The "true" 1-year incidence of dislocation after primary total hip arthroplasty: validation of an algorithm identifying dislocations in the Danish National Patient Register based on 5,415 patients from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: Dislocations continue to be a serious complication after primary total hip arthroplasty (THA). Our primary aim was to report the "true" incidence of dislocations in Denmark and secondarily to validate a previously developed algorithm designed to identify THA dislocations in the updated version of the Danish National Patient Register (DNPR), based on data from the Danish Hip Arthroplasty Register (DHR). METHODS: We included 5,415 primary THAs from the DHR performed from July 1 to December 31, 2019. Version 3 of the DNPR was launched in February 2019, and a combination of data from the DNPR and a comprehensive national review of 1,762 hospital contacts enabled us to identify every dislocation occurring during the 1st year after THA to determine the "true" 1-year incidence of dislocation. The results were presented as proportions with 95% confidence intervals (CI), and validation was performed by calculating sensitivity and predictive values. RESULTS: The "true" 1-year incidence of dislocation was 2.8% (CI 2.4-3.3). Of these, 37% suffered recurrent dislocations during the follow-up period. Between-hospital variation ranged from 0.0% to 9.6%. The algorithm demonstrated a sensitivity close to 95%, while maintaining a positive predictive value of above 94%. CONCLUSION:  The "true" 1-year incidence of dislocation of 2.8% is comparable to earlier findings, and large variation among hospitals continues to be evident. We have proven the algorithm to be valid in the latest DNPR (version 3), enabling it to be employed as a new quality indicator in future annual DHR reports.

What is the optimal surgical approach for ductal adenocarcinoma of the pancreatic neck? - a retrospective cohort study.

BACKGROUND: The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS: Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS: Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION: While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.

Functionalized magnetic nanoparticles remove donor-specific antibodies (DSA) from patient blood in a first ex vivo proof of principle study.

The presence of donor-specific antibodies (DSA) such as antibodies directed against donor class I human leucocyte antigen (e.g., HLA-A) is a major barrier to kidney transplant success. As a proof of concept, functionalized magnetic nanoparticles have been designed to eliminate DSA from saline, blood and plasma of healthy donors and sensitized patients. Specific HLA-A1 protein was covalently bound to functionalized cobalt nanoparticles (fNP), human serum albumin (HSA) as control. fNP were added to anti-HLA class I-spiked saline, spiked volunteers' whole blood, and to whole blood and plasma of sensitized patients ex vivo. Anti-HLA-A1 antibody levels were determined with Luminex technology. Antibodies' median fluorescent intensity (MFI) was defined as the primary outcome. Furthermore, the impact of fNP treatment on blood coagulation and cellular uptake was determined. Treatment with fNP reduced MFI by 97 ± 2% and by 94 ± 4% (p < 0.001 and p = 0.001) in spiked saline and whole blood, respectively. In six known sensitized anti-HLA-A1 positive patients, a reduction of 65 ± 26% (p = 0.002) in plasma and 65 ± 33% (p = 0.012) in whole blood was achieved. No impact on coagulation was observed. A minimal number of nanoparticles was detected in peripheral mononuclear blood cells. The study demonstrates-in a first step-the feasibility of anti-HLA antibody removal using fNP. These pilot data might pave the way for a new personalized DSA removal technology in the future.

Cohesin composition and dosage independently affect early development in zebrafish.

Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed "cohesinopathies" are characterised by germline mutations in cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear if mutations in individual cohesin subunits have independent developmental consequences. Here we show that zebrafish rad21 or stag2b mutants independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygous rad21 mutation affects cell cycle gene expression. stag2b mutants have narrower notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single cell RNA-sequencing. Stimulation of Wnt signaling rescues transcription and morphology in stag2b, but not rad21 mutants. Our results suggest that mutations altering the quantity versus composition of cohesin have independent developmental consequences, with implications for the understanding and management of cohesinopathies.

