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Administrative claims databases often do not capture date or fact of death, so studies using these data may inappropriately treat death as a censoring event-equivalent to other withdrawal reasons-rather than a competing event. We examined 1-, 3-, and 5-year inverse-probability-of-treatment-weighted cumulative risks of a composite cardiovascular outcome among 34,527 initiators of telmisartan (exposure) and ramipril (referent) ages ≥55 in Optum claims from 2003 to 2020. Differences in cumulative risks of the cardiovascular endpoint due to censoring of death (cause-specific), as compared to treating death as a competing event (sub-distribution), increased with greater follow-up time and older age, where event and mortality risks were higher. Among ramipril users (selected results), 5-year cause-specific and sub-distribution cumulative risk estimates per 100, respectively, were 16.4 (95% CI 15.3, 17.5) and 16.2 (95% CI 15.1, 17.3) among ages 55-64 (difference=0.2) and were 43.2 (95% CI 41.3, 45.2) and 39.7 (95% CI 37.9, 41.4) among ages ≥75 (difference=3.6). Plasmode simulation results demonstrated the differences in cause-specific versus sub-distribution cumulative risks to increase with increasing mortality rate. We suggest researchers consider the cohort's baseline mortality risk when deciding whether real-world data with incomplete death information can be used without concern.
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Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer's disease (AD). The spreading of misfolded tau "seeds" along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the "ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein" (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.
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Doença de Alzheimer , Tauopatias , Camundongos , Humanos , Animais , Encéfalo/patologia , Proteínas tau/metabolismo , Tauopatias/patologia , Doença de Alzheimer/patologia , Neurônios/patologia , Camundongos Transgênicos , Mamíferos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
INTRODUCTION: Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown. METHODS: We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5,573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered "sequentially exposed"; those for whom neither contained IMiDs were "never exposed." RESULTS: For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history. CONCLUSION: Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.
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Background: Approximately 6% of people will report Achilles tendon pain during their lifetime, and one-third of these individuals will have Achilles insertional tendinopathy (AIT). For patients who have failed conservative treatment, surgical repair is performed. Achilles tendon repair can occur through various techniques, including a single-row or double-row repair. Purpose: To determine if there are significant advantages to double-row repair over single-row repair with respect to biomechanical and clinical outcomes. Study design: Systematic review; Level of evidence, 3. Methods: A systematic review of the literature was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. An electronic search of the EMBASE and PubMed databases was performed for all studies related to surgical treatment of AIT, which yielded 1431 unique results. These included both biomechanical and clinical studies. Clinical studies in which patients were not diagnosed with AIT, underwent surgery for repair of acute Achilles tendon rupture, or studies that included additional procedures such as a concomitant flexor hallucis longus transfer were excluded. Eligible studies were independently screened by 2 reviewers. A risk-of-bias assessment was conducted using the Cochrane Risk Of Bias In Non-randomized Studies-of Interventions and risk-of-bias tool for randomized trials tools. Results: A total of 23 studies were included, 4 of which were biomechanical studies and 19 were clinical studies. Biomechanical comparison found that there was a significant advantage to using double-row versus single-row fixation with respect to load at yield (354.7 N vs 198.7 N; P = .01) and mean peak load (433.9 N vs 212 N; P = .042). There was no significant difference between double-row and single-row repair with respect to load to failure. Significant heterogeneity of the studies did not allow for a statistical comparison of the clinical outcomes between double-row and single-row repairs. Conclusion: Although biomechanical studies favor double-row repair for AIT, the current data available on the clinical outcomes are not sufficient to determine if there is a clinical advantage of double-row repair. Larger, prospective randomized controlled trials utilizing validated outcome measures are needed to further elucidate whether the biomechanical advantages associated with double-row repair also translate into improved patient-reported outcomes.
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Purpose: Observational postapproval safety studies are needed to inform medication safety during pregnancy. Real-world databases can be valuable for supporting such research, but fitness for regulatory purpose must first be vetted. Here, we demonstrate a fit-for-purpose assessment of the Japan Medical Data Center (JMDC) claims database for pregnancy safety regulatory decision-making. Patients and Methods: The Duke-Margolis framework considers a database's fitness for regulatory purpose based on relevancy (capacity to answer the research question based on variable availability and a sufficiently sized, representative population) and quality (ability to validly answer the research question based on data completeness and accuracy). To assess these considerations, we examined descriptive characteristics of infants and pregnancies among females ages 12-55 years in the JMDC between January 2005 and March 2022. Results: For relevancy, we determined that critical data fields (maternal medications, infant major congenital malformations, covariates) are available. Family identification codes permitted linkage of 385,295 total mother-infant pairs, 57% of which were continuously enrolled during pregnancy. The prevalence of specific congenital malformation subcategories and maternal medical conditions were representative of the general population, but preterm births were below expectations (3.6% versus 5.6%) in this population. For quality, our methods are expected to accurately identify the complete set of mothers and infants with a shared health insurance plan. However, validity of gestational age information was limited given the high proportion (60%) of missing live birth delivery codes coupled with suppression of infant birth dates and inaccessibility of disease codes with gestational week information. Conclusion: The JMDC may be well suited for descriptive studies of pregnant people in Japan (eg, comorbidities, medication usage). More work is needed to identify a method to assign pregnancy onset and delivery dates so that in utero medication exposure windows can be defined more precisely as needed for many regulatory postapproval pregnancy safety studies.
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Despite theoretical benefits of collaborative robots, disappointing outcomes are well documented by clinical studies, spanning rehabilitation, prostheses, and surgery. Cognitive load theory provides a possible explanation for why humans in the real world are not realizing the benefits of collaborative robots: high cognitive loads may be impeding human performance. Measuring cognitive availability using an electrocardiogram, we ask 25 participants to complete a virtual-reality task alongside an invisible agent that determines optimal performance by iteratively updating the Bellman equation. Three robots assist by providing environmental information relevant to task performance. By enabling the robots to act more autonomously-managing more of their own behavior with fewer instructions from the human-here we show that robots can augment participants' cognitive availability and decision-making. The way in which robots describe and achieve their objective can improve the human's cognitive ability to reason about the task and contribute to human-robot collaboration outcomes. Augmenting human cognition provides a path to improve the efficacy of collaborative robots. By demonstrating how robots can improve human cognition, this work paves the way for improving the cognitive capabilities of first responders, manufacturing workers, surgeons, and other future users of collaborative autonomy systems.
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BACKGROUND AND OBJECTIVES: Arterial dissection during endovascular therapy rarely occurs but can be lethal. A fabric-based covered graft stents yield poor clinical outcomes. A novel balloon-expandable stent with biodegradable film graft for overcoming these issues was evaluated in a rabbit iliac artery model. METHOD: Eighteen rabbits with iliac artery dissections were induced by balloon over-inflation on angiography (Ellis type 2 or 3) and treated using the test device (3.0×24 mm). Subsequently, survived twelve animals underwent histologic examinations and micro-computed tomography (CT) at 0, 2, 4, and 8 weeks and 3, 6, 9, and 12 months and angiography at one-year. RESULTS: There were no adverse cardiovascular events during the one-year. Early-stage histologic examination revealed complete sealing of disrupted vessels by the device, exhibiting mural hematoma, peri-stent red thrombi, and dense infiltration of inflammatory cells. Mid- and long-term histologic examination showed patent stents with neointimal hyperplasia over the stents (% area stenosis: 11.8 at 2 weeks, 26.1 at 1 month, 29.7 at 3 months, 49.2 at 9 months, and 51.0 at 1 year), along with mild peri-strut inflammatory response (Grade: 1-2 at mid-term and 0-1 at long-term). The graft film became scarcely visible after six months. Both CT and angiography revealed no instances of thrombotic occlusion or in-stent restenosis (% diameter stenosis: 5.7 at 2 weeks, 12.3 at 1 month, 14.2 at 3 months, 25.1 at 9 months, and 26.6 at 1 year). CONCLUSIONS: The novel balloon-expandable stent with a biodegradable film graft demonstrates feasibility in managing severe artery dissection and preventing lethal vascular events in animal model.
