Role of STIM1 in Stretch-induced Signaling in Human Airway Smooth Muscle.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca2+ regulatory proteins, including STIM1, Orai1 and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca2+]i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling.

Screw Diameter and Use of a Washer Affect Symptomatic Implant Removal Rates in Pediatric Medial Epicondyle Fractures.

OBJECTIVE: Medial epicondyle fractures are a common pediatric injury. When operative, cannulated partially threaded screws, with or without a washer, are commonly utilized. These implants may need to be removed after full healing if symptomatic. There is mixed evidence regarding the influence of a washer on rates of implant removal, and the influence of screw size has not been studied. We aim to determine the rate of symptomatic deep implant removal for each fixation type and identify factors associated with the need for removal. METHODS: This was an IRB-reviewed, retrospective, case-cohort study. Patients treated at our institution between January 1, 2004 and December 31, 2019, age 18 years old or younger, with a medial epicondyle fracture managed operatively with 4.0 or 4.5 mm cannulated screws with or without washers were included. Patients with multiple operative ipsilateral elbow fractures and those who underwent implant removal for reasons other than pain or irritation were excluded. Removal rates were compared between screw sizes (4.0 vs 4.5 mm), as well as with and without a washer using a Cox proportional hazards model. RESULTS: In total, 151 patients met the inclusion criteria, 54 with symptomatic hardware removed and 97 without symptomatic hardware removed. A significantly higher number of patients treated with 4.5 mm screws compared with 4.0 mm screws underwent removal of symptomatic deep implants (50% vs 30%, P = 0.033). In a multivariable Cox regression model adjusting for age and ulnar nerve status, when no washer was used, the hazard ratio (HR) for symptomatic hardware removal for 4.5 mm screws was 2.92 times the HR for 4.0 mm screws (95% CI: 1.35-6.29). When a 4.0 mm screw was used, the HR for symptomatic hardware removal for a washer was 3.24 times the HR without a washer (95% CI: 1.53-6.84). CONCLUSION: Implant removal rates are influenced by screw size and the use of a washer. These results may help guide implant choice and counsel families regarding the rate of symptomatic implant removal. LEVEL OF EVIDENCE: Level III-therapeutic level, case-control study.

Insulin's Legacy: A Century of Breakthroughs and Innovation.

The clinical use of insulin to treat diabetes started just over 100 years ago. The past century has witnessed remarkable innovations in insulin therapy, evolving from animal organ extracts to bioengineered human insulins with ultra-rapid onset or prolonged action. Insulin delivery systems have also progressed to current automated insulin delivery systems. In this review, we discuss the history of insulin and the pharmacology and therapeutic indications for a variety of available insulins, especially newer analog insulins. We highlight recent advances in insulin pump therapy and review evidence on the therapeutic benefits of automated insulin delivery. As with any form of progress, there have been setbacks, and insulin has recently faced an affordability crisis. We address the challenges of insulin accessibility, along with recent progress to improve insulin affordability. Finally, we mention research on glucose-responsive insulins and hepato-preferential insulins that are likely to shape the future of insulin therapy.

Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference.

TadA-derived cytosine base editors (TadCBEs) enable programmable C•G-to-T•A editing while retaining the small size, high on-target activity, and low off-target activity of TadA deaminases. Existing TadCBEs, however, exhibit residual A•T-to-G•C editing at certain positions and lower editing efficiencies at some sequence contexts and with non-SpCas9 targeting domains. To address these limitations, we use phage-assisted evolution to evolve CBE6s from a TadA-mediated dual cytosine and adenine base editor, discovering mutations at N46 and Y73 in TadA that prevent A•T-to-G•C editing and improve C•G-to-T•A editing with expanded sequence-context compatibility, respectively. In E. coli, CBE6 variants offer high C•G-to-T•A editing and no detected A•T-to-G•C editing in any sequence context. In human cells, CBE6 variants exhibit broad Cas domain compatibility and retain low off-target editing despite exceeding BE4max and previous TadCBEs in on-target editing efficiency. Finally, we show that the high selectivity of CBE6 variants is well-suited for therapeutically relevant stop codon installation without creating unwanted missense mutations from residual A•T-to-G•C editing.