TBP facilitates RNA Polymerase I transcription following mitosis.

The TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II and III). Although TBP is central to transcription by the three RNA Pols in various species, the emergence of TBP paralogs throughout evolution has expanded the complexity in transcription initiation. Furthermore, recent studies have emerged that questioned the centrality of TBP in mammalian cells, particularly in Pol II transcription, but the role of TBP and its paralogs in Pol I transcription remains to be re-evaluated. In this report, we show that in murine embryonic stem cells TBP localizes onto Pol I promoters, whereas the TBP paralog TRF2 only weakly associates to the Spacer Promoter of rDNA, suggesting that it may not be able to replace TBP for Pol I transcription. Importantly, acute TBP depletion does not fully disrupt Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.

Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study.

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. OBJECTIVES: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. METHODS: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB.

Staphylococcus aureus signal peptidase IB (SpsB) is an essential enzyme for protein secretion. While inhibition of its activity by small molecules is a well-precedented mechanism to kill bacteria, the mode of activation is however less understood. We here investigate the activation mechanism of a recently introduced activator, the antibiotic compound PK150, and demonstrate by combined experimental and Molecular Dynamics (MD) simulation studies a unique principle of enzyme stimulation. Mass spectrometric studies with an affinity-based probe of PK150 unravel the binding site of PK150 in SpsB which is used as a starting point for MD simulations. Our model shows the localization of the molecule in an allosteric pocket next to the active site which shields the catalytic dyad from excess water that destabilizes the catalytic geometry. This mechanism is validated by the placement of mutations aligning the binding pocket of PK150. While the mutants retain turnover of the SpsB substrate, no stimulation of activity is observed upon PK150 addition. Overall, our study elucidates a previously little investigated mechanism of enzyme activation and serves as a starting point for the development of future enzyme activators.

Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients.

INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.

EEG subject-dependent neurofeedback training selectively impairs declarative memories consolidation process.

The process of stabilization and storage of memories, known as consolidation, can be modulated by different interventions. Research has shown that self-regulation of brain activity through Neurofeedback (NFB) during the consolidation phase significantly impacts memory stabilization. While some studies have successfully modulated the consolidation phase using traditional EEG-based Neurofeedback (NFB) that focuses on general parameters, such as training a specific frequency band at particular electrodes, they often overlook the unique and complex neurodynamics that underlie each memory content in different individuals, potentially limiting the selective modulation of memories. The main objective of this study is to investigate the effects of a Subject-Dependent NFB (SD-NFB), based on individual models created from the brain activity of each participant, on long-term declarative memories. Participants underwent an experimental protocol involving three sessions. In the first session, they learned images of faces and houses while their brain activity was recorded. This EEG data was used to create individualized models to identify brain patterns related to learning these images. Participants were then divided into three groups, with one group receiving SD-NFB to enhance brain activity linked to faces, another to houses, and a CONTROL SHAM group that did not receive SD-NFB. Memory performance was evaluated 24 h and seven days later using an 'old-new' recognition task, where participants distinguished between 'old' and 'new' images. The results showed that memory contents (faces or houses) whose brain patterns were trained via SD-NFB scored lower in recognition compared to untrained contents, as evidenced 24 h and seven days post-training. In summary, this study demonstrates that SD-NFB can selectively impact the consolidation of specific declarative memories. This technique could hold significant implications for clinical applications, potentially aiding in the modulation of declarative memory strength in neuropsychiatric disorders where memories are pathologically exacerbated.

