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Arrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin-3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin-3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active "open" conformation of parkin. Arrestin-3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin-1 and facilitates parkin-mediated mitophagy in HeLa cells. Furthermore, arrestin-3 and its mutant with enhanced parkin binding rescue mitofusin-1 ubiquitination and mitophagy in the presence of the Parkinson's disease-associated R275W parkin mutant, which is defective in both functions. Thus, modulation of parkin activity via arrestin-3 might be a novel strategy of anti-parkinsonian therapy., (© 2024 International Society for Neurochemistry.)

Ocular involvement of lymphoma may present as a primary orbital or intraocular lymphoma or as a manifestation of metastatic disease. Involvement of various ocular structures may be difficult to diagnose due to its rarity and nonspecific clinical presentation. Primary high-grade B-cell lymphoma with MYC and BCL2 rearrangements of the orbit has rarely been reported in the adult population and has not previously been reported in the pediatric population. Herein we present a unique case of orbital high-grade B-cell lymphoma in a pediatric patient, initially diagnosed as preseptal cellulitis. Careful observation and escalation of care ultimately led to the accurate diagnosis and complete remission of the disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Objective: To evaluate patients' satisfaction with opioid versus opioid-sparing postoperative analgesia in patients undergoing outpatient head and neck surgery., Study Design: Prospective randomized trial., Setting: Tertiary care academic hospital., Methods: Adult patients undergoing outpatient head and neck surgery were randomly assigned to 1 of 3 analgesic regimens. First- and second-line medications were the following by group (1) Hydrocodone-acetaminophen with ibuprofen, (2) ibuprofen with hydrocodone-acetaminophen, and (3) ibuprofen with acetaminophen. Preoperative counseling was provided to patients regarding expected pain and proper medication use. Postoperative questionnaires were administered to assess satisfaction., Results: One hundred three patients were enrolled in the study (mean age, 56.5 years; women, 75 [73%]). The mean satisfaction score with the pain regimen assigned was similar between the 3 groups (scale 0-10, [7.7, 8.3, 8.5, P = .46]). A similar percentage of patients in each group reported that surgery was more painful than anticipated (25%, 32%, 26%, P = .978), and a similar percentage of patients reported willingness to utilize the same analgesic regimen following future surgeries (75%, 83%, 76%, P = .682). Additional questions evaluating the side effect profile, maximum and minimum pain scores, and difficulty of recovery were not statistically different between the 3 groups., Conclusion: In the postoperative population for outpatient head and neck surgeries, there was no significant difference in patient satisfaction and pain control between the opioid and nonopioid arms. Providers should discuss opioid-sparing regimens preoperatively with patients and describe them as effective in providing adequate pain control without a significant impact on patient's perception of care., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Genetic variants in TRIO are associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associated Trio variants - +/ K1431M (ASD), +/ K1918X (SCZ), and +/ M2145T (bipolar disorder, BPD) - impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. Trio variants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in +/ K1431M and +/ M2145T cortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but +/ K1431M mice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in +/ K1431M variant cortex. Our work reveals that discrete NDD-associated Trio variants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo., Competing Interests: CONFLICT OF INTEREST Authors declare no conflict of interest.

Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This transmission necessitates rapid and sustained neurotransmitter release, which depends on a large pool of synaptic vesicles at the hair-cell presynapse. While previous work in neurons has shown that kinesin motor proteins traffic synaptic material along microtubules to the presynapse, the mechanisms of this process in hair cells remain unclear. Our study demonstrates that the kinesin motor protein Kif1a, along with an intact microtubule network, is essential for enriching synaptic vesicles at the presynapse in hair cells. Through genetic and pharmacological approaches, we disrupt Kif1a function and impair microtubule networks in hair cells of the zebrafish lateral-line system. These manipulations led to a significant reduction in synaptic-vesicle populations at the presynapse in hair cells. Using electron microscopy, in vivo calcium imaging, and electrophysiology, we show that a diminished supply of synaptic vesicles adversely affects ribbon-synapse function. Kif1aa mutants exhibit dramatic reductions in spontaneous vesicle release and evoked postsynaptic calcium responses. Furthermore, kif1aa mutants exhibit impaired rheotaxis, a behaviour reliant on the ability of hair cells in the lateral line to respond to sustained flow stimuli. Overall, our results demonstrate that Kif1a-mediated microtubule transport is critical to enrich synaptic vesicles at the active zone, a process that is vital for proper ribbon-synapse function in hair cells. KEY POINTS: Kif1a mRNAs are present in zebrafish hair cells. Loss of Kif1a disrupts the enrichment of synaptic vesicles at ribbon synapses. Disruption of microtubules depletes synaptic vesicles at ribbon synapses. Kif1aa  mutants have impaired ribbon-synapse and sensory-system function., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory. We observed that priming of wild type (WT) mice with MPLA potently facilitated accumulation of the TCA cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in immuneresponsive gene 1 (Irg1) -deficient mice. We further observed that MPLA potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to WT macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. MPLA-induced augmentation of glycolysis, oxidative phosphorylation and accumulation of the TCA cycle metabolites succinate and malate was decreased in Irg1 KO macrophages compared to WT controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

A new carvotacetone sphaeranthone A and four known compounds 3-angeloyloxy-5-[2″,3″-epoxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone ( 2 ), 3-angeloyloxy-5-[3″-chloro-2″-hydroxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone ( 3 ), chrysosplenol D ( 4 ), and 3- O -methylquercetin ( 5 ) were isolated from leaves of Sphaeranthus africanus growing in Vietnam. Their chemical structures were elucidated by extensive 1D and 2D NMR analysis and high-resolution mass spectroscopy as well as comparisons in literature. Compounds 1-3 were evaluated for the alpha-glucosidase inhibition. They showed moderate activity with IC 50 values of 103 ± 1.7, 146.8 ± 2.5, 49 ± 0.8 µg/mL, respectively.

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients., (© 2024. The Author(s).)

Salmonella enterica subsp. enterica serovar Agona has a history of causing food-borne outbreaks and any emergence of multidrug-resistant (MDR) isolates in novel food products is of concern. Particularly, in food products frequently consumed without sufficient heating prior to consumption. Here, we report about the MDR isolate, 18-SA00377, which had been isolated from a dietary supplement in Germany in 2018 and submitted to the German National Reference Laboratory for Salmonella . WGS-based comparative genetic analyses were conducted to find a potential reservoir of the isolate itself or mobile genetic elements associated with MDR. As a phylogenetic analysis did not yield any closely related S. Agona isolates, either globally or from Germany, a detailed analysis of the largest plasmid (295,499 bp) was performed as it is the main carrier of resistances. A combined approach of long-read and short-read sequencing enabled the assembly of the isolate's chromosome and its four plasmids. Their characterization revealed the presence of 23 different antibiotic resistance genes (ARGs), conferring resistance to 12 different antibiotic drug classes, as well as genes conferring resistance to six different heavy metals. The largest plasmid, pSE18-SA00377-1, belongs to the IncHI2 plasmid family and carries 16 ARGs, that are organized as two distinct clusters, with each ARG associated with putative composite transposons. Through a two-pronged approach, highly similar plasmids to pSE18-SA00377-1 were identified in the NCBI database and a search for Salmonella isolates with a highly similar ARG resistance profile was conducted. Mapping and structural comparisons between pSE18-SA00377-1 and these plasmids and Salmonella isolates showed that both the plasmid backbone and identical or similar ARG clusters can be found not only in Salmonella isolates, originating mostly from a wide variety of livestock, but also in a diverse range of bacterial genera of varying geographical origins and isolation sources. Thus, it can be speculated that the host range of pSE18-SA00377-1 is not restricted to Salmonella and its spread already occurred in different bacterial populations. Overall, this hints at a complex history for pSE18-SA00377-1 and highlights the importance of surveilling multidrug-resistant S. enterica isolates, especially in novel food items that are not yet heavily regulated., 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 Bartsch, Borowiak, Deneke, Gruetzke, Hammerl, Malorny, Szabo, Alter, Nguyen and Fischer.)

In today's machine learning (ML), the need for vast amounts of training data has become a significant challenge. Transfer learning (TL) offers a promising solution by leveraging knowledge across different domains/tasks, effectively addressing data scarcity. However, TL encounters computational and communication challenges in resource-constrained scenarios, and negative transfer (NT) can arise from specific data distributions. This article presents a novel focus on maximizing the accuracy of instance-based TL in multisource resource-constrained environments while mitigating NT, a key concern in TL. Previous studies have overlooked the impact of resource consumption in addressing the NT problem. To address these challenges, we introduce an optimization model named multisource resource-constrained optimized TL (MSOPTL), which employs a convex combination of empirical sources and target errors while considering feasibility and resource constraints. Moreover, we enhance one of the generalization error upper bounds in domain adaptation setting by demonstrating the potential to substitute the H ∆ H divergence with the Kullback-Leibler (KL) divergence. We utilize this enhanced error upper bound as one of the feasibility constraints of MSOPTL. Our suggested model can be applied as a versatile framework for various ML methods. Our approach is extensively validated in a neural network (NN)-based classification problem, demonstrating the efficiency of MSOPTL in achieving the desired trade-offs between TL's benefits and associated costs. This advancement holds tremendous potential for enhancing edge artificial intelligence (AI) applications in resource-constrained environments.

Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates. We compared the roles of arrestin-3 conformational equilibrium and Lys-295 in GPCR binding and JNK3 activation. Several mutants with enhanced ability to bind GPCRs showed much lower activity towards JNK3, whereas a mutant that does not bind GPCRs was more active. The subcellular distribution of mutants did not correlate with GPCR recruitment or JNK3 activation. Charge neutralization and reversal mutations of Lys-295 differentially affected receptor binding on different backgrounds but had virtually no effect on JNK3 activation. Thus, GPCR binding and arrestin-3-assisted JNK3 activation have distinct structural requirements, suggesting that facilitation of JNK3 activation is the function of arrestin-3 that is not bound to a GPCR.

Most eukaryotic secretory proteins are cotranslationally translocated through Sec61 into the endoplasmic reticulum (ER). Because these proteins have evolved to fold in the ER, their mistargeting is associated with toxicity. Genetic experiments have implicated the ER heat shock protein 70 (Hsp70) Hspa13/STCH as involved in processing of nascent secretory proteins. Herein, we evaluate the role of Hspa13 in protein import and the maintenance of cellular proteostasis in human cells, primarily using the human embryonic kidney 293T cell line. We find that Hspa13 interacts primarily with the Sec61 translocon and its associated factors. Hspa13 overexpression inhibits translocation of the secreted protein transthyretin, leading to accumulation and aggregation of immature transthyretin in the cytosol. ATPase-inactive mutants of Hspa13 further inhibit translocation and maturation of secretory proteins. While Hspa13 overexpression inhibits cell growth and ER quality control, we demonstrate that HSPA13 knockout destabilizes proteostasis and increases sensitivity to ER disruption. Thus, we propose that Hspa13 regulates import through the translocon to maintain both ER and cytosolic protein homeostasis. The raw mass spectrometry data associated with this article have been deposited in the PRIDE archive and can be accessed at PXD033498., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Endoscopic screening is used widely to minimize the rates of colorectal cancer cases and deaths. During highly virulent infectious disease pandemics such as the coronavirus disease 2019 (COVID-19) pandemic, it is essential to weigh the risks and benefits of receiving endoscopy, especially in regions with moderately high viral infection rates. An observational study was conducted to assess the number of patients seen for endoscopic procedure at 2 of our surgery centers. Reasons for their procedure were collected in addition to information regarding any positive COVID-19 cases. This study considers the rate of severe acute respiratory syndrome coronavirus 2 infection along with the number of colorectal cancer cases encountered at a community endoscopy center to suggest that the benefits of undergoing endoscopic evaluation may outweigh the risks of attending an endoscopy procedure during the COVID-19 pandemic. One of the main reasons patients underwent endoscopic procedure was for colon cancer screenings (41.9%), and 5 of 1020 patients seen during the observation period were diagnosed with cancer. Of these 1020 patients, 8 were found to have positive tests for COVID-19 within 2 to 4 weeks after their procedure., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The proper trafficking of eukaryotic proteins is essential to cellular function. Genetic, environmental, and other stresses can induce protein mistargeting and, in turn, threaten cellular protein homeostasis. Current methods for measuring protein mistargeting are difficult to translate to living cells, and thus the role of cellular signaling networks in stress-dependent protein mistargeting processes, such as ER pre-emptive quality control (ER pQC), is difficult to parse. Herein, we use genetically encoded peroxidases to characterize protein import into the endoplasmic reticulum (ER). We show that the ER HRP/ cyt APEX pair provides good selectivity and sensitivity for both multiplexed protein labeling and for identifying protein mistargeting, using the known ER pQC substrate transthyretin (TTR). Although ER HRP labeling induces formation of detergent-resistant TTR aggregates, this is minimized by using low ER HRP expression, without loss of labeling efficiency. cyt APEX labeling recovers TTR that is mistargeted as a consequence of Sec61 inhibition or ER stress-induced ER pQC. Furthermore, we discover that stress-free activation of the ER stress-associated transcription factor ATF6 recapitulates the TTR import deficiency of ER pQC. Hence, proximity labeling is an effective strategy for characterizing factors that influence ER protein import in living cells.

Background: Current heart failure therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (ie, calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents-myotropes-activates the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine., Methods: We determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine and ATP concentrations, and ATP production were assessed by 31 P nuclear magnetic resonance spectroscopy on isolated perfused rat hearts., Results: TA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased the rate-pressure product. Dobutamine increased both developed pressure and heart rate accompanied by decreased phosphocreatine-to-ATP ratio and decreased free energy of ATP hydrolysis (ΔG ~ATP ) and elevated left ventricular end diastolic pressure. In contrast, the TA1 increased developed pressure without any effect on heart rate, left ventricular end diastolic pressure, phosphocreatine/ATP ratio, or ΔG ~ATP ., Conclusions: Novel myotrope TA1 increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long-term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.

Background: Little is known about cancer survivors who discontinue survivorship care. The objective of this study was to characterize patients with head and neck cancer who discontinue survivorship care with their treating institution and identify factors associated with discontinuation., Methods: This was a retrospective cohort study of patients diagnosed with head and neck cancer between January 1, 2014, and December 31, 2016, who received cancer-directed therapy at the University of Iowa Hospitals and Clinics (UIHC). Eligible patients achieved a cancer-free status after curative-intent treatment and made at least 1 visit 90+ days after treatment completion. The primary outcome was discontinuation of survivorship care, which was defined as a still living survivor who had not returned to a UIHC cancer clinic for twice the expected interval. Demographic and oncologic factors were examined to identify associations with discontinuation., Results: Ninety-seven of the 426 eligible patients (22.8%) discontinued survivorship care at UIHC during the study period. The mean time in follow-up for those who discontinued treatment was 15.4 months. Factors associated with discontinuation of care included an unmarried status (P = .036), a longer driving distance to the facility (P = .0031), and a single-modality cancer treatment (P < .0001). Rurality was not associated with discontinuation (24.3% vs 21.6% for urban residence; P = .52), nor was age, gender, or payor status., Conclusions: The study results indicate that a sizeable percentage of head and neck cancer survivors discontinue care with their treating institution. Both demographic and oncologic factors were associated with discontinuation at the treating institution, and this points to potential clinical and care delivery interventions., (© 2021 American Cancer Society.)

The continued proliferation of superbugs in hospitals and the coronavirus disease 2019 (COVID-19) has created an acute worldwide demand for sustained broadband pathogen suppression in households, hospitals, and public spaces. In response, we have created a highly active, self-sterilizing copper configuration capable of inactivating a wide range of bacteria and viruses in 30-60 seconds. The highly active material destroys pathogens faster than any conventional copper configuration and acts as quickly as alcohol wipes and hand sanitizers. Unlike the latter, our copper material does not release volatile compounds or leave harmful chemical residues and maintains its antimicrobial efficacy over sustained use; it is shelf stable for years. We have performed rigorous testing in accordance with guidelines from U.S. regulatory agencies and believe that the material could offer broad spectrum, non-selective defense against most microbes via integration into masks, protective equipment, and various forms of surface coatings., Competing Interests: Authors AAZ, MI, RLB, RR, AV, KKN, NTN, HTZ, NA, and RMS are employed by Kuprion®, Inc. Authors MI and HK are employed by Integrated Pharma Services. This study was funded by Kuprion®, Inc. All authors declare no other competing interests., (Copyright © 2021 Zinn, Izadjoo, Kim, Brody, Roth, Vega, Nguyen, Ngo, Zinn, Antonopoulos and Stoltenberg.)

The current research aimed to investigate justifications behind the perception of stealthing-the act of nonconsensual condom removal in previously consented intercourse. Based upon an article by Brodsky that conducted real-life interviews of stealthing activities, justifications for the act were experimentally manipulated after the participants read a scenario involving a depiction of stealthing. A four (Justification: Control, Instinct, Right, Pleasure) × two (Participant Gender: female, male) multivariate analysis on the assessment of various criminality, morality, harm, blame/responsibility items yielded a significant difference in terms of rape determination, but not other criminality measures. Implications for future research are discussed.

This study attempted to characterize the microbial community and its role in anaerobic digestion of lipid. Reactors were fed semi-continuously with three related substrates, oil and its degradation intermediates (glycerol and long chain fatty acids (LCFAs)), with a stepwise increase in organic loading rate for 90 days. Microbial community analysis using next-generation sequencing (NGS) with the MiSeq Illumina platform revealed that Anaerolineaceae was the most dominant group of bacteria in all experiments, whereas Clostridium, Desulfovibrio, Rikenellaceae, and Treponema were observed characteristically in glycerol degradation and Leptospirales, Synergistaceae, Thermobaculaceae and Syntrophaceae were seen with high abundance in LCFA and oil mineralization. Furthermore, it was discovered that Methanosaeta was the most dominant archaea. The role of these microorganisms in the methane production from oil was estimated by comparing the microbial groups in the fermentation using three substrates, and a hypothetical pathway of the methane production was proposed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This article reports the development and psychometric properties of the 27-item Barriers to Seeking Mental Health Counseling (BMHC) scale, which assesses perceived help-seeking barriers among college-aged students. Across 2 studies involving ethnically diverse samples (e.g., Latinx majority students), the authors provided evidence for this new measure's validity and reliability. Exploratory and confirmatory factor analyses (including a bifactor analysis) provided support for the BMHC scale's multidimensionality reflecting 6 barriers: Negative Perceived Value, Discomfort with Emotions, Ingroup Stigma, Lack of Knowledge, Lack of Access, and Cultural Barriers. Evidence for criterion-related validity was shown through significant but differential correlations with self-stigma, emotional control, and the 4 components of Ajzen's (1991) Theory of Planned Behavior model-attitude, subjective norm of social stigma, perceived behavioral control, and mental health help-seeking intention. Discriminant evidence of validity was established through nonsignificant or small correlations between BMHC subscales and 2 measures of socially desirable responding. The authors also found evidence for incremental validity and measurement invariance across race, and evidence for internal reliability and temporal stability of the BMHC subscales. Findings are discussed in light of the conceptual, methodological, and clinical contributions of the BMHC scale. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

: Despite widespread concerns about HIV incidence in pregnant and postpartum women, there are few data from Africa on HIV acquisition in breastfeeding and subsequent mother-to-child transmission. We measured HIV incidence in a prospective cohort of 413 peripartum and breastfeeding women who tested HIV-negative during pregnancy. In 377 woman-years accrued postpartum (median duration of follow-up, 1 year), there were seven women infected after delivery (postpartum incidence, 1.86/100 person-years; 95% confidence interval 0.88-3.89) with transmission to 2/7 (28%) infants.

Influenza infection requires viral escape from early endosomes into the cytosol, which is enabled by an acid-induced irreversible conformational transformation in the viral protein hemagglutinin. Despite the direct relationship between this conformational change and infectivity, label-free methods for characterizing this and other protein conformational changes in biological mixtures are limited. While the chemical reactivity of the protein backbone and side-chain residues is a proxy for protein conformation, coupling this reactivity to quantitative mass spectrometry is a challenge in complex environments. Herein, we evaluate whether electrophilic amidination coupled with pseudo-parallel reaction monitoring is an effective label-free approach to detect the fusion-associated conformational transformation in recombinant hemagglutinin (rHA). We identified rHA peptides that are differentially amidinated between the pre- and post-fusion states, and validated that this difference relies upon the fusion-associated conformational switch. We further demonstrate that we can distinguish the fusion profile in a matrix of digested cellular lysate. This fusion assay can be used to evaluate fusion competence for modified HA. Graphical abstract.

Objective: To compare the efficacy of pain control and opioid consumption between patients who receive opioid as primary analgesic therapy and those who receive ibuprofen., Study Design: Prospective randomized trial., Setting: Tertiary care academic hospital., Subject and Methods: Adult patients undergoing outpatient otolaryngology surgery were assigned to take hydrocodone/acetaminophen or ibuprofen for postoperative analgesia. Patient-recorded pain scores and analgesic consumption were analyzed., Results: Out of 185 recruits, 108 (58%) completed responses. Fifty-six patients (52%) received opioid medication for primary analgesic treatment versus 52 (48%) who received ibuprofen. There was no difference in reported pain scores between the treatment groups. Those who received ibuprofen as primary therapy reported a significantly lower consumption of opioid medication at 2.04 tablets/pills (95% CI, 0.9-3.1) versus 4.86 (3.6-6.1; P = .001). Based on multivariate analysis, male sex and older age exhibited lower reported pain scores, while older age and use of ibuprofen as primary therapy exhibited lower opioid requirements., Conclusion: For postoperative pain management in outpatient otolaryngology procedures, ibuprofen as primary therapy can provide equally effective pain control as compared with hydrocodone/acetaminophen while decreasing overall opioid requirement. Prescription pill counts are further described to help guide physician practices in the era of an opioid epidemic.

