Citations

AbstractBackgroundSleep’s crucial role in maintaining brain health is increasingly recognized, particularly due to the rising prevalence of neurodegenerative diseases. It not only supports cognitive function but also aids in clearing brain metabolic waste through cerebrospinal fluid (CSF) dynamics. During sleep, especially in the non‐rapid eye movement (NREM) phase, CSF flow increases, essential for removing neurotoxic substances like amyloid‐beta proteins. This study explores the link between sleep respiratory patterns and CSF flow promotion.MethodElectroencephalography (EEG), and functional magnetic resonance imaging (fMRI) were simultaneously acquired during sleep from Gu, et al. (n = 29) (Gu et al. 2022). Respiration, measured via a respiratory belt, calculated respiratory volume (RV) as the standard deviation within a 5 second sliding window. EEG data processed delta band power (1‐4Hz) averaged across channels. Parcellated fMRI data using the brain template followed by the calculation of the averaged gray matter (GM) blood‐oxygen‐level‐dependent (BOLD) signal using the GM mask. CSF inflow was manually extracted from the fMRI’s bottom slice at the foramen magnum level. Subsequently, all signals were temporally aligned to the peak of the CSF inflow signal.ResultAt the time of CSF inflow (time = 0 sec. in the Figure 1A‐D), we observed an earlier increase in RV and EEG delta power, followed by changes in the GM BOLD signal (Figure 1). EEG and RV changes preceded the BOLD signal changes, which, in turn, preceded changes in CSF flow. Sensitivity to detect RV involvement during MRI varied with the placement of the respiratory belt, being least sensitive on the chest and more on the abdomen.ConclusionThese findings raise an interesting question on the role respiratory patterns during sleep, particularly in the NREM phase. Speculatively, RV change may influence CSF circulation during NREM sleep (Figure 1E). This enhancement in CSF flow is crucial for the clearance of metabolic waste from the brain, potentially reducing the risk of neurodegenerative diseases. Our findings indicate that respiratory volume may serve as a significant marker for CSF circulation during sleep.

ABSTRACT Hypoxic stress responses are essential for cellular and organismal survival and drive gene regulation across diverse biological pathways, including cell cycle progression and energy metabolism. Here, we show that topoisomerase IIβ (TOP2B) regulates DNA topology and transcription of hypoxia-inducible genes (HIGs) in a DNA-dependent protein kinase (DNA-PK)-dependent manner. Integrated cellular, biochemical, and genomic analyses reveal an antagonistic yet correlated relationship between TOP2B and DNA-PK activities. Under normoxic conditions, TOP2B associates with HIGs and represses transcription by suppressing DNA negative supercoiling formation and accessibility. Under hypoxic exposure, TOP2B dissociates from HIGs, while DNA-PK and HIF1α are recruited to activate HIGs. Notably, DNA-PK is required for the repressive function of TOP2B, as DNA-PK knockout abrogates TOP2B release and activity, resulting in elevated expression of a number of HIGs. Mechanistically, DNA-PK phosphorylates TOP2B at T1403, stimulating its catalytic activity to restrain DNA unwinding and accessibility, thereby suppressing HIG transcription. Collectively, these findings identify a novel role for TOP2B and DNA-PK-mediated regulation of TOP2B as key transcriptional regulators of HIG expression. We propose that phosphorylation-dependent modulation of TOP2B activity is coordinated with transcriptional states and determines DNA topology to regulate Pol II transcription.

