Policy Instruments to Improve Energy Performance of Existing Owner Occupied Dwellings:

The aim of this thesis is to add knowledge to the role and impact of policy instruments in meeting energy performance ambition in the existing owner occupied housing stock. The focus was instruments available in the Netherlands in 2011 and 2012. These instruments represented the ‘on the ground’ efforts to meet climate change targets and many continue to do so today in the same or slightly altered forms.  At international level there is a recognized need to keep global temperatures within the range of 1.5 - 2°C above pre-industrial levels (Carrington, 2016). At European level, the 2020 package contains a series of binding legislation to help the EU meet its more immediate climate and energy targets. 2020 targets include 20% reduction in greenhouse gas emission, 20% of EU energy obtained from renewable sources and 20% improvement in energy efficiency. 2020 targets for the Netherlands are a 20% reduction in greenhouse gas emissions and a 14% increase in energy generation from renewable sources (Vringer et al., 2014).  A raft of policies has been produced over the last number of decades from international to local level to orientate action towards targets. At European level the Energy Performance of Buildings Directive (EPBD) drives efforts at reducing energy among one of the biggest players, the building sector. By requiring a mandatory certificate at the point of sale and rent of buildings and making regulatory demands on existing buildings the EPBD upped the ante of what could be expected from the building sector, but especially the existing dwelling stock.  National governments have already been tackling existing dwellings for decades propelled by the energy crisis and later by climate change policy. Information campaigns, subsidies, energy taxes, energy loans and tailored advice are among the instruments that have been available to homeowners to carry out works on their dwellings to reduce energy consumption. In recent years, the pace of efforts has increased due to, inter alia, the realization that the revolution in energy use that must occur for climate change targets to be met means major changes in the fabric of the existing dwelling stock, dwellings constructed before building regulations demanded high energy performance standards. It is argued that the building sector, in general, and the existing dwelling stock, in particular, can contribute more cost effectively and more significantly in quality and quantity terms than any other sector (Amstalden et al., 2007; Lomas, 2010; Ürge-Vorsatz, et al., 2007). This has provoked calls for new and improved instruments to meet the energy saving potential of existing dwellings. Despite many of the same instruments being used for decades there is little solid information on many crucial dimensions of how instruments operate and on what impact they have. The few evaluations and reviews that do take place are commonly focused on theoretical energy savings and costs and instrument strengths and weaknesses. Instruments commonly appear and disappear without undergoing improvement or change or contributing to policy learning. Many instruments are laden with assumptions about the target group that are never formally or comprehensively proved or debunked. Little theorizing takes place on the type of instruments most suited to the target group. Fundamentally, there is a serious lack of information surrounding the effectiveness of instruments assumed to be making climate change targets a reality. It is the above mentioned information deficits that influenced the objectives and structure of this thesis. Instruments are examined from different angles and viewpoints, from experts, owner occupiers, official evaluations and front-runner countries. Assessment frameworks were developed to tease out how well instruments truly function. Households in receipt of instruments such as the EPC and energy audit were compared to households not in receipt of instruments. Moreover, the complete range of national instruments available at the time of the survey were studied to present a complete picture

Policy Instruments to Improve Energy Performance of Existing Owner Occupied Dwellings