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AIMS: It is unclear whether activated partial thromboplastin time (aPTT) or anti-Xa is more accurate for monitoring heparin anticoagulation in mechanical circulatory support (MCS) patients. This study investigates the relationship between aPTT and anti-Xa in MCS patients and identifies predictors of discordance. METHODS AND RESULTS: aPTT and anti-Xa were simultaneously measured in a prospective cohort of MCS patients receiving unfractionated heparin at a tertiary academic medical centre. Therapeutic aPTT and anti-Xa levels were 60-100 s and 0.3-0.7 IU/mL, respectively, and concordance was defined as both levels being subtherapeutic, therapeutic, or supratherapeutic. To identify predictors of discordance, both a machine learning random forest model and a multivariate regression model were applied to patient demographics, device type, and 14 laboratory variables; 23 001 pairs of simultaneously measured aPTT/anti-Xa were collected from 699 MCS patients. aPTT and anti-Xa were concordant in 35.5% of paired observations and discordant in 64.5% (aPTT > antiXa 61.5%; aPTT < antiXa 3.0%). Discordance with a high aPTT relative to anti-Xa (aPTT > antiXa) was associated with high INR, eGFR, and total bilirubin, as well as low platelets, haemoglobin, pre-albumin, white blood cell count, and haptoglobin. Total artificial heart and durable ventricular assist devices were more likely to be associated with aPTT > anti-Xa than temporary MCS devices. CONCLUSIONS: aPTT and anti-Xa were frequently discordant in MCS patients receiving heparin anticoagulation. Clinical conditions common in MCS patients such as concurrent warfarin use, malnutrition, haemolysis, and thrombocytopenia, as well as durable type of MCS devices were associated with a high aPTT relative to anti-Xa.
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Understanding the global epidemiology of AML is critical for assessing therapeutic demand and informing healthcare resource allocation. This study estimated current and future AML incidence in 27 countries, described AML survival trends in the United States, and calculated average years of life lost (AYLL). Incidence rates were age-standardized using rates from IARC's Cancer Incidence in Five Continents and SEER databases and ranged from 0.70 to 3.23 cases per 100,000 persons. Crude incidence rates were projected from 2024 to 2040; growth varied from +1% to +46%. Median overall survival was derived from SEER databases and increased from 4 to 11 months over the last 40 years. Median AYLL of 18.6 years was estimated for 27 countries. This study projected significant growth in new AML diagnoses over the next two decades. Despite improvements in survival over the last four decades, median survival among AML patients remains poor highlighting the need for novel treatments.
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Introduction: Research suggests that sacroiliac joint (SIJ) dysfunction is responsible for 15% to 30% of reported low back pain cases. Recently, there has been an increasing interest in SIJ fusion using minimally invasive surgery (MIS) due to safety. Initially, devices designed for MIS were intended for lateral approaches. A minimally invasive sacroiliac fusion implant for use with a posterior approach has been developed and is regulated for clinical use under the regulatory framework required for human cells, tissues, or cellular or tissue-based products (HCT/Ps). Methods: A multi-center, prospective, single-arm study was launched after initial studies provided preliminary data to support safety, efficacy, and durability of this minimally invasive sacroiliac posterior fusion LinQ allograft implant (NCT04423120). Preliminary results were reported previously. Final results for the full participant cohort are presented here. Results: One-hundred and fifty-nine (159) participants were enrolled across 16 investigational sites in the US between January 2020 and March 2022. One-hundred and twenty-two (122) participants were implanted. At the 1-month follow-up, 82 participants satisfied all criteria for the composite responder endpoint, representing 73.2% of the study cohort. These results stayed consistent across the remaining study timepoints with 66.0%, 74.4%, and 73.5% of participants classified as responders at the 3-, 6- and 12-month follow-up visits, respectively. VAS scores were significantly reduced (p < 0.0001) and ODI scores were significantly improved (p < 0.0001). All domains of the PROMIS-29 were also significantly improved (all p's <0.0001). Only one procedure-related serious AE was reported in the study. Conclusion: These results suggest that the posterior approach LinQ Implant System is a safe and effective treatment for sacroiliac joint dysfunction at 12 months, with results that are favorable compared to outcomes reported for an FDA-cleared lateral approach.
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INTRODUCTION: A novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements. METHODS: 41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain. RESULTS: The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively). CONCLUSION: The results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.