11.4%; 95% CI, 0.2-23.1) and were directly breastfeeding at discharge (35.2% vs 19.5%; absolute difference, 15.7%; 95% CI, 4.1-27.3). There was no difference in proportion of infants with weight loss greater than 10% or maximum percentage weight loss, although infants cared for with ESC had a lower weight z score on day of life 3 (-1.08 vs -1.01; absolute difference, 0.07; 95% CI, 0.02-0.12). When pharmacologic treatment was added into the model, no breastfeeding outcomes were statistically significant. Conclusions and Relevance: In this study, infants cared for with ESC were more likely to initiate and continue breastfeeding and had no difference in percentage weight loss. The improvement in breastfeeding with ESC may be driven by reduction in pharmacologic treatment and provision of effective nonpharmacologic care. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

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Compared to its electronic counterpart, optically performed matrix convolution can accommodate phase-encoded data at high rates while avoiding optical-to-electronic-to-optical (OEO) conversions. We experimentally demonstrate a reconfigurable matrix convolution of quadrature phase-shift keying (QPSK)-encoded input data. The two-dimensional (2-D) input data is serialized, and its time-shifted replicas are generated. This 2-D data is convolved with a 1-D kernel with coefficients, which are applied by adjusting the relative phase and amplitude of the kernel pumps. Time-shifted data replicas (TSDRs) and kernel pumps are coherently mixed using nonlinear wave mixing in a periodically poled lithium niobate (PPLN) waveguide. To show the tunability and reconfigurability of this approach, we vary the kernel coefficients, kernel sizes (e.g., 2 × 1 or 3 × 1), and input data rates (e.g., 6-20 Gbit/s). The convolution results are verified to be error-free under an applied: (a) 2 × 1 kernel, resulting in a 16-quadrature amplitude modulation (QAM) output with an error vector magnitude (EVM) of ∼5.1-8.5%; and (b) 3 × 1 kernel, resulting in a 64-QAM output with an EVM of ∼4.9-5.5%.

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This meta-analysis review undertakes a comprehensive examination of various approaches for identifying myopathic fillets and meticulously evaluates the effects of bird age, deboning time, and different cooking and storage conditions on woody breast (WB) myopathic conditions in broiler deboned fillets. The data, meticulously collected from 20 articles based on predefined inclusion criteria sourced from various databases and online resources, reveal significant insights. For instance, the analysis uncovers that deboning time significantly affects Meullenet-Owens Razor Shear (MORS), Blunt Meullenet-Owens Razor Shear (BMORS), and descriptive analysis values (p < 0.001). Instrumentation techniques, such as compression force and shear force, along with different cooking conditions, strongly impact BMORS shear force values (R2 = 86.80%), with significance levels ranging from 0.01 to 0.001. Deboning time also substantially impacts MORS shear force values (R = 64.03%). In contrast, the effects of deboning time, bird age, and cooking conditions on descriptive sensory evaluation are minimal when compared to woody breast fillets (age of birds: R2 = 26.53%; cooking conditions: R2 = 32.57%; deboning time: R2 = 10.06%). The overall effect of bird age on chicken breast meat quality shows significant differences for the evaluated parameters (Hedges' g [95% CI] = -0.72 [0.17, 1.26], I2 = 93%, p < 0.01). The sous vide cooking method significantly affects shear force energies and sensory descriptive evaluation for woody breast fillets (Hedges' g [95% CI] = 5.30 [-50.30, 83.40], I2 = 98%, p < 0.01). These findings, with their significant implications, provide valuable insights for optimizing processing conditions in the poultry industry to reduce woody breast occurrences and enhance meat quality, instilling confidence in the robustness of the research.

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OBJECTIVE: The Multidimensional Assessment of Interoceptive Awareness, version 2 (MAIA-2) is a commonly utilized self-report instrument to assess individuals' ability to perceive bodily sensations. The MAIA-2 has displayed variable psychometric properties across samples. Thus, we examine the psychometric properties of the MAIA-2 in a Southeastern United States college sample. PARTICIPANTS: Our studies consisted of 710 (study 1) and 66 (study 2) college students. METHODS: Study 1 used a cross-sectional research design where we investigated the factor structure, and measurement invariance (e.g., measured similarly across genders). Study 2 examined the test-retest reliability across a three-week period. RESULTS: The MAIA-2 displayed adequate to good internal consistencies and factor loadings, strict invariance, and questionable temporal stability. CONCLUSION: The MAIA-2 demonstrates adequate psychometric properties in this college sample that were similar to the original MAIA sample characteristics. Contextual and cultural factors may influence the subjective experience of interpreting bodily sensations.