Background & Aims: The American Association for the Study of Liver Diseases (AASLD) guidelines for treatment of chronic hepatitis B virus (HBV) infection have changed with time. We assessed rates of treatment evaluation and initiation in patients with chronic HBV infection from different practice settings in the past 14 years., Methods: Treatment-naive patients with chronic HBV infection were recruited from different practice settings in California from January 2002 through December 2016. The study population comprised 4130 consecutive, treatment-naive patients with chronic HBV infection seen by community primary care physicians (n = 616), community gastroenterologists (n = 2251), or university hepatologists (n = 1263). Treatment eligibility was assessed using data from the first 6 months after initial presentation based on AASLD criteria adjusted for changes over time., Results: Within the first 6 months of care, the proportions of patients evaluated by all 3 relevant tests (measurements of alanine aminotransferase, hepatitis B virus e antigen, and HBV DNA levels) were as follows: 36.69% in community primary care, 59.80% in gastroenterologist care, and 79.97% in hepatology care (P < .0001 among the 3 groups). Higher proportions of patients were eligible for treatment in specialty practices: 12.76% in community primary care, 24.96% in gastroenterologist care, and 29.43% in hepatology care (P < .0001). Among treatment-eligible patients, there was no significant difference in the proportions of patients who began antiviral therapy between those receiving treatment from a gastroenterologist (55.65%) vs a hepatologist (57.90%; P = .56). Of 243 evaluable patients receiving community primary care, only 31 were eligible for treatment and only 12 of these (38.71%) received treatment., Conclusions: In an analysis of patients receiving care for chronic HBV infection, we found the proportions evaluated and receiving treatment to be suboptimal, according to AASLD criteria, in all practice settings. However, rates of evaluation and treatment were lowest for patients receiving community primary care., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Over 1 million HIV-exposed uninfected (HEU) children are born in sub-Saharan Africa annually. Little data exist on the risk of impaired growth in this population under current policies of universal maternal antiretroviral therapy (ART) with breastfeeding. We aimed to study the growth of breastfed HEU children born to women who initiated ART during pregnancy and compare their growth with that of breastfed HIV-unexposed (HU) children drawn from the same community., Methods: A prospective cohort of HIV-uninfected and HIV-infected pregnant women, who were initiating ART, were enrolled at their first antenatal care visit in a primary care centre in Gugulethu, Cape Town, South Africa. HIV infected women were participants of the Maternal Child Health Antiretroviral Therapy (MCH-ART) study, and HIV-uninfected pregnant women were participants in the HIV-Unexposed-Uninfected (HU2) study. All women were followed up during pregnancy, through delivery, to the early postnatal visit, which was scheduled for the first week after birth. At this visit, eligible breastfeeding mother-child pairs were recruited for continuation of postnatal follow-up until approximately age 12 months. Child anthropometry was measured at around 6 weeks, and every 3 months from month 3 to month 12. Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), head circumference-for-age, and body-mass index-for-age Z scores were compared between HEU and HU children longitudinally using mixed effects linear regression. At 12 months, proportions of HEU and HU children with moderate or severe malnutrition were compared cross-sectionally using logistic regression. MCH-ART is registered with ClinicalTrials.gov, number NCT01933477., Findings: Between June, 2013, and April, 2016, 884 breastfeeding mothers and their newborn babies (HEU, n=471; HU, n=413) were enrolled into postnatal follow-up. Excluding 12 children who tested HIV positive during follow-up, 461 HEU and 411 HU children attended 4511 study visits in total, with a median of 6 visits (IQR 5-6) per child. Birth characteristics were similar (overall, 94 [11%] of 872 preterm [<37 weeks] and 90 [10%] small-for-gestational age [birthweight <10th percentile]). Median duration of breastfeeding was shorter among HEU than HU children (3·9 months [IQR 1·4-12·0] vs 9·0 months [IQR 3·0-12·0]). Although WAZ scores increased over time in both groups, HEU children had consistently lower mean WAZ scores than HU children (overall β -0·34, 95% CI -0·47 to -0·21). LAZ scores decreased in both groups after 9 months. At 12 months, HEU children had lower mean LAZ scores than HU children (β -0·43, -0·61 to -0·25), with a higher proportion of children stunted (LAZ score <-2: 35 [10%] of 342 HEU vs 14 [4%] of 342 HU children; odds ratio [OR] 2·67, 95% CI 1·41 to 5·06). Simultaneously, overweight (WLZ score >2) was common in both groups of children at 12 months (54 [16%] of 342 HEU vs 60 [18%] of 340 HU children; OR 0·87, 95% CI 0·58 to 1·31)., Interpretation: Compared with HU children, HEU children have small deficits in early growth trajectories under policies of universal maternal ART and breastfeeding. Large proportions of both HEU and HU children were overweight by 12 months, indicating substantial risks for early onset obesity among South African children. Although the longer-term metabolic effects of ART exposure in the context of childhood obesity warrants further investigation, addressing childhood obesity should be an urgent public health priority in this setting., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, and the Fogarty Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: This study sought to develop a novel targeted delivery therapy to ablate the major atrial ganglionated plexi (GP) using magnetic nanoparticles carrying a CaCl 2 payload., Background: Prior studies indicated the role of hyperactivity of the cardiac autonomic nervous system in the genesis of atrial fibrillation., Methods: Twenty-eight male mongrel dogs underwent a bilateral thoracotomy. CaCl 2 -encapsulated magnetic nanoparticles (Ca-MNP) included magnetite in a sphere of biocompatible, biodegradable poly(lactic-co-glycolic acid). A custom external electromagnet focusing the magnetic field gradient (2,600 G) on the epicardial surface of the targeted GP was used to pull Ca-MNP into and release CaCl 2 within the GP. The ventricular rate slowing response to high frequency stimulation (20 Hz, 0.1 ms) of the GP was used to assess the GP function., Results: The minimal effective concentration of CaCl 2 to inhibit the GP function was 0.5 mmol/l. Three weeks after CaCl 2 (0.5 mmol/l, n = 18 GP) or saline (n = 18 GP) microinjection into GP, the increased GP function, neural activity, and atrial fibrillation inducibility, as well as shortened effective refractory period in response to 6 h of rapid atrial pacing (1,200 beats/min) were suppressed by CaCl 2 microinjection. After intracoronary infusion of Ca-MNP, the external electromagnet pulled Ca-MNP to the targeted GP and suppressed the GP function (n = 6 GP) within 15 min., Conclusions: Ca-MNP can be magnetically targeted to suppress GP function by calcium-mediated neurotoxicity. This novel approach may be used to treat arrhythmias related to hyperactivity of the cardiac autonomic nervous system, such as early stage of atrial fibrillation, with minimal myocardial injury., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess neurodevelopment of breastfed HIV-exposed uninfected (HEU) and breastfed HIV-unexposed children in the context of universal maternal antiretroviral therapy (ART)., Design: Prospective study with antenatal enrolment and follow-up of breastfeeding HEU and HIV-unexposed mother-infant pairs through 12-18 months postpartum., Setting: Peri-urban community, Cape Town, South Africa., Participants: HEU (n = 215) and HIV-unexposed (n = 306) children., Main Outcome Measures: Cognitive, motor and language development at median 13 (interquartile range 12-14) months of age: continuous and dichotomous Bayley Scales of Infant and Toddler Development Third Edition (delay defined as composite score <85)., Results: Incidence of preterm delivery (<37 weeks) was similar among HEU and HIV-unexposed children (11 vs. 9%, P = 0.31; median gestation 39 weeks); 48% were boys. Median breastfeeding duration was shorter among HEU vs. HIV-unexposed children (6 vs. 10 months). All HIV-infected mothers initiated lifelong ART (tenofovir-emtricitabine-efavirenz) antenatally. HEU (vs. HIV-unexposed) children had higher odds of cognitive delay [odds ratio (OR) 2.28 (95% confidence interval (CI) 1.13-4.60)] and motor delay [OR 2.10 (95% CI 1.03-4.28)], but not language delay, in crude and adjusted analysis. Preterm delivery modified this relationship for motor development: compared with term HIV-unexposed children, term HEU children had similar odds of delay, preterm HIV-unexposed children had five-fold increased odds of delay (adjusted OR 4.73, 95% CI 1.32; 16.91) and preterm HEU children, 16-fold increased odds of delay (adjusted OR 16.35, 95% CI 5.19; 51.54)., Conclusion: Young HEU children may be at increased risk for cognitive and motor delay despite universal maternal ART and breastfeeding; those born preterm may be particularly vulnerable.

Poplar hybrids can be used for selenium (Se) and boron (B) phytoremediation under saline conditions. The phenolic antioxidant stress response of two salt and B tolerant poplar hybrids of parentage Populus trichocarpa × nigra × deltoides was studied using high-performance liquid chromatography (HPLC) and absorption-based assays to determine the antioxidant capacity, total phenolic content, hydroxycinnamic acid levels, and the enzyme activity of l-phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), phenol peroxidase (POD), and laccase. Most remarkable was the contrasting response of the two poplar clones for PPO activity and phenolic levels to irrigation with high salt/B water. To cope with stressful growing conditions, only one clone increased its phenolic antioxidant level, and each clone displayed different PPO isoform patterns. Our study shows that poplar hybrids of the same parentage can differ in their salt/B stress coping mechanism.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus., (© 2017 John Wiley & Sons Ltd.)

Massive all-atom molecular dynamics simulations were conducted across a distributed computing network to study the folding, unfolding, misfolding and conformational plasticity of the high-efficiency frameshifting double mutant of the 26 nt potato leaf roll virus RNA pseudoknot. Our robust sampling, which included over 40 starting structures spanning the spectrum from the extended unfolded state to the native fold, yielded nearly 120 μs of cumulative sampling time. Conformational microstate transitions on the 1.0 ns to 10.0 μs timescales were observed, with post-equilibration sampling providing detailed representations of the conformational free energy landscape and the complex folding mechanism inherent to the pseudoknot motif. Herein, we identify and characterize two alternative native structures, three intermediate states, and numerous misfolded states, the latter of which have not previously been characterized via atomistic simulation techniques. While in line with previous thermodynamics-based models of a general RNA folding mechanism, our observations indicate that stem-strand-sequence-separation may serve as an alternative predictor of the order of stem formation during pseudoknot folding. Our results contradict a model of frameshifting based on structural rigidity and resistance to mechanical unfolding, and instead strongly support more recent studies in which conformational plasticity is identified as a determining factor in frameshifting efficiency., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Regenerative medicine holds substantial promise for repairing or replacing tissues and organs damaged by disease, injury, and degeneration. Much of the field has focused on development of cell-based therapeutics, gene-based therapeutics, and tissue engineering-based therapeutics. In contrast, development of small molecule regenerative medicine therapies is an emerging area. Using the adult zebrafish as a novel screening platform, we identified MSI-1436 as a first-in-class regenerative medicine drug candidate. MSI-1436 is a naturally occurring aminosterol that inhibits protein tyrosine phosphatase 1B. Treatment of adult zebrafish by intraperitoneal injection of MSI-1436 increased the rate of regeneration of the amputated caudal fin, which is comprised of bone, connective, skin, vascular and nervous tissues and also increased the rate of adult zebrafish heart regeneration. Intraperitoneal administration of MSI-1436 to adult mice for 4 weeks after induction of myocardial infarction increased survival, improved heart function, reduced infarct size, reduced ventricular wall thinning and increased cardiomyocyte proliferation. Satellite cell activation in injured mouse skeletal muscle was stimulated by MSI-1436. MSI-1436 was well tolerated by patients in Phase 1 and 1b obesity and type 2 diabetes clinical trials. Doses effective at stimulating regeneration are 5-50-times lower than the maximum well tolerated human dose. The demonstrated safety and well established pharmacological properties of MSI-1436 underscore the potential of this molecule as a novel treatment for heart attack and multiple other degenerative diseases.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations., (© 2016 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Background and Aims: Despite available effective therapies, only a minority of patients with chronic hepatitis B (CHB) receive treatment. Our goal is to study treatment rates and time to treatment initiation in patients who meet treatment criteria on long-term follow-up., Methods: We performed a retrospective cohort study of 608 consecutive treatment-eligible patients with CHB (by 2008 US Panel or 2009 American Association for the Study of Liver Disease (AASLD) criteria) at a US community gastroenterology clinic and a university liver clinic between 2007 and 2011. Patients were observed until they started treatment or last follow-up if untreated., Results: Mean age was 44 and most were Asian (96%) with community patients being younger and having lower alanine aminotransferase (ALT) levels. A total of 62% started treatment, and 38% remained untreated after median follow-up of 17 months (IQR=1-40 months). Overall, treatment rate was significantly higher at university liver clinic than in the community (66.7% vs 59.9%, p=0.01). In multivariate analysis, older age (HR 1.02, p=0.002), male gender (HR 1.37, p=0.02), and baseline ALT >45 U/L for males and >29 U/L for females (HR 2.24, p<0.0001) were significant predictors of treatment initiation, but not practice setting., Conclusions: Approximately 40% of treatment-eligible patients still have not started treatment on longer follow-up. Treatment rates were higher at university clinics, but practice setting was not a predictor for treatment, but older age, male gender, and higher ALT levels were. Further studies are needed to determine the barriers for treatment initiation and to improve treatment rates in treatment-eligible patients.

Background and Aim: Suboptimal viral suppression with adefovir (ADV) poses a challenge in managing chronic hepatitis B. Few studies have evaluated the efficacy of entecavir (ETV) in ADV-experienced patients. Our aim is to assess treatment effectiveness of ETV in ADV-experienced patients., Methods: ADV-experienced patients switched to ETV were enrolled from six US clinics. Patients completed a median of 24 months of ETV after switch. Patients were categorized into partial responders (detectable HBV-DNA at switch) or complete responders (undetectable HBV-DNA at switch) to ADV. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV-DNA < 60 IU/mL) and biochemical response (BR, alanine aminotransferase [ALT] < 40 U/L), respectively., Results: A total of 120 patients were included in the analysis (80 ADV partial responders; 40 ADV complete responders). In partial responders, CVS rate was 84% after 24 months of ETV. BR rate was 58% at switch to ETV and increased to 90% after 24 months. All complete responders continued to experience CVS after switch. On multivariate analysis inclusive of age, male gender, ALT level at switch, and history of lamivudine (LAM) exposure, we identified positive, hepatitis B e antigen status before ADV and higher HBV-DNA level at time of switch as significant independent negative predictors of CVS. In eight patients with ADV resistance, seven achieved CVS after 24 months of ETV, and all achieved BR., Conclusion: In ADV-experienced patients, high rates of CVS and BR can be achieved/sustained after switching to ETV, including those with ADV resistance or with prior exposure to LAM., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR- or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden.CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background and Aims: The dose recommendation for entecavir (ETV) is 0.5 mg daily for treatment-naïve chronic hepatitis B (CHB) patients and 1.0 mg daily for lamivudine-refractory patients; however, few data are available for the efficacy of a 1.0-mg daily dose in treatment-naïve CHB patients. Our goal is to examine the treatment outcome of treatment-naïve patients placed on ETV 0.5 mg or ETV 1.0 mg daily through week 48., Methods: Cases were 40 consecutive hepatitis B e antigen (HBeAg)-positive CHB patients treated with ETV 1.0 mg daily between January 2005 and September 2010, and controls were 40 consecutive CHB patients treated with ETV 0.5 mg daily between January 2005 and September 2010 at three US gastroenterology/liver clinics. Controls were matched for age (±5 years), sex, HBeAg, and baseline hepatitis B virus (HBV) DNA (±0.5 log10 IU/ml). Complete viral suppression was defined as undetectable HBV DNA by polymerase chain reaction (<100 IU/ml)., Results: Both groups had similar distributions of age (38 ± 11 years), male patients (55 %), and mean HBV DNA (7.7 ± 1.1 log10 IU/ml). The complete viral suppression rate was similar in both cases and controls through week 24 (15 vs. 15 %, p = 1.00) and week 48 (22 vs. 36 %, p = 0.17). Non-adherence was reported in three patients in the ETV 1.0 mg daily cohort at week 48., Conclusions: There were no significant differences in the proportion of patients with complete viral suppression in patients treated with ETV 0.5 mg daily or the higher daily dose of 1.0 mg.

Background and Aims: The Centers for Disease Control and Prevention recommend screening for hepatitis C virus (HCV) in patients with injection drug use, blood transfusion before 1992, stigmata of liver disease, or born between 1945 and 1965. The purpose of this study was to examine risk factors for HCV acquisition in Asian Americans., Methods: This was a case-controlled study, with 471 consecutive patients testing positive for anti-HCV between January 2001 and December 2008. Controls included 471 patients with negative HCV matched at a one-to-one ratio for sex, age (±5 years), and ethnicity., Results: For Asian patients, the most common risk factors were blood transfusion and acupuncture or exposure to dirty needles (27 and 20 %, respectively). On multiple logistic regression, potential predictors for a positive anti-HCV test in Asians were acupuncture or exposure to dirty needles (OR = 12.9, P < 0.0001), body tattoo (OR = 12.0, P = 0.001), and history of blood transfusion (OR = 5.7, P < 0.0001)., Discussion: Acupuncture and exposure to dirty needles are independent risk factors of HCV infection. Asians coming from endemic areas should be screened for HCV even when commonly-known risk factors for Western patients are not present.

Background and Aim: Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates., Methods: We conducted a retrospective cohort study of 333 consecutive treatment-naïve HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion-loss of HBeAg and antibody to HBeAg (anti-HBe) development., Results: The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26-52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA < 7.5 log10  IU/mL (hazard ratio [HR] = 2.59 [1.04-6.44]), P = 0.041) and alanine transaminase (ALT) > 1.5 × upper normal limit (HR = 2.86 [1.05-7.81], P = 0.040), but not the choice of nucleos(t)ides., Conclusions: The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Despite its high potency against hepatitis B virus (HBV), entecavir (ETV) 0.5 mg daily may not be sufficient to induce complete viral suppression in some patients with very high pretreatment viremia. It is not clear whether ETV 1.0 mg daily would have additive effect in such patients., Goals: Our goal was to examine virologic outcome of ETV 1.0 mg daily in patients with partial response to ETV 0.5 mg daily., Methods: We retrospectively studied 31 consecutive treatment-naive patients who were switched to ETV 1.0 mg daily after partial response [reduction of HBV DNA ≥2 log10 IU/mL but with detectable HBV DNA levels (>100 IU/mL) after 24 weeks of therapy or longer] with ETV 0.5 mg daily from January 2005 to January 2010 at 2 clinics., Results: All patients were Asians and 90% had positive hepatitis B e antigen. Mean HBV DNA was 8.04±0.65 log10 IU/mL before therapy and 3.64±0.91 log10 IU/mL at the time of switch. Overall rate of complete viral suppression were 29% (n=9/31) after 24 weeks of ETV 1.0 mg daily and 22% (n=5/23) after 48 weeks. Complete viral suppression after 24 weeks with ETV 1.0 mg daily was significantly higher in patients with lower HBV DNA (<3 log10 IU/mL) at time of switch: 75% versus 5%, P<0.0001., Conclusions: The majority of patients with partial response to ETV 0.5 mg daily did not achieve complete viral suppression with the higher dose of ETV 1.0 mg daily except those with minimal residual viremia (HBV DNA <3 log10 IU/mL).

Goals and Background: Besides United States population born between 1945 and 1965, screening for hepatitis C virus (HCV) is not recommended for the general US population. However, HCV may be more prevalent in certain subgroups and screening may be warranted. The goal of this study was to examine the proportion of HCV in a large sample of community Asian American patients presenting for non-liver-related complaints., Study: We conducted a cross-sectional study of 1246 patients tested for hepatitis C virus antibodies (anti-HCV) referred to 2 gastroenterology clinics for non-liver-related gastrointestinal reasons between January 2001 and February 2011. We determined HCV status and patient history via electronic medical record review., Results: Of the 1246 study patients tested for anti-HCV, the majority were Asian (81.4%) and 29 Asian patients (2.9%) had positive anti-HCV. HCV proportion in the remaining 232 non-Asians (non-Hispanic whites and Hispanics) was 1.7%. Asians with positive anti-HCV were more likely to have had blood transfusions (31.0% vs. 6.6%, P<0.0001) or acupuncture (10.3% vs. 1.5%, P<0.0001). Of the 976 Asian patients with hepatitis B surface antigen testing, 38 (3.9%) also had detectable hepatitis B surface antigen., Conclusions: Among patients seen at community gastroenterology clinics for non-liver-related reasons, HCV proportion was 1.7% for non-Asians and 2.9% for Asians. Screening for HCV should be offered to high-risk patients presenting to gastroenterology clinics with unrelated gastrointestinal complaints.

Background and Purpose: Automatic brightness control (ABC), a function of modern fluoroscopy machines, adjusts radiation intensity in real time to enhance image quality. While shielding reduces radiation exposure to protected areas, it is unknown how much radiation adjacent unshielded areas receive when using ABC settings. Our purpose was to assess radiation dosage to shielded and unshielded tissue when using fluoroscopic ABC mode compared with fixed exposure settings., Materials and Methods: In a simulated ureteroscopy, thermoluminescent dosimeters (TLDs) were placed at three sites in a female human cadaver, including the right renal hilum, right distal ureter adjacent to the uterus, and directly over the uterus. The cadaver received 60 seconds of radiation exposure using a C-arm fluoroscopy system under ABC and fixed settings (1.38 mAs, 66 kVp) with and without uterine shielding. Radiation dosage absorbed by the TLDs was compared using two-way analysis of variance and least-squares confidence intervals., Results: Shielding significantly reduced radiation dose to the uterus by 62% and 82% (P<0.05 for both) in ABC and fixed settings, respectively. Shielding of the uterus in ABC, however, resulted in an approximately twofold increase in radiation dosage to the ureter and ipsilateral kidney (P<0.05 for both) and a decrease in image quality. Using fixed settings, shielding of the uterus did not increase radiation dose to the ipsilateral ureter and kidney., Conclusion: There is a significant increase in radiation dosage to surrounding tissues when shielding is used with ABC mode during fluoroscopy. Radiation can be reduced and image quality improved by using fixed settings when shielding is indicated.

Background: An increasing number of patients with chronic hepatitis B (CHB) have experienced treatment failure to adefovir (ADV) and their management poses a growing challenge. Very limited data are available on the efficacy of entecavir (ETV) in patients previously treated with ADV., Aim: To examine the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response., Methods: Study candidates were enrolled from five community gastroenterology clinics in the U.S. Each completed at least 12 months of ETV treatment after being previously treated with ADV and experiencing suboptimal response. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV DNA <100 IU/mL) and biochemical response (BR, ALT < 40 U/L), respectively., Results: A total of 60 patients were included in this analysis. Twelve were lamivudine (LAM)-experienced and none were LAM-resistant. At time of switch to ETV, no patients had experienced CVS. The CVS rate was 68% after 12 months of ETV therapy. The BR rate was 67% at switch to ETV and 80% after 12 months. There was no significant difference in response rates between LAM-experienced and naïve patients. Among the eight patients with ADV resistance, each achieved CVS after 12 months of ETV therapy and seven achieved BR., Conclusions: In patients with suboptimal response to adefovir, complete viral suppression and biochemical response can be achieved in the majority by 12 months after switching to entecavir, including patients with prior exposure to lamivudine and those with adefovir resistance., (© 2011 Blackwell Publishing Ltd.)