Tobacco Cessation Interventions in Non-Respiratory Cancers: A Systematic Review With Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Considering the high rates of persistent tobacco use, effective cessation interventions are needed for cancer patients and caregivers. Despite the need, there is a significant lack of research on tobacco cessation, especially for non-respiratory cancers (breast, prostate, colorectal, cervical, and bladder cancer). PURPOSE: The objective was to evaluate tobacco use and tobacco cessation interventions among patients and caregivers for non-respiratory cancers. METHODS: Randomized controlled trials assessing tobacco cessation interventions were identified. Five electronic databases were searched in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines through July 2023. Studies exclusive to lung, oral, thoracic, and head and neck cancers were excluded. Effect sizes were estimated; risk of bias was assessed. RESULTS: Of 3,304 studies, 17 were included. Interventions included behavioral (n = 6), pharmacotherapy (n = 2), and a combination (n = 9) treatment. Eight studies included a health behavior model; mean behavioral change techniques were 5.57. Pooled magnitude of the odds of cessation was positive and significant (odds ratio = 1.24, 95% confidence interval [Lower Limit 1.02, Upper Limit 1.51]) relative to usual care/placebo. Cumulative meta-analysis examined the accumulation of results over-time and demonstrated that studies have been significant since 2020. Two studies included caregivers' who were involved in the provision of social support. CONCLUSIONS: Current interventions have the potential to reduce tobacco use in non-respiratory cancers. Results may be beneficial for promoting tobacco cessation among non-respiratory cancers. There is a considerable lack of dyadic interventions for cancer survivors and caregivers; researchers are encouraged to explore dyadic approaches.

We aimed to understand effective ways for cancer patients and caregivers to quit using tobacco. We focused on non-respiratory cancers (cancers not related to breathing issues) like breast, prostate, and colorectal cancer. We reviewed 17 randomized controlled trials designed to help people quit tobacco, which included behavioral therapies (e.g., education and counseling), pharmacotherapy (i.e., medicine), and combinations of both. We found that people in these studies quit using tobacco, especially when more than one approach was used. The studies also showed that these approaches have been more successful since 2020. The research highlighted a need for more studies that include both patients and their caregivers together in the quitting process. This approach, called dyadic intervention, could be more effective in supporting patients and their caregivers. Overall, while the current approaches are promising, more research is needed to develop better ways to help cancer patients and caregivers quit smoking for longer.

Improving postsurgical fall detection for older Americans using LLM-driven analysis of clinical narratives.

Postsurgical falls have significant patient and societal implications but remain challenging to identify and track. Detecting postsurgical falls is crucial to improve patient care for older adults and reduce healthcare costs. Large language models (LLMs) offer a promising solution for reliable and automated fall detection using unstructured data in clinical notes. We tested several LLM prompting approaches to postsurgical fall detection in two different healthcare systems with three open-source LLMs. The Mixtral-8×7B zero-shot had the best performance at Stanford Health Care (PPV = 0.81, recall = 0.67) and the Veterans Health Administration (PPV = 0.93, recall = 0.94). These results demonstrate that LLMs can detect falls with little to no guidance and lay groundwork for applications of LLMs in fall prediction and prevention across many different settings.

Skeletal effects of sleeve gastrectomy, by sex and menopausal status and in comparison to Roux-en-Y gastric bypass surgery.

Context: Roux-en-Y gastric bypass (RYGB) has deleterious effects on bone mass, microarchitecture, and strength. Data are lacking on the skeletal effects of sleeve gastrectomy (SG), now the most commonly performed bariatric surgical procedure. Objective: We examined changes in bone turnover, areal and volumetric bone mineral density (aBMD, vBMD), and appendicular bone microarchitecture and estimated strength after SG. We compared the results to those previously reported after RYGB, hypothesizing lesser effects after SG than RYGB. Design Setting Participants: Prospective observational cohort study of 54 adults with obesity undergoing SG at an academic center. Main Outcome Measures: Skeletal characterization with biochemical markers of bone turnover, dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) was performed preoperatively and 6- and 12-months postoperatively. Results: Over 12 months, mean percentage weight loss was 28.8%. Bone turnover marker levels increased, and total hip aBMD decreased -8.0% (95% CI -9.1%, -6.7%, p<0.01). Spinal aBMD and vBMD declines were larger in postmenopausal women than men. Tibial and radial trabecular and cortical microstructure worsened, as did tibial estimated strength, particularly in postmenopausal women. When compared to data from a RYGB cohort with identical design and measurements, some SG biochemical, vBMD, and radial microstructural parameters were smaller, while other changes were not. Conclusions: Bone mass, microstructure, and strength decrease after SG. Some skeletal parameters change less after SG than after RYGB, while for others, we find no evidence for smaller effects after SG. Postmenopausal women may be at highest risk of skeletal consequences after SG.

A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist.

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1-11)-NH2) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure-activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide's affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [35S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (Ki = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [35S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.

Variability in the Timing of Respiratory Syncytial Virus Epidemics in Guatemala, 2008-2018.

BACKGROUND: The description of local seasonality patterns in respiratory syncytial virus (RSV) incidence is important to guide the timing of administration of RSV immunization products. METHODS: We characterized RSV seasonality in Guatemala using the moving epidemic method (MEM) with absolute counts of RSV-associated acute respiratory infections (ARI) from hospital surveillance in Santa Rosa and Quetzaltenango departments of Guatemala. RESULTS: From Week 17 of 2008 through Week 16 of 2018, 8487 ARI cases tested positive for RSV by rRT-PCR. Season onsets varied up to 5 months; early seasons starting in late May to early August and finishing in September to November were most common, but late seasons starting in October to November and finishing in March to April were also observed. Both epidemic patterns had similar durations ranging from 4 to 6 months. Epidemic thresholds (the levels of virus activity that signal the onset and end of a seasonal epidemic) calculated prospectively using previous seasons' data captured between 70% and 99% of annual RSV detections. Onset weeks differed by 2-10 weeks, and offset weeks differed by 2-16 weeks between the two surveillance sites. CONCLUSIONS: Variability in the timing of seasonal RSV epidemics in Guatemala demonstrates the difficulty in precisely predicting the timing of seasonal RSV epidemics based on onset weeks from past seasons and suggests that maximal reduction in RSV disease burden would be achieved through year-round vaccination and immunoprophylaxis administration to at-risk infants.

Access to expensive therapies and diagnostics for kidney care in Switzerland.

BACKGROUND: In Switzerland, nephrologists must frequently obtain pre-authorizations from health insurers for certain medications/tests for individual patients. These are time consuming and outcomes are inconsistent. Clinical experience suggest inequities in access to expensive medications, related to need for and processes involved with medication pre-authorization requests. METHODS: An anonymous survey was conducted between November 2021 and March 2022 regarding experiences in applying for pre-authorizations for medications and genetic testing required for kidney care conducted among nephrologists in Switzerland. RESULTS: Ninety-four responses were received. The most common medications reported to require pre-approvals were rituximab, sodium glucose cotransporter-2 inhibitors (SGLT2i), mycophenolate mofetil (MMF) and eculizumab. Rebuttals were reported to be most frequently required for rituximab, eculizumab and SGLT2i, also the most frequently denied medications. Most frequent genetic testing requests were for complement and Alports spectrum disorders. Requests for genetic testing were reported to be most frequently denied for cystic renal diseases, congenital syndromes and nephrotic syndrome.Most nephrologists found requests for further information from the health insurers were seldom reasonable; 72% reported it was rarely/never possible to engage with the insurance physicians, 69% were concerned insurance physicians did not have relevant expertise. Respondents reported receiving different responses from different insurers for similar requests more frequently than from the same insurer (58% vs 8%). One in three nephrologists reported that the pre-authorizations process frequently resulted in a clinically relevant delay in treatment. Four of five respondents reported that the pre-authorization process frequently made them feel that they could not do their best for the patient. CONCLUSION: From the perspective of nephrologists, the pre-authorizations process in Switzerland is cumbersome, not transparent and inequitable, may result in denial or delays of important treatment for patients and contributes to moral distress.

Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet reactivity.

INTRODUCTION: Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. METHODS: Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. RESULTS: LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. CONCLUSIONS: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.