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Background: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in‐person assessment can be unavailable or burdensome. The current study compares in‐person and remote assessments of the Penn computerised neurocognitive battery (CNB). Methods: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in‐person at a laboratory (n = 222) or remotely (n = 162). Results: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. Conclusions: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains. [ABSTRACT FROM AUTHOR]

Ramana K Naidu,1 Oth V Tran,2 Michael E Schatman3,4 1Pain Management, Marin Health Medical Center, Greenbrae, CA, USA; 2Health Economics & Outcomes Research, Boston Scientific, Marlborough, MA, USA; 3Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 4Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Oth V Tran, Email Oth.v.tran@gmail.comBackground: Evidence regarding the frequency and timing of treatment for lumbar spinal stenosis (LSS) fails to offer clear consensus. We describe the LSS care journey from initial diagnosis to first surgical intervention.Methods: Using Medicare claims database from 2009 through 2020, we identified patients who were diagnosed with LSS. The use and timing of conservative and surgical treatments during the entire follow-up from the initial diagnosis were reported.Results: Of the 143,849 patients identified, 68% received conservative care within 8.4 months and 25.3% received a surgical or minimally invasive intervention over 5.7 years following initial diagnosis, with 12.6% undergoing open decompression alone, 10.2% undergoing open decompression with fusion, and 5.1% undergoing fusion surgery alone. Fewer than 1% were provided with interspinous spacers or a percutaneous image-guided lumbar decompression.Conclusion: Approximately three-quarters of patients in the study received no surgical or non-invasive interventions for approximately six years following diagnosis with LSS.Keywords: lumbar spinal stenosis, interspinous spacer, lumbar decompression, chronic pain

Robert Jason Yong,1 Oth V Tran,2 Alysha M McGovern,2 Parag G Patil,3 Christopher J Gilligan1 1Pain Management Center, Brigham and Women’s Hospital, Chestnut Hill, MA, USA; 2Health Economics and Outcomes Research, Boston Scientific Corporation, Marlborough, MA, USA; 3Neurological Surgery, University of Michigan, Ann Arbor, MI, USACorrespondence: Alysha M McGovern, Health Economics and Outcomes Research, Boston Scientific Corporation, 300 Boston Scientific Way, Marlborough, MA, 01752, USA, Tel +1 774-249-5560, Email alysha.mcgovern@bsci.comPurpose: Chronic, non-cancer pain significantly and negatively impacts patient quality of life. Neuromodulation is a major component of multi-modal interdisciplinary approaches to chronic pain management, which includes opioid and nonopioid medications. In randomized controlled trials, spinal cord stimulation (SCS) has been shown to reduce pain and decrease short-term opioid use for patients. This study sought to evaluate the effect of SCS on longer term opioid and non-opioid pain medication usage among patients over ≥ 3 years of follow-up.Patients and Methods: Claims analysis was conducted using the Merative™ MarketScan® Commercial Database. Patients aged ≥ 18 who initiated SCS between 1/1/2010 and 3/31/2021 with ≥ 1 year of baseline data and ≥ 3 years of follow-up data were included. Opioid discontinuation, daily dose (DD) reduction, proportion of days covered (PDC), concomitant co-medication with benzodiazepines and/or gabapentinoids, and polypharmacy were evaluated during the baseline and follow-up periods. Adjusted logistic regression was used to evaluate the impact of baseline dosages on discontinuation and dose reduction.Results: During follow-up, 60% of 2,669 SCS patients either discontinued opioid use or reduced opioid DD by at least 20% from baseline; another 15% reduced DD by 1– 19%. Logistic regression showed patients with higher baseline dosages were less likely to discontinue opioids completely (odds ratio[OR] 95% confidence intervals[CI]: 0.31[0.18,0.54]) but more likely to reduce their daily dose (OR[CI]: 7.14[4.00,12.73], p< 0.001). Mean PDC with opioids decreased from 0.58 (210 of 365 days) at baseline to 0.51 at year 3 (p< 0.001). With SCS, co-medication with benzodiazepines decreased from 47.3% at baseline to 30.3% at year 3, co-medication with gabapentinoids reduced from 58.6% to 42.2%, and polypharmacy dropped from 15.6% to 9.6% (all p< 0.001).Conclusion: Approximately three-quarters of patients who received SCS therapy either discontinued or reduced systemic opioid use over the study period. SCS could assist in reducing long-term reliance on opioids and other pain medications to treat chronic non-cancer pain.Keywords: chronic pain, opioid misuse, spinal cord stimulation, opioid medication