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BACKGROUND: Postacute sequelae of COVID-19 (PASC), also known as long COVID, is a broad grouping of a range of long-term symptoms following acute COVID-19. These symptoms can occur across a range of biological systems, leading to challenges in determining risk factors for PASC and the causal etiology of this disorder. An understanding of characteristics that are predictive of future PASC is valuable, as this can inform the identification of high-risk individuals and future preventative efforts. However, current knowledge regarding PASC risk factors is limited. OBJECTIVE: Using a sample of 55,257 patients (at a ratio of 1 patient with PASC to 4 matched controls) from the National COVID Cohort Collaborative, as part of the National Institutes of Health Long COVID Computational Challenge, we sought to predict individual risk of PASC diagnosis from a curated set of clinically informed covariates. The National COVID Cohort Collaborative includes electronic health records for more than 22 million patients from 84 sites across the United States. METHODS: We predicted individual PASC status, given covariate information, using Super Learner (an ensemble machine learning algorithm also known as stacking) to learn the optimal combination of gradient boosting and random forest algorithms to maximize the area under the receiver operator curve. We evaluated variable importance (Shapley values) based on 3 levels: individual features, temporal windows, and clinical domains. We externally validated these findings using a holdout set of randomly selected study sites. RESULTS: We were able to predict individual PASC diagnoses accurately (area under the curve 0.874). The individual features of the length of observation period, number of health care interactions during acute COVID-19, and viral lower respiratory infection were the most predictive of subsequent PASC diagnosis. Temporally, we found that baseline characteristics were the most predictive of future PASC diagnosis, compared with characteristics immediately before, during, or after acute COVID-19. We found that the clinical domains of health care use, demographics or anthropometry, and respiratory factors were the most predictive of PASC diagnosis. CONCLUSIONS: The methods outlined here provide an open-source, applied example of using Super Learner to predict PASC status using electronic health record data, which can be replicated across a variety of settings. Across individual predictors and clinical domains, we consistently found that factors related to health care use were the strongest predictors of PASC diagnosis. This indicates that any observational studies using PASC diagnosis as a primary outcome must rigorously account for heterogeneous health care use. Our temporal findings support the hypothesis that clinicians may be able to accurately assess the risk of PASC in patients before acute COVID-19 diagnosis, which could improve early interventions and preventive care. Our findings also highlight the importance of respiratory characteristics in PASC risk assessment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1101/2023.07.27.23293272.

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BACKGROUND CONTEXT: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH. PURPOSE: The Discover 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH. STUDY DESIGN/SETTING: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States. PATIENT SAMPLE: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks. OUTCOME MEASURES: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings. METHODS: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery. RESULTS: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred. CONCLUSIONS: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.

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BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.

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When an initial antiretroviral therapy (ART) regimen is effective and well-tolerated, it can be maintained for years as long as the patient adheres. Prior research has revealed that shorter initial ART duration is associated with regimen type, female sex, injection drug use as the HIV transmission category, and lower baseline CD4 count. We examined potential factors associated with initial regimen discontinuation among a subset of newly diagnosed virally unsuppressed PWH in the DC Cohort, an ongoing prospective observation study that uses electronic health record data from clinic sites to collect relevant information, including demographic and clinical information. Participants were excluded from the analysis if they had less than 6 months of follow-up and were virally suppressed at enrollment. There were 479 individuals included in the study. The median age of participants was 33.9 years [interquartile range (IQR) 26-43.9]. The sample was predominantly male (79.1%) and of Black race (70.8%). Over half of the study participants (56.4%) attended community-based clinic sites. The median time to the discontinuation of initial ART was 2.7 years [95% confidence interval (CI): 2.3, 3.4]. Females had a shorter time to ART discontinuation [adjusted hazard ratio (aHR) 1.55, 95% CI: 1.14, 2.11] as did individuals who started on a protease inhibitor-based regimen versus integrase strand transfer inhibitors (aHR 1.87, 95% CI: 1.34, 2.61) and those receiving HIV care at a community-based site (aHR 1.46, 95% CI: 1.11,1.93). Although limited by lack of reason for discontinuation, we demonstrated that ART-naïve women, community clinic attendees, and patients starting on PIs had a shorter duration of initial ART. More anticipatory guidance may be needed to help patients stay on their initial therapy and manage the side effects or to be flexible in trying different regimens.