Volenrelaxin (LY3540378) increases Renal Plasma Flow: A Randomized Phase 1 Trial.

BACKGROUND AND HYPOTHESIS: Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. METHODS: In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n = 56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n = 77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. RESULTS: Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p < 0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and + 4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. CONCLUSION: Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.

Modelling science return from the lunar crater radio telescope on the far side of the moon.

The era following the separation of CMB photons from matter, until the emergence of the first stars and galaxies, is known as the Cosmic Dark Ages. Studying the electromagnetic radiation emitted by neutral hydrogen having the 21 cm rest wavelength is the only way to explore this significant phase in the Universe's history, offering opportunities to investigate essential questions about dark matter physics, the standard cosmological model and inflation. Due to cosmological redshift, this signal is now only observable at frequencies inaccessible from the Earth's surface due to ionospheric absorption and reflection. With the Lunar Crater Radio Telescope (LCRT), we aim to conduct unprecedented measurements of the sky-averaged redshifted signal spectrum in the 4.7-47 MHz band, by deploying a 350 m diameter parabolic reflector mesh inside a lunar crater on the far side of the Moon and suspending a receiver at its focus. This work discusses the feasibility of the LCRT science goals through the development of a science model, with emphasis on post-processing techniques to extract the Dark Ages signal from the galactic foreground dominating the expected raw data. This model can be used to vary critical instrument and mission parameters to understand their effect on the quality of the retrieved signal. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.

Mutual Cooperativity of Three Allosteric Sites on the Dopamine D1 Receptor.

An amine-containing molecule called Compound A has been reported by a group from Bristol-Myers Squibb to act as a positive allosteric modulator (PAM) at the dopamine D1 receptor. We synthesized the more active enantiomer of Compound A (BMS-A1) and compared it with the D1 PAMs DETQ and MLS6585, which are known to bind to intracellular loop 2 and the extracellular portion of transmembrane helix 7, respectively. Results from D1/D5 chimeras indicated that PAM activity of BMS-A1 tracked with the presence of D1 sequence in the N-terminal/extracellular region of the D1 receptor, a unique location compared with either of the other PAMs. In pairwise combinations, BMS-A1 potentiated the small allo-agonist activity of each of the other PAMs, while the triple PAM combination (in the absence of dopamine) produced a cAMP response about 64% of the maximum produced by dopamine. Each of the pairwise PAM combinations produced a much larger leftward shift of the dopamine EC50 than either single PAM alone. All three PAMs in combination produced a 1000-fold leftward shift of the dopamine curve. These results demonstrate the presence of three non-overlapping allosteric sites that cooperatively stabilize the same activated state of the human D1 receptor. SIGNIFICANCE STATEMENT: Deficiencies in dopamine D1 receptor activation are seen in Parkinson disease and other neuropsychiatric disorders. In this study, three positive allosteric modulators of the dopamine D1 receptor were found to bind to distinct and separate sites, interacting synergistically with each other and dopamine, with the triple combination causing a 1000-fold leftward shift of the response to dopamine. These results showcase multiple opportunities to modulate D1 tone and highlight new pharmacological approaches for allosteric modulation of G-protein-coupled receptors.

Multidisciplinary management of a complex abdominal wound post necrotising fasciitis: a case study.

A 59-year-old male patient presented with abdominal necrotising fasciitis secondary to a bowel perforation through a previous drain site that he had waited at home with for two weeks. Enteric contents were found within the abdominal wall. Surgery required extensive abdominal wall debridement and the formation of a double-barrel ileostomy within the debrided area. The resulting abdominal wound was large, initially covering an area of approximately 424cm2, and had continuous contamination from enteric leakage that could not be isolated. Achieving wound healing was challenging due to the enteric output and resultant continuous contamination of the wound bed.

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography.

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC50 2.4-7.0 nM, Emax 43%-73%), displaying binding selectivity for M1 mAChRs (Kd = 1.5 nM) that was conserved across species (native tissue Kd = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

Salmonella typhimurium in the Australian egg industry: Multidisciplinary approach to addressing the public health challenge and future directions.

