The importance of interaural time differences and level differences in spatial release from masking

Numerous studies have described improvements in speech understanding when interaural time differences (ITDs) and interaural level differences (ILDs) are present. The present study aimed to investigate whether either cue in isolation can elicit spatial release from masking (SRM) in a speech-on-speech masking paradigm with maskers positioned symmetrically around the listener. Twelve adults were tested using three presentations of the Listening in Spatialized Noise-Sentences Test, with each presentation modified to contain different interaural cues in the stimuli. Results suggest that ILDs provide a similar amount of SRM as ITDs and ILDs combined. ITDs alone provide significantly less benefit. (C) 2013 Acoustical Society of Americ

System Integration and Its Influence on the Quality of Life of Children with Complex Needs

Purpose. To explore the interactions between child and parents psychosocial factors and team integration variables that may explain improvements in physical dimensions of the PEDS QL quality of life of children with complex needs after 2 years. Methods. In this 2-year study, parents were identified by the Children's Treatment Network. Families were eligible if the child was aged 0–19 years, had physical limitations, resided in either Simcoe County or the Region of York, Ontario, and there were multiple other family needs. Regression analysis used to explore associations and interactions; n = 110. Results. A child's physical quality of life was affected by interacting factors including child's behavior, parenting, and integrated care. Statistically significant interactions between team integration, processes of care, and child/parent variables highlight the complexity of the rehabilitation approach in real-life situations. Conclusions. Rehabilitation providers working with children with complex needs and their families should also address child and parent problematic behaviors. When this was the case in high integrated teams, the child's physical quality of life improved after two years

Effect of audibility on spatial release from speech-on-speech masking

This study investigated to what extent spatial release from masking (SRM) deficits in hearing-impaired adults may be related to reduced audibility of the test stimuli. Sixteen adults with sensorineural hearing loss and 28 adults with normal hearing were assessed on the Listening in Spatialized Noise–Sentences test, which measures SRM using a symmetric speech-on-speech masking task. Stimuli for the hearing-impaired listeners were delivered using three amplification levels (National Acoustic Laboratories - Revised Profound prescription (NAL-RP) +25%, and NAL-RP +50%), while stimuli for the normal-hearing group were filtered to achieve matched audibility. SRM increased as audibility increased for all participants. Thus, it is concluded that reduced audibility of stimuli may be a significant factor in hearing-impaired adults' reduced SRM even when hearing loss is compensated for with linear gain. However, the SRM achieved by the normal hearers with simulated audibility loss was still significantly greater than that achieved by hearing-impaired listeners, suggesting other factors besides audibility may still play a role

Predicting 1-year mortality among patients with decompensated cirrhosis:results of a multicentre evaluation of the Bristol Prognostic Score

Objective Chronic liver disease continues to be a significant cause of morbidity and mortality yet remains challenging to prognosticate. This has been one of the barriers to implementing palliative care, particularly at an early stage. The Bristol Prognostic Score (BPS) was developed to identify patients with life expectancy less than 12 months and to act as a trigger for referral to palliative care services. This study retrospectively evaluated the BPS in a cohort of patients admitted to three Scottish hospitals. Method Routinely collated healthcare data were used to obtain demographics, BPS and analyse 1-year mortality for patients with decompensated liver disease admitted to three gastroenterology units over two 90-day periods. Statistical analysis was undertaken to assess performance of BPS in predicting mortality. Results 276 patients were included in the final analysis. Participants tended to be late middle-aged men, socioeconomically deprived and have alcohol-related liver disease. A similar proportion was BPS+ve (>3) in this study compared with the original Bristol cohort though had more hospital admissions, higher ongoing alcohol use and poorer performance status. BPS performed poorer in this non-Bristol group with sensitivity 54.9% (72.2% in original study), specificity 58% (83.8%) and positive predictive value (PPV) 43.4% (81.3%). Conclusion BPS was unable to accurately predict mortality in this Scottish cohort. This highlights the ongoing challenge of prognostication in patients with chronic liver disease, furthering the call for more work in this field.Publisher PDFPeer reviewe

Ablation of Enpp6 results in transient bone hypomineralization

C.F. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) via an Institute Strategic Programme Grant Funding (BB/J004316/1). S.D. was supported through a BBSRC EASTBIO Doctoral Training Partnership studentship award (1803936) and N.M.M. was supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z). S.D. wrote the manuscript. S.D., K.S., S-N.H., and L.A.S. carried out experimental work. W.P.C., R.W. and N.M.M. provided reagents and materials. A.J.S., F.N. and C.F. contributed to conceptualization of the study and experimental design. All authors reviewed and edited the manuscript and approved the final version. All authors state that they have no conflicts of interest.Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. The biochemical pathways which generate intravesicular PHOSPHO1 substrates are however currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase (ENPP6) is an upstream source of PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6‒/‒). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6‒/‒ tibiae (p 0.01) and osteoid surface (p < 0.05) which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6‒/‒ mice, revealing transient hypomineralization in young animals compared to wild-type controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles.Publisher PDFPeer reviewe

A Comprehensive Measurement of the Local Value of the Hubble Constant with 1 km/s/Mpc Uncertainty from the Hubble Space Telescope and the SH0ES Team

We report observations from HST of Cepheids in the hosts of 42 SNe Ia used to calibrate the Hubble constant (H0). These include all suitable SNe Ia in the last 40 years at z1000 orbits, more than doubling the sample whose size limits the precision of H0. The Cepheids are calibrated geometrically from Gaia EDR3 parallaxes, masers in N4258 (here tripling that Cepheid sample), and DEBs in the LMC. The Cepheids were measured with the same WFC3 instrument and filters (F555W, F814W, F160W) to negate zeropoint errors. We present multiple verifications of Cepheid photometry and tests of background determinations that show measurements are accurate in the presence of crowding. The SNe calibrate the mag-z relation from the new Pantheon+ compilation, accounting here for covariance between all SN data, with host properties and SN surveys matched to negate differences. We decrease the uncertainty in H0 to 1 km/s/Mpc with systematics. We present a comprehensive set of ~70 analysis variants to explore the sensitivity of H0 to selections of anchors, SN surveys, z range, variations in the analysis of dust, metallicity, form of the P-L relation, SN color, flows, sample bifurcations, and simultaneous measurement of H(z). Our baseline result from the Cepheid-SN sample is H0=73.04+-1.04 km/s/Mpc, which includes systematics and lies near the median of all analysis variants. We demonstrate consistency with measures from HST of the TRGB between SN hosts and NGC 4258 with Cepheids and together these yield 72.53+-0.99. Including high-z SN Ia we find H0=73.30+-1.04 with q0=-0.51+-0.024. We find a 5-sigma difference with H0 predicted by Planck+LCDM, with no indication this arises from measurement errors or analysis variations considered to date. The source of this now long-standing discrepancy between direct and cosmological routes to determining the Hubble constant remains unknown.Comment: 67 pages, 31 figures, replaced to match ApJ accepted version (March 2022), Table 6 distances included here, long form of photometry tables, fitting code, compact form of data, available from Github page, https://pantheonplussh0es.github.i

Design and Synthesis of a Quintessential Self-Transmissible IncX1 Plasmid, pX1.0

DNA exchange in bacteria via conjugative plasmids is believed to be among the most important contributing factors to the rapid evolution- and diversification rates observed in bacterial species. The IncX1 plasmids are particularly interesting in relation to enteric bacteria, and typically carry genetic loads like antibiotic resistance genes and virulence factors. So far, however, a “pure” version of these molecular parasites, without genetic loads, has yet to be isolated from the environment. Here we report the construction of pX1.0, a fully synthesized IncX1 plasmid capable of horizontal transfer between different enteric bacteria. The designed pX1.0 sequence was derived from the consensus gene content of five IncX1 plasmids and three other, more divergent, members of the same phylogenetic group. The pX1.0 plasmid was shown to replicate stably in E. coli with a plasmid DNA per total DNA ratio corresponding to approximately 3–9 plasmids per chromosome depending on the growth phase of the host. Through conjugation, pX1.0 was able to self-transfer horizontally into an isogenic strain of E. coli as well as into two additional species belonging to the family Enterobacteriaceae. Our results demonstrate the immediate applicability of recent advances made within the field of synthetic biology for designing and constructing DNA systems, previously existing only in silica

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer : a study protocol of a randomised phase II trial (PRIME-RT)

Acknowledgements We are grateful to Mr George Davidson and Ms Monica Jeffers for their input with writing the PRIME-RT protocol and patient information sheet. This study is co-sponsored by the University of Glasgow and NHS Greater Glasgow and Clyde. Funding PRIME-RT is funded by Astrazeneca and receives core funding from CRUK Clinical Trials Unit Glasgow for the purposes of trial set-up and data collection. The trial is co-sponsored by the University Of Glasgow and NHS Greater Glasgow and Clyde.Peer reviewedPublisher PD

T-replete cord transplants give superior outcomes in high risk and relapsed/refractory paediatric myeloid malignancy

Stem cell transplant (SCT) outcomes in high-risk (HR) and relapsed/refractory (R/R) paediatric acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) have been poor historically. Cord blood allows T-cell replete transplant (TRCB), enabling enhanced graft-versus-leukaemia. We collected data from 367 consecutive patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for paediatric AML/MDS in the UK and Ireland between January 2014 and December 2021. Data was collected about patient's demographics, disease and its treatment including previous transplant, measurable residual disease (MRD) status at transplant, HLA-match, relapse, death, graft versus host disease (GvHD) and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6% and 5.1% respectively in the comparator group (all p <0.001). Within the TRCB cohort, Event Free Survival (EFS) was 64.1%, 50% in MRD positive patients and 79% in MRD negative (p= 0.009). To allow for the imbalance in baseline characteristics, a multivariable analysis was performed: the TRCB cohort had significantly improved EFS (0.57[0.35-0.91], p=0.019), time to relapse (0.46[0.26-0.81), p=0.008), and reduced chronic GVHD (HR 0.28 [95% CI 0.11-0.70]; p=0.007), with some evidence of improved Overall Survival (OS) (0.65[0.39-1.07], p = 0.088). The effect appeared similar regardless of MRD status, (interaction p-value= 0.29). CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy

ASEPTIC:primary antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis-study protocol for an interventional randomised controlled trial

Background: Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites. Methods: The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients’ health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events. Discussion: This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis. Trial registration: ClinicalTrials.gov NCT043955365. Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central – Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA)