Well rounded Postdoctoral Researchers with initiative, who are not always “tied to the bench” are more successful academically

This article reports the development, application and results of a baseline investigation of contract research staff in 2007 in the Medical School at the University of Sheffield which was carried out in order to develop a specifically tailored training and career development programme and allow for future impact evaluation of the scheme. Postdoctoral researchers reported on their perceived skill levels, academic achievements, career motivations and the current research environment. Results indicated that transferable skills related to communication and awareness of the process of research (i.e. the process of acquisition of funding, commercialisation of research outputs) were lacking. Furthermore, these skills were associated with higher publication outputs, and improved with mobility between institutions at postdoctoral level. This paper also describes how the findings from the baseline evaluation were used to develop a programme to address the lower ranking skills and evaluate the impact of the programme

Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention

The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.Fil: Nocera, Nadia F.. University of Pennsylvania; Estados UnidosFil: Lee, M. Catherine. H. Lee Moffitt Cancer Center; Estados UnidosFil: De La Cruz, Lucy M.. University of Pennsylvania; Estados UnidosFil: Rosemblit, Cinthia. University of Pennsylvania; Estados UnidosFil: Czerniecki, Brian J.. H. Lee Moffitt Cancer Center; Estados Unido

Skill-based Model-based Reinforcement Learning

Model-based reinforcement learning (RL) is a sample-efficient way of learning complex behaviors by leveraging a learned single-step dynamics model to plan actions in imagination. However, planning every action for long-horizon tasks is not practical, akin to a human planning out every muscle movement. Instead, humans efficiently plan with high-level skills to solve complex tasks. From this intuition, we propose a Skill-based Model-based RL framework (SkiMo) that enables planning in the skill space using a skill dynamics model, which directly predicts the skill outcomes, rather than predicting all small details in the intermediate states, step by step. For accurate and efficient long-term planning, we jointly learn the skill dynamics model and a skill repertoire from prior experience. We then harness the learned skill dynamics model to accurately simulate and plan over long horizons in the skill space, which enables efficient downstream learning of long-horizon, sparse reward tasks. Experimental results in navigation and manipulation domains show that SkiMo extends the temporal horizon of model-based approaches and improves the sample efficiency for both model-based RL and skill-based RL. Code and videos are available at \url{https://clvrai.com/skimo}Comment: Website: \url{https://clvrai.com/skimo

Trajectories of objectively measured physical activity in free-living older men.

BACKGROUND: The steep decline in physical activity (PA) among the oldest old is not well understood; there is little information about the patterns of change in PA and sedentary behaviour (SB) in older people. Longitudinal data on objectively measured PA data can give insights about how PA and SB change with age. METHODS: Men age 70-90 yr, from a United Kingdom population-based cohort wore a GT3X accelerometer over the hip annually on up to three occasions (56%, 50%, and 51% response rates) spanning 2 yr. Multilevel models were used to estimate change in activity. Men were grouped according to achieving ≥150 min·wk of MVPA in bouts of ≥10 min (current guidelines) at two or three time points. RESULTS: A total of 1419 ambulatory men had ≥600 min wear time on ≥3 d at ≥2 time points. At baseline, men took 4806 steps per day and spent 72.5% of their day in SB, 23.1% in light PA, and 4.1% in moderate-to-vigorous PA (MVPA). Mean change per year was -341 steps, +1.1% SB, -0.7% light PA, and -0.4% MVPA each day (all P 30 min increased from 5.1 by 0.1 per year (P = 0.02). CONCLUSIONS: Among older adults, the steep decline in total PA occurred because of reductions in MVPA, while light PA is relatively spared and sedentary time and long sedentary bouts increase

Theory of Change: a theory-driven approach to enhance the Medical Research Council's framework for complex interventions.