The aim of this thesis is to add knowledge to the role and impact of policy instruments in meeting energy performance ambition in the existing owner occupied housing stock. The focus was instruments available in the Netherlands in 2011 and 2012. These instruments represented the ‘on the ground’ efforts to meet climate change targets and many continue to do so today in the same or slightly altered forms. At international level there is a recognized need to keep global temperatures within the range of 1.5 - 2°C above pre-industrial levels (Carrington, 2016). At European level, the 2020 package contains a series of binding legislation to help the EU meet its more immediate climate and energy targets. 2020 targets include 20% reduction in greenhouse gas emission, 20% of EU energy obtained from renewable sources and 20% improvement in energy efficiency. 2020 targets for the Netherlands are a 20% reduction in greenhouse gas emissions and a 14% increase in energy generation from renewable sources (Vringer et al., 2014). A raft of policies has been produced over the last number of decades from international to local level to orientate action towards targets. At European level the Energy Performance of Buildings Directive (EPBD) drives efforts at reducing energy among one of the biggest players, the building sector. By requiring a mandatory certificate at the point of sale and rent of buildings and making regulatory demands on existing buildings the EPBD upped the ante of what could be expected from the building sector, but especially the existing dwelling stock. National governments have already been tackling existing dwellings for decades propelled by the energy crisis and later by climate change policy. Information campaigns, subsidies, energy taxes, energy loans and tailored advice are among the instruments that have been available to homeowners to carry out works on their dwellings to reduce energy consumption. In recent years, the pace of efforts has increased due to, inter alia, the realization that the revolution in energy use that must occur for climate change targets to be met means major changes in the fabric of the existing dwelling stock, dwellings constructed before building regulations demanded high energy performance standards. It is argued that the building sector, in general, and the existing dwelling stock, in particular, can contribute more cost effectively and more significantly in quality and quantity terms than any other sector (Amstalden et al., 2007; Lomas, 2010; Ürge-Vorsatz, et al., 2007). This has provoked calls for new and improved instruments to meet the energy saving potential of existing dwellings. Despite many of the same instruments being used for decades there is little solid information on many crucial dimensions of how instruments operate and on what impact they have. The few evaluations and reviews that do take place are commonly focused on theoretical energy savings and costs and instrument strengths and weaknesses. Instruments commonly appear and disappear without undergoing improvement or change or contributing to policy learning. Many instruments are laden with assumptions about the target group that are never formally or comprehensively proved or debunked. Little theorizing takes place on the type of instruments most suited to the target group. Fundamentally, there is a serious lack of information surrounding the effectiveness of instruments assumed to be making climate change targets a reality. It is the above mentioned information deficits that influenced the objectives and structure of this thesis. Instruments are examined from different angles and viewpoints, from experts, owner occupiers, official evaluations and front-runner countries. Assessment frameworks were developed to tease out how well instruments truly function. Households in receipt of instruments such as the EPC and energy audit were compared to households not in receipt of instruments. Moreover, the complete range of national instruments available at the time of the survey were studied to present a complete picture. A more detailed description of the methodologies adopted is presented below. Methodology An aim of research was to offer qualified accounts and a deeper analysis of how instruments for energy performance improvement in existing dwellings function. Research components focused on both individual instruments and combinations using a triangulation of methods and sources: expert interviews, a survey and literature review. The first step towards meeting the aim of research was to characterise and assess national instruments in the Netherlands. In the absence of an assessment framework for policy instruments in this domain one was created using elements of the theory based evaluation method and concepts from literature. All national energy performance instruments operating at the time that could influence energy performance improvement for space and water heating in existing dwellings were included in the evaluation. Data was obtained from face to face semi-structured interviews with 19 stakeholders involved in lobbying, designing, implementing and evaluating instruments. Interviewee data was complemented with secondary sources, including; evaluations of the national climate change programme, evaluations of individual instruments, cross country evaluations and European projects in which the Netherlands participated. An online survey of owner-occupiers covering the same instruments as the characterization and assessment of instruments described above was conducted to expand the investigation into instruments. More than 5,000 Dutch owner-occupiers participated in the survey. The survey consisted of 96 questions about energy saving measures adopted within the years preceding the survey. The focus lay on measures that involved significant investment