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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.

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.

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.

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.

Transarterial chemoembolization (TACE) is a palliative procedure frequently used in patients with advanced hepatocellular carcinoma (HCC). We examined the national inpatient trends of TACE and related outcomes in the United States over the last decade.We utilized the National Inpatient Sample (2002 to 2012) and performed trend analyses of TACE for HCC in all adult patients (age18 years). Multivariate analyses for the outcomes of in-hospital "procedure-related complications" (PRCs) and "post-procedure complications" (PPCs) were performed. We also compared early (2002 to 2006) and late (2007 to 2012) eras by multivariate analyses to identify predictors of complications, healthcare resource utilization and mortality.Overall, 19058 patients underwent TACE for HCC where PRCs and PPCs were seen in 24.2% and 17.6% of patients, respectively. The overall trends in the use of TACE (P0.001) and associated PRCs (P=0.006) were observed to be increasing. There was less mortality [adjusted Odds ratio (aOR): 0.58; 95% CI: 0.41, 0.82], reduced length of hospital stay (-1.87 days; 95% CI: -2.77, -0.97) and increased hospital charges ($19232; 95% CI: 11013, 27451) in the late era. Additionally, there was increased mortality (aOR: 4.07; 95% CI: 2.96, 5.59), PRCs (aOR: 3.21; 95% CI: 2.56, 4.02), and PPCs (aOR: 2.70; 95% CI: 2.11, 3.46) among patients with coagulopathy.There is an increasing trend of TACE utilization in HCC. However, the outcomes are worse in patients with coagulopathy. Although PRCs have increased, mortality has decreased in recent years. These findings should be considered during TACE evaluation in patients with HCC.

Virus purification in a high-containment setting provides unique challenges due to barrier precautions and operational safety approaches that are not necessary in lower biosafety level (BSL) 2 environments. The need for high risk group pathogen diagnostic assay development, anti-viral research, pathogenesis and vaccine efficacy research necessitates work in BSL-3 and BSL-4 labs with infectious agents. When this work is performed in accordance with BSL-4 practices, modifications are often required in standard protocols. Classical virus purification techniques are difficult to execute in a BSL-3 or BSL-4 laboratory because of the work practices used in these environments. Orthopoxviruses are a family of viruses that, in some cases, requires work in a high-containment laboratory and due to size do not lend themselves to simpler purification methods. Current CDC purification techniques of orthopoxviruses uses 1,1,2-trichlorotrifluoroethane, commonly known as Genetron®. Genetron® is a chlorofluorocarbon (CFC) that has been shown to be detrimental to the ozone and has been phased out and the limited amount of product makes it no longer a feasible option for poxvirus purification purposes. Here we demonstrate a new Orthopoxvirus purification method that is suitable for high-containment laboratories and produces virus that is not only comparable to previous purification methods, but improves on purity and yield.

AIM To determine the impact of transjugular intrahepatic porto-systemic shunt (TIPS) on post liver transplantation (LT) outcomes. METHODS Utilizing the United Network for Organ Sharing (UNOS) database, we compared patients who underwent LT from 2002 to 2013 who had underwent TIPS to those without TIPS for the management of ascites while on the LT waitlist. The impact of TIPS on 30-d mortality, length of stay (LOS), and need for re-LT were studied. For evaluation of mean differences between baseline characteristics for patients with and without TIPS, we used unpaired t-tests for continuous measures and χ2 tests for categorical measures. We estimated the impact of TIPS on each of the outcome measures. Multivariate analyses were conducted on the study population to explore the effect of TIPS on 30-d mortality post-LT, need for re-LT and LOS. All covariates were included in logistic regression analysis. RESULTS We included adult patients (age ≥ 18 years) who underwent LT from May 2002 to September 2013. Only those undergoing TIPS after listing and before liver transplant were included in the TIPS group. We excluded patients with variceal bleeding within two weeks of listing for LT and those listed for acute liver failure or hepatocellular carcinoma. Of 114770 LT in the UNOS database, 32783 (28.5%) met inclusion criteria. Of these 1366 (4.2%) had TIPS between the time of listing and LT. We found that TIPS increased the days on waitlist (408 ± 553 d) as compared to those without TIPS (183 ± 330 d), P < 0.001. Multivariate analysis showed that TIPS had no effect on 30-d post LT mortality (OR = 1.26; 95%CI: 0.91-1.76) and re-LT (OR = 0.61; 95%CI: 0.36-1.05). Pre-transplant hepatic encephalopathy added 3.46 d (95%CI: 2.37-4.55, P < 0.001), followed by 2.16 d (95%CI: 0.92-3.38, P = 0.001) by TIPS to LOS. CONCLUSION TIPS did increase time on waitlist for LT. More importantly, TIPS was not associated with 30-d mortality and re-LT, but it did lengthen hospital LOS after transplantation.