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Jeffrey D Miller,1 Xin Ye,2 Gregory M Lenhart,1 Amanda M Farr,1 Oth V Tran,1 W Jackie Kwong,2 Elizabeth A Magnuson,3 William S Weintraub41Truven Health Analytics Inc, Cambridge, MA, 2Daiichi Sankyo Inc, Parsippany, NJ, 3St Luke Mid-America Heart Institute, Kansas City, MO, 4Center for Heart and Vascular Health, Christiana Care Health System, Newark, DE, USABackground: Understanding the value of new anticoagulation therapies compared with existing therapies is of paramount importance in today’s cost-conscious and efficiency-driven health care environment. Edoxaban and rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥2 have been evaluated in pivotal trials versus warfarin. The relative value of edoxaban versus rivaroxaban would be of interest to health care stakeholders and patients who prefer a once-daily treatment option for long-term stroke prevention in NVAF.Objective: To evaluate the relative cost-effectiveness of two once-daily regimens of novel oral anticoagulation therapy – edoxaban (60 mg/30 mg dose-reduced) versus rivaroxaban (20 mg/15 mg dose-reduced) – for stroke prevention in NVAF patients from a US health-plan perspective.Materials and methods: A Markov model simulated lifetime risk and treatment of stroke, systemic embolism, major bleeding, clinically relevant nonmajor bleeding, myocardial infarction, and death in NVAF patients treated with edoxaban or rivaroxaban. Efficacy and safety data were derived from a network meta-analysis that utilized data from patients enrolled in ENGAGE AF-TIMI 48 and ROCKET-AF. Health care cost and utility data were obtained from published sources. Incremental cost-effectiveness ratios of $150,000 per quality-adjusted life year (QALY) gained were used as thresholds for “highly cost-effective”, “cost-effective”, and “not cost-effective” treatment options, respectively, as per American Heart Association/American College of Cardiology guidelines.Results: Edoxaban was dominant relative to rivaroxaban, such that it was associated with lower total health care costs and better effectiveness in terms of QALYs in the base-case analysis. Results were supported by probabilistic sensitivity analyses that showed edoxaban as either dominant or a highly cost-effective alternative (incremental cost-effectiveness ratio

Background: In mild to moderate lumbar spinal stenosis (LSS) where conservative care treatments fail, minimally invasive treatments, such as interspinous spacers without decompression or fusion (ISD), may be appropriate. While previous studies have demonstrated racial and socioeconomic disparities in the surgical treatment of LSS, there are limited data on how those factors impact accessibility to these procedures. This study explored demographic, socioeconomic, and geographic differences in the use of ISD., Methods: Using the Medicare 100% files from 2017 through 2022, this retrospective claims analysis identified when and if patients diagnosed with LSS received ISD implantation. Cox proportional hazards regression was used to examine the association between racial and socioeconomic characteristics and the rate of ISD implantation, stratified by geographic region., Results: A total of 1,316,622 individuals met the inclusion criteria; 4730 (0.4%) underwent ISD implantation, with a mean (standard deviation) time to treatment of 11.9 (13.2) months after diagnosis. The likelihood of ISD implantation was higher for older patients (except for the oldest group), males, those with lower disease burden, and White patients. Cox regression revealed that the associations of racial and socioeconomic factors with ISD implantation varied by U.S. region. In the Midwest and Northeast, lower median household income was associated with a decreased likelihood of ISD implantation regardless of race, while in the South, Black patients were less likely to undergo ISD implantation regardless of income., Conclusions: The observed disparities in access to ISD implantation mirror existing trends in surgical interventions for LSS, suggesting further study and interventions are needed to address inequities., (© 2024. The Author(s).)

Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis., Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome., Study Design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site., Results: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019)., Conclusion: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Downregulation of intercellular communication through suppression of gap junctional conductance is necessary during wound healing. Connexin 43 (Cx43), a prominent gap junction protein in skin, is downregulated following wounding to restrict communication between keratinocytes. Previous studies found that PKCμ, a novel PKC isozyme, regulates efficient cutaneous wound healing. However, the molecular mechanism by which PKCμ regulates wound healing remains unknown. We have identified that PKCμ suppresses intercellular communication and enhances cell migration in an in vitro wound healing model by regulating Cx43 containing gap junctions. PKCμ can directly interact with and phosphorylate Cx43 at S368, which leads to Cx43 internalization and downregulation. Finally, utilizing phosphomimetic and non-phosphorylatable S368 substitutions and gap junction inhibitors, we confirmed that PKCμ regulates intercellular communication and in vitro wound healing by controlling Cx43-S368 phosphorylation. These results define PKCμ as a critical regulator of Cx43 phosphorylation to control cell migration and wound healing in keratinocytes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Aurones are a minor subgroup of flavonoids. Unlike other subgroups such as chalcones, flavones, and isoflavones, aurones have not been extensively explored as pancreatic lipase inhibitors. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. Thirty-six compounds belonging to four series (4,6-dihydroxyaurone, 6-hydroxyaurone, 4,6-dialkoxyaurone, and 6-alkoxyaurone) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbons) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC 50 of 1.945 ± 0.520 µM) relative to quercetin (IC 50 of 86.98 ± 3.859 µM) and orlistat (IC 50 of 0.0334 ± 0.0015 µM). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed that 8 inhibited lipase through a competitive mechanism (K i of 1.288 ± 0.282 µM). Molecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Treatment for degenerative lumbar spinal stenosis (LSS) typically begins with conservative care and progresses to minimally invasive procedures, including interspinous spacer without decompression or fusion (ISD) or minimally invasive lumbar decompression (MILD). This study examined safety outcomes and the rate of subsequent spinal procedures among LSS patients receiving an ISD versus MILD as the first surgical intervention., Methods: 100% Medicare Standard Analytical Files were used to identify patients with an ISD or MILD (first procedure=index date) from 2017 to 2021. ISD and MILD patients were matched 1:1 using propensity score matching based on demographics and clinical characteristics. Safety outcomes and subsequent spinal procedures were captured from index date until end of follow-up. Cox models were used to analyze rates of subsequent surgical interventions, LSS-related interventions, open decompression, fusion, ISD, and MILD. Cox models were used to assess postoperative complications during follow-up and logistic regression to analyze life-threatening complications within 30 days of index procedure., Results: A total of 3682 ISD and 5499 MILD patients were identified. After matching, 3614 from each group were included in the analysis (mean age=74 years, mean follow-up=20.0 months). The risk of undergoing any intervention, LSS-related intervention, open decompression, and MILD were 21%, 28%, 21%, and 81% lower among ISD compared with MILD patients. Multivariate analyses showed no significant differences in the risk of undergoing fusion or ISD, experiencing postoperative complications, or life-threatening complications (all p≥0.241) between the cohorts., Conclusions: These results showed ISD and MILD procedures have an equivalent safety profile. However, ISDs demonstrated lower rates of open decompression and MILD., Competing Interests: Competing interests: OT is a full-time employee of Boston Scientific., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Introduction: U.S. Military healthcare providers increasingly perform prolonged casualty care because of operations in settings with prolonged evacuation times. Varied training and experience mean that this care may fall to providers unfamiliar with providing critical care. Telemedicine tools with audiovisual capabilities, artificial intelligence (AI), and augmented reality (AR) can enhance inexperienced personnel's competence and confidence when providing prolonged casualty care. Furthermore, implementing offline functionality provides assistance options in communications-limited settings. The intent of the Trauma TeleHelper for Operational Medical Procedure Support and Offline Network (THOMPSON) is to develop (1) a voice-controlled mobile application with video references for procedural guidance, (2) audio narration of each video using procedure mentoring scripts, and (3) an AI-guided intervention system using AR overlay and voice command to create immersive video modeling. These capabilities will be available offline and in downloadable format., Materials and Methods: The Trauma THOMPSON platform is in development. Focus groups of subject matter experts will identify appropriate procedures and best practices. Procedural video recordings will be collected to develop reference materials for the Trauma THOMPSON mobile application and to train a machine learning algorithm on action recognition and anticipation. Finally, an efficacy evaluation of the application will be conducted in a simulated environment., Results: Preliminary video collection has been initiated for tube thoracostomy, needle decompression, cricothyrotomy, intraosseous access, and tourniquet application. Initial results from the machine learning algorithm show action recognition and anticipation accuracies of 20.1% and 11.4%, respectively, in unscripted datasets "in the wild," notably on a limited dataset. This system performs over 100 times better than a random prediction., Conclusions: Developing a platform to provide real-time, offline support will deliver the benefits of synchronous expert advice within communications-limited and remote environments. Trauma THOMPSON has the potential to fill an important gap for clinical decision support tools in these settings., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Summary: Protein kinases are a family of signaling proteins, crucial for maintaining cellular homeostasis. When dysregulated, kinases drive the pathogenesis of several diseases, and are thus one of the largest target categories for drug discovery. Kinase activity is tightly controlled by switching through several active and inactive conformations in their catalytic domain. Kinase inhibitors have been designed to engage kinases in specific conformational states, where each conformation presents a unique physico-chemical environment for therapeutic intervention. Thus, modeling kinases across conformations can enable the design of novel and optimally selective kinase drugs. Due to the recent success of AlphaFold2 in accurately predicting the 3D structure of proteins based on sequence, we investigated the conformational landscape of protein kinases as modeled by AlphaFold2. We observed that AlphaFold2 is able to model several kinase conformations across the kinome, however, certain conformations are only observed in specific kinase families. Furthermore, we show that the per residue predicted local distance difference test can capture information describing structural flexibility of kinases. Finally, we evaluated the docking performance of AlphaFold2 kinase structures for enriching known ligands. Taken together, we see an opportunity to leverage AlphaFold2 models for structure-based drug discovery against kinases across several pharmacologically relevant conformational states., Availability and Implementation: All code used in the analysis is freely available at https://github.com/Harmonic-Discovery/AF2-kinase-conformational-landscape., Competing Interests: The authors are or have been employees of Harmonic Discovery Inc., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: For individuals with lumbar spinal stenosis (LSS), minimally invasive procedures such as an interspinous spacer device without decompression or fusion (ISD) or open surgery (i.e., open decompression or fusion) may relieve symptoms and improve functions when patients fail to respond to conservative therapies. This research compares longitudinal postoperative outcomes and rates of subsequent interventions between LSS patients treated with ISD and those with open decompression or fusion as their first surgical intervention., Methods: This retrospective, comparative claims analysis identified patients age ≥ 50 years with LSS diagnosis and with a qualifying procedure during 2017-2021 in the Medicare database which includes healthcare encounters in inpatient and outpatient settings. Patients were followed from the qualifying procedure until end of data availability. The outcomes assessed during the follow-up included subsequent surgical interventions, including subsequent fusion and lumbar spine surgeries, long-term complications, and short-term life-threatening events. Additionally, the costs to Medicare during a 3-year follow-up were calculated. Cox proportional hazards, logistic regression, and generalized linear models were used to compare outcomes and costs, adjusted for baseline characteristics., Results: A total of 400,685 patients who received a qualifying procedure were identified (mean age 71.5 years, 50.7% male). Compared to ISD patients, patients receiving open surgery (i.e., decompression and/or fusion) were more likely to have a subsequent fusion [hazard ratio (HR), 95% confidence intervals (CI): 1.49 (1.17, 1.89)-2.54 (2.00, 3.23)] or other lumbar spine surgery [HR (CI): 3.05 (2.18, 4.27)-5.72 (4.08, 8.02)]. Short-term life-threatening events [odds ratio (CI): 2.42 (2.03, 2.88)-6.36 (5.33, 7.57)] and long-term complications [HR (CI): 1:31 (1.13, 1.52)-2.38 (2.05, 2.75)] were more likely among the open surgery cohorts. Adjusted mean index costs were lowest for decompression alone (US$7001) and highest for fusion alone ($33,868). ISD patients had significantly lower 1-year complication-related costs than all surgery cohorts and lower 3-year all-cause costs than fusion cohorts., Conclusions: ISD resulted in lower risks of short- and long-term complications and lower long-term costs than open decompression and fusion surgeries as a first surgical intervention for LSS., (© 2023. The Author(s).)

Introduction: Genetically encoded biosensors for monitoring intracellular calcium changes have advanced our understanding of cell signaling and neuronal activity patterns in health and disease. Successful application of GCaMP biosensors to a wide range of biological questions requires that sensor properties such as brightness and dynamic range, ligand affinity and response kinetics be tuned to the specific conditions or phenomena to be investigated. Random as well as rational targeted mutations of such sensor molecules have led to a number of important breakthroughs in this field, including the calcium sensors GCaMP6f and GCaMP6f u . jGCaMP8f of the most recently developed generation is promising a step-change in in vivo imaging with further increased fluorescence dynamic range. Here, we critically examine the biophysical properties of jGCaMP8f and report development by rational design of two novel variants of jGCaMP8f., Methods: We determined the in vitro biophysical properties of jGCaMP8f and selected variants by fluorescence spectroscopies and compared their performance monitoring intracellular Ca 2+ transients with previously developed fast and bright GCaMP sensors by live cell imaging., Results: We demonstrate that the physiologically highly relevant Mg 2+ not only majorly affects the kinetic responses of GCaMPs but also their brightness and fluorescence dynamic range. We developed novel variants jGCaMP8f L27A which has threefold faster off-kinetics and jGCaMP8f F366H which shows a ∼3-fold greater dynamic range than jGCaMP8f, in vitro as well as in HEK293T cells and endothelial cell line HUVEC in response to ATP stimulation., Discussion: We discuss the importance of optimization of biosensors for studying neurobiology in the context of the novel variants of jGCaMP8f. The jGCaMP8f F366H variant with a large dynamic range has the potential to improve in vivo imaging outcomes with increased signal-to-noise ratio. The L27A variant with faster kinetics than jGCaMP8f has larger cellular responses than previous fast GCaMP variants. The jGCaMP8f generation and novel improved variants presented here will further increase the application potential of GECIs in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tran, Hughes, Carter and Török.)

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

Ca 2+ /calmodulin (Ca 2+ /CaM) interaction with connexins (Cx) is well-established; however, the mechanistic basis of regulation of gap junction function by Ca 2+ /CaM is not fully understood. Ca 2+ /CaM is predicted to bind to a domain in the C-terminal portion of the intracellular loop (CL2) in the vast majority of Cx isoforms and for a number of Cx-s this prediction has proved correct. In this study, we investigate and characterise both Ca 2+ /CaM and apo-CaM binding to selected representatives of each of the α, β and γ connexin family to develop a better mechanistic understanding of CaM effects on gap junction function. The affinity and kinetics Ca 2+ /CaM and apo-CaM interactions of CL2 peptides of β-Cx32, γ-Cx35, α-Cx43, α-Cx45 and α-Cx57 were investigated. All five Cx CL2 peptides were found to have high affinity for Ca 2+ /CaM with dissociation constants ( K d(+Ca) ) from 20 to 150 nM. The limiting rate of binding and the rates of dissociation covered a broad range. In addition, we obtained evidence for high affinity Ca 2+ -independent interaction of all five peptides with CaM, consistent with CaM remaining anchored to gap junctions in resting cells. However, for the α-Cx45 and α-Cx57 CL2 peptides, Ca 2+ -dependent association at resting [Ca 2+ ] of 50-100 nM is indicated in these complexes as one of the CaM Ca 2+ binding sites displays high affinity with K d of 70 and 30 nM for Ca 2+ , respectively. Furthermore, complex conformational changes were observed in peptide-apo-CaM complexes with the structure of CaM compacted or stretched by the peptide in a concentration dependent manner suggesting that the CL2 domain may undergo helix-to-coil transition and/or forms bundles, which may be relevant in the hexameric gap junction. We demonstrate inhibition of gap junction permeability by Ca 2+ /CaM in a dose dependent manner, further cementing Ca 2+ /CaM as a regulator of gap junction function. The motion of a stretched CaM-CL2 complex compacting upon Ca 2+ binding may bring about the Ca 2+ /CaM block of the gap junction pore by a push and pull action on the CL2 C-terminal hydrophobic residues of transmembrane domain 3 (TM3) in and out of the membrane.

Background: The influence of allergist management on peanut allergy (PA)-related health care utilization is unknown., Objective: To determine whether allergist care lowers PA costs., Methods: IBM MarketScan Commercial Claims and Encounters Database was analyzed for PA diagnosis/reaction-related codes (January 2010-June 2019) in patients 64 years or younger, with demographically matched non-PA food allergy controls (NPAFACs). Outcomes were measured and compared 12 months before/after first claim date., Results: Among 72,854 persons with PA (39,068 with ≥1 allergist visit, 53.6%), and 166,825 NPAFACs, the number of National Drug Codes and International Classification of Diseases, 10th Revision codes was higher for persons with PA with versus without an allergist visit during both baseline and follow-up (all P < .001). Persons with PA with versus without an allergist visit were prescribed epinephrine at significantly higher rates (RR, 1.67; P < .001). Rates of epinephrine claims, mean epinephrine costs, and proportion with peanut anaphylaxis were higher among the PA group with versus without an allergist visit (69.9% vs 63.3%; $676 vs $493, 48.9% vs 20.7%; all P < .001). The proportion with anaphylaxis episodes was higher in the PA group versus the NPAFAC group (53.1% vs 31.6%; P < .001). Total health care costs were higher in the NPAFAC group versus the PA group ($7863 vs $7261; P < .001) and lower for persons with PA with versus without an allergist visit ($6347 vs $8270; P < .001), with no significant differences in PA reaction-related costs between PA groups., Conclusions: Higher rates of anaphylaxis were seen among the PA group with versus without an allergist visit during the follow-up period (53.6% of overall PA group). Allergist care was associated with a reduction in total health care costs and higher rates of epinephrine prescription., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The total economic burden of cancer reflects direct and indirect costs, including productivity loss due to employment change, absenteeism, and presenteeism of patients and caregivers., Objective: This study estimated the magnitude of employment decrease, work absence (WA), short-term disability (STD), long-term disability (LTD), and associated indirect costs among employees newly diagnosed with metastatic versus non-metastatic cancer in the USA., Methods: IBM ® MarketScan ® Commercial Claims and Encounters and Health and Productivity Management databases were used to identify employees aged 18-64 years and newly diagnosed with any cancer from 2009 to 2019. Proportions of patients with employment decrease, WA, STD, and LTD claims, and number of days missing from work were summarized by metastatic status during the first 12 months after diagnosis and the entire follow-up period. Subgroup analyses were conducted by age (< 50 years, ≥ 50 years) and cancer type (breast, lung, colon, pancreatic, and liver cancer)., Results: During the first year after diagnosis, compared to patients without metastases, significantly higher proportions of patients with metastases had employment decrease and STD or LTD claims (p < 0.001). The mean total number of days missing from work for patients with versus without metastases was 33.39 versus 14.91 (ratio = 2.40), 64.05 versus 27.15 (ratio = 2.36), and 105.93 versus 46.29 (ratio = 2.29) days within 3, 6, and 12 months after diagnosis, respectively. Estimates of indirect cost differences between the two groups ranged from $6,877 to $22,283 in the first year., Conclusion: Earlier detection of cancer may reduce productivity loss of patients and indirect costs by initiating treatment before cancer progresses to late stage., (© 2022. The Author(s).)

Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50−116 vs. 67; range 50−96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50−86 vs. 71.5, range 58−96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual's 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual's risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father's normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion.

The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics., Competing Interests: The authors have declared that no competing interests exist.

Cancers are highly heterogeneous and typically contain a small subset of drug-resisting cells called tumor initiating cells or cancer stem cells (CSCs). CSCs can self-renew, divide asymmetrically, and often cause tumor invasion and metastasis. Therefore, treatments specifically targeting CSCs are critical to improve patient survival. Recently, we identified a highly specific peptidomimetic (peptoid - PCS2) that selectively binds to the CSC subpopulation of lung cancer over the remaining cancer cells (non-CSCs). Subsequently, we identified plectin as the target of PCS2. Plectin is an intracellular structural protein, which is involved in tumor invasion and metastasis when it appears on cell surface. While PCS2 monomer did not display any anti-cancer activity, we designed a series of homo-dimeric versions of PCS2, and identified PCS2D1.2 optimized homo-dimer that displayed highly specific cytotoxicity towards CSCs over non-CSCs. PCS2D1.2 effectively blocked the in vitro colony formation and cell migration, hallmarks of CSCs. Furthermore, PCS2D1.2 reduced the in vivo tumor formation. In both in vitro and in vivo studies, PCS2D1.2 effectively reduced plectin expression and/or plectin-rich CSCs, but had no effect on non-CSCs. Therefore, PCS2D1.2 has the potential to be developed as a highly CSC specific drug candidate, which can be used in combination with current anti-cancer drugs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj  = 6.73 × 10 -6 ). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

The study examined long-term direct and indirect economic burden of osteoporotic fractures among postmenopausal women. Healthcare costs among fracture patients were substantial in first year after fracture and remained higher than fracture-free controls for 5 years which highlight needs for early detection of high-risk patients and continued management for osteoporosis., Introduction: This study compared direct and indirect healthcare costs between postmenopausal women and demographically matched controls in the 5 years after incident non-traumatic fracture, and by fracture type in commercially insured and Medicare populations., Methods: Two hundred twenty-six thousand one hundred ninety women (91,925 aged 50-64 years; 134,265 aged ≥ 65 years) with incident non-traumatic fracture (hip, vertebral, and non-hip non-vertebral (NHNV)) from 2008 to 2017 were identified. Patients with fracture were directly matched (1:1) to non-fracture controls based on demographic characteristics. Direct healthcare costs were assessed using general linear models, adjusting for baseline costs, comorbidities, osteoporosis diagnosis, and treatment. Indirect costs associated with work loss due to absenteeism and short-term disability (STD) were assessed among commercially insured patients. Costs were standardized to 2019 US dollars., Results: Osteoporosis diagnosis and treatment rates prior to fracture were low. Patients with fracture incurred higher direct costs across 5-year post-index compared with non-fracture controls, regardless of fracture type or insurance. For commercially insured hip fracture patients, the mean adjusted incremental direct healthcare costs in years 1, 3, and 5 were $59,327, $6885, and $3241, respectively. Incremental costs were lower, but trends were similar for vertebral and NHNV fracture types and Medicare-insured patients. Commercially insured patients with fracture had higher unadjusted indirect costs due to absenteeism and STD in year 1 and higher adjusted indirect costs due to STD at year 1 (incremental cost $5848, $2748, and $2596 for hip, vertebral, and NHNV fracture)., Conclusions: A considerable and sustained economic burden after a non-traumatic fracture underscores the need for early patient identification and continued management.

