Cryogenic Characterization of FBK HD Near-UV Sensitive SiPMs

We report on the characterization of near-ultraviolet high density silicon photomultiplier (\SiPM) developed at Fondazione Bruno Kessler (\FBK) at cryogenic temperature. A dedicated setup was built to measure the primary dark noise and correlated noise of the \SiPMs\ between 40 and 300~K. Moreover, an analysis program and data acquisition system were developed to allow the precise characterization of these parameters, some of which can vary up to 7 orders of magnitude between room temperature and 40~K. We demonstrate that it is possible to operate the \FBK\ near-ultraviolet high density \SiPMs\ at temperatures lower than 100~K with a dark rate below 0.01 cps/mm$^2$ and total correlated noise probability below 35\% at an over-voltage of 6~V. These results are relevant for the development of future cryogenic particle detectors using \SiPMs\ as photosensors

Effect of Salt Addition and Fermentation Time on Phenolics, Microbial Dynamics, Volatile Organic Compounds, and Sensory Properties of the PDO Table Olives of Gaeta (Italy)

‘Oliva di Gaeta’ is almost certainly the most important and well-known PDO denomination for table olives in Italy. Their production is based on a specific two-stage trade preparation called the ‘Itrana’ method. In this work, we investigated how variations in the duration of the initial water fermentation (i.e., 15 and 30 days) and the salt concentration (i.e., 6% and 8% NaCl) influence the chemical features, microbial dynamics, polyphenols, volatile organic compounds, and sensory features of ‘Oliva di Gaeta’. The time of the addition of salt did not affect the final concentration in the brine, but a longer initial water fermentation (before salt addition) led to lower pH values. The bacterial count constantly increased until the salt addition (i.e., either 15 or 30 days), while the yeast population peaked on day 30. Generally, the two different salt concentrations did not affect the count of microorganisms at the end of fermentation, with the only exception being a higher lactic acid bacteria count for the treatment with 6% salt added at 30 days. At commercial maturity, the crucial bitter tastant oleuropein was not completely removed from the drupes, and differences in salt concentration and the length of the first-stage water fermentation did not influence its content at the end of olive curing. Richer volatile profiles of olives were detected with higher-salt treatments, while the combination of low salt and early saline treatment provided a more distinct profile. Longer initial water fermentation caused a small increase in some phenolic compounds (e.g., iso-verbascoside, verbascoside, and hydroxytyrosol-glucoside). A panel test indicated that salt application at 30 days resulted in a more “Sour” and “Bitter” taste, irrespective of the salt concentration. The low salt concentration coupled with the late saline treatment resulted in more “Fruity” notes, probably due to the higher production of esters by lactobacilli. The slightly bitter perception of the olives was consistent with the partial removal of oleuropein. Our work revealed the characteristics of the ‘Itrana’ method and that the variation in salt concentration and its time of application changes parameters ranging from the microbial dynamics to the sensory profile. Specifically, our data indicate that 6% NaCl coupled with a longer initial water fermentation is the most different condition: it is less effective in blocking microbial growth but, at the same time, is more potent in altering the nutritional (e.g., polyphenols) and sensorial qualities (e.g., bitterness and fruitiness) of ‘Oliva di Gaeta’

Topical rifampicin for prevention of deep sternal wound infections in patients undergoing coronary artery bypass grafting

Deep sternal wound infections (DSWI), although an infrequent complication, significantly impair postoperative outcomes after coronary artery bypass grafting (CABG) surgery. Among several preventive strategies, topical antibiotic therapy immediately before sternal closure has been strongly advocated. In this retrospective analysis, the incidence of DSWI in 517 patients undergoing isolated CABG and receiving rifampicin irrigation of mediastinum, sternum and suprasternal tissues was compared to an historical consecutive cohort of 448 patients. To account for the inherent selection bias, a 1:1 propensity matched analysis was performed. Patients receiving topical rifampicin experienced significantly less occurrence of postoperative DSWI (0.2% vs 2.5%, p = 0.0016 in the unmatched analysis; 0.3% vs 2.1%, p = 0.0391 in the matched analysis). Intensive care unit stay, hospital stay, and operative mortality were similar between groups. This study shows that topical rifampicin in combination with commonly prescribed preventative strategies significantly reduces the incidence of DSWI to less than 0.3% in unselected patients undergoing a full median sternotomy for CABG. Further studies, including a larger number of patients and with a randomization design, would establish the potential preventative role of topical rifampicin in reducing the occurrence of DSWI

