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Purpose: There is a need for effective and affordable treatments that achieve hepatitis B virus (HBV) functional cure and prevent long-term complications. The use of immune-modulators combined with HBV antivirals is a promising therapeutic strategy to achieve these goals. Based on ribavirin (RBV) monotherapy data, we hypothesized that RBV could improve virological responses when used in combination with tenofovir. Methods: In this randomized, open label, controlled pilot trial, we evaluated RBV (n=4) dosed for the initial 24 weeks of treatment versus no RBV (n=4) in tenofovir recipients dosed over 48 weeks. Results: Although well tolerated and safe in combination with tenofovir, RBV demonstrated no beneficial effects on virologic, biochemical or immunological markers of chronic HBV infection over 48 weeks of serial evaluation. Conclusions: Our data does not suggest a HBV-specific immunomodulatory effect or an impact of RBV on HBV virological and antigen suppression.

Hepatitis B virus (HBV) nucleos(t)ide analog (NA) therapy reduces liver disease but requires prolonged therapy to achieve hepatitis B surface antigen (HBsAg) loss. There is limited North American real-world data using non-invasive tools for fibrosis assessment and few have compared 1To assess impact of NA on virological response and fibrosis regression using liver stiffness measurement (LSM) (Retrospective, observational cohort study from the Canadian HBV Network. Data collected included demographics, NA, HBV DNA, alanine aminotransferase (ALT), and LSM. Patients were HBV monoinfected patients, treatment naïve, and received 1 NA with minimum 1 year follow-up.In 465 (median 49 years, 37% female, 35% hepatitis B e antigenIn this real-world North American study, approximately 5 years of NA achieves liver fibrosis regression rarely leads to HBsAg loss.

In the last three decades, the notion of bioequivalence has gotten a lot of attention as it has been applied to new branded and generic medications. Generic medications must meet the same quality, efficacy, and safety requirements. Conventional products should be therapeutically equal to the reference product and compatible. The evolution of regulatory standards for bioequivalence in the United States, Europe, and Australia are examined in this paper. There is no international harmonization of regulatory requirements for bioequivalence, but the scope of bioequivalence and statistical analysis is partially harmonized; however, there are differences in applying single-dose trials and in vitro dissolution tests due to subject selection and reference product selection. The drug management system and drug regulating laws determine the pharmaceutical market's share. A bioequivalence study is one of the essential elements in the generic medicine approval process. The plasma time-concentration curve is frequently used in bioequivalence studies to determine absorption pace and absorption. The bioequivalence of the goods examined can be determined using the selected pharmacokinetic parameters and predefined acceptability thresholds. Recent advancements and information on crucial areas of bioequivalence study design and specification recommendations for each endpoint are included in this review.

Purpose During the 2014–2016 Ebola outbreak in West Africa, the Sierra Leone Ministry of Health and Sanitation (MoHS), the US Centers for Disease Control and Prevention, and responding partners under the coordination of the National Ebola Response Center (NERC) and the MoHS's Emergency Operation Center (EOC) systematically recorded information from the 117 Call Center system and district alert phone lines, case investigations, laboratory sample testing, clinical management, and safe and dignified burial records. Since 2017, CDC assisted MoHS in building and managing the Sierra Leone Ebola Database (SLED) to consolidate these major data sources. The primary objectives of the project were helping families to identify the location of graves of their loved ones who died at the time of the Ebola epidemic through the SLED Family Reunification Program and creating a data source for epidemiological research. The objective of this paper is to describe the process of consolidating epidemic records into a useful and accessible data collection and to summarize data characteristics, strength, and limitations of this unique information source for public health research. Methods Because of the unprecedented conditions during the epidemic, most of the records collected from responding organizations required extensive processing before they could be used as a data source for research or the humanitarian purpose of locating burial sites. This process required understanding how the data were collected and used during the outbreak. To manage the complexity of processing the data obtained from various sources, the Sierra Leone Ebola Database (SLED) Team used an organizational strategy that allowed tracking of the data provenance and lifecycle. Results The SLED project brought raw data into one consolidated data collection. It provides researchers with secure and ethical access to the SLED data and serves as a basis for the research capacity building in Sierra Leone. The SLED Family Reunification Program allowed Sierra Leonean families to identify location of the graves of loved ones who died during the Ebola epidemic. Conclusions The SLED project consolidated and utilized epidemic data recorded during the Sierra Leone Ebola Virus Disease outbreak that were collected and contributed to SLED by national and international organizations. This project has provided a foundation for developing a method of ethical and secure SLED data access while preserving the host nation's data ownership. SLED serves as a data source for the SLED Family Reunification Program and for epidemiological research. It presents an opportunity for building research capacity in Sierra Leone and provides a foundation for developing a relational database. Large outbreak data systems such as SLED provide a unique opportunity for researchers to improve responses to epidemics and indicate the need to include data management preparedness in the plans for emergency response.

Ambulatory hemodynamic monitoring has demonstrated the ability to reduce heart failure-related hospitalization, regardless of left ventricular ejection fraction; however, real-world data in a Veterans Affairs patient population are limited. The present study retrospectively reviewed 53 patients with New York Heart Association class III heart failure, regardless of left ventricular ejection fraction, implanted with a pulmonary artery pressure sensor (CardioMEMS) at our single Veterans Affairs institution. Heart failure-related hospitalizations were assessed in patients for 6 and 12 months after the implantation of the device and compared with the 6- and 12- month periods before implantation in the same patient cohort. Pulmonary arterial pressures and medication doses were also recorded at baseline, 6- months, and 12- months and procedural safety data were also assessed. Implantation of a remote pulmonary artery pressure sensor was associated with a 52% (95% confidence interval 30% to 68%, p0.001) and a 44% (95% confidence interval 24% to 59%, p0.001) reduction in heart failure-related hospitalization at 6 and 12 months after implant, respectively, compared with the 6- and 12-month preimplant periods. Mean pulmonary arterial pressures also demonstrated significant reductions from baseline to 6 and 12 months after implant. A total of 3 procedure-related adverse events were noted. In conclusion, pulmonary artery pressure sensor implantation is relatively safe and associated with significant reductions in heart failure-related hospitalization and decreased mean pulmonary artery pressures in patients within the Veterans Affairs system with New York Heart Association class III symptoms, regardless of ejection fraction.

This chapter provides an overview of the pharmacological and pharmacokinetic principles of administered drugs. Pharmacological principles of drug response when a drug binds to a receptor as an agonist or antagonist as well as their affinity and intrinsic activity are described and illustrated with examples. Pharmacokinetic principles of absorption, distribution, metabolism, and excretion are also described after discussing the passage of the drug across the cell membrane.

Historic observations suggest that survivors of smallpox maintained lifelong immunity and protection to subsequent infection compared to vaccinated individuals. Although protective immunity by vaccination using a related virus (vaccinia virus (VACV) strains) was the key for smallpox eradication, it does not uniformly provide long term, or lifelong protective immunity (Heiner et al., 1971). To determine differences in humoral immune responses, mice were inoculated with VACV either systemically, using intranasal inoculation (IN), or locally by an intradermal (ID) route. We hypothesized that sub-lethal IN infections may mimic systemic or naturally occurring infection and lead to an immunodominance reaction, in contrast to localized ID immunization. The results demonstrated systemic immunization through an IN route led to enhanced adaptive immunity to VACV-expressed protein targets both in magnitude and in diversity when compared to an ID route using a VACV protein microarray. In addition, cytokine responses, assessed using a Luminex® mouse cytokine multiplex kit, following IN infection was greater than that stemming from ID infection. Overall, the results suggest that the route of immunization (or infection) influences antibody responses. The greater magnitude and diversity of response in systemic infection provides indirect evidence for anecdotal observations made during the smallpox era that survivors maintain lifelong protection. These findings also suggest that systemic or disseminated host immune induction may result in a superior response, that may influence the magnitude of, as well as duration of protective responses.

In March 2015, a patient in Colombia with HIV/AIDS was hospitalized for disseminated ulcers after milking cows that had vesicular lesions on their udders. Vaccinia virus was detected, and the case met criteria for progressive vaccinia acquired by zoonotic transmission. Adherence to an optimized antiretroviral regimen resulted in recovery. © 2020 Centers for Disease Control and Prevention (CDC). All rights reserved.

Child Health and Mortality Prevention Surveillance (CHAMPS) laboratories are employing a variety of laboratory methods to identify infectious agents contributing to deaths of children 100 real-time polymerase chain reaction (PCR) targets in total (30–45 per card depending on configuration). Multipathogen panels were configured by syndrome and customized to include pathogens of significance in young children within the regions where CHAMPS is conducted, including bacteria (57 targets covering 30 genera), viruses (48 targets covering 40 viruses), parasites (8 targets covering 8 organisms), and fungi (3 targets covering 3 organisms). The development and application of multiplex real-time PCR reactions to the TAC microfluidic platform increased the number of targets in each panel while maintaining assay efficiency and replicates for heightened sensitivity. These advances represent a substantial improvement in the utility of this technology for infectious disease diagnostics and surveillance. We optimized all aspects of the CHAMPS molecular laboratory testing workflow including nucleic acid extraction, quality assurance, and data management to ensure comprehensive molecular testing of specimens and high-quality data. Here we describe the development and implementation of multiplex TACs and associated laboratory protocols for specimen processing, testing, and data management at CHAMPS site laboratories., We developed and implemented custom TaqMan Array Cards for testing postmortem specimens for pathogens of significance in young children. All aspects of the CHAMPS molecular laboratory workflow were optimized to ensure generation and management of comprehensive and high-quality data.

Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 ×10³ pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.

Machine Learning (ML) and Internet of Things (IoT) has become a pioneering and radical assistant in a wide range of applications and fields of data management. Currently, looking towards the rapid expansion of various trends and communication technology, it is surveyed that almost all the Sensor enabled devices are now connected with each other through the Internet. The widespread use of IoT devices and sensors produces huge amounts of raw data which also increases published data that increases the need of efficient data analysis and data processing mechanisms. The article contributes the detailed survey of different data processing and analyzing techniques of machine learning which can be applied to data generated by IoT devices to offer various services. In addition, the challenges and potential of Machine Learning (ML) for data analysis in IoT are also explored. The machine learning methods to overcome various challenges of IoT are also accessed.

Background: Due to the Coronavirus Disease of 2019 pandemic many clinics began to utilize virtual visits in lieu of traditional office visits. It is unclear what effect this will have on outcomes and admission rates for heart failure (HF). We describe our approach and outcomes in managing HF in a Veteran’s Affairs population with previously implanted CardioMEMS™ during this time. Methods: Starting February 15 th 2020, virtual visits were utilized in patients with CardioMEMS™ during which their symptoms were discussed and medications adjusted. Patients also received weekly phone calls to ensure that they had medications and to adjust diuretics based on pulmonary artery (PA) pressure readings. They received text message reminders if a reading was missed. A nurse was also tasked to follow up on lab results. Data was collected by reviewing the charts of CardioMEMS™ patients followed in our clinic by cardiology fellows and divided into pre pandemic period of July 1 st 2018 to February 14 th 2020 and a post pandemic period of February 15 th 2020 to May 15 th 2020. Data collected included baseline demographics, number of in-office and virtual visits, hospital admissions for HF, PA pressures, and compliance with CardioMEMS™ readings. Phone calls to adjust diuretics or review labs were not counted as virtual visits. Results: In the pre-pandemic period we identified 49 patients with prior CardioMEMS™; baseline demographics are shown in Table 1A. Table 1B shows our results comparing the pre pandemic and post pandemic periods when our telemedicine program was started. Although in the post pandemic period our encounter rate was lower, our virtual program was able to maintain stable PA pressures and a lower overall hospital admission rate. Compliance with CardioMEMS™ also increased though this was not statistically significant. Conclusion: Both CardioMEMS™ and virtual visits may be used effectively to maintain low PA pressures and reduce hospital admissions for in patients with chronic HF.

The Internet of Things (IoT) is rapidly becoming a part of our regular activities and environment. According to Cisco, by 2030, it is expected that 500 billion devices will be connected to the IoT. Every passing day, new devices and sensors coming in the market, which use different protocols to connect to the network. With this expected growth of the Internet of Things and the emergence of Fog and Cloud Computing, there is a need for a standard protocol suite to handle different aspects of standardization and cloud protocols in the IoT environment that is not covered by currently existing Three, four, and five-layered IoT models. A T2C architecture is proposed that provides the most prominent standard protocols into nine layers and shows why this extension is essential. The proposed T2C architecture fulfills the prescribed activities for smart sensors and fog networking in the backbone, which brings significant benefits, scalability, and low-power consumption in the IoT architecture. It emphasizes on how IoT device classification can be mapped to our proposed nine-layered T2C Architecture.

OBJECTIVES: Few studies have evaluated national readmission rates after acute pancreatitis (AP) in the United States. We sought to evaluate modifiable factors impacting 30-day readmissions following AP hospitalizations. METHODS: We utilized the Nationwide Readmission Database (2013) involving all adults with a primary discharge diagnosis of AP. Multivariable logistic regression models assessed independent predictors for specific outcomes. RESULTS: Among 180,480 patients with AP index admissions, 41,094 (23%) had biliary-AP, of which 10.5% were readmitted within 30-days. The 30-day readmission rate for patients who underwent same-admission cholecystectomy (CCY) was 6.5%, compared to 15.1% in those who did not (P < 0.001). Failure of index-admission CCY increased the risk of readmissions (odds ratio [OR], 2.27; 95% confidence interval [CI], 2.04–2.56). Same-admission CCY occurred in 55% (n = 19,274) of patients without severe-AP. Severe-AP (OR, 0.73; 95% CI, 0.65–0.81), sepsis (OR, 0.63; 95% CI, 0.52–0.75), ≥3 comorbidities (OR, 0.74; 95% CI, 0.68–0.79), and admissions to small (OR, 0.76; 95% CI, 0.64–0.91) or rural (OR, 0.78; 95% CI, 0.65–0.95) hospitals were less likely to undergo same-admission CCY. CONCLUSIONS: Same-admission CCY should be considered in patients with biliary-AP when feasible. This national appraisal recognizes modifiable risk factors to reduce readmission in biliary-AP and reinforces adherence to major society guidelines.

Background: Intrathecal drug delivery is known to reduce pain in patients where conventional systemic analgesia has been ineffective or intolerable. However, there is little information regarding the effects of intrathecal drug delivery on quality of life and function in those with advanced, incurable cancer. Aim: Retrospective exploration of the views of bereaved carers regarding the physical and psychosocial effects of external tunnelled intrathecal drug delivery in patients with advanced incurable cancer. Design: Thematic analysis of qualitative interviews with carers of deceased individuals who received percutaneous external tunnelled intrathecal drug delivery as part of their pain management, within two UK centres. Setting: A total of 11 carers were recruited from two UK Palliative Care centres. Family carers of adult patients who had received external tunnelled intrathecal drug delivery analgesia for cancer pain and had died between 6 and 48 months prior to contact were included. Carer relatives who were considered likely to be too vulnerable or who had lodged a complaint about treatment within the recruiting department or who had been treated directly by the interviewer were excluded. Results: In total, 11 interviews took place. The emerging themes were (1) making the decision to have the intrathecal – relatives described desperate situations with severe pain and/or sedation, meaning that the individual would try anything; (2) timing and knowing they were having the best – an increased access to pain and palliative care services, meant carers felt everything possible was being done, making the situation more bearable; (3) was it worth it? – the success of the external tunnelled intrathecal drug delivery was judged on its ability to enable the individual to be themselves through their final illness. Side effects were often considered acceptable, if the external tunnelled intrathecal drug delivery enabled improvements in quality of life. Conclusion: Carers perceived external tunnelled intrathecal drug delivery as most valuable when it improved quality of life towards the end of life, by reducing pain and side effects of conventional systemic analgesia to enable individuals ‘to be themselves’. Under these circumstances, the carers judged significant side effects to be acceptable.

Summary A resident of interior Alaska, was diagnosed with an Orthopoxvirus infection. Phylogenetic analysis revealed it is a novel, previously undescribed Orthopoxvirus species. Phylogenetically, the virus is sister to recognized Old World orthopoxviruses, rather than North American Orthopoxvirus species., Background. Human infection by orthopoxviruses is being reported with increasing frequency, attributed in part to the cessation of smallpox vaccination and concomitant waning of population-level immunity. In July 2015, a female resident of interior Alaska presented to an urgent care clinic with a dermal lesion consistent with poxvirus infection. Laboratory testing of a virus isolated from the lesion confirmed infection by an Orthopoxvirus. Methods. The virus isolate was characterized by using electron microscopy and nucleic acid sequencing. An epidemiologic investigation that included patient interviews, contact tracing, and serum testing, as well as environmental and small-mammal sampling, was conducted to identify the infection source and possible additional cases. Results. Neither signs of active infection nor evidence of recent prior infection were observed in any of the 4 patient contacts identified. The patient’s infection source was not definitively identified. Potential routes of exposure included imported fomites from Azerbaijan via the patient’s cohabiting partner or wild small mammals in or around the patient’s residence. Phylogenetic analyses demonstrated that the virus represents a distinct and previously undescribed genetic lineage of Orthopoxvirus, which is most closely related to the Old World orthopoxviruses. Conclusions. Investigation findings point to infection of the patient after exposure in or near Fairbanks. This conclusion raises questions about the geographic origins (Old World vs North American) of the genus Orthopoxvirus. Clinicians should remain vigilant for signs of poxvirus infection and alert public health officials when cases are suspected.

Vagus nerve stimulation (VNS) paired with rehabilitative training enhances recovery of function in models of stroke and is currently under investigation for use in chronic stroke patients. Dosing is critical in translation of pharmacological therapies, but electrical stimulation therapies often fail to comprehensively explore dosing parameters in preclinical studies. Varying VNS parameters has non-monotonic effects on plasticity in the central nervous system, which may directly impact efficacy for stroke. We sought to optimize stimulation intensity to maximize recovery of motor function in a model of ischemic stroke. The study design was preregistered prior to beginning data collection (DOI: https://doi.org/10.17605/OSF.IO/BMJEK ). After training on an automated assessment of forelimb function and receiving an ischemic lesion in motor cortex, rats were separated into groups that received rehabilitative training paired with VNS at distinct stimulation intensities (sham, 0.4 mA, 0.8 mA, or 1.6 mA). Moderate-intensity VNS at 0.8 mA enhanced recovery of function compared with all other groups. Neither 0.4 mA nor 1.6 mA VNS was sufficient to improve functional recovery compared with equivalent rehabilitation without VNS. These results demonstrate that moderate-intensity VNS delivered during rehabilitation improves recovery and defines an optimized intensity paradigm for clinical implementation of VNS therapy.

Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 × 10(3) pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPV-infected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.