Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Observation of an Unusual Upward-Going Cosmic-Ray-like Event in the Third Flight of ANITA.

We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events could be produced by the atmospheric decay of an upward-propagating τ lepton produced by a ν_{τ} interaction, although their relatively steep arrival angles create tension with the standard model neutrino cross section. Each of the two events have a posteriori background estimates of ≲10^{-2} events. If these are generated by τ-lepton decay, then either the charged-current ν_{τ} cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos.

MALDI-TOF MS in Anaerobiospirillum succiniciproducens bacteremia: A report of 4 cases in different hosts.

Anaerobiospirillum succiniciproducens is known as an uncommon cause of diarrhea and bacteremia in humans, usually in immunocompromised hosts. We report four cases of A. succiniciproducens bloodstream infection in different hosts, including a previously healthy man. We describe clinical features, antibiotics susceptibility profile, treatment and outcomes. Strains were identified by 16S rRNA gene sequences which contributed to the extension of our MALDI-TOF MS database.

Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015.

The fifth "Melanoma Bridge Meeting" took place in Naples, December 1-5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient's clinical outcome. Moreover, incredible progress comes from the discovery of mutation-encoded tumor neoantigens. In fact, as tumors grow, they acquire mutations that are able to influence the response of patients to immune checkpoint inhibitors. It has been demonstrated that sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. The road ahead is still very long, but the knowledge of the mechanisms of immune escape, the study of tumor neo-antigens as well as of tumor microenvironment and the development of new immunotherapy strategies, will make cancer a more and more treatable disease.

Characteristics of Four Upward-Pointing Cosmic-Ray-like Events Observed with ANITA.

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.

A WHO reference reagent to standardize haemagglutination testing for anti-A and anti-B in serum and plasma: international collaborative study to evaluate a candidate preparation.

BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate a lyophilized serum preparation, 14/300, for its suitability to serve as a World Health Organization (WHO) Reference Reagent to standardize and control haemagglutination titrations for anti-A and anti-B in serum and plasma, in an international collaborative study. MATERIALS AND METHODS: Serum preparation 14/300 and two plasma-based reserve preparations, 14/304 (high titre anti-A) and 14/208 (high titre anti-B), were titrated by 24 laboratories in 13 countries using direct (DRT) and indirect (IAT) haemagglutination techniques. RESULTS: There was eightfold to 64-fold variation in reported titres per preparation and method across laboratories, that is, titres extended over 4-7 dilutions, although intralaboratory variability was generally good, with over 90% of replicate titres within a twofold range. There was a reduction in interlaboratory variability when titres of the reserve preparations were adjusted relative to those of the candidate Reference Reagent. CONCLUSION: The establishment of 14/300 as a WHO Reference Reagent for high titre anti-A and anti-B in serum, with nominal anti-A and anti-B titres of 128 for DRT, and nominal anti-A and anti-B titres of 256 for IAT, will facilitate global standardization of haemagglutination titrations for anti-A and anti-B in patient samples and blood components.

Lobar distribution in non-cystic fibrosis bronchiectasis predicts bacteriologic pathogen treatment.

Non-cystic fibrosis bronchiectasis (NCFBr) is a major cause of morbidity due to frequent infectious exacerbations. We analyzed the influence of patient age and bronchiectasis location on the bacterial profile of patients with NCFBr. This retrospective cohort study included 339 subjects diagnosed with an infectious exacerbation of NCFBr during the 9-year period between January 2006 and December 2014. Bronchoalveolar lavage (BAL) cultures and high-resolution computed tomography scans (HRCT) were utilized to characterize the location of the bronchiectasis and bacteriologic pathogenic profile. In univariate logistic regression, the frequency of Haemophilus influenzae was higher in patients aged ≤64 years (OR = 0.969, p < 0.0001, 95 % CI 0.954-0.983), whereas the frequency of Pseudomonas aeruginosa (OR = 1.027, p = 0.008, 95 % CI 1.007-1.048) and Enterobacteriaceae (OR = 1.039, p = 0.01, 95 % CI 1.009-1.069) were significantly higher in patients aged >64 years. The lobar distribution of bronchiectasis in the subjects was 25.9 % in the right middle lobe (RML), 20.7 % in the right lower lobe (RLL), 20.4 % in the left lower lobe (LLL), 13.8 % in the lingula, 13 % in the right upper lobe (RUL), and 6.2 % in the left upper lobe (LUL). In the lower lobes, H. influenzae was the dominant species isolated, whereas in the RUL it was P. aeruginosa and in the LUL it was non- tuberculous mycobacterium (NTM). H. influenzae was more prevalent in younger patients, whereas P. aeruginosa, Enterobacteriaceae and NTM predominated in older patients. Different pathogens were associated with different lobar distributions. The RML, RLL and LLL showed a greater tendency to develop bronchiectasis than other lobes.

Association of Anaesthetists of Great Britain and Ireland: Safe vascular access 2016.

Safe vascular access is integral to anaesthetic and critical care practice, but procedures are a frequent source of patient adverse events. Ensuring safe and effective approaches to vascular catheter insertion should be a priority for all practitioners. New technology such as ultrasound and other imaging has increased the number of tools available. This guidance was created using review of current practice and literature, as well as expert opinion. The result is a consensus document which provides practical advice on the safe insertion and removal of vascular access devices.

International collaborative study to assess new stocks of candidate reference preparations to control the level of anti-D in IVIG

The level of anti-D antibodies in human immunoglobulin products for intravenous administration (IVIG) is controlled by the direct haemagglutination method prescribed by the European Pharmacopoeia (Ph. Eur.) that requires 2 control reference reagents. The World Health Organization (WHO) positive control International Reference Reagent (IRR; 02/228) with a nominal titre of 8 defines the highest acceptable titre, while the negative control preparation (02/226) has a nominal titre of <2. Working reference preparations (04/132 and 04/140) were subsequently established as Biological Reference Preparations (BRPs) for the Ph. Eur., and for distribution by the United States Food and Drug Administration (US FDA) and the National Institute for Biological Standards and Control (NIBSC). Due to diminishing stocks of these working reference preparations across the 3 institutions, a joint international study was organised to establish harmonised replacement batches. Sixteen laboratories contributed data to the study to evaluate positive and negative candidate replacement batches (13/148 and 12/300, respectively) against the WHO positive and negative control IRRs and the current working reference preparations (BRPs). The results show that the candidate reference preparations (13/148 and 12/300) are indistinguishable from the corresponding IRRs and current BRPs. The candidate preparations 13/148 and 12/300 were adopted by the Ph. Eur. Commission as Immunoglobulin (anti-D antibodies test) BRP batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 with nominal haemagglutination titres of 8 and <2, respectively. The same materials were also adopted as NIBSC and US FDA reference preparations, thus ensuring full harmonisation.

Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma.

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

International reference reagents to standardise blood group genotyping: evaluation of candidate preparations in an international collaborative study.

BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate, in an international collaboration, four lyophilised genomic DNA preparations, selected from genotyped and phenotyped donors by the study organisers, for their suitability to standardise and control blood group genotyping procedures for common ancestral Caucasian and Black African alleles. MATERIALS AND METHODS: Twenty-nine laboratories performed 'blind' testing of replicated ampoules of the candidate reference reagents, RBC1 (10/232), RBC4 (10/236), RBC5 (10/238) and RBC12 (10/234), using a range of genotyping procedures, most commonly classical PCR using allele or sequence specific primers. RESULTS: The majority of laboratories reported blood group genotypes in accordance with those determined by the study organisers and the serological phenotypes. Despite an overall high level of accuracy in genotyping, the identified errors and inconsistencies, and the limited genotyping capabilities of many laboratories, confirmed the need for validated reference materials to control test procedures. CONCLUSIONS: The establishment of RBC1, RBC4, RBC5 and RBC12 as World Health Organization Reference Reagents will facilitate international standardisation of blood group genotyping and ensure that such tests are sufficiently sensitive and specific.

The increasing role of endoscopic ultrasound (EUS) in the management of pancreatic and biliary disease.

Pancreatic and biliary disease continues to have a significant impact on the workload of the National Health Service (NHS), for which there exists a multimodality approach to investigation and diagnosis. Endoscopic ultrasound (EUS) is fast becoming a fundamental tool in this cohort of patients, not only because of its ability to provide superior visualization of a difficult anatomical region, but also because of its valuable role as a problem-solving tool and ever-improving ability in an interventional capacity. We provide a comprehensive review of the benefits of EUS in everyday clinical practice.

Increased serum ß2-microglobulin is associated with clinical and immunological markers of disease activity in systemic lupus erythematosus patients.

The objective of this study was to explore the relationship between serum levels of ß2-microglobulin (ß2MG), which some studies suggest reflect disease activity in systemic lupus erythematosus (SLE), and various clinical and immunological markers of disease activity in SLE. Twenty-six SLE patients and 10 healthy controls were included. Disease activity was assessed by: SLEDAI, 24 hr-proteinuria, circulating levels of complement C3, anti-double-stranded DNA (anti-dsDNA), ß2MG and various pro-inflammatory and anti-inflammatory cytokines (IL-6, IL-8, IL-10, IL-18) measured with a multiplex assay, IFN-α assessed with a reporter gene assay, and a combined expression score of 12 IFN-α inducible genes in peripheral blood mononuclear cells. Median serum levels of ß2MG were significantly higher in SLE patients vs controls (2.8 mg/L, range: 1.1-21.6 and 1.2 mg/L, range: 0.9-1.7, respectively, p < 0.001). ß2MG was correlated with SLEDAI score (R = 0.68, p < 0.001), 24 hr-proteinuria (R = 0.64, p < 0.001), and complement C3 (R = -0.52, p = 0.007). The cytokines were significantly correlated with ß2MG: IL-6 (R = 0.45, p = 0.02), IL-8 (R = 0.75, p < 0.001), IL-10 (R = 0.67, p < 0.001) and IL-18 (R = 0.71, p < 0.001) as were serum IFN-α (R = 0.45, p = 0.02) and the IFN-α inducible gene-score (R = 0.51, p = 0.01). The results support that ß2MG may serve as a marker of disease activity in SLE. The correlations with the measured cytokines indicate that increased ß2MG in SLE reflects immunological activity.

PET/CT in anal cancer - is it worth doing?

AIM: To evaluate the role of 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/ computed tomography (CT) in the current multidisciplinary management of anal cancer, both in initial staging and in follow-up post-treatment. MATERIALS AND METHODS: All patients referred to the region-wide multidisciplinary meeting for anal cancer during the study period received PET/CT imaging in addition to conventional imaging [CT and magnetic resonance imaging (MRI)]. Whether PET/CT altered the stage of the tumour from that suggested by conventional imaging was retrospectively assessed. The effect on management was evaluated. RESULTS: Fifty PET/CT examinations were performed on 44 patients with anal cancer. Thirty were part of initial staging, and 20 were post-chemo/radiotherapy or surgery. Two PET/CTs produced inadequate contemporaneous conventional imaging to allow comparison. Overall PET/CT increased the stage of the anal cancer in 17% of cases (8/48), decreased the stage in 19% (9/48), and did not alter the stage in 65% (31/48). The tumour stage was altered more frequently in initial staging than in follow up imaging. The PET/CT findings altered patient management in 29% (14/48) of cases. The majority (11) of these were cases in which PET/CT was used as part of initial staging. CONCLUSION: PET/CT alters the initial staging sufficiently frequently that it should be used routinely in anal cancer, where it is available. The role of PET/CT in the follow-up of anal cancer is not as clear. Routine follow-up with PET/CT may not be justified, but selected use is of definite benefit in problem solving or if salvage surgery is planned, after multidisciplinary discussion.

Surgical treatment for combined hemifacial spasm and atypical trigeminal neuralgia caused by a tortuous basilar artery. Case report and review of the literature.

Simultaneous hemifacial spasm (HFS) and trigeminal neuralgia caused by cranial nerve (CN) compression from a tortuous basilar artery (BA) is very rare. We report a case of a 66-year-old man who presented with both HFS and "atypical" trigeminal neuralgia. The patient had a tortuous BA compressing both CN V and VII. The patient underwent microvascular decompression after failing conservative medical management. To the best of our knowledge this is the first reported case of both HFS and "atypical" trigeminal neuralgia that were both successfully treated by surgical intervention. We report the management of this rare combination and review the literature.

NOD2 signaling in CD11c + cells is critical for humoral immune responses during oral vaccination and maintaining the gut microbiome.

Nucleotide-binding oligomerization domain containing 2 (NOD2) is a critical regulator of immune responses within the gastrointestinal tract. This innate immune receptor is expressed by several cell types, including both hematopoietic and nonhematopoietic cells within the gastrointestinal tract. Vaccination targeting the gastrointestinal mucosal immune system is especially difficult due to both physical and mechanistic barriers to reaching inductive sites. The use of lactic acid bacteria is appealing due to their ability to persist within harsh conditions, expression of selected adjuvants, and manufacturing advantages. Recombinant Lactobacillus acidophilus (rLA) has shown great promise in activating the mucosal immune response with minimal impacts on the resident microbiome. To better classify the kinetics of mucosal vaccination with rLA, we utilized mice harboring knockouts of NOD2 expression specifically within CD11c + cells. The results presented here show that NOD2 signaling in CD11c + cells is necessary for mounting a humoral immune response against exogenous antigens expressed by rLA. Additionally, disruption of NOD2 signaling in these cells results in an altered bacterial microbiome profile in both control mice and mice receiving L. acidophilus strain NCK1895 and vaccine strain LaOVA.

A case study: The deployment of a novel in situ fluorimeter for monitoring biological contamination within the urban surface waters of Kolkata, India.

The quality and health of many of our vital freshwater systems are poor. To tackle this with ever increasing pressures from anthropogenic and climatic changes, we must improve water quality monitoring and devise and implement more appropriate water quality parameters. Recent research has highlighted the potential for Peak T fluorescence (tryptophan-like fluorescence, TLF) to monitor microbial activity in aquatic systems. The VLux TPro (Chelsea Technologies Ltd., UK), an in situ real-time fluorimeter, was deployed in different urban freshwater bodies within Kolkata (West Bengal, India) during March 2019. This study is the first to apply this technology in surface waters within a densely populated urban area. Spot-sampling was also undertaken at 13 sampling locations enabling physicochemical analysis, bacterial enumeration and determination of nutrient (nitrate and phosphate) concentrations. This case study has demonstrated the ability of an in situ fluorimeter, VLux TPro, to successfully identify both biological contamination events and potential elevated microbial activity, related to nutrient loading, in complex surface freshwaters, without the need for expensive and time-consuming laboratory analysis.

Complete Genome Sequence of Finnry, a Subcluster L3 Mycobacteriophage from Charleston, South Carolina.

Subcluster L3 bacteriophage Finnry was isolated from soil collected in Charleston, South Carolina, using Mycobacterium smegmatis mc2155 as a host. The genome of this temperate siphovirus is 75,632 bp long (130 predicted protein-coding genes, 9 tRNAs, and no transfer-messenger RNAs), and BLASTn alignment revealed 99.86% identity with the genome of L3 mycobacteriophage Samty.