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neuropathologically‐defined disease, and it is frequently comorbid with Alzheimer’s disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE‐NC) is not defined. We propose a set of clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE‐NC. These criteria assess degree of certainty (highest, high, moderate, low) based on features that are measurable in vivo, including older age at evaluation, a mild clinical syndrome, impaired semantic knowledge, disproportionate hippocampal atrophy, limbic hypometabolism, absence of neocortical degeneration patterns and low likelihood of neocortical tau. We operationalized these criteria using two large datasets with clinical and pathologic outcomes.MethodWe screened autopsied patients from Mayo Clinic and ADNI cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). We compared frequencies of neuropathological diagnoses across LANS likelihoods, compared longitudinal CDR‐SB trajectories across LANS likelihoods, and stratified ADNC/LATE‐NC patients according to their LANS likelihood and compared their longitudinal CDR‐SB trajectories to those with ADNC or LATE‐NC.ResultADNC, ADNC/LATE‐NC and LATE‐NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively (Fig. 1). ADNC cases had the lowest LANS likelihoods, LATE‐NC patients had the highest likelihoods, and ADNC/LATE‐NC patients had intermediate likelihoods. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo‐limbic degeneration compared to those with low likelihoods (Fig. 2). ADNC/LATE‐NC patients with higher likelihoods had more temporo‐limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo‐parietal degeneration and a faster rate of cognitive decline (Fig. 3).ConclusionThe implementation of LANS criteria has implications for disambiguating the different driving etiologies of progressive amnestic presentations in older age to guide prognosis, treatment, and clinical trial design and enrollment. The development of in vivo biomarkers specific to TDP‐43 pathology are needed to further refine molecular associations between LANS and LATE‐NC and precise antemortem diagnoses of LATE.

ABSTRACT Background Patients with erosive oesophagitis, and those with persistent symptomatic non‐erosive gastro‐oesophageal reflux disease, require long‐term maintenance treatment with acid‐suppressing agents. Aim To evaluate the safety of vonoprazan, a potassium‐competitive acid blocker, in an integrated analysis of data from clinical trials in adults. Methods We included 14 clinical trials of vonoprazan conducted in multiple countries. Mean duration of exposure in person‐years to vonoprazan ( n = 5318) was 2068, to comparators lansoprazole ( n = 1925) or esomeprazole ( n = 86) was 751, and to placebo ( n = 779) was 59. We report adverse events, serum gastrin, and liver enzyme levels as the main outcomes. Post‐marketing safety data from December 26, 2014 (date of commercialisation in Japan) to December 25, 2023, are also provided. Results Nasopharyngitis was the only adverse event reported by at least 5.0% of patients (6.94% vonoprazan, 5.07% proton pump inhibitor (PPI), 4.49% placebo). Incidence rates per 100 person‐years for serious adverse events were 10.39 for vonoprazan, 10.65 for PPIs, and 1.69 for placebo. One patient each on vonoprazan and lansoprazole was diagnosed with gastric cancer. Mean serum gastrin levels were higher on vonoprazan than lansoprazole but normalised by 4 weeks after discontinuation. Elevated liver enzyme levels were infrequent and of low magnitude with no differences between vonoprazan and PPIs. There were four deaths; none was considered related to study drug. Conclusions Vonoprazan was well tolerated. Its safety profile from both clinical trial and post‐marketing data were consistent and comparable to that of its PPI comparators with respect to treatment‐emergent adverse events.

Purpose: We report the first multicenter, prospective, randomized noninferiority controlled trial of steerable ureteroscopic renal evacuation (SURE) for nephrolithiasis treatment. Materials and Methods: Candidates for laser lithotripsy ≥18 years with ≥1 renal stone ≥7 mm and 7–20 mm stone burden were randomized 1:1 SURE vs ureteroscopy (URS). SURE was performed using the CVAC Aspiration System, a novel steerable irrigation–aspiration catheter. The primary efficacy end point was noninferiority in stone-free rate (SFR) based on zero residual fragments (RFs) 30 days postprocedure on noncontrast computed tomography. Secondary end points were superiority tests, stone clearance (percent stone volume reduction), residual stone volume (RSV), SFR (no RF >2 mm), and SFR (no RF >4 mm) 30 days postprocedure. Results: Of the subjects, 123 were randomized and 101 qualified for efficacy analysis (SURE 46 vs URS 55). Despite randomization, baseline URS stone volume was higher (SURE 485.0 ± 432.5 mm 3 vs URS 713.3 ± 558.5 mm 3 ). The primary noninferiority end point was achieved (SURE SFR 48% vs URS SFR 49%, p = 0.027, −1.3% [90% confidence interval; −18%, 15%]). Stone clearance was significantly higher for SURE vs URS subjects (SURE 96.9 ± 5.6% vs URS 92.9 ± 11.6%, p = 0.036); RSV was significantly lower (SURE 14.3 ± 3 0.9 mm 3 vs URS 70.2 ± 144.9 mm 3 , p = 0.012). SURE stone clearance and RSV were independent of baseline stone volume, but for URS degraded with increasing baseline stone volume. Safety was comparable between groups. Conclusions: SFR for SURE subjects was noninferior compared with URS subjects; stone clearance and RSV were significantly better with SURE, independent of baseline stone volume.

Background: Bucket-handle meniscal tears (BHMTs) are a common subtype of meniscal tears that represent a clinical challenge. Arthroscopic inside-out repair has been considered the gold standard in treatment; however, an all-inside approach has gained widespread popularity, with limited long-term evidence. Purpose/Hypothesis: The purpose of this study was to (1) compare long-term clinical outcomes and rates of failure after surgical repair of BHMTs using the all-inside versus inside-out technique, and 2) identify risk factors for failure at long-term follow-up. It was hypothesized that clinical outcomes and rates of failure would be similar between the 2 techniques. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who had undergone surgical repair of BHMTs between 2003 and 2013 at a single institution were identified. Patient-reported outcome measures (PROMs) were assessed preoperatively and at the latest follow-up using the Tegner scale, International Knee Documentation Committee questionnaire, and visual analog scale pain at rest and with activity. A univariate Cox proportional hazards model was used to identify predictors for repair failure, defined as revision meniscal surgery and/or documented meniscal retear. Results: In total, 63 patients were included (37 with inside-out repair, 26 with all-inside repair). At a mean follow-up of 11.2 years, the survival rate for BHMT repair was 63% overall, 70% for all-inside repairs, and 60% for inside-out repairs ( P = .37). The mean time to failure was 2.6 years for all-inside repairs and 2.5 years for inside-out repairs ( P = .98). PROM scores were not significantly different between the 2 repair groups ( P > .22). Univariate Cox proportional hazards model for failure demonstrated that increasing age at surgery was associated with lower failure rates (hazard ratio, 0.91 change per 1-year increase in age; 95% CI, 0.84-0.98) and medial meniscus repair was associated with higher failure rates (hazard ratio, 3.12; 95% CI, 1.14-8.77). Conclusion: Long-term follow-up of BHMT repair demonstrated satisfactory clinical outcomes and failure rates. In appropriately selected patients, the all-inside technique did not compromise outcome as compared with the inside-out repair techniques. For both methods, older age was associated with lower failure rates and medial meniscus repair was associated with increased failure.

Abstract Objectives Fluorescence resonance energy transfer (FRET)–based ADAMTS13 activity assays are critical for the diagnosis of thrombotic thrombocytopenic purpura. However, these assays are susceptible to interference. As iodide has been suggested to interfere in laboratory testing via fluorophore quenching or promotion, we aimed to determine whether iodinated contrast (Omnipaque) interferes with the ATS-13 ADAMTS13 Activity Assay 2.0. Methods We evaluated the excitation, emission, and absorbance spectrum of Omnipaque alone and spiked in patient plasma with known ADAMTS13 activity and ADAMTS13 activity on Omnipaque alone, an abnormal control of patient plasma previously observed to display elevated baseline relative fluorescent units, and variable concentrations of patient plasma with known ADAMTS13 activity spiked with Omnipaque. Results No atypical fluorescent peaks were observed on any sample (Omnipaque alone or spiked in plasma) between 250 and 700 nm. There was no difference in the mean ADAMTS13 activity among the various concentrations of plasma spiked with Omnipaque or plasma spiked with saline. Conclusions Iodinated contrast does not appear to interfere—either via spectral overlap of the fluorophore or through physiologic inhibition of the ADAMTS13 enzyme—with ADAMTS13 activity FRET-based assays based on the findings from this in vitro analysis. Delaying sample collection for ADAMTS13 activity testing from suspected patients with thrombotic thrombocytopenic purpura following administration of iodinated radiocontrast agents is not necessary, and recent contrast administration should not yield erroneous ADAMTS13 activity results.

Introduction: Laboratory identification of a lupus anticoagulant (LAC) requires evidence of: a) prolongation of a phospholipid-dependent screening test, usually a LAC-responsive dilute Russell's viper venom time (DRVVT) or activated partial thromboplastin time (APTT); b) inhibition on mixing with normal pooled plasma (NPP); c) confirmation of phospholipid-dependent inhibition by repeating the prolonged test with excess phospholipid. Despite decades of assay development and re-design and numerous attempts at standardization, diagnosis of a LAC remains challenging due to the heterogeneity of antiphospholipid antibodies, the marked variations in reagents, inconsistencies in post-analytic processes, and not least, the multitude of interferences, such as anticoagulant drugs, which influence test results. Guidelines recommend interruption of anticoagulation, if possible, prior to LAC testing to prevent obtaining false test results. While this is attempted in some instances for direct-acting anticoagulants, it is typically not considered for warfarin, and it is also not always possible. Our laboratory has observed a concerning pattern of potentially false-negative DRVVT screen/ confirm ratios in samples collected from patients on warfarin anticoagulation or with a factor deficiency (e.g. hypoprothrombinemia). The goal of this study is to replicate this observation using in vitro dilution experiments, mixing LAC-positive samples with either NPP or warfarin plasma. Methods: DRVVT Screen, Mix and Confirm assays (Precision Biologic, Dartmouth, NS) were performed using archived LAC-positive plasmas from 5 unique patients not on anticoagulation, and titered with normal pooled plasma (NPP) (Precision Biologic, Dartmouth, NS) to a screen/confirm ratio of 1.20-1.35, near the assay cutoff for DRVVTC (<1.20) and analyzed on the ACL TOP 750 (Werfen, Bedford, MA). Warfarin donor plasma was then mixed in the same dilution scheme with each of the LAC-positive plasmas so that the final dilution factors for LAC-NPP and LAC-Warfarin contrived samples were the same. The DRVVT screen/ confirm ratios of the LAC-NPP and LAC-Warfarin plasma contrived samples were compared. Additionally, a DRVVT Mix Screen and Mix Confirm were performed after mixing in a 1:1 ratio with NPP. Results: The average prothrombin time (PT) in the LAC-Warfarin samples was significantly longer than the LAC-NPP samples (20.7±8.5s vs 10.6±0.2s, p=0.03). All 5 LAC-NPP contrived samples had a positive DRVVT screen/ confirm ratio >1.20, while all of the LAC-Warfarin contrived samples had a negative DRVVT screen/ confirm ratio (1.26±0.04 vs 1.02±0.11, p<0.01). When the DRVVT screening time was divided by the DRVVT Mix Confirm time, 4 of the 5 LAC-Warfarin contrived samples reverted to positive using a cutoff of 1.20 (values of 1.30, 1.21, 1.21, 1.02 and 1.23 for LAC-Warfarin samples) and a similar pattern was observed with the LAC-NPP samples (values of 1.32, 1.29, 1.27, 1.14, 1.27, respectively, for LAC-NPP samples). Conclusion: This study confirms our anecdotal observation that warfarin and/ or factor deficiencies in the common pathway can result in a false-negative DRVVT screen/ confirm ratio using the Precision Biologic LA Sure and LA Check reagents, similar to findings described for apixaban. The DRVVT assay is widely considered to be the most sensitive or responsive to LAC and this in vitro observation raises questions about whether negative DRVVT screen/ confirm ratios can reliably be used to exclude the presence of a LAC in patients on warfarin using this reagent system. Larger studies are required using pre-treatment and on-treatment paired specimens to confirm these findings, and to further explore the utility of the DRVVT Screen/Mix Confirm ratio in this patient population.