Can Ganciclovir and Quercetin-P188 Ameliorate Cytomegalovirus Induced Hearing Loss?

OBJECTIVE: Determine whether combination therapy with ganciclovir (GCV) and a Quercetin-P188 solution improves hearing outcomes in a murine cytomegalovirus (CMV) model. METHODS: BALB/c mice were infected with murine CMV on postnatal day 3 (p3). Quercetin was solubilized in saline using P188 (QP188). Treatment groups received either GCV, QP188, GCV and QP188, or P188 delivery vehicle BID at 12-hour intervals via intraperitoneal injection. All treatment groups were treated for 14 days starting at p3. Uninfected controls were treated with the combined regimen, saline or P188 delivery vehicle. Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing at 4, 6, and 8 weeks of age. Temporal bones from separate CMV-infected groups were harvested at p10, and viral load was determined by quantitative polymerase chain reaction. RESULTS: CMV-infected mice receiving combination therapy GCV+QP188 demonstrated statistically significant lower ABR (p < 0.001) and DPOAE thresholds (p < 0.001) compared with mice treated with GCV monotherapy, QP188 monotherapy, and P188 delivery vehicle at 4, 6, and 8 weeks of age. GCV+QP188 combination therapy, GCV monotherapy, and QP188 monotherapy resulted in a nonsignificant reduction in mean viral titers compared to P188 monotherapy (p = 0.08). CONCLUSION: Combining GCV with the excipients quercetin and P188 effectively ameliorated CMV-induced sensorineural hearing loss in a murine model. This result may be partially explained by a reduction in viral titers in mouse temporal bones that correlate with in vitro studies demonstrating additive antiviral effect in cell culture. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1457-1463, 2024.

Occult Nodal Metastases in Individuals with Clinically Node-Negative Salivary Gland Malignancies.

OBJECTIVES: Salivary gland malignancies comprise a heterogeneous group of pathologies, for which treatment of the clinically negative neck may vary depending on numerous factors. Herein we present data on occult nodal metastases (ONM) as well as survival and recurrence from a large series of cN0 salivary gland malignancies. METHODS: Retrospective chart review was conducted on 532 patients, with 389 patients with major salivary gland cancers and 143 patients with minor salivary gland cancers. Demographic and treatment data were included and rates of ONM, overall survival, local recurrence, regional recurrence, and distant recurrence were analyzed. RESULTS: We found that the overall rate of ONM for parotid was 27% (63/235), for submandibular/sublingual was 35% (18/52), and for minor was 15% (4/26). Analysis of ONM rate at each nodal level was also performed, finding higher rates of level IV and V ONM than prior studies. Submandibular/sublingual and minor salivary gland malignancies showed a predominance of ONMs at levels I-III. Our survival and recurrence rates were similar to those found in previous studies. CONCLUSION: Our data also demonstrate a predominance of ONM in levels I-III for submandibular/sublingual and minor salivary gland cancers, suggesting elective dissection in these levels. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1705-1715, 2024.

Neurophysiological responses to emotional faces predict dynamic fluctuations in affect in adolescents.

The ability to accurately identify and interpret others' emotions is critical for social and emotional functioning during adolescence. Indeed, previous research has identified that laboratory-based indices of facial emotion recognition and engagement with emotional faces predict adolescent mood states. Whether socioemotional information processing relates to real-world affective dynamics using an ecologically sensitive approach, however, has rarely been assessed. In the present study, adolescents (N = 62; ages 13-18) completed a Facial Recognition Task, including happy, angry, and sad stimuli, while EEG data were acquired. Participants also provided ecological momentary assessment (EMA) data probing their current level of happiness, anger, and sadness for 1-week, resulting in indices of emotion (mean-level, inertia, instability). Analyses focused on relations between (1) accuracy for and (2) prolonged engagement with (LPP) emotional faces and EMA-reported emotions. Greater prolonged engagement with happy faces was related to less resistance to changes in happiness (i.e., less happiness inertia), whereas greater prolonged engagement with angry faces associated with more resistance to changes in anger (i.e., greater anger inertia). Results suggest that socioemotional processes captured by laboratory measures have real-world implications for adolescent affective states and highlight potentially actionable targets for novel treatment approaches (e.g., just-in-time interventions). Future studies should continue to assess relations among socioemotional informational processes and dynamic fluctuations in adolescent affective states.

Detecting adolescent depression through passive monitoring of linguistic markers in smartphone communication.

BACKGROUND: Cross sectional studies have identified linguistic correlates of major depressive disorder (MDD) in smartphone communication. However, it is unclear whether monitoring these linguistic characteristics can detect when an individual is experiencing MDD, which would facilitate timely intervention. METHODS: Approximately 1.2 million messages typed into smartphone social communication apps (e.g. texting, social media) were passively collected from 90 adolescents with a range of depression severity over a 12-month period. Sentiment (i.e. positive vs. negative valence of text), proportions of first-person singular pronouns (e.g. 'I'), and proportions of absolutist words (e.g. 'all') were computed for each message and converted to weekly aggregates temporally aligned with weekly MDD statuses obtained from retrospective interviews. Idiographic, multilevel logistic regression models tested whether within-person deviations in these linguistic features were associated with the probability of concurrently meeting threshold for MDD. RESULTS: Using more first-person singular pronouns in smartphone communication relative to one's own average was associated with higher odds of meeting threshold for MDD in the concurrent week (OR = 1.29; p = .007). Sentiment (OR = 1.07; p = .54) and use of absolutist words (OR = 0.99; p = .90) were not related to weekly MDD. CONCLUSIONS: Passively monitoring use of first-person singular pronouns in adolescents' smartphone communication may help detect MDD, providing novel opportunities for early intervention.

Lateralized grey matter volume changes in adolescents versus adults with major depression: SDM-PSI meta-analysis.

The current study is the first meta-analysis to examine grey matter volume (GMV) changes in adolescents and across the lifespan in major depressive disorder (MDD). Seed-based d mapping-with permutation of subject images (SDM-PSI) has advantages over previous coordinate-based meta-analytical methods (CBMA), such as reducing bias (via the MetaNSUE algorithm) and including non-statistically significant unreported effects. SDM-PSI was used to analyze 105 whole-brain GMV voxel-based morphometry (VBM) studies comparing 6,530 individuals with MDD versus 6,821 age-matched healthy controls (HC). A laterality effect was observed in which adults with MDD showed lower GMV than adult HC in left fronto-temporo-parietal structures (superior temporal gyrus, insula, Rolandic operculum, and inferior frontal gyrus). However, these abnormalities were not statistically significant for adolescent MDD versus adolescent HC. Instead, adolescent MDD showed lower GMV than adult MDD in right temporo-parietal structures (angular gyrus and middle temporal gyrus). These regional differences may be used as potential biomarkers to predict and monitor treatment outcomes as well as to choose the most effective treatments in adolescents versus adults. Finally, due to the paucity of youth, older adult, and longitudinal studies, future studies should attempt to replicate these GMV findings and examine whether they correlate with treatment response and illness severity.

Mechanosensitive Channels in Lung Health and Disease.

The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157-5178, 2023.

A comprehensive assessment of the applicability of RoboColumn as a chromatography scale-down model for use in biopharmaceutical process validation.

High-throughput process development has become a standard practice in the biopharmaceutical industry to enable time, cost, and material savings. In downstream biopharmaceutical process development, miniaturized, parallelized chromatography columns, known as RoboColumn, have become the standard for process development, as RoboColumn have shown generally comparable performance to bench and manufacturing scale columns. However, RoboColumn have yet to be widely implemented in process validation and characterization, where many multifactor experiments are typically executed, and there is a strong value proposition for performing high-throughput experiments. The hesitancy to utilize RoboColumn in process validation arises from scale differences that result in exacerbated peak broadening at RoboColumn scale relative to traditional bench or manufacturing scales. Thus, to support reliable application of RoboColumn in process validation, the present study provides a comprehensive investigation to understand how scale differences affect chromatographic performance by comparing RoboColumn, bench, and manufacturing scales using seven different production processes covering three different antibody formats, five different resin types, and three chromatographic modes of operation. RoboColumn chromatographic performance was compared at target and off-target conditions to emulate scale-down model qualification and multifactor studies, respectively. RoboColumn demonstrated good comparability at both target and off-target process conditions. To further demonstrate an understanding of comparability, a study was performed to show a rare case in which product quality offsets may occur as a result RoboColumn scale differences. By showing scale comparability and an understanding of potential offsets, this work demonstrates that RoboColumn can be used in any stage of process development, including process validation and characterization.

Piezo channels in stretch effects on developing human airway smooth muscle.

The use of respiratory support strategies such as continuous positive airway pressure in premature infants can substantially stretch highly compliant perinatal airways, leading to airway hyperreactivity and remodeling in the long term. The mechanisms by which stretch detrimentally affects the airway are unknown. Airway smooth muscle cells play a critical role in contractility and remodeling. Using 18-22-wk gestation human fetal airway smooth muscle (fASM) as an in vitro model, we tested the hypothesis that mechanosensitive Piezo (PZ) channels contribute to stretch effects. We found that PZ1 and PZ2 channels are expressed in the smooth muscle of developing airways and that their expression is influenced by stretch. PZ activation via agonist Yoda1 or stretch results in significant [Ca2+]i responses as well as increased extracellular matrix production. These data suggest that functional PZ channels may play a role in detrimental stretch-induced airway changes in the context of prematurity.NEW & NOTEWORTHY Piezo channels were first described just over a decade ago and their function in the lung is largely unknown. We found that piezo channels are present and functional in the developing airway and contribute to intracellular calcium responses and extracellular matrix remodeling in the setting of stretch. This may improve our understanding of the mechanisms behind development of chronic airway diseases, such as asthma, in former preterm infants exposed to respiratory support, such as continuous positive airway pressure (CPAP).

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease.

Chronic airway diseases, such as wheezing and asthma, remain significant sources of morbidity and mortality in the pediatric population. This is especially true for preterm infants who are impacted both by immature pulmonary development as well as disproportionate exposure to perinatal insults that may increase the risk of developing airway disease. Chronic pediatric airway disease is characterized by alterations in airway structure (remodeling) and function (increased airway hyperresponsiveness), similar to adult asthma. One of the most common perinatal risk factors for development of airway disease is respiratory support in the form of supplemental oxygen, mechanical ventilation, and/or CPAP. While clinical practice currently seeks to minimize oxygen exposure to decrease the risk of bronchopulmonary dysplasia (BPD), there is mounting evidence that lower levels of oxygen may carry risk for development of chronic airway, rather than alveolar disease. In addition, stretch exposure due to mechanical ventilation or CPAP may also play a role in development of chronic airway disease. Here, we summarize the current knowledge of the impact of perinatal oxygen and mechanical respiratory support on the development of chronic pediatric lung disease, with particular focus on pediatric airway disease. We further highlight mechanisms that could be explored as potential targets for novel therapies in the pediatric population.

Capturing mood dynamics through adolescent smartphone social communication.

Most adolescents with depression remain undiagnosed and untreated-missed opportunities that are costly from both personal and public health perspectives. A promising approach to detecting adolescent depression in real-time and at a large scale is through their social communication on the smartphone (e.g., text messages, social media posts). Past research has shown that language from online social communication reliably indicates interindividual differences in depression. To move toward detecting the emergence of depression symptoms intraindividually, the present study tested whether sentiment (i.e., words connoting positive and negative affect) from smartphone social communication prospectively predicted daily mood fluctuations in 83 adolescents (Mage = 16.49, 73.5% female) with a wide range of depression severity. Participants completed daily mood ratings across a 90-day period, during which 354,278 messages were passively collected from social communication apps. Greater positive sentiment (i.e., more positive weighted composite valence score and a greater proportion of words expressing positive sentiment) predicted more positive next-day mood, controlling for previous-day mood. Moreover, greater proportions of positive and negative sentiment were, respectively, associated with lower anhedonia and greater dysphoria symptoms measured at baseline. Exploratory analyses of nonaffective linguistic features showed that greater use of social engagement words (e.g., friends and affiliation) and emojis (primarily consisting of hearts) predicted more positive changes in mood. Collectively, findings suggest that language from smartphone social communication can detect mood fluctuations in adolescents, laying the foundation for language-based tools to identify periods of heightened depression risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neuropsychological Performance in Alzheimer's Disease versus Late-Life Depression: A Systematic Review and Meta-Analysis.

OBJECTIVE: Despite decades of research, neuropsychological tests (NPTs) that clearly differentiate between Alzheimer's disease (AD) and late-life depression (LLD) have yet to be agreed upon. Given this gap in knowledge and the rapid deployment of disease-modifying drugs for the two disorders, accurate clinical diagnosis using evidence-based assessment is essential. This study aims to systematically examine the literature to identify NPTs that would be able to differentiate AD and LLD. METHOD: Databases and bibliographies were searched to identify articles for analysis. Two major inclusion criteria were that the studies compared neuropsychological functioning of AD versus LLD using normed NPTs and provided data for effect size calculation. Risk of bias was minimized by having independent coders for all steps in the review. RESULTS: Forty-one studies met inclusion criteria (N = 2,797) and provided effect sizes for tests that were classified as belonging to 15 domains of functioning. The two groups were well differentiated by tasks of delayed contextual verbal memory as compared to immediate or non-contextual memory, recognition cueing, confrontation naming, visuospatial construction, and conceptualization. Specific NPTs that appear to be useful for differential diagnosis include the Rey Auditory Verbal Learning Test-Delayed Recognition; Boston Naming Test; the Dementia Rating Scale's memory, conceptualization, and construction subscales; and the CERAD Constructional Praxis. CONCLUSIONS: The NPTs highlighted in this systematic review could be used as a relatively simple and cost-effective method to differentiate between patients with cognitive dysfunction due to AD versus LLD.

Hemiepiphysiodesis for Lower Extremity Coronal Plane Angular Correction in the Distal Femur and Proximal Tibia in Children With Achondroplasia.

BACKGROUND: Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee. METHODS: The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle. RESULTS: Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment. CONCLUSIONS: Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum. LEVEL OF EVIDENCE: Therapeutic level IV, Case series.

Functional α7 nicotinic receptors in human airway smooth muscle increase intracellular calcium concentration and contractility in asthmatics.

Although nicotinic acetylcholine receptors (nAChRs) are commonly associated with neurons in the brain and periphery, recent data indicate that they are also expressed in non-neuronal tissues. We recently found the alpha7 (α7nAChR) subunit is highly expressed in human airway smooth muscle (hASM) with substantial increase in asthmatics, but their functionality remains unknown. We investigated the location and functional role of α7nAChRs in hASM cells from normal versus mild-moderate asthmatic patients. Immunostaining and protein analyses showed α7nAChR in the plasma membrane including in asthmatics. In asthmatic hASM, patch-clamp recordings revealed significantly higher functional homomeric α7nAChR channels. Real-time fluorescence imaging showed nicotine, via α7nAChR, increases intracellular Ca2+ ([Ca2+]i) independent of ACh effects, particularly in asthmatic hASM, while cellular traction force microscopy showed nicotine-induced contractility including in asthmatics. These results indicate functional homomeric and heteromeric nAChRs that are increased in asthmatic hASM, with pharmacology that likely differ owing to different subunit interfaces that form the orthosteric sites. nAChRs may represent a novel target in alleviating airway hyperresponsiveness in asthma.NEW & NOTEWORTHY Cigarette smoking and vaping exacerbate asthma. Understanding the mechanisms of nicotine effects in asthmatic airways is important. This study demonstrates that functional alpha7 nicotinic acetylcholine receptors (α7nAChRs) are expressed in human airway smooth muscle, including from asthmatics, and enhance intracellular calcium and contractility. Although a7nAChRs are associated with neuronal pathways, α7nAChR in smooth muscle suggests inhaled nicotine (e.g., vaping) can directly influence airway contractility. Targeting α7nAChR may represent a novel approach to alleviating airway hyperresponsiveness in asthma.

Linear time complexity de novo long read genome assembly with GoldRush.

Current state-of-the-art de novo long read genome assemblers follow the Overlap-Layout-Consensus paradigm. While read-to-read overlap - its most costly step - was improved in modern long read genome assemblers, these tools still often require excessive RAM when assembling a typical human dataset. Our work departs from this paradigm, foregoing all-vs-all sequence alignments in favor of a dynamic data structure implemented in GoldRush, a de novo long read genome assembly algorithm with linear time complexity. We tested GoldRush on Oxford Nanopore Technologies long sequencing read datasets with different base error profiles sourced from three human cell lines, rice, and tomato. Here, we show that GoldRush achieves assembly scaffold NGA50 lengths of 18.3-22.2, 0.3 and 2.6 Mbp, for the genomes of human, rice, and tomato, respectively, and assembles each genome within a day, using at most 54.5 GB of random-access memory, demonstrating the scalability of our genome assembly paradigm and its implementation.

Functional neuroanatomy of craving in heroin use disorder: voxel-based meta-analysis of functional magnetic resonance imaging (fMRI) drug cue reactivity studies.

Background: The neuroanatomy of craving, typically investigated using the functional magnetic resonance imaging (fMRI) drug cue reactivity (FDCR) paradigm, has been shown to involve the mesocorticolimbic, nigrostriatal, and corticocerebellar systems in several substances. However, the neuroanatomy of craving in heroin use disorder is still unclear.Objective: The current meta-analysis examines previous research on the neuroanatomy of craving in abstinent individuals with opioid use disorder (OUD).Method: Seven databases were searched for studies comparing abstinent OUD versus healthy controls on drug > neutral contrast interaction at the whole-brain level. Voxel-based meta-analysis was performed using seed-based d mapping with permuted subject images (SDM-PSI). Thresholds were set at a family-wise error rate of less than 5% with the default pre-processing parameters of SDM-PSI.Results: A total of 10 studies were included (296 OUD and 187 controls). Four hyperactivated clusters were identified with Hedges' g of peaks that ranged from 0.51 to 0.82. These peaks and their associated clusters correspond to the three systems identified in the previous literature: a) mesocorticolimbic, b) nigrostriatal, and c) corticocerebellar. There were also newly revealed hyperactivation regions including the bilateral cingulate, precuneus, fusiform gyrus, pons, lingual gyrus, and inferior occipital gyrus. The meta-analysis did not reveal areas of hypoactivation.Conclusion: Recommendations based on the functional neuroanatomical findings of this meta-analysis include pharmacological interventions such as buprenorphine/naloxone and cognitive-behavioral treatments such as cue-exposure combined with HRV biofeedback. In addition, research should utilize FDCR as pre- and post-measurement to determine the effectiveness and mechanism of action of such interventions.

Meralgia Paresthetica Review: Update on Presentation, Pathophysiology, and Treatment.

Purpose of Review: Meralgia paresthetica (MP) is a condition characterized by paresthesias, neuropathic pain, and alterations in sensorium of the anterolateral thigh secondary to impingement of the lateral femoral cutaneous nerve (LFCN). MP is generally diagnosed by clinical history and is often a diagnosis of exclusion. When diagnosis remains a challenge, diagnostic modalities such as ultrasound, MRI, electromyography, and nerve conduction studies have been utilized as an adjunct. This review summarizes the most recent medical literature regarding MP, its pathophysiology, presentation, and current treatment options. Recent Findings: Treatment options for patients with MP range from lifestyle modifications and conservative management to surgical procedures. Initial management is often conservative with symptoms managed with medications. When conservative management fails, the next step is regional blocks followed by surgical management. The conflicting data for treatment options for MP highlight how the evidence available does not point to a single approach that's universally effective for treating all patients with MP. Summary: Despite the apparent success at treating MP with regional blocks and surgical interventions, much remains to be known about the dosing, frequency, and optimal interventions due to the inconclusive results of current studies. Further research including randomized controlled trials are needed to better understand the most optimal treatment options for MP including studies with a larger number of participants.