Objectives: To describe ixekizumab treatment patterns, all-cause healthcare utilization, and costs among psoriasis patients. Methods: Adults diagnosed with psoriasis having ≥1 ixekizumab claim were selected from MarketScan ® databases between March 01, 2016 and July 31, 2017. Patients were continuously enrolled for ≥6 months prior and ≥3 months after the index date (first ixekizumab claim) and followed until inpatient death, end of enrollment, or end of data. Treatment patterns included persistence, switching, and re-initiation. All-cause utilization and costs were reported per-patient-per-month (PPPM). Results: 801 patients (mean age 49 years; 55.8% male; median follow-up 201 days) were included. Among all patients, 87.4% were persistent (mean (median) duration 86 (75) days) Of the 12.6% of patients who discontinued ixekizumab, 11.9% re-initiated and 6.9% switched treatments. Mean (median) time to switching was 208 (206) days. Mean number of all-cause inpatient admissions and physician office visits PPPM were 0.01 and 0.72, respectively. Mean total cost PPPM was $8,371, of which pharmacy comprised $7,792. Ixekizumab costs, $7,079, occurred primarily during induction and were paid predominantly by health plans ($6,810 [96.2%]). Conclusion: Most (87.4%) ixekizumab users remained persistent during follow-up. Pharmacy was the primary driver of total healthcare costs, with the majority covered by health plans and <4% as patient out-of-pocket expense.

The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.

Aim: To compare healthcare resource use and costs between newly diagnosed multiple myeloma (NDMM) patients with and without skeletal-related events (SREs)., Methods: Adults newly diagnosed with MM (1 January 2006 and 30 June 2017) with at least 12 months continuous health coverage prior to diagnosis were identified using the IBM MarketScan administrative claims. To control for baseline differences, NDMM patients with SREs were propensity score matched to NDMM patients without SREs. Outcomes included annual HRU and costs during follow-up along with number and type of SREs (SRE cohort only). Patients with SREs were stratified by number of SREs, and annual SRE-related costs were reported. Student's t test and Chi-squared test were used to compare outcomes., Results: Before matching, the 6648 patients in the SRE cohort had more comorbidities, were more likely to have MM treatment, and had higher pre-index healthcare costs than the 7458 patients in the non-SRE cohort. After matching, cohorts of 3432 patients were well balanced on baseline characteristics. Patients with SREs (vs. without SREs) had significantly higher inpatient, outpatient, and pharmacy HRU. Patients with SREs had significantly higher mean annual all-cause healthcare costs ($213,361 vs. $94,896, p  < 0.001) with hospitalization being the leading driver of increased costs (38.7% of total). Among 6648 patients with SREs, the mean annual SRE-related healthcare costs were $39,603, $45,463, and $50,111 for patients with one, two, and three or more events, respectively., Conclusions: NDMM patients with SREs have more than twice the all-cause healthcare costs than matched patients without SREs. Costs increase with the number of SRE events.

Background: Peanut allergy (PA) affects approximately 1.6 million US children. The current standard of care is strict avoidance and prompt reaction treatment. Peanut allergy health care costs and health care resource utilization (HCRU) are poorly understood., Objective: To estimate PA health care costs and HCRU using a nationally representative commercial payer database., Methods: The IBM MarketScan Commercial Claims and Encounters Database was examined for PA diagnosis/reaction codes between January 2010 and October 2016 in patients 64 years of age or younger, with age cohort-matched controls. Outcomes were measured 12 months before and after the first claim date. Health care costs and HCRU were compared using Student's t tests and χ 2 tests., Results: Patients with a PA-related diagnostic code (n = 41,675) incurred almost double all-cause health care costs vs controls ($6436 vs $3493, P < .001), mainly from inpatient and outpatient medical costs ($5002 vs $2832, P < .001). More than one third of the PA group patients (36%) had a code indicative of an anaphylactic reaction during follow-up. Mean PA or reaction-related code costs per visit totaled $7921 for hospitalizations and $1115 for emergency department (ED) visits. Costs were 30% lower in patients with asthma codes without PA codes vs those with both codes ($5678 vs $8112, P < .001); all-cause ED costs were more than double in patients with atopic dermatitis codes with PA codes vs those without PA codes ($654 vs $308, P < .001)., Conclusion: National commercial payer claims data indicate a significant health care burden associated with a PA-related code, including over $6400/patient in annual all-cause costs and increased health care utilization., (Copyright © 2020. Published by Elsevier Inc.)