In Australia, numerous egg-related human Salmonella typhimurium outbreaks have prompted significant interest among public health authorities and the egg industry to jointly address this human health concern. Nationwide workshops on Salmonella and eggs were conducted in Australia for egg producers and regulatory authorities. State and national regulators represented Primary Production, Communicable Disease Control, Public Health and Food Safety, and Food Standards Australia and New Zealand. All attendees participated in discussions aimed at evaluating current evidence-based information, issues related to quality of egg production, and how to ensure safe eggs in the supply chain, identifying research gaps and practical recommendations. The perceptions from egg producers and regulatory authorities from various states were recorded during the workshops. We presented the issues discussed during the workshops, including Salmonella in the farm environment, Salmonella penetration across eggshell, virulence in humans, food/egg handling in the supply chain, and intervention strategies. We also discussed the perceptions from egg producers and regulators. Recommendations placed emphasis on the future research needs, communication between industry and regulatory authorities, and education of food handlers. Communication between regulators and industry is pivotal to control egg-borne S. typhimurium outbreaks, and collaborative efforts are required to design effective and appropriate control strategies.

A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma.

BACKGROUND: There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma. METHODS: This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting ß-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days. RESULTS: Overall, 157 patients completed the study. There were no significant differences between QAW039 and placebo for trough forced expiratory volume in 1 s (FEV1) or Asthma control questionnaire (ACQ) in the total population. Subgroup analyses demonstrated that patients with a FEV1 <70% of predicted at baseline treated with QAW039 had significant improvement compared with placebo in trough FEV1 (QAW039- Placebo [Δ] = 207 mL; 90% confidence interval [CI]: 96, 319; P = 0.002) and ACQ7 (Δ = -0.41; 90%CI: -0.69, -0.13; P = 0.009). QAW039 reached a mean maximum concentration (Cmax) of 3440 ng/mL on day 28 at a median Tmax of 1 h (range 0.5-4 h). Most adverse events (AEs) were mild/moderate and balanced between both groups, with no serious AEs. CONCLUSIONS: In the general study population, no improvement in lung function was observed with QAW039. However, a subgroup analysis revealed that patients with greater severity of airflow limitation (FEV1 < 70%) had improved lung function and asthma control when treated with QAW039. QAW039 also demonstrated a favorable safety profile. TRIALS REGISTRATION: ClinicalTrials.govNCT01253603.

Optimal reaction coordinate as a biomarker for the dynamics of recovery from kidney transplant.

The evolution of disease or the progress of recovery of a patient is a complex process, which depends on many factors. A quantitative description of this process in real-time by a single, clinically measurable parameter (biomarker) would be helpful for early, informed and targeted treatment. Organ transplantation is an eminent case in which the evolution of the post-operative clinical condition is highly dependent on the individual case. The quality of management and monitoring of patients after kidney transplant often determines the long-term outcome of the graft. Using NMR spectra of blood samples, taken at different time points from just before to a week after surgery, we have shown that a biomarker can be found that quantitatively monitors the evolution of a clinical condition. We demonstrate that this is possible if the dynamics of the process is considered explicitly: the biomarker is defined and determined as an optimal reaction coordinate that provides a quantitatively accurate description of the stochastic recovery dynamics. The method, originally developed for the analysis of protein folding dynamics, is rigorous, robust and general, i.e., it can be applied in principle to analyze any type of biological dynamics. Such predictive biomarkers will promote improvement of long-term graft survival after renal transplantation, and have potentially unlimited applications as diagnostic tools.

Do clinical incidents, complaints and medicolegal claims overlap?

PURPOSE: Error reporting by healthcare staff, patient-derived complaints and patient-derived medico-legal claims are three separate processes present in most healthcare systems. It is generally assumed that all relate to the same cases. Given the high costs associated with these processes and strong desire to maximise quality and standards, the purpose of this paper is to see whether it was indeed the case that most complaints and claims related to medical errors and the relative resource allocation to each group. DESIGN/METHODOLOGY/APPROACH: Electronic databases for clinical error recording, patient complaints and medico-legal claims in a large NHS healthcare provider organisation were reviewed and case overlap analysed. FINDINGS: Most complaints and medico-legal claims do not associate with a prior clinical error. Disproportionate resource is required for a small number of complaints and the medico-legal claims process. Most complaints and claims are not upheld. RESEARCH LIMITATIONS/IMPLICATIONS: The authors have only looked at data from one healthcare provider and for one period. It would be useful to analyse other healthcare organisations over a longer time period. The authors were unable to access data on secondary staffing costs, which would have been informative. As the medico-legal process can go on for many years, the authors do not know the ultimate outcomes for all cases. The authors also do not know how many medico-legal cases were settled out of court pragmatically to minimise costs. Practical implications - Staff error reporting systems and patient advisory services seem to be efficient and working well. However, the broader complaints and claims process is costing considerable time and money, yet may not be useful in driving up standards. System changes to maximise helpful complaints and claims, from a quality and standards perspective, and minimise unhelpful ones are recommended. ORIGINALITY/VALUE: This study provides important data on the lack of overlap between errors, complaints and claims cases.

Label-retaining liver cancer cells are relatively resistant to sorafenib.

OBJECTIVE: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. METHODS: We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. RESULTS: LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. CONCLUSIONS: Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.

Peritoneal inclusion cyst presenting as an umbilical hernia: case report and systematic review of the literature.

Peritoneal inclusion cysts (PICs) are a rare and benign condition of uncertain pathogenesis. The fluid-filled, mesothelial-lined cysts manifest within the abdominopelvic cavity. This case report details an unusual occurrence of a 97 mm PIC- presenting as an umbilical hernia- in a 26-year-old male patient with no prior surgical history. Following pre-operative cross-sectional imaging, this was managed through open excision without complication. A systematic review of the literature highlighted 30 previous cases [26F, 4M] with a mean age of 34 years (std ±15.4) and a median diameter of 93 mm [IQR, 109 mm]. A total of 53% (n = 16) of cases had a history of previous abdominal surgery. Surgical excision is safe and laparoscopic modality should be considered (<1% recurrence). Accepting the limited evidence base, image guided drainage should be avoided (50% recurrence, n = 2).

Budget Impact of RefluxStop™ as a Treatment for Patients with Refractory Gastro-oesophageal Reflux Disease in the United Kingdom.

Background: Gastro-oesophageal reflux disease (GORD) is a common condition associated with heartburn and regurgitation. Standard of care for GORD patients in the UK involves initial treatment with proton pump inhibitors (PPIs) and laparoscopic antireflux surgery in patients unwilling to continue or intolerant of long-term PPI treatment. Recently, RefluxStop™, a novel, implantable medical device, has proven to be an efficacious and cost-effective treatment for patients with GORD. The current analysis aimed to describe the budget impact of introducing RefluxStop™ within National Health Service (NHS) England and Wales. Objectives: To estimate the more immediate, short-term clinical and economic effects of introducing RefluxStop™ as a therapeutic option for patients with GORD treated within NHS England and Wales. Methods: A model adherent to international best practice guidelines was developed to estimate the budget impact of introducing RefluxStop™ over a 5-year time horizon, from an NHS perspective. Two hypothetical scenarios were considered, one without RefluxStop™ (comprising PPI treatment, laparoscopic Nissen fundoplication, and magnetic sphincter augmentation using the LINX® system) and one with RefluxStop™ (adding RefluxStop™ to the aforementioned treatment options). Clinical benefits and costs associated with each intervention were included in the analysis. Results: Over 5 years, introducing RefluxStop™ allowed the avoidance of 347 surgical failures, 39 reoperations, and 239 endoscopic esophageal dilations. The financial impact of introducing RefluxStop™ was £3 029 702 in year 5, corresponding to a 1.68% increase in annual NHS spending on GORD treatment in England and Wales. Discussion: While the time horizon was too short to capture some of the adverse events of PPIs and complications of GORD, such as the development of Barrett's esophagus or esophageal cancer, the use of RefluxStop™ was associated with a substantial reduction in surgical complications, including surgical failures, reoperations, and endoscopic esophageal dilations. This favorable clinical profile resulted in cost offsets for the NHS and contributed to the marginal budget impact of RefluxStop™ estimated in the current analysis. Conclusions: Introducing RefluxStop™ as a treatment option for patients with GORD in England and Wales may be associated with clinical benefits at the expense of a marginal budget impact on the NHS.

Migraine as an allostatic reset triggered by unresolved interoceptive prediction errors.

Until now, a satisfying account of the cause and purpose of migraine has remained elusive. We explain migraine within the frameworks of allostasis (the situationally-flexible, forward-looking equivalent of homeostasis) and active inference (interacting with the environment via internally-generated predictions). Due to its multimodality, and long timescales between cause and effect, allostasis is inherently prone to catastrophic error, which might be impossible to correct once fully manifest, an early indicator which is elevated prediction error (discrepancy between prediction and sensory input) associated with internal sensations (interoception). Errors can usually be resolved in a targeted manner by action (correcting the physiological state) or perception (updating predictions in light of sensory input); persistent errors are amplified broadly and multimodally, to prioritise their resolution (the migraine premonitory phase); finally, if still unresolved, progressive amplification renders further changes to internal or external sensory inputs intolerably intense, enforcing physiological stability, and facilitating accurate allostatic prediction updating. As such, migraine is an effective 'failsafe' for allostasis, however it has potential to become excessively triggered, therefore maladaptive.

Personalized Antihypertensive Treatment Optimization With Smartphone-Enabled Remote Precision Dosing of Amlodipine During the COVID-19 Pandemic (PERSONAL-CovidBP Trial).

BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074.

Absolute quantitation of endogenous proteins with precision and accuracy using a capillary Western system.

Precise and accurate quantification of protein expression levels in a complex biological setting is challenging. Here, we describe a method for absolute quantitation of endogenous proteins in cell lysates using an automated capillary immunoassay system, the size-based Simple Western system (recently developed by ProteinSimple). The method was able to accurately measure the absolute amounts of target proteins at picogram or sub-picogram levels per nanogram of cell lysates. The measurements were independent of the cell matrix or the cell lysis buffer and were not affected by different antibody affinities for their specific epitopes. We then applied this method to quantitate absolute levels of expression of protein kinase C (PKC) isoforms in LNCaP and U937 cells, two cell lines used extensively for probing the downstream biological responses to PKC targeted ligands. Our absolute quantitation confirmed the predominance of PKCδ in both cells, supporting the important functional role of this PKC isoform in these cell lines. The method described here provides an approach to accurately quantitate levels of protein expression and correlate protein level with function. In addition to enhanced accuracy relative to conventional Western analysis, it circumvents the distortions inherent in comparison with signal intensities from different antibodies with different affinities.

TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection.

Maturation of dendritic cells (DC) to competent APC is essential for the generation of acquired immunity and is a major function of adjuvants. dsRNA, a molecular signature of viral infection, drives DC maturation by activating TLR3, but the size of dsRNA required to activate DC and the expression patterns of TLR3 protein in DC subsets have not been established. In this article, we show that cross-priming CD8α(+) and CD103(+) DC subsets express much greater levels of TLR3 than other DC. In resting DC, TLR3 is located in early endosomes and other intracellular compartments but migrates to LAMP1(+) endosomes on stimulation with a TLR3 ligand. Using homogeneous dsRNA oligonucleotides (ONs) ranging in length from 25 to 540 bp, we observed that a minimum length of ∼90 bp was sufficient to induce CD86, IL-12p40, IFN-ß, TNF-α, and IL-6 expression, and to mature DC into APC that cross-presented exogenous Ags to CD8(+) T cells. TLR3 was essential for activation of DC by dsRNA ONs, and the potency of activation increased with dsRNA length and varied between DC subsets. In vivo, dsRNA ONs, in a size-dependent manner, served as adjuvants for the generation of Ag-specific CTL and for inducing protection against lethal challenge with influenza virus when given with influenza nucleoprotein as an immunogen. These results provide the basis for the development of TLR3-specific adjuvants capable of inducing immune responses tailored for viral pathogens.

Cost-effectiveness of a novel, non-active implantable device as a treatment for refractory gastro-esophageal reflux disease.

AIMS: Gastro-esophageal reflux disease (GERD) is a common, chronic gastrointestinal condition characterized by heartburn, chest pain, regurgitation, and bloating. The current standard of care includes chronic treatment with proton pump inhibitors (PPIs) or, in selected patients, laparoscopic anti-reflux surgery. RefluxStop is a novel implantable device indicated for GERD patients eligible for laparoscopic surgical treatment. The aim of this analysis was to assess the cost-effectiveness of RefluxStop against available treatment options for GERD. MATERIAL AND METHODS: A Markov model was developed to assess the cost-effectiveness of RefluxStop compared with PPI-based medical management (MM) and two surgical management options, LNF and magnetic sphincter augmentation (MSA, LINX system), in people with GERD. Clinical outcomes and costs were estimated over a lifetime horizon from the UK National Health Service perspective and an annual discount rate of 3.5% was applied. RESULTS: RefluxStop showed favorable surgical outcomes compared with both LNF and MSA. The base case incremental cost-effectiveness ratios compared with MM, LNF, and MSA were £4,156, £6,517, and £249 per QALY gained, respectively. At the UK cost-effectiveness threshold of £20,000 per QALY gained, the probability that RefluxStop was cost-effective against MM, LNF, and MSA was 100%, 93%, and 100%, respectively. LIMITATIONS: The model presented the results of a comparison, with evidence for RefluxStop derived from its single-arm CE mark trial and that for comparators from the literature. The varied clinical care pathway of individual GERD patients was necessarily simplified for modeling purposes, and necessary assumptions were made; however, the model results proved robust to sensitivity analyses. CONCLUSIONS: Introduction of RefluxStop was estimated to extend life expectancy and improve quality-of-life of GERD patients when compared with MM, LNF, and MSA. The results of the cost-effectiveness analysis demonstrated that RefluxStop is highly likely to be a cost-effective treatment option within NHS England.

A multistate outbreak of hepatitis A associated with semidried tomatoes in Australia, 2009.

BACKGROUND: A large outbreak of hepatitis A affected individuals in several Australian states in 2009, resulting in a 2-fold increase in cases reported to state health departments compared with 2008. Two peaks of infection occurred (April-May and September-November), with surveillance data suggesting locally acquired infections from a widely distributed food product. METHODS: Two case-control studies were completed. Intensive product trace-back and food sampling was undertaken. Genotyping was conducted on virus isolates from patient serum and food samples. Control measures included prophylaxis for close contacts, public health warnings, an order by the chief health officer under the Victorian Food Act 1984, and trade-level recalls on implicated batches of semidried tomatoes. RESULTS: A multijurisdictional case-control study in April-May found an association between illness and consumption of semidried tomatoes (odds ratio [OR], 3.0; 95% CI 1.4-6.7). A second case-control study conducted in Victoria in October-November also implicated semidried tomatoes as being associated with illness (OR, 10.3; 95% CI, 4.7-22.7). Hepatitis A RNA was detected in 22 samples of semidried tomatoes. Hepatitis A virus genotype IB was identified in 144 of 153 (94%) patients tested from 2009, and partial sequence analysis showed complete identity with an isolate found in a sample of semidried tomatoes. CONCLUSIONS: The results of both case-control studies and food testing implicated the novel vehicle of semidried tomatoes as the cause of this hepatitis A outbreak. The outbreak was extensive and sustained despite public health interventions, the design and implementation of which were complicated by limitations in food testing capability and complex supply chains.

Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-ß in breast cancer progression.

One great challenge in our understanding of TGF-ß cancer biology and the successful application of TGF-ß-targeted therapy is that TGF-ß works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-ß regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-ß neutralization. Two mechanisms were involved: first, treatment with TGF-ß neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-ß neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-ß-targeted therapy.