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Optimisation of tissue engineering (TE) processes requires models that can identify relationships between the parameters to be optimised and predict structural and performance outcomes from both physical and chemical processes. Currently, Design of Experiments (DoE) methods are commonly used for optimisation purposes in addition to playing an important role in statistical quality control and systematic randomisation for experiment planning. DoE is only used for the analysis and optimisation of quantitative data (i.e., number-based, countable or measurable), while it lacks the suitability for imaging and high dimensional data analysis. Machine learning (ML) offers considerable potential for data analysis, providing a greater flexibility in terms of data that can be used for optimisation and predictions. Its application within the fields of biomaterials and TE has recently been explored. This review presents the different types of DoE methodologies and the appropriate methods that have been used in TE applications. Next, ML algorithms that are widely used for optimisation and predictions are introduced and their advantages and disadvantages are presented. The use of different ML algorithms for TE applications is reviewed, with a particular focus on their use in optimising 3D bioprinting processes for tissue-engineered construct fabrication. Finally, the review discusses the future perspectives and presents the possibility of integrating DoE and ML in one system that would provide opportunities for researchers to achieve greater improvements in the TE field.

The COVID-19 pandemic has had an extensive impact on the global higher education sector. In a written survey, staff and students at the Lucerne School of Social Work reported how they had coped with the challenges to their teaching or respective learning situation. The initial survey was conducted during the lockdown in spring 2020, and the follow-up survey was performed in the period of relaxed sanitary measures in summer 2020. During the first wave of the survey, 51 employees and 225 students participated. In the follow-up survey, 28 employees and 117 students partook. Findings indicate that the increased workload created by the transition was stressful for both staff and students but overall was handled well. Staff and students who felt supported by the university management experienced less psychological distress. Since the outbreak of the pandemic, there has been an effort to develop hybrid forms of teaching. Because the social work curriculum contains building blocks that are difficult to implement in the form of distance learning, the transition posed challenges for both staff and students. During times of transition, university management must carefully assess the support needs of staff and students and take appropriate action.

Introduction: Hospitals commonly use Press Ganey (PG) patient satisfaction surveys for benchmarking physician performance. PG scores range from 1 to 5, with 5 being the highest, which is known as the “topbox” score. Our objective was to identify patient and physician factors associated with topbox PG scores in the emergency department (ED). Methods: We looked at PG surveys from January 2015–December 2017 at an academic, urban hospital with 78,000 ED visits each year. Outcomes were topbox scores for the questions: “Likelihood of your recommending our ED to others”; and “Courtesy of the doctor.” We analyzed topbox scores using generalized estimating equation models clustered by physician and adjusted for patient and physician factors. Patient factors included age, gender, race, ethnicity, and ED area where patient was seen. The ED has four areas based on patient acuity: emergent; urgent; vertical (urgent but able to sit in a recliner rather than a gurney); and fast track (non-urgent). Physician factors included age, gender, race, ethnicity, and number of years at current institution. Results: We analyzed a total of 3,038 surveys. For “Likelihood of your recommending our ED to others,” topbox scores were more likely with increasing patient age (odds ratio [OR] 1.07; 95% confidence interval [CI], 1.03–1.12); less likely among female compared to male patients (OR 0.81; 95% CI, 0.70–0.93); less likely among Asian compared to White patients (OR 0.71; 95% CI, 0.60–0.83); and less likely in the urgent (OR 0.71; 95% CI, 0.54–0.93) and vertical areas (OR 0.71; 95% CI 0.53–0.95) compared to fast track. For “Courtesy of the doctor,” topbox scores were more likely with increasing patient age (OR 1.1; CI, 1.06–1.14); less likely among Asian (OR 0.70; 95% CI, 0.58–0.84), Black (OR 0.66; 95% CI, 0.45–0.96), and Hispanic patients (OR 0.68; 95% CI, 0.55–0.83) compared to White patients; and less likely in urgent area (OR 0.69; 95% CI, 0.50–0.95) compared to fast track. Conclusion: Increasing patient age was associated with increased likelihood of topbox scores, while Asian patients, and urgent and vertical areas had decreased likelihood of topbox scores. We encourage hospitals that use PG topbox scores as financial incentives to understand the contribution of non-service factors to these scores.

Abstract Increasing exploitation of marine natural resources and expansion of energy infrastructure, shipping, and aquaculture across the oceans are placing increased pressure on marine life. Biodiversity offsets, as the last stage of the mitigation hierarchy, provide an opportunity to promote a more sustainable basis for development by addressing residual impacts and achieving “no net loss” for biodiversity. Despite debate around their effectiveness, biodiversity offsets are seeing increasing application on land but remain a rarely used tool in the marine environment. We assess how offsets can be applied in the marine environment to achieve better biodiversity outcomes, and identify implications for conservation policy and practice. For instance, spatial conservation planning provides opportunities to move away from a siloed, project‐by‐project, approach by pooling offsets on a regional scale. There are real differences between marine and terrestrial environments in relation to ecology, connectivity, data availability, management options, and impact perception, and marine offsets are therefore often regarded as challenging. However, fundamental offset principles, types, and approaches apply equally on land and at sea. Marine biodiversity offset approaches can build on the experience of terrestrial offsets but can also innovate to help achieve biodiversity gains and contribute toward global and national biodiversity targets.

Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.

Cartilage is an avascular tissue with extremely limited self-regeneration capabilities. At present, there are no existing treatments that effectively stop the deterioration of cartilage or reverse its effects; current treatments merely relieve its symptoms and surgical intervention is required when the condition aggravates. Thus, cartilage damage remains an ongoing challenge in orthopaedics with an urgent need for improved treatment options. In recent years, major advances have been made in the development of three-dimensional (3D) bioprinted constructs for cartilage repair applications. 3D bioprinting is an evolutionary additive manufacturing technique that enables the precisely controlled deposition of a combination of biomaterials, cells, and bioactive molecules, collectively known as bioink, layer-by-layer to produce constructs that simulate the structure and function of native cartilage tissue. This review provides an insight into the current developments in 3D bioprinting for cartilage tissue engineering. The bioink and construct properties required for successful application in cartilage repair applications are highlighted. Furthermore, the potential for translation of 3D bioprinted constructs to the clinic is discussed. Overall, 3D bioprinting demonstrates great potential as a novel technique for the fabrication of tissue engineered constructs for cartilage regeneration, with distinct advantages over conventional techniques.

The River Basin Management Plan (RBMP) is an essential component of the European Union Water Framework Directive that details an integrated approach required to protect, improve and sustainably manage water resources. RBMP were intended to be produced for the periods 2009–2015, 2016–2021 and 2022–2027. However, after two years of delays in the development processes, the Republic of Ireland produced its first RBMP in 2010. The second RBMP cycle was also implemented in 2018 and is expected to run until the end of 2021 to give way to the third RBMP, whose consultation processes have been ongoing since December 2019. This paper contributes to the forthcoming RBMP by assessing stakeholders’ perspectives on the second RBMP through a desk-based review and by conducting interviews with nine institutions (14 interviewees). The qualitatively analysed interviews reveal a broad spectrum of actors associated with water management and governance in the Republic of Ireland through a three-tier governance structure that has been delivered (with amendment) through the first two RBMPs. Organisations such as the An Fóram Uisce|The Water Forum, the Environmental Protection Agency, the Local Authority Waters, and the Agricultural Sustainability Support and Advisory Programme have responsibilities designated in the RBMPs to deliver improved water quality, integrated catchment management, community engagement and awareness-raising. Trust has also been building up among these organisations and other agencies in the water sector. Despite these responsibilities and progress made, the interviews identified communication lapses, ineffective collaboration and coordination among stakeholders and late implementation to be hampering the successful delivery of the second RBMP, in addition to significant pressures acting on water bodies from agricultural activities and urban wastewater treatment. Towards the third RBMP, the paper concludes that optimised water sector finance, enhanced and well-resourced communications, and improved stakeholder collaboration are needed to foster effective and efficient water services delivery and quality. More so, given the cross-cutting impact of the Sustainable Development Goals on water resources and the interconnected relations among the goals, the paper further recommends the integration of the SDGs in the various plans of actions and a co-benefits approach to derive the triple benefits from biodiversity, climate change initiatives and water quality measures.

The objective of our study was the alignment of microsatellite or simple sequence repeat (SSR) marker data across germplasm collections of cherry within Europe. Through the European Cooperative program for Plant Genetic Resources ECPGR, a number of European germplasm collections had previously been analysed using standard sets of SSR loci. However, until now these datasets remained unaligned. We used a combination of standard reference genotypes and ad-hoc selections to compile a central dataset representing as many alleles as possible from national datasets produced in France, Great Britain, Germany, Italy, Sweden and Switzerland. Through the comparison of alleles called in data from replicated samples we were able to create a series of alignment factors, supported across 448 different allele calls, that allowed us to align a dataset of 2241 SSR profiles from six countries. The proportion of allele comparisons that were either in agreement with the alignment factor or confounded by null alleles ranged from 67% to 100% and this was further improved by the inclusion of a series of allele-specific adjustments. The aligned dataset allowed us to identify groups of previously unknown matching accessions and to identify and resolve a number of errors in the prior datasets. The combined and aligned dataset represents a significant step forward in the co-ordinated management of field collections of cherry in Europe.

ObjectivesSixty-five per cent of older people have hypertension, but little is known about their preferences and concerns regarding hypertension management. Guidelines on hypertension lack consensus on how to treat older people without previous cardiovascular disease (CVD). This asks for explicit consideration of patient preferences in decision making. Therefore, the aim of this study was to explore older peoples’ experiences, preferences, concerns and perceived involvement regarding hypertension management.DesignQualitative interview study.SettingParticipants were selected from 11 general practitioner (GP) practices in the Netherlands and purposively sampled until data saturation was achieved. Semistructured interviews were conducted, audio recorded and analysed by two researchers using thematic analysis.ParticipantsFifteen community dwelling older people aged 74–93 years with hypertension and without previous CVD participated.ResultsInterviewees rarely started the conversation about hypertension management with their GP, although they did have concerns. Reasons for not discussing the subject included low priority of hypertension concerns, reliance on GPs or trust in GPs to make the right decision on their behalf. Also, interviewees anticipated regret of reducing medication, fearing vascular incidents. Interviewees would like to discuss tailoring treatment to their needs, deprescription of medication and ways to reduce side effects. They expected GPs to be more transparent on treatment effects.ConclusionOlder people describe having little involvement in hypertension management, although they have several concerns. Since GPs are also known to be hesitant to bring up this subject, we signal a conspiracy of silence about antihypertensive medication. Through breaking this silence, GPs can facilitate shared decision-making on hypertension management and better tailored care.

Cytoplasmic Actin Gamma 1 (ACTG1) gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). ACTG1 anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an ACTG1 gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with ACTG1 variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the ACTG1 variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the ACTG1 variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the ACTG1 variant. The caudal ganglionic eminence and the PVWM regions in the ACTG1 variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the ACTG1 gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.

The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent cellular cytotoxicity (ADCC) by neutrophils toward solid cancer cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface FcγRIIIb expression. Individuals with one copy of FCGR3B showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG1 heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.

Source protection is part of a multi-solution approach for the provision of safe drinking water. In the Republic of Ireland, community-led Group Water Schemes (GWS) provide treated drinking water to approximately 69,000 rural households. Between 2009 and 2019, preliminary source protection assessments were undertaken for 70 GWS abstracting from surface water sources to provide physical catchment characterisation and untreated and treated water quality analysis. Catchment areas upstream of abstraction points varied in size, with 51.5% being less than 5 km2 and only 10.7% being larger than 100 km2. The majority (91%) of assessed GWS serve a population of less than 3000 people, and 94% supply less than 1500 m3 per day. Exceedances of the EU Drinking Water Regulations were recorded for 27 parameters, with the greatest number of exceedances due to total trihalomethanes followed by microbial contamination. The most frequent recommendation for improving GWS drinking water quality was associated with managing livestock access to local water bodies. Improving stakeholder engagement represented 38% of all recommendations made. Drinking water source protection measures and catchment-scale actions can be an additional model to assist in the delivery of Integrated Catchment Management and river basin management planning in the Republic of Ireland. For the GWS sector, challenges lie in securing resources to improve both source water and drinking water quality to deliver integrated catchment management plans for source protection.

Background: GPs are frequently confronted with patients with acute onset chest pain. Although usually benign, approximately 5% is due to acute coronary syndrome (ACS). Unfortunately, ACS is not always recognised, leading to a missed diagnosis in 2–5% of presentations. Aim: The authors set out to study the level of risk GPs are willing to accept with regards to missing an ACS diagnosis, and the receptiveness of implementing new clinical decision aids. Design & setting: This study involved an online survey among GPs in the Netherlands. Method: A concept survey was constructed, which was tested among a panel of 24 GPs. The survey was then modified to achieve content validity. This survey was electronically distributed among 1000 GPs. Results: A total of 313 (31.3%) GPs completed the survey. Of those surveyed, the median age was 50 years (interquartile range 41–57), 53.0% were female, and 6.4% were specialist GPs ('kaderarts') in cardiology or acute care. GPs estimated the missed ACS rate to be

Summary: Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo. : In this article, Greaves and colleagues show that tumor-propagating cells in glioblastoma are genetically and functionally heterogeneous. When used in in vivo experiments, these cells show a variable competitive capacity for tumor propagation and further genetic diversification, suggesting that glioblastoma evolves through complex dynamics of subclonal fitness advantage and acquisition of mutations and copy number alterations.

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Internationally, water management is moving from the traditional top-down approach to more integrated initiatives focussing on community-led action. With inadequacies in previous engagement initiatives undertaken through the first cycle of River Basin Management Planning for the EU Water Framework Directive (WFD), the Republic of Ireland has only recently embraced this bottom-up approach. The attempted introduction of national charging for domestic water use in 2015 has resulted in significant public disquiet and protest movements against the national government. In April 2015 we undertook a survey of current opinion on water management and community engagement initiatives in the Republic of Ireland and the United Kingdom. A total of 520 survey responses identified that although freshwater bodies are important in peoples' lives, respondents were typically unaware of global initiatives such as Integrated Water Resources Management and Integrated Catchment Management. Overall, 81% of respondents did not feel included in decisions about their water environment despite an overwhelming 95% believing that local communities should have a say in how the water environment is managed. However, only 35.1% of respondents stated that they would be willing to attend local water management engagement initiatives. Rather than supporting individual gain, respondents identified social gains for the local community as avenues for increasing local involvement in water initiatives. In the Republic of Ireland, a water engagement initiative that implements the national framework local delivery model should be developed and implemented. This would 1) contribute to the second round of WFD River Basin Management Planning; 2) facilitate stronger connections between local communities and their water environment; and 3) foster bottom-up initiatives that empower communities regarding local water management issues.

Understanding hydrological processes in large, open areas, such as catchments, and further modelling these processes are still open research questions. The system proposed in this work provides an automatic end-to-end pipeline from data collection to information extraction that can potentially assist hydrologists to better understand the hydrological processes using a data-driven approach. In this work, the performance of a low-cost off-the-shelf self contained sensor unit, which was originally designed and used to monitor liquid levels, such as AdBlue, fuel, lubricants etc., in a sealed tank environment, is first examined. This process validates that the sensor does provide accurate water level information for open water level monitoring tasks. Utilising the dataset collected from eight sensor units, an end-to-end pipeline of automating the data collection, data processing and information extraction processes is proposed. Within the pipeline, a data-driven anomaly detection method that automatically extracts rapid changes in measurement trends at a catchment scale. The lag-time of the test site (Dodder catchment Dublin, Ireland) is also analyzed. Subsequently, the water level response in the catchment due to storm events during the 27 month deployment period is illustrated. To support reproducible and collaborative research, the collected dataset and the source code of this work will be publicly available for research purposes.

Abstract (E): Chats perchés (2004) presents itself as a digression on an amusing piece of graffiti, arambling through Paris with recent political demonstrations in mind. Yet, Marker's film also leads oneto think about urban nomadism and suggests the possibility of a cinema of the territory.Abstract (F): Chats perchés (2004) se présente comme une digression autour d'un graffiti amusant etcomme une divagation parisienne qui se souvient des manifestations politiques récentes. Mais le filmde Marker ouvre aussi à la pensée d'un nomadisme urbain et suggère la possibilité d'un cinémadu territoire.

Periodontitis is a progressive disease of the periodontium with a complex, polymicrobial etiology. Recent Next-Generation Sequencing (NGS) studies of the microbial diversity associated with periodontitis have revealed strong, community-level differences in bacterial assemblages associated with healthy or diseased periodontal sites. In this study, we used NGS approaches to characterize changes in periodontal pocket bacterial diversity after standard periodontal treatment. Despite consistent changes in the abundance of certain taxa in individuals whose condition improved with treatment, post-treatment samples retained the highest similarity to pre-treatment samples from the same individual. Deeper phylogenetic analysis of periodontal pathogen-containing genera Prevotella and Fusobacterium found both unexpected diversity and differential treatment response among species. Our results highlight how understanding interpersonal variability among microbiomes is necessary for determining how polymicrobial diseases respond to treatment and disturbance.

Disclosure of financial conflicts of interest (COI) is intended to help reviewers assess the impact of potential bias on the validity of research results; however, there have been no empiric assessments of how reviewers understand and use disclosures in article evaluation. We investigate reviewers' perceptions of potential bias introduced by particular author disclosures, and whether reviewer characteristics are associated with a greater likelihood of perceiving bias.Of the 911 active reviewers from the Annals of Emergency Medicine, 410 were randomly selected and invited to complete our web-based, 3-part survey. We completed descriptive analysis of all survey responses and compared those responses across reviewer characteristics using 2 × 2 analyses and the Fisher exact test. We had a response rate of 54%. The majority of reviewers surveyed reported a high level of skepticism regarding financial relationships between authors and industry without a clear or consistent translation of that skepticism into the self-reported actions that characterize manuscript assessment. Only 13% of respondents believed physician consultants authoring articles based on company data are likely to have unlimited data access. 54% believed that bias most likely exists with any honorarium, regardless of monetary amount. Between 46% and 64%, depending on the type of financial relationship disclosed, reported that their recommendation for publication remains unchanged. Respondents reporting personal financial ties to industry were less likely to perceive bias in industry relationships and less likely to believe that bias exists with any monetary amount of honoraria.We recommend that the monetary amount of all financial relationships be reported with manuscript submissions, lead authors certify that they have unrestricted access to data, and reviewers disclose any financial ties to industry whether or not they are related to the manuscript under review. Further research is required to better understand reviewers' perceptions of financial relationships between authors and industry in order to develop clear and consistent guidelines for incorporating the perception of potential bias into manuscript assessments.