Germination of Bacillus anthracis spores involves rehydration of the spore interior and rapid degradation of several of the protective layers, including the spore coat. Here, we examine the temporal changes that occur during B. anthracis spore germination using an isobaric tagging system. Over the course of 17 min from the onset of germination, the levels of at least 19 spore proteins significantly decrease. Included are acid-soluble proteins, several known and predicted coat proteins, and proteins of unknown function. Over half of these proteins are small (less than 100 amino acids) and would have been undetectable by conventional gel-based analysis. We also identified 20 proteins, whose levels modestly increased at the later time points when metabolism has likely resumed. Taken together, our data show that isobaric labeling of complex mixtures is particularly effective for temporal studies. Furthermore, we describe a rigorous statistical approach to define relevant changes that takes into account the nature of data obtained from multidimensional protein identification technology coupled with the use of isobaric tags. This study provides an expanded list of the proteins that may be involved in germination of the B. anthracis spore and their relative levels during germination.

Monkeypox virus(MPXV) infection of the prairie dog is valuable to studying systemic orthopoxvirus disease. To further characterize differences in MPXV clade pathogenesis, groups of prairie dogs were intranasally infected (8×103 p.f.u.) with Congo Basin (CB) or West African (WA) MPXV, and 28 tissues were harvested on days 2, 4, 6, 9, 12, 17, and 24 postinfection. Samples were evaluated for the presence of virus and gross and microscopic lesions. Virus was recovered from nasal mucosa, oropharyngeal lymph nodes, and spleen earlier in CB challenged animals (day 4) than WA challenged animals (day 6). For both groups, primary viremia (indicated by viral DNA) was seen on days 6–9 through day 17. CB MPXV spread more rapidly, accumulated to greater levels, and caused greater morbidity in animals compared to WA MPXV. Histopathology and immunohistochemistry (IHC) findings, however, were similar. Two animals that succumbed to disease demonstrated abundant viral antigen in all organs tested, except for brain. Dual-IHC staining of select liver and spleen sections showed that apoptotic cells (identified by TUNEL) tended to colocalize with poxvirus antigen. Interestingly splenocytes were labelled positive for apoptosis more often than hepatocytes in both MPXV groups. These findings allow for further characterization of differences between MPXV clade pathogenesis, including identifying sites that are important during early viral replication and cellular response to viral infection.

Background Intrathecal Drug Delivery (ITDD) is known to reduce pain in patients where conventional systemic analgesia has been ineffective or intolerable. However more information about how this intervention affects quality of life (QOL) and function in those with advanced incurable cancer is required. Aim To explore the views of bereaved carers regarding the physical and psychosocial effects of ITDD in patients with advanced incurable cancer. Methods Qualitative interviews were undertaken with carers of deceased individuals who received ITDD (percutaneous, external system) as part of their pain management. Interviews were analysed using thematic analysis. Results Eleven interviews were conducted in two United Kingdom centres with established ITDD services. The themes were: (1) ‘making the decision to have the ITDD’, family carers described very severe pain and/or sedation, in which the suffering individual would try anything; (2) ‘timing and knowing they were having the best’, ITDD and the associated increased access to pain and palliative care services, meant relatives felt everything possible was being done, making the situation more bearable; (3) ‘was it worth it?’, the perceived benefits were weighed up against the inconveniences and side effects of the ITDD; family carers judged the ITDD to be of overall benefit, despite side effects, where it had enabled the individual to be themselves through their final illness and dying phase. Conclusion ITDD was perceived to be of greatest value when it improved QOL for patients by reducing pain and systemic side effects, thus enabling individuals to be themselves for as long as possible; under these circumstances significant side effects were judged to be acceptable. The family carers conveyed comfort in knowing that the patient was receiving what they felt was the best available management, support and specialist care. These findings should inform discussions between patients, physicians and palliative care teams around the management of severe uncontrolled pain in advanced malignancy.

Three quarters of patients with advanced cancer experience moderate to severe pain, often at multiple sites. Despite advancements in the understanding of appropriate multimodal analgesia 5–14% of patients do not have adequate pain control. This has led to the suggestion that the WHO ladder should be modified with a fourth step, that of interventional procedures and techniques. This article focuses on the commonly used interventional techniques, including nerve blockade and nerve destruction techniques and will cover epidural injections, radiofrequency (RF) ablation, cryo-lesioning and trigger point injections. Vertebroplasty and kyphoplasty techniques used in the treatment of vertebral metastases associated pain is also discussed. In addition this article will consider some of the unique challenges that physicians face when treating this group of patients. Although there is limited evidence looking into the efficacy of interventional procedures in this group of patients they are nevertheless an important and accepted part of the armory against complex cancer pain and should be considered in refractory cases.

Despite the eradication of smallpox, orthopoxviruses (OPV) remain public health concerns. Efforts to develop new therapeutics and vaccines for smallpox continue through their evaluation in animal models despite limited understanding of the specific correlates of protective immunity. Recent monkeypox virus challenge studies have established the black-tailed prairie dog ( Cynomys ludovicianus ) as a model of human systemic OPV infections. In this study, we assess the induction of humoral immunity in humans and prairie dogs receiving Dryvax, Acam2000, or Imvamune vaccine and characterize the proteomic profile of immune recognition using enzyme-linked immunosorbent assays (ELISA), neutralization assays, and protein microarrays. We confirm anticipated similarities of antigenic protein targets of smallpox vaccine-induced responses in humans and prairie dogs and identify several differences. Subsequent monkeypox virus intranasal infection of vaccinated prairie dogs resulted in a significant boost in humoral immunity characterized by a shift in reactivity of increased intensity to a broader range of OPV proteins. This work provides evidence of similarities between the vaccine responses in prairie dogs and humans that enhance the value of the prairie dog model system as an OPV vaccination model and offers novel findings that form a framework for examining the humoral immune response induced by systemic orthopoxvirus infection.

The 2003 monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog is susceptible to MPXV infection and that the ensuing rash illness is similar to human systemic orthopoxvirus (OPXV) infection, including a 7- to 9-day incubation period and, likely, in some cases a respiratory route of infection; these features distinguish this model from others. The need for safe and efficacious vaccines for OPVX in areas where it is endemic or epidemic is important to protect an increasingly OPXV-naïve population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. None of the smallpox vaccines caused illness in this model, and all vaccinated animals showed anti-OPXV antibody responses and neutralizing antibody. We tested vaccine efficacy by challenging the animals with 10 5 or 10 6 PFU Congo Basin MPXV 30 days postvaccination and evaluating morbidity and mortality. Our results demonstrated that vaccination with either Dryvax or Acambis2000 protected the animals from death with no rash illness. Vaccination with IMVAMUNE also protected the animals from death, albeit with (modified) rash illness. Based on the results of this study, we believe prairie dogs offer a novel and potentially useful small animal model for the safety and efficacy testing of smallpox vaccines in pre- and postexposure vaccine testing, which is important for public health planning.

Hepatorenal syndrome (HRS) plays an important role in patients with liver cirrhosis on the wait list for liver transplantation (LT). The 1 and 5-year probability of developing HRS in cirrhotic with ascites is 20% and 40%, respectively. In this article, we reviewed current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver alone vs simultaneous liver kidney transplant (SLKT) in transplant candidates. Many treatment options including albumin, vasoconstrictors, renal replacement therapy, and eventual LT have remained a mainstay in the treatment of HRS. Unfortunately, even after aggressive measures such as terlipressin use, the rate of recovery is less than 50% of patients. Moreover, current SLKT guidelines include: (1) estimation of glomerular filtration rate of 30 mL/min or less for 4-8 wk; (2) proteinuria > 2 g/d; or (3) biopsy proven interstitial fibrosis or glomerulosclerosis. Even with these updated criteria there is a lack of consistency regarding long-term benefits for SLKT vs LT alone. Finally, in regards to kidney dysfunction in the post-transplant setting, an estimation of glomerular filtration rate < 60 mL/min per 1.73 m(2) may be associated with an increased risk of patients having long-term end stage renal disease. HRS is common in patients with cirrhosis and those on liver transplant waitlist. Prompt identification and therapy initiation in transplant candidates with HRS may improve post-transplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of SLKT in patients with HRS remains controversial and requires further evidence by the transplant community.

Since the eradication of Smallpox, researchers have attempted to study Orthopoxvirus pathogenesis and immunity in animal models in order to correlate results human smallpox. A solely human pathogen, Orthopoxvirus variola fails to produce authentic smallpox illness in any other animal species tested to date. In 2003, an outbreak in the USA of Orthopoxvirus monkeypox, revealed the susceptibility of the North American black-tailed prairie dog (Cynomys ludovicianus) to infection and fulminate disease. Prairie dogs infected with Orthopoxvirus monkeypox present with a clinical scenario similar to ordinary smallpox, including prodrome, rash, and high mortality. This study examines if Black-tailed prairie dogs can become infected with O. variola and serve as a surrogate model for the study of human smallpox disease. Substantive evidence of infection is found in immunological seroconversion of animals to either intranasal or intradermal challenges with O. variola, but in the absence of overt illness.

A Drosophila protein-protein interaction map was constructed using the LexA system, complementing a previous map using the GAL4 system and adding many new interactions., Background Maps depicting binary interactions between proteins can be powerful starting points for understanding biological systems. A proven technology for generating such maps is high-throughput yeast two-hybrid screening. In the most extensive screen to date, a Gal4-based two-hybrid system was used recently to detect over 20,000 interactions among Drosophila proteins. Although these data are a valuable resource for insights into protein networks, they cover only a fraction of the expected number of interactions. Results To complement the Gal4-based interaction data, we used the same set of Drosophila open reading frames to construct arrays for a LexA-based two-hybrid system. We screened the arrays using a novel pooled mating approach, initially focusing on proteins related to cell-cycle regulators. We detected 1,814 reproducible interactions among 488 proteins. The map includes a large number of novel interactions with potential biological significance. Informative regions of the map could be highlighted by searching for paralogous interactions and by clustering proteins on the basis of their interaction profiles. Surprisingly, only 28 interactions were found in common between the LexA- and Gal4-based screens, even though they had similar rates of true positives. Conclusions The substantial number of new interactions discovered here supports the conclusion that previous interaction mapping studies were far from complete and that many more interactions remain to be found. Our results indicate that different two-hybrid systems and screening approaches applied to the same proteome can generate more comprehensive datasets with more cross-validated interactions. The cell-cycle map provides a guide for further defining important regulatory networks in Drosophila and other organisms.