An Association of PTPN11 and SHOX Mutations in a Male Presenting With Syndromic Growth Failure

In children with genetic syndromes, short stature is frequently a characteristic feature that, when associated with other specific manifestations, significantly aids in clinical diagnosis. In this report, an atypical case of Noonan syndrome (NS) in a 5.5-year-old child with mesomelic short stature is described. Genetic tests revealed two different mutations in this child. As expected in an NS case, a mutation in PTPN11 gene related to the RAS/MAPK signal transduction pathway was identified. Moreover, a mutation in the SHOX gene that was able to cause disproportionate short stature was detected. A clinical picture of NS with mesomelic short stature makes the diagnosis even more difficult as haploinsufficiency and complete loss of function of SHOX gene are associated with the typical differentiation and proliferation of chondrocytes, leading to mesomelic appearance. This case exemplifies the difficulties that can be encountered in achieving proper diagnoses for children with syndromic diseases and highlights the role of genetic tests in identifying final diagnoses in these patient

372. Prevalence of Anti-AAV8 Neutralizing Antibodies and ARSB Cross-Reactive Immunologic Material in MPS VI Patients Candidates for a Gene Therapy Trial

Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Pre-existing immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for Mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder due to arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. To the best of our knowledge, four mutations had not been previously described. These include: one missense (c.1178 A>G p.H393R) and three frameshift mutations [883-884duplTT (p.F295FfsX42), c.1036delG (p.E346SfsX11), c.1475delC (pP492LfsX80)] predicted to result in truncated proteins. The detection of ARSB protein in twenty-four patients out of 34 (71%) was predicted by the type of mutations. Pre-existing Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8

Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction

Aims: No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results: In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions: Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials

A second generation radiation hybrid map to aid the assembly of the bovine genome sequence

BACKGROUND: Several approaches can be used to determine the order of loci on chromosomes and hence develop maps of the genome. However, all mapping approaches are prone to errors either arising from technical deficiencies or lack of statistical support to distinguish between alternative orders of loci. The accuracy of the genome maps could be improved, in principle, if information from different sources was combined to produce integrated maps. The publicly available bovine genomic sequence assembly with 6× coverage (Btau_2.0) is based on whole genome shotgun sequence data and limited mapping data however, it is recognised that this assembly is a draft that contains errors. Correcting the sequence assembly requires extensive additional mapping information to improve the reliability of the ordering of sequence scaffolds on chromosomes. The radiation hybrid (RH) map described here has been contributed to the international sequencing project to aid this process. RESULTS: An RH map for the 30 bovine chromosomes is presented. The map was built using the Roslin 3000-rad RH panel (BovGen RH map) and contains 3966 markers including 2473 new loci in addition to 262 amplified fragment-length polymorphisms (AFLP) and 1231 markers previously published with the first generation RH map. Sequences of the mapped loci were aligned with published bovine genome maps to identify inconsistencies. In addition to differences in the order of loci, several cases were observed where the chromosomal assignment of loci differed between maps. All the chromosome maps were aligned with the current 6× bovine assembly (Btau_2.0) and 2898 loci were unambiguously located in the bovine sequence. The order of loci on the RH map for BTA 5, 7, 16, 22, 25 and 29 differed substantially from the assembled bovine sequence. From the 2898 loci unambiguously identified in the bovine sequence assembly, 131 mapped to different chromosomes in the BovGen RH map. CONCLUSION: Alignment of the BovGen RH map with other published RH and genetic maps showed higher consistency in marker order and chromosome assignment than with the current 6× sequence assembly. This suggests that the bovine sequence assembly could be significantly improved by incorporating additional independent mapping information

Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog

10.1016/j.stem.2013.04.023Cell Stem Cell125531-54