Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

Low-Frequency Ground Vibrations Generated by Debris Flows Detected by a Lab-Fabricated Seismometer.

A lab-fabricated ocean bottom seismometer was modified and deployed terrestrially to detect low-frequency (<10 Hz) ground vibrations produced by debris flows. A frequency−response test of the new seismometer revealed that it can detect seismic signals at frequencies of 0.3−120 Hz. Its seismic ground motion detection ability was investigated by comparing its measurements of seismic signals produced by rockfalls with those of a geophone. Two new seismometers were deployed at the Aiyuzi Stream, Nantou County, Taiwan, in September 2012. Seismic signals produced by two local earthquakes, two teleseisms, and three debris flows detected by the seismometer in 2013 and 2014 were discussed. The seismic signal frequencies of the local earthquakes and teleseisms (both approximately 1800 km apart) were 0.3−30 and <1 Hz, respectively. Moreover, seismometer measurements revealed that seismic signals generated by debris flows can have minimum frequencies as low as 2 Hz. Time-matched CCD camera images revealed that debris flow surge fronts with larger rocks have lower minimum frequencies. Finally, because the seismometer can detect low-frequency seismic waves with low spatial decay rates, it was able to detect one debris flow approximately 3 min and 40 s before it arrived.

Total Alanine Aminotransferase (ALT) Flares in Pregnant North American Women With Chronic Hepatitis B Infection: Results From a Prospective Observational Study.

INTRODUCTION: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. RESULTS: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. DISCUSSION: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Gene duplications are extensive and contribute significantly to the toxic proteome of nematocysts isolated from Acropora digitifera (Cnidaria: Anthozoa: Scleractinia).

BACKGROUND: Gene duplication followed by adaptive selection is a well-accepted process leading to toxin diversification in venoms. However, emergent genomic, transcriptomic and proteomic evidence now challenges this role to be at best equivocal to other processess . Cnidaria are arguably the most ancient phylum of the extant metazoa that are venomous and such provide a definitive ancestral anchor to examine the evolution of this trait. METHODS: Here we compare predicted toxins from the translated genome of the coral Acropora digitifera to putative toxins revealed by proteomic analysis of soluble proteins discharged from nematocysts, to determine the extent to which gene duplications contribute to venom innovation in this reef-building coral species. A new bioinformatics tool called HHCompare was developed to detect potential gene duplications in the genomic data, which is made freely available ( https://github.com/rgacesa/HHCompare ). RESULTS: A total of 55 potential toxin encoding genes could be predicted from the A. digitifera genome, of which 36 (65 %) had likely arisen by gene duplication as evinced using the HHCompare tool and verified using two standard phylogeny methods. Surprisingly, only 22 % (12/55) of the potential toxin repertoire could be detected following rigorous proteomic analysis, for which only half (6/12) of the toxin proteome could be accounted for as peptides encoded by the gene duplicates. Biological activities of these toxins are dominatedby putative phospholipases and toxic peptidases. CONCLUSIONS: Gene expansions in A. digitifera venom are the most extensive yet described in any venomous animal, and gene duplication plays a significant role leading to toxin diversification in this coral species. Since such low numbers of toxins were detected in the proteome, it is unlikely that the venom is evolving rapidly by prey-driven positive natural selection. Rather we contend that the venom has a defensive role deterring predation or harm from interspecific competition and overgrowth by fouling organisms. Factors influencing translation of toxin encoding genes perhaps warrants more profound experimental consideration.

CHOP is a critical regulator of acetaminophen-induced hepatotoxicity.

BACKGROUND & AIMS: The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. METHODS: A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed. RESULTS: CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells. CONCLUSIONS: CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication.

Addition of nitazoxanide to PEG-IFN and ribavirin to improve HCV treatment response in HIV-1 and HCV genotype 1 coinfected persons naïve to HCV therapy: results of the ACTG A5269 trial.

BACKGROUND: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons. METHODS: Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR). RESULTS: Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated. CONCLUSION: Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.

Calibration and deployment of a fiber-optic sensing system for monitoring debris flows.

This work presents a novel fiber-optic sensing system, capable of monitoring debris flows or other natural hazards that produce ground vibrations. The proposed sensing system comprises a demodulator (BraggSCOPE, FS5500), which includes a broadband light source and a data logger, a four-port coupler and four Fiber Bragg Grating (FBG) accelerometers. Based on field tests, the performance of the proposed fiber-optic sensing system is compared with that of a conventional sensing system that includes a geophone or a microphone. Following confirmation of the reliability of the proposed sensing system, the fiber-optic sensing systems are deployed along the Ai-Yu-Zi and Chu-Shui Creeks in Nautou County of central Taiwan for monitoring debris flows. Sensitivity test of the deployed fiber-optic sensing system along the creek banks is also performed. Analysis results of the seismic data recorded by the systems reveal in detail the frequency characteristics of the artificially generated ground vibrations. Results of this study demonstrate that the proposed fiber-optic sensing system is highly promising for use in monitoring natural disasters that generate ground vibrations.

Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005-2016 NHANES.

A well-functioning immune system is essential for human health and well-being. Micronutrients such as vitamins A, C, D, E, and zinc have several functions throughout the immune system, yet inadequate nutrient intakes are pervasive in the US population. A large body of research shows that nutrient inadequacies can impair immune function and weaken the immune response. Here, we present a new analysis of micronutrient usual intake estimates based on nationally representative data in 26,282 adults (>19 years) from the 2005-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the prevalence of inadequacy (% of population below estimated average requirement [EAR]) in four out of five key immune nutrients is substantial. Specifically, 45% of the U.S. population had a prevalence of inadequacy for vitamin A, 46% for vitamin C, 95% for vitamin D, 84% for vitamin E, and 15% for zinc. Dietary supplements can help address nutrient inadequacy for these immune-support nutrients, demonstrated by a lower prevalence of individuals below the EAR. Given the long-term presence and widening of nutrient gaps in the U.S.-specifically in critical nutrients that support immune health-public health measures should adopt guidelines to ensure an adequate intake of these micronutrients. Future research is needed to better understand the interactions and complexities of multiple nutrient shortfalls on immune health and assess and identify optimal levels of intake in at-risk populations.

Asking Sensitive Questions Using the Randomized Response Approach in Public Health Research: An Empirical Study on the Factors of Illegal Waste Disposal.

A survey study is a research method commonly used to quantify population characteristics in biostatistics and public health research, two fields that often involve sensitive questions. However, if answering sensitive questions could cause social undesirability, respondents may not provide honest responses to questions that are asked directly. To mitigate the response distortion arising from dishonest answers to sensitive questions, the randomized response technique (RRT) is a useful and effective statistical method. However, research has seldom addressed how to apply the RRT in public health research using an online survey with multiple sensitive questions. Thus, we help fill this research gap by employing an innovative unrelated question design method. To illustrate how the RRT can be implemented in a multivariate analysis setting, we conducted a survey study to examine the factors affecting the intention of illegal waste disposal. This study demonstrates an application of the RRT to investigate the factors affecting people's intention of illegal waste disposal. The potential factors of the intention were adopted from the theory of planned behavior and the general deterrence theory, and a self-administered online questionnaire was employed to collect data. Using the RRT, a covariance matrix was extracted for examining the hypothesized model via structural equation modeling. The survey results show that people's attitude toward the behavior and their perceived behavioral control significantly positively affect their intention. This paper is useful for showing researchers and policymakers how to conduct surveys in environmental or public health related research that involves multiple sensitive questions.

Comparative proteomics reveals recruitment patterns of some protein families in the venoms of Cnidaria.

Cnidarians are probably the oldest group of animals to be venomous, yet our current picture of cnidarian venom evolution is highly imbalanced due to limited taxon sampling. High-throughput tandem mass spectrometry was used to determine venom composition of the scyphozoan Chrysaora lactea and two cubozoans Tamoya haplonema and Chiropsalmus quadrumanus. Protein recruitment patterns were then compared against 5 other cnidarian venom proteomes taken from the literature. A total of 28 putative toxin protein families were identified, many for the first time in Cnidaria. Character mapping analysis revealed that 17 toxin protein families with predominantly cytolytic biological activities were likely recruited into the cnidarian venom proteome before the lineage split between Anthozoa and Medusozoa. Thereafter, venoms of Medusozoa and Anthozoa differed during subsequent divergence of cnidarian classes. Recruitment and loss of toxin protein families did not correlate with accepted phylogenetic patterns of Cnidaria. Selective pressures that drive toxin diversification independent of taxonomic positioning have yet to be identified in Cnidaria and now warrant experimental consideration.

Routine chest X-ray after percutaneous tracheostomy is unnecessary.

Percutaneous tracheostomy (PT) is an increasingly common procedure in the management of critically ill patients. Current practice for both open and percutaneous tracheostomies is a post-procedure chest X-ray to rule out potentially life-threatening complications such as a pneumothorax or tube malposition. Our study evaluated the utility of chest X-ray after PT. A retrospective chart review was conducted for patients undergoing PT at Kern Medical Center between January 1999 and December 2003. Charts were reviewed for age, sex, and clinical outcome as well as the radiologist's interpretation of the postprocedure chest X-ray. A total of 73 procedures were completed in 47 men and 26 women. The majority of the tracheostomies were in trauma patients who needed prolonged ventilatory support. There were no complications identified on postprocedure chest X-ray. A single patient was converted to an open procedure secondary to bleeding. We conclude that routine chest X-ray after PT is unnecessary.

Role of drains in laparoscopic appendectomy for complicated appendicitis at a busy county hospital.

Laparoscopic appendectomy (LA) has become the treatment of choice for acute appendicitis with equal or better outcomes than traditional open appendectomy (OA). LA in patients with a gangrenous or perforated appendicitis carries increased rate of pelvic abscess formation when compared with OA. We hypothesized routine placement of pelvic drains in gangrenous or perforated appendicitis decreases pelvic abscess formation after LA. Three hundred thirty-one patients undergoing LA between January 2007 and June 2011 were reviewed. Patients with perforated or gangrenous appendicitis were included. Group I had a Jackson-Pratt (JP) drain(s) placed and Group II had no JP drain. Data included patient demographics, emergency department laboratory values and vital signs, and computed axial tomography scan findings, intra-abdominal or pelvic abscess postoperatively, interventional radiology drainage, and length of stay. Clinic follow-up notes were reviewed. One hundred forty-eight patients were identified. Forty-three patients had placement of JP drains (Group I) and 105 patients had no JP drain (Group II). Three patients (three of 43 [6%]) in Group I developed pelvic abscess and 21 of 105 (20%) patients in Group II developed pelvic abscesses requiring subsequent drainage. This was statistically significant. Patient demographics, temperature, and mean white blood count before surgery were similar. Presurgery computed tomography (CT) with appendicolith and CT with abscess were more prevalent in Group I. The use of JP drainage in patients with perforated or gangrenous appendicitis during LA has decreased rates of pelvic abscess. This was demonstrated despite the drain group having appendicolith or abscess on preoperative CT.

Proteomic characterisation of toxins isolated from nematocysts of the South Atlantic jellyfish Olindias sambaquiensis.

Surprisingly little is known of the toxic arsenal of cnidarian nematocysts compared to other venomous animals. Here we investigate the toxins of nematocysts isolated from the jellyfish Olindias sambaquiensis. A total of 29 unique ms/ms events were annotated as potential toxins homologous to the toxic proteins from diverse animal phyla, including cone-snails, snakes, spiders, scorpions, wasp, bee, parasitic worm and other Cnidaria. Biological activities of these potential toxins include cytolysins, neurotoxins, phospholipases and toxic peptidases. The presence of several toxic enzymes is intriguing, such as sphingomyelin phosphodiesterase B (SMase B) that has only been described in certain spider venoms, and a prepro-haystatin P-IIId snake venom metalloproteinase (SVMP) that activates coagulation factor X, which is very rare even in snake venoms. Our annotation reveals sequence orthologs to many representatives of the most important superfamilies of peptide venoms suggesting that their origins in higher organisms arise from deep eumetazoan innovations. Accordingly, cnidarian venoms may possess unique biological properties that might generate new leads in the discovery of novel pharmacologically active drugs.

GB virus C coinfection in advanced HIV type-1 disease is associated with low CCR5 and CXCR4 surface expression on CD4(+) T-cells.

BACKGROUND: Coinfection with the flavivirus GB virus C (GBV-C) is frequent in patients suffering from HIV type-1 (HIV-1) infection because of shared routes of transmission. GBV-C coinfection has been proposed to exert a beneficial influence on HIV-1 infection. In vitro studies demonstrated down-regulation of C-C chemokine receptor type 5 (CCR5) as a potential mechanism by which GBV-C modulates HIV-1 disease progression. We therefore studied surface expression of the two major HIV-1 coreceptors, CCR5 and CXC chemokine receptor type 4 (CXCR4), on CD4(+) and CD8(+) T-cells in 128 HIV-1-positive patients stratified with respect to their GBV-C status, immune function and highly active antiretroviral therapy (HAART) status in vivo. METHODS: GBV-C infection was studied in 128 HIV-1-infected patients by nested reverse transcriptase PCR. Fluorescence-activated cell sorting analysis was used to measure CCR5 and CXCR4 surface expression on CD4(+) and CD8(+) T-cells. RESULTS: GBV-C RNA replication was detected in 30% (38/128) of patients. In HIV-1-positive patients with advanced immunodeficiency, we found up-regulation of CCR5 surface expression on CD4(+) T-cells; however, in patients with GBV-C coinfection, no up-regulation of CCR5 CD4(+) T-cells was detected. Furthermore, CXCR4 surface expression was reduced in GBV-C-coinfected patients. These findings were independent of HAART status and HIV-1 viral load. HIV-1 coreceptor expression on CD8(+) T-cells was not altered in patients with GBV-C coinfection. CONCLUSIONS: GBV-C coinfection in HIV-1 disease leads to reduced expression of the two major HIV-1 coreceptors, CCR5 and CXCR4, on CD4(+) T-cells in patients at an advanced stage of immunodeficiency, providing a possible molecular explanation for the clinical benefit of GBV-C coinfection in late-stage HIV-1 disease.