to reduce energy consumed for space and water heating. The questionnaire consisted of multiple choice and open ended questions divided into several categories; the adoption and planned adoption of energy saving measures, energy audits, the EPC, building regulations, the energy tax, financial incentives, information tools and socio-economic and dwelling characteristics. Data on motivations for energy use and perceived influences of instruments was also gathered. The questionnaire was used to meet several objectives. To survey the overall effectiveness of the national instruments available to owner occupiers at that time, to compare owner-occupiers who received an EPC to those who did not along several parameters and to compare owner-occupiers who received an energy audit to those who did not along several parameters. Required sample sizes were calculated on the basis of assumptions and several critical components of the questionnaire that required a set response rate to allow statistical comparison (See Appendix 2). Approximately, 30,000 households from the national EPC/energy audit database were sent a link to the questionnaire. The comparison group was created by sending approximately 16,000 members of the Home Owners Association a link to the questionnaire. Following a reminder, a response rate of 17% was received for the EPC/energy audit database and 10% for the Association of Home Owners database. Both descriptive and statistical analysis was conducted on response data. Descriptive analysis focused on whether householders reported an association between the adoption of energy saving measures and instrument use. Pearson’s chi square tests were used to identify whether an association between adopting measures and instruments could be statistically proven. The final research component consisted of a comparative study of several front-runner countries to gather knowledge and examine the instruments associated with success in meeting climate change targets for existing dwellings. Literature from comparative public policy was used to structure this research component. Denmark, Germany, Sweden and the UK were chosen as front-runner cases. Based on document analysis the instruments considered to dominate action in these front-runner countries were characterised. As with the first research component an evaluation framework was developed and the main instruments were assessed against concepts drawn from literature. Using concepts from literature was an effort to go beyond traditional ‘strength and weakness’ based evaluations by searching for how instruments tackle, or fail to tackle, salient issues in this policy domain. Therefore, ‘effectiveness’ of instruments was interpreted as both the documented results of goal achievement and the extent to which instruments deal with aspects unique to this policy domain. Results from document analysis and instrument assessments based on concepts were verified in phone interviews with national experts. Findings A qualitative evaluation of national instruments Instruments were evaluated using 1) elements from the theory based evaluation method and 2) a set of ‘ideal’ concepts. An overview of the first phase of the evaluation is presented in the table below. Fundamental problems with how instruments were implemented were identified in this phase of the evaluation. Most notable was how the EPC was implemented without an enforcement regime resulting in poor visibility, confusion and lack of confidence in the market distancing the EPC from its original ambitious theory and objectives. Similarly, the Meer met Minder sectoral agreement was associated with financial issues and lack of clarity on responsibilities. Economic incentives were heavily criticised by interviewees and found wanting from evaluations being described as ‘modest’ and ‘highly fragmented’. Meanwhile, the energy tax was unanimously described as revenue raising. Little could be obtained from published sources or expert interviewees on the impact of information tools although some interviewees believed that tools are designed for the already informed. Building regulations were found to lack the innovative dimensions visible within other countries, such as consequential works, though few interviewees saw potential to strengthen this instrument. The second phase of the evaluation examined how instruments functioned compared to normative concepts. Concepts chosen were: Policy instrument combinations Obligating/incentivising balance Long term programme Non-generic Primacy to energy efficiency Whole house/deep retrofit Energy sufficiency (the notion that instruments actually lead to energy use reduction) Elements of some concepts were present but far from pervasive. Instruments were: Typically stand alone instead of operating in combinations Largely short term instead of being embedded in a long term framework Almost entirely incentivising thus lacking the obligating balance suggested from theory Generic thus ignoring the great diversity associated with households Largely bypassing the important role of first securing energy efficiency before implementing other measures (i.e. renewable technologies) Piecemeal in place of whole house Disassociated from an end point of energy use reduction. Some ingredients for a successful strategy for existing dwellings were however present. The Meer met Minder subsidy was the only performance based subsidy in place at the time of research and was associated with positive results. With subsidy amounts linked to rating changes in the EPC/energy audit it also demonstrates a successful coupling of instruments. Furthermore, interviewees, though regretful of how the EPC had been progressing, remained hopeful for a better future for this instrument with scope for different manipulations for example, with links to property taxes