BACKGROUND: The Medical Research Councils' framework for complex interventions has been criticized for not including theory-driven approaches to evaluation. Although the framework does include broad guidance on the use of theory, it contains little practical guidance for implementers and there have been calls to develop a more comprehensive approach. A prospective, theory-driven process of intervention design and evaluation is required to develop complex healthcare interventions which are more likely to be effective, sustainable and scalable. METHODS: We propose a theory-driven approach to the design and evaluation of complex interventions by adapting and integrating a programmatic design and evaluation tool, Theory of Change (ToC), into the MRC framework for complex interventions. We provide a guide to what ToC is, how to construct one, and how to integrate its use into research projects seeking to design, implement and evaluate complex interventions using the MRC framework. We test this approach by using ToC within two randomized controlled trials and one non-randomized evaluation of complex interventions. RESULTS: Our application of ToC in three research projects has shown that ToC can strengthen key stages of the MRC framework. It can aid the development of interventions by providing a framework for enhanced stakeholder engagement and by explicitly designing an intervention that is embedded in the local context. For the feasibility and piloting stage, ToC enables the systematic identification of knowledge gaps to generate research questions that strengthen intervention design. ToC may improve the evaluation of interventions by providing a comprehensive set of indicators to evaluate all stages of the causal pathway through which an intervention achieves impact, combining evaluations of intervention effectiveness with detailed process evaluations into one theoretical framework. CONCLUSIONS: Incorporating a ToC approach into the MRC framework holds promise for improving the design and evaluation of complex interventions, thereby increasing the likelihood that the intervention will be ultimately effective, sustainable and scalable. We urge researchers developing and evaluating complex interventions to consider using this approach, to evaluate its usefulness and to build an evidence base to further refine the methodology. TRIAL REGISTRATION: Clinical trials.gov: NCT02160249

The HIV Genomic Incidence Assay Meets False Recency Rate and Mean Duration of Recency Infection Performance Standards.

HIV incidence is a primary metric for epidemic surveillance and prevention efficacy assessment. HIV incidence assay performance is evaluated via false recency rate (FRR) and mean duration of recent infection (MDRI). We conducted a meta-analysis of 438 incident and 305 chronic specimens' HIV envelope genes from a diverse global cohort. The genome similarity index (GSI) accurately characterized infection stage across diverse host and viral factors. All except one chronic specimen had GSIs below 0.67, yielding a FRR of 0.33 [0-0.98] %. We modeled the incidence assay biomarker dynamics with a logistic link function assuming individual variabilities in a Beta distribution. The GSI probability density function peaked close to 1 in early infection and 0 around two years post infection, yielding MDRI of 420 [361, 467] days. We tested the assay by newly sequencing 744 envelope genes from 59 specimens of 21 subjects who followed from HIV negative status. Both standardized residuals and Anderson-Darling tests showed that the test dataset was statistically consistent with the model biomarker dynamics. This is the first reported incidence assay meeting the optimal FRR and MDRI performance standards. Signatures of HIV gene diversification can allow precise cross-sectional surveillance with a desirable temporal range of incidence detection

Immunisation status of children receiving care and support in Wales: a national data linkage study

Background: In the UK, a robust childhood immunisation programme ensures children are offered protection against serious infections; identifying inequalities in vaccination coverage is essential. This is one of the first data linkage studies to examine coverage of primary, as well as pre-school booster and second dose of MMR vaccines, in children receiving support from social care services across Wales. Methods: By accessing records held within the Secure Anonymised Information Linkage (SAIL) Databank, vaccination status of children receiving social care and support between April 2016 and March 2021 (n = 24,540) was ascertained. This was achieved through linkage of the Children Receiving Care and Support (CRCS) Census and National Community Child Health Database which holds vaccination records for all children in Wales registered for NHS care. This sample was split into three groups – those children who had never been recorded on the Child Protection Register (CPR) or as ‘Looked After’ but in CRCS (n = 12,480), children ever on the CPR (n = 6,225) and those ever recorded as ‘Looked After’ but who were never on the CPR (n = 5,840). The comparison group of children and young people (CYP) never receiving welfare support consisted of 624,905 children. Results: Children receiving care or support were more likely to be up-to-date with all six vaccines (no recorded vaccines: 0.6–6.3%) compared to children in the comparison group (no recorded vaccines: 3–10.3%). However, of those who were vaccinated, they were less likely to be vaccinated in a timely manner; both early (5.2% vs. 22.2%; margin of error [ME] = 0.52, 95% CI [confidence interval] = −0.18 – −0.17, p < 0.001) and delayed vaccinations were more common (62.7% vs. 71.3%; ME = 0.58, 95% CI = 0.08–0.09, p < 0.001). Validation of the CRCS immunisation flag showed moderate levels of accuracy. Around 70% of immunisation flags were correct across all three groups. Discussion: Findings suggest a positive association between receiving services under a care and support plan and being up-to-date with immunisations; children receiving support under a care and support plan were more likely to have experienced early or late vaccinations, demonstrating that there is still more inter-disciplinary co-ordination and planning needed to improve these outcomes. Thus, identifying inequalities in vaccination coverage is essential to target interventions and to prioritise geographic areas for catch-up

Estimating the coverage of mental health programmes: a systematic review.

BACKGROUND: The large treatment gap for people suffering from mental disorders has led to initiatives to scale up mental health services. In order to track progress, estimates of programme coverage, and changes in coverage over time, are needed. METHODS: Systematic review of mental health programme evaluations that assess coverage, measured either as the proportion of the target population in contact with services (contact coverage) or as the proportion of the target population who receive appropriate and effective care (effective coverage). We performed a search of electronic databases and grey literature up to March 2013 and contacted experts in the field. Methods to estimate the numerator (service utilization) and the denominator (target population) were reviewed to explore methods which could be used in programme evaluations. RESULTS: We identified 15 735 unique records of which only seven met the inclusion criteria. All studies reported contact coverage. No study explicitly measured effective coverage, but it was possible to estimate this for one study. In six studies the numerator of coverage, service utilization, was estimated using routine clinical information, whereas one study used a national community survey. The methods for estimating the denominator, the population in need of services, were more varied and included national prevalence surveys case registers, and estimates from the literature. CONCLUSIONS: Very few coverage estimates are available. Coverage could be estimated at low cost by combining routine programme data with population prevalence estimates from national surveys

Toward a better understanding of tool wear effect through a comparison between experiments and SPH numerical modelling of machining hard materials

The aim of this study is to improve the general understanding of tungsten carbide (WC–Co) tool wear under dry machining of the hard-to-cut titanium alloy Ti6Al4V. The chosen approach includes experimental and numerical tests. The experimental part is designed to identify wear mechanisms using cutting force measurements, scanning electron microscope observations and optical profilometer analysis. Machining tests were conducted in the orthogonal cutting framework and showed a strong evolution of the cutting forces and the chip profiles with tool wear. Then, a numerical method has been used in order to model the machining process with both new and worn tools. The use of smoothed particle hydrodynamics model (SPH model) as a numerical tool for a better understanding of the chip formation with worn tools is a key aspect of this work. The redicted chip morphology and the cutting force evolution with respect to the tool wear are qualitatively compared with experimental trends. The chip formation mechanisms during dry cutting process are shown to be quite dependent from the worn tool geometry. These mechanisms explain the high variation of the experimental and numerical feed force between new and worn tools

Evidence for renoxification in the tropical marine boundary layer

We present 2 years of NOx observations from the Cape Verde Atmospheric Observatory located in the tropical Atlantic boundary layer. We find that NOx mixing ratios peak around solar noon (at 20-30pptV depending on season), which is counter to box model simulations that show a midday minimum due to OH conversion of NO2 to HNO3. Production of NOx via decomposition of organic nitrogen species and the photolysis of HNO3 appear insufficient to provide the observed noontime maximum. A rapid photolysis of nitrate aerosol to produce HONO and NO2, however, is able to simulate the observed diurnal cycle. This would make it the dominant source of NOx at this remote marine boundary layer site, overturning the previous paradigm according to which the transport of organic nitrogen species, such as PAN, is the dominant source. We show that observed mixing ratios (November-December 2015) of HONO at Cape Verde (∼ 3.5pptV peak at solar noon) are consistent with this route for NOx production. Reactions between the nitrate radical and halogen hydroxides which have been postulated in the literature appear to improve the box model simulation of NOx. This rapid conversion of aerosol phase nitrate to NOx changes our perspective of the NOx cycling chemistry in the tropical marine boundary layer, suggesting a more chemically complex environment than previously thought