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Policy Instruments to Improve Energy Performance of Existing Owner Occupied Dwellings

The aim of this thesis is to add knowledge to the role and impact of policy instruments in meeting energy performance ambition in the existing owner occupied housing stock. The focus was instruments available in the Netherlands in 2011 and 2012. These instruments represented the ‘on the ground’ efforts to meet climate change targets and many continue to do so today in the same or slightly altered forms. At international level there is a recognized need to keep global temperatures within the range of 1.5 - 2°C above pre-industrial levels (Carrington, 2016). At European level, the 2020 package contains a series of binding legislation to help the EU meet its more immediate climate and energy targets. 2020 targets include 20% reduction in greenhouse gas emission, 20% of EU energy obtained from renewable sources and 20% improvement in energy efficiency. 2020 targets for the Netherlands are a 20% reduction in greenhouse gas emissions and a 14% increase in energy generation from renewable sources (Vringer et al., 2014). A raft of policies has been produced over the last number of decades from international to local level to orientate action towards targets. At European level the Energy Performance of Buildings Directive (EPBD) drives efforts at reducing energy among one of the biggest players, the building sector. By requiring a mandatory certificate at the point of sale and rent of buildings and making regulatory demands on existing buildings the EPBD upped the ante of what could be expected from the building sector, but especially the existing dwelling stock. National governments have already been tackling existing dwellings for decades propelled by the energy crisis and later by climate change policy. Information campaigns, subsidies, energy taxes, energy loans and tailored advice are among the instruments that have been available to homeowners to carry out works on their dwellings to reduce energy consumption. In recent years, the pace of efforts has increased due to, inter alia, the realization that the revolution in energy use that must occur for climate change targets to be met means major changes in the fabric of the existing dwelling stock, dwellings constructed before building regulations demanded high energy performance standards. It is argued that the building sector, in general, and the existing dwelling stock, in particular, can contribute more cost effectively and more significantly in quality and quantity terms than any other sector (Amstalden et al., 2007; Lomas, 2010; Ürge-Vorsatz, et al., 2007). This has provoked calls for new and improved instruments to meet the energy saving potential of existing dwellings. Despite many of the same instruments being used for decades there is little solid information on many crucial dimensions of how instruments operate and on what impact they have. The few evaluations and reviews that do take place are commonly focused on theoretical energy savings and costs and instrument strengths and weaknesses. Instruments commonly appear and disappear without undergoing improvement or change or contributing to policy learning. Many instruments are laden with assumptions about the target group that are never formally or comprehensively proved or debunked. Little theorizing takes place on the type of instruments most suited to the target group. Fundamentally, there is a serious lack of information surrounding the effectiveness of instruments assumed to be making climate change targets a reality. It is the above mentioned information deficits that influenced the objectives and structure of this thesis. Instruments are examined from different angles and viewpoints, from experts, owner occupiers, official evaluations and front-runner countries. Assessment frameworks were developed to tease out how well instruments truly function. Households in receipt of instruments such as the EPC and energy audit were compared to households not in receipt of instruments. Moreover, the complete range of national instruments available at the time of the survey were studied to present a complete picture. A more detailed description of the methodologies adopted is presented below. Methodology An aim of research was to offer qualified accounts and a deeper analysis of how instruments for energy performance improvement in existing dwellings function. Research components focused on both individual instruments and combinations using a triangulation of methods and sources: expert interviews, a survey and literature review. The first step towards meeting the aim of research was to characterise and assess national instruments in the Netherlands. In the absence of an assessment framework for policy instruments in this domain one was created using elements of the theory based evaluation method and concepts from literature. All national energy performance instruments operating at the time that could influence energy performance improvement for space and water heating in existing dwellings were included in the evaluation. Data was obtained from face to face semi-structured interviews with 19 stakeholders involved in lobbying, designing, implementing and evaluating instruments. Interviewee data was complemented with secondary sources, including; evaluations of the national climate change programme, evaluations of individual instruments, cross country evaluations and European projects in which the Netherlands participated. An online survey of owner-occupiers covering the same instruments as the characterization and assessment of instruments described above was conducted to expand the investigation into instruments. More than 5,000 Dutch owner-occupiers participated in the survey. The survey consisted of 96 questions about energy saving measures adopted within the years preceding the survey. The focus lay on measures that involved significant investment to reduce energy consumed for space and water heating. The questionnaire consisted of multiple choice and open ended questions divided into several categories; the adoption and planned adoption of energy saving measures, energy audits, the EPC, building regulations, the energy tax, financial incentives, information tools and socio-economic and dwelling characteristics. Data on motivations for energy use and perceived influences of instruments was also gathered. The questionnaire was used to meet several objectives. To survey the overall effectiveness of the national instruments available to owner occupiers at that time, to compare owner-occupiers who received an EPC to those who did not along several parameters and to compare owner-occupiers who received an energy audit to those who did not along several parameters. Required sample sizes were calculated on the basis of assumptions and several critical components of the questionnaire that required a set response rate to allow statistical comparison (See Appendix 2). Approximately, 30,000 households from the national EPC/energy audit database were sent a link to the questionnaire. The comparison group was created by sending approximately 16,000 members of the Home Owners Association a link to the questionnaire. Following a reminder, a response rate of 17% was received for the EPC/energy audit database and 10% for the Association of Home Owners database. Both descriptive and statistical analysis was conducted on response data. Descriptive analysis focused on whether householders reported an association between the adoption of energy saving measures and instrument use. Pearson’s chi square tests were used to identify whether an association between adopting measures and instruments could be statistically proven. The final research component consisted of a comparative study of several front-runner countries to gather knowledge and examine the instruments associated with success in meeting climate change targets for existing dwellings. Literature from comparative public policy was used to structure this research component. Denmark, Germany, Sweden and the UK were chosen as front-runner cases. Based on document analysis the instruments considered to dominate action in these front-runner countries were characterised. As with the first research component an evaluation framework was developed and the main instruments were assessed against concepts drawn from literature. Using concepts from literature was an effort to go beyond traditional ‘strength and weakness’ based evaluations by searching for how instruments tackle, or fail to tackle, salient issues in this policy domain. Therefore, ‘effectiveness’ of instruments was interpreted as both the documented results of goal achievement and the extent to which instruments deal with aspects unique to this policy domain. Results from document analysis and instrument assessments based on concepts were verified in phone interviews with national experts. Findings A qualitative evaluation of national instruments Instruments were evaluated using 1) elements from the theory based evaluation method and 2) a set of ‘ideal’ concepts. An overview of the first phase of the evaluation is presented in the table below. Fundamental problems with how instruments were implemented were identified in this phase of the evaluation. Most notable was how the EPC was implemented without an enforcement regime resulting in poor visibility, confusion and lack of confidence in the market distancing the EPC from its original ambitious theory and objectives. Similarly, the Meer met Minder sectoral agreement was associated with financial issues and lack of clarity on responsibilities. Economic incentives were heavily criticised by interviewees and found wanting from evaluations being described as ‘modest’ and ‘highly fragmented’. Meanwhile, the energy tax was unanimously described as revenue raising. Little could be obtained from published sources or expert interviewees on the impact of information tools although some interviewees believed that tools are designed for the already informed. Building regulations were found to lack the innovative dimensions visible within other countries, such as consequential works, though few interviewees saw potential to strengthen this instrument. The second phase of the evaluation examined how instruments functioned compared to normative concepts. Concepts chosen were: • Policy instrument combinations • Obligating/incentivising balance • Long term programme • Non-generic • Primacy to energy efficiency • Whole house/deep retrofit • Energy sufficiency (the notion that instruments actually lead to energy use reduction) Elements of some concepts were present but far from pervasive. Instruments were: • Typically stand alone instead of operating in combinations • Largely short term instead of being embedded in a long term framework • Almost entirely incentivising thus lacking the obligating balance suggested from theory • Generic thus ignoring the great diversity associated with households • Largely bypassing the important role of first securing energy efficiency before implementing other measures (i.e. renewable technologies) • Piecemeal in place of whole house • Disassociated from an end point of energy use reduction. Some ingredients for a successful strategy for existing dwellings were however present. The Meer met Minder subsidy was the only performance based subsidy in place at the time of research and was associated with positive results. With subsidy amounts linked to rating changes in the EPC/energy audit it also demonstrates a successful coupling of instruments. Furthermore, interviewees, though regretful of how the EPC had been progressing, remained hopeful for a better future for this instrument with scope for different manipulations for example, with links to property taxes

Diverse human VH antibody fragments with bio-therapeutic properties from the Crescendo Mouse

© 2019 The Authors.We describe the ‘Crescendo Mouse’, a human VH transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3’ regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely ‘heavy chain only’ antibodies. Heavy chain variable (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial

Background: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. Methods: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1–4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. Findings: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [–10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference −0·2 [–0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference −0·4 [95% CI −0·5 to −0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference −1·8 [–2·7 to −0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference −218 [–353 to −82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference −1·41 [–2·6 to −0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). Interpretation: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy.The trial was funded by the Canadian Institutes of Health Research, the Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada, and the Department of Medicine, University of Toronto, Toronto, ON, Canada

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science. © The Author(s) 2019. Published by Oxford University Press

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally