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Background The management of patients presenting with an out of hospital cardiac arrest (OHCA) is resource intensive, and mortality remains very high. Several scoring systems have been developed to predict mortality and adverse neurological outcomes, and thus aid decision making for patients arriving to heart attack centres. Two of the most commonly used scoring systems are NULL-PLEASE (1) and MIRACLE2 (2). Purpose The MIRCALE2 score predicts poor neurological outcome at 6 months, as measured by Cerebral Performance Category (CPC). The NULL-PLEASE score predicts in-hospital morality. We aimed to compare both scores in predicting their primary end-points in a large tertiary centre in the UK. Method and results This was a retrospective analysis of 435 patient who were admitted with OHCA via the primary PCI pathway to a large tertiary cardiac centre between January 2016 and September 2020. Only comatosed OHCA survivors requiring pre-hospital ventilatory support were included. 319 patients were eligible 238 patients had complete set of data and were included in the final analysis. The association of the primary outcome was examined using logistic regression analysis. The predictive ability of the scores for the primary endpoint was tested using AUC analysis. In-hospital mortality was 45% (108 patients), with 53% having good neurological outcome at 6 months (CPC 3 had 74% sensitivity to predict in hospital mortality. Conclusion To our knowledge, this is the first study to compare the MIRCLE2 and NULL-PLEASE scoring systems. Both scores did not perform as expected in our large retrospective analysis. The NULL-PLEASE was more sensitive in predicting in-hospital mortality, although MIRACLE 2 score was easier to use as it had less variables to collect. Funding Acknowledgement Type of funding sources: None.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1–5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7–9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

A tremendous research and development effort was exerted toward combating chronic hepatitis C, ultimately leading to curative oral treatments, all of which are targeting viral proteins. Despite the advantage of numerous targets allowing for broad hepatitis C virus (HCV) genotype coverage, the only host target inhibitors that advanced into clinical development were Cyclosporin A based cyclophilin inhibitors. While cyclosporin-based molecules typically require a fermentation process, Gilead successfully pursued a fully synthetic, oral program based on Sanglifehrin A. The drug discovery process, though greatly helped by facile crystallography, was still hampered by the limitations in the accuracy of predictive computational methods for prioritizing compound ideas. Recent advances in accuracy and speed of free energy perturbation (FEP) methods, however, are attractive for prioritizing and derisking synthetically challenging molecules and potentially could have had a significant impact on the speed of the development of this program. Here in our simulated prospective study, the binding free energies of 26 macrocyclic cyclophilin inhibitors were blindly predicted using FEP+ to test this hypothesis. The predictions had a low mean unsigned error (MUE) (1.1 kcal/mol) and accurately reproduced many design decisions from the program, suggesting that FEP+ has the potential to drive synthetic chemistry efforts by more accurately ranking compounds with nonintuitive structure-activity relationships (SARs).

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

An excellent insight, using the example of the Chesapeake Bay fur trade, into how the different elements of transatlantic trade in the seventeenth century fitted together.

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

Food security and sustainability are paramount goals of global policy in the Twenty First Century. What are the contributions of applied ethology and animal welfare in delivering these major goals? Livestock plays a major role in food security and nutrition (FSN), because meat and animal products are important in people’s diets and the livestock sector is central to food systems’ development. And many aspects of the welfare of livestock are important for production, as expressed in the advice, ‘Look after your animals and they will look after you,’ for example, reduction of disease. Consideration of animal welfare can enable advantages for production that have not otherwise been identified, and is therefore not just compatible with but important for achieving good management of livestock for production, livelihoods and FSN. Furthermore, understanding of animal behaviour and care for livestock welfare contribute to all three pillars of sustainable agriculture: economic profitability, social equity and environmental health. Ethology clarifies the interactions between animals, humans and the environment, and thus helps to optimise livestock management for the best balance between these complex priorities. However, although considering behaviour and welfare is valuable for production and FSN, people do not always recognise or act on this value. They may need information or help to do so: mechanisms are needed to provide information, help and sometimes financial assistance to producers. These mechanisms need input from experts in applied ethology and animal welfare, at both practical and policy level. Six policy areas are briefly outlined. Each requires (to a variable degree) understanding of animal behaviour and welfare and implementation of that understanding. (1) Development of humane, sustainable food security strategies; (2) Promotion of humane, sustainable livestock systems; (3) Reduction of livestock reliance on human-edible arable crops, especially cereals; (4) Development of specific food and livestock policies to assist vulnerable sectors of the population; (5) Sustainable diets; and (6) Development of markets for humane, sustainable livestock production. Urgent efforts are needed to achieve food security and sustainability, by producers, governments and intergovernmental organisations in consultation with other stakeholders including scientists and non-governmental organisations. The livestock sector has both positive and negative impacts. Consideration of animal behaviour and welfare helps to ensure and increase the positive impacts, and to reduce and avoid the negative, and should therefore be a priority for countries worldwide.

Using available cryo-EM and x-ray crystal structures of the nonstructural proteins that are responsible for SARS-CoV-2 viral RNA replication and transcription, we have constructed an atomistic model of how the proteins assemble into a functioning superstructure. Our principal finding is that the complex is hexameric, centered around nsp15. The nsp15 hexamer is capped on two faces by trimers of nsp14/nsp16/(nsp10)2, where nsp14 is seen to undergo a large conformational change between its two domains. This conformational change facilitates binding of six nsp12/nsp7/(nsp8)2 polymerase subunits to the complex. To this, six subunits of nsp13 are arranged around the superstructure, but not evenly distributed. Two of the six polymerase subunits are each proposed to carry dimers of nsp13, while two others are proposed to carry monomers. The polymerase subunits that coordinate nsp13 dimers also bind the nucleocapsid, which positions the 5’-UTR TRS-L RNA over the polymerase active site, a state distinguishing transcription from replication. Analyzing the path of the viral RNA indicates the dsRNA that exits the polymerase passes over the nsp14 exonuclease and nsp15 endonuclease sites before being unwound by a convergence of zinc fingers from nsp10 and nsp14. The template strand is then directed away from the complex, while the nascent strand is directed to the sites responsible for mRNA capping (the nsp12 NiRAN and the nsp14 and nsp16 methyltransferases). The model presents a cohesive picture of the multiple functions of the coronavirus replication-transcription complex and addresses fundamental questions related to proofreading, template switching, mRNA capping and the role of the endonuclease. It provides a platform to guide biochemical and structural research to address the stoichiometric and spatial configuration of the replication-transcription complex.Author SummaryThe replication of the coronavirus genome and the synthesis of subgenomic mRNA is a complex process involving multiple viral proteins. Despite a fairly complete structural picture of the individual proteins that are believed to coalesce into a larger replication-transcription complex, there is no clear model of how these proteins interact. Here we present the first detailed atomistic model of a complete replication-transcription complex for SARS-CoV-2, made up of the non-structural proteins nsp7-nsp16, as well as the nucleocapsid. Forming a large, hexameric superstructure centered around nsp15, the model provides new perspective on the function of its individual components, including the exonuclease, the endonuclease, the NiRAN site, the helicase, the multiple zinc fingers, and the nucleocapsid. It offers a cohesive view of replication, proofreading, template switching and mRNA capping, which should serve as a guide for future experimental exploration.

Undergraduate psychology programs have not always provided the same level of support for their job-seeking students than they have for those preparing to become psychologists. This is a particularly unfortunate situation because, according to the American Psychological Association's Center for Workforce Studies (American Psychological Association, 2017), only 13% of the 3.4 million people in the United States who have earned a bachelor's degree in psychology have gone on to earn a higher psychology degree. The first part of this article uses quotations from seven national reports on the psychology curriculum to identify the genesis and gradual amelioration of this unfortunate situation. The remainder of this article focuses on strategies that psychology faculty can use to help their job-seeking students successfully accomplish Goal 5: Professional Development of the APA Guidelines for the Undergraduate Psychology Major. These strategies include referring advisees to professionally trained advisors and becoming aware of careers in which baccalaureate-level psychology majors have entered or can prepare to enter and the sets of knowledge, skills, and characteristics important for success in these careers.

Two studies examined the effectiveness of a flashcard-based study strategy, Flashcards-Plus, in an ecologically valid context. The strategy requires students to create flashcards designed to increase their ability to retain, comprehend, and apply textbook material to exams. In Studies 1a ( n = 73) and 1b ( n = 62), we introduced all students to the Flashcards-Plus method and compared their exam scores. Students who used this strategy scored significantly higher than those who did not. In Study 2 ( n = 434), we randomly assigned six introductory psychology courses to either receive a classroom lecture with the Flashcards-Plus strategy (i.e., three experimental courses) or no lecture (i.e., three control courses). Students in the experimental courses scored significantly higher than those in the control courses after the lecture. The results from all three studies demonstrate that students who were introduced to the Flashcards-Plus study strategy scored significantly higher on exams following the lecture than students who were not. These findings suggest that this easily implemented teaching strategy can help students achieve deeper levels of processing (i.e., comprehension and application) in a self-directed manner, which benefit students’ performance.

This article uses evidence from the English High Court of Admiralty to examine the problem of mutiny and indiscipline among seafarers in the transatlantic trades during the 1680s and 1690s. It focuses on a venture of 1688, which is of particular interest not only for the light it sheds on maritime conditions, but also because it involved Daniel Defoe, a young and ambitious trader who was trying to establish a commercial opening in Chesapeake Bay. The article contextualizes this previously unknown venture, relating it to the development of the tobacco trade and its dependence on an expanding market and widening patterns of consumption. The failure of the voyage, in association with other business problems, had serious consequences for Defoe, leading to bankruptcy in 1692 and his withdrawal from direct involvement in overseas trade. Against a broader background of other voyages, the legal testimony heard by the court draws attention to the wider problem of mutinous conduct at sea. These cases were provoked by a range of grievances including pay, labour conditions and discipline. Repeatedly they raise questions about the conduct of masters at sea, including their rights and responsibilities. At the same time, the article argues that the upsurge in mutiny and indiscipline at sea, while revealing the inexorable tension between pay and productivity, also exposed deeper issues regarding seafaring custom and contract.

Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.

Blocking interactions between PD-1 and PD-L1 opens a new era of cancer treatment involving immunity modulation. Although most immunotherapies use monoclonal antibodies, small-molecule inhibitors offer advantages. To facilitate development of small-molecule therapeutics, we implemented a rapid approach to characterize the binding interfaces of small-molecule inhibitors with PD-L1. We determined its interaction with a synthetic macrocyclic peptide by using two mass spectrometry-based approaches, hydrogen-deuterium exchange and fast photochemical oxidation of proteins (FPOP), and corroborated the findings with our X-ray structure of the PD-L1/macrocycle complex. Although all three approaches show that the macrocycle binds directly to PD-L1 over the regions of residues 46-87 and 114-125, the two protein footprinting approaches show additional binding at the N-terminus of PD-L1, and FPOP reveals some critical binding residues. The outcomes not only show the binding regions but also demonstrate the utility of MS-based footprinting in probing protein/ligand inhibitory interactions in cancer immunotherapy.

The physical environment of an animal is sometimes altered if it is found to cause problems for animal welfare. These changes are commonly quite specific (making changes to space, food, water, aspects of housing design such as flooring, or to other environmental factors such as air quality) and may be effective in preventing injuries or disease. However, such measures may not be implemented in practice (usually for economic reasons), and where implemented may cause other problems, as when concern for hygiene leads to animals being kept in barren conditions. Numerous ways have also been tried to diversify feeding methods in order to improve animal welfare, but specific changes to the environment such as these often have widespread effects, some of which may be detrimental. For example, inclusion of novel pen structures meant to enrich the environment may lead to increased aggression. A more general approach is therefore appropriate. One area where this is particularly relevant is handling and transport, when animals encounter environments that are wholly new to them. For environments where animals spend more time, several studies have attempted a 'biological approach' in which a biological functioning is considered while avoiding simplistic assumptions of 'natural is best'. We consider as examples systematic tests of environmental enrichment for pigs, novel designs for loose housing of lactating sows and their litters, and furnished cages for laying hens. Stringent tests of every design feature and their interactions are necessary to produce commercial designs from such studies.

This slim, beautifully illustrated volume is published to coincide with the tenth anniversary of the establishment of the International Slavery Museum in Liverpool, where the author worked for many...

Furnished cages for laying hens have advantages in allowing normal behaviors and maintaining productivity. As the cost of introduction is a barrier for farms, we developed furnished cages that re-use conventional cages. To determine the minimum and functional cage design, we compared six designs, combinations of two floor designs (artificial turf or wire cage floor) and three screening designs in the integrated area (no screening, one entrance side or four sides). In total, 144 hens were used, and we measured behavior, physical condition and productivity. Comparing the floors, the percentages of hens performing dust-bathing and laying eggs in the integrated area were higher in cages with turf than wire floor (P

Several dietary factors have been studied in relation to prostate cancer; however, most studies have not reported on subtypes of fruit and vegetables or tumor characteristics, and results obtained so far are inconclusive. This study aimed to examine the prospective association of total and subtypes of fruit and vegetable intake with the incidence of prostate cancer overall, by grade and stage of disease, and prostate cancer death. Lifestyle information for 142,239 men participating in the European Prospective Investigation into Cancer and Nutrition from 8 European countries was collected at baseline. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average follow-up time of 13.9 years, 7,036 prostate cancer cases were identified. Compared with the lowest fifth, those in the highest fifth of total fruit intake had a significantly reduced prostate cancer risk (HR = 0.91; 95% CI = 0.83-0.99; p-trend = 0.01). No associations between fruit subtypes and prostate cancer risk were observed, except for citrus fruits, where a significant trend was found (HR = 0.94; 95% CI = 0.86-1.02; p-trend = 0.01). No associations between total and subtypes of vegetables and prostate cancer risk were observed. We found no evidence of heterogeneity in these associations by tumor grade and stage, with the exception of significant heterogeneity by tumor grade (p(heterogeneity)

Confessions have a greater impact on juries than other types of evidence, sometimes in the face of contradictory evidence. Twenty false confessions were content-analyzed to determine the substance of false confessions and perhaps help to explain why judges, juries, and others are prone to believe these statements. Our analysis indicated that most false confessions contained references to specific visual and auditory details concerning the crime and victim(s) as well as references to the confessor's thoughts, feelings, and motives during and after committing the crime. In a second study, mock jurors read confessions that were varied in terms of the presence of crime details, motive statements, and apologies, to determine the impact of these common aspects of confessions on a mock jury. Although a simple admission of guilt was often sufficient for conviction, more elaborate narrative confessions in which the defendant recounted how and why he committed the crime further increased confidence in thes...

Matrix metalloproteinase 9 (MMP9) is a member of a large family of proteases that are secreted as inactive zymogens. It is a key regulator of the extracellular matrix, involved in the degradation of various extracellular matrix proteins. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745, a potent, highly selective humanized monoclonal antibody inhibitor of MMP9, has shown promise in treating ulcerative colitis and gastric cancer. Here we describe the crystal structure of GS-5745·MMP9 complex and biochemical studies to elucidate the mechanism of inhibition of MMP9 by GS-5745. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain, and inhibits MMP9 by two mechanisms. Binding to pro-MMP9 prevents MMP9 activation, whereas binding to active MMP9 allosterically inhibits activity.

Background Laser capture microdissection (LCM) is an established technique for the procurement of enriched cell populations that can undergo further downstream analysis, although it does have limitations. Expression microdissection (xMD) is a new technique that begins to address these pitfalls, such as operator dependence and contamination. New method xMD utilises immunohistochemistry in conjunction with a chromogen to isolate specific cell types by extending the fundamental principles of LCM to create an operator-independent method for the procurement of specific CNS cell types. Results We report how xMD enables the isolation of specific cell populations, namely neurones and astrocytes, from rat formalin fixed-paraffin embedded (FFPE) tissue. Subsequent reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirms the enrichment of these specific populations. RIN values after xMD indicate samples are sufficient to carry out further analysis. Comparison with existing method xMD offers a rapid method of isolating specific CNS cell types without the need for identification by an operator, reducing the amount of unintentional contamination caused by operator error, whilst also significantly reducing the time required by the current basic LCM technique. Conclusions xMD is a superior method for the procurement of enriched cell populations from post-mortem tissue, which can be utilised to create transcriptome profiles, aiding our understanding of the contribution of these cells to a range of neurological diseases. xMD also addresses the issues associated with LCM, such as reliance on an operator to identify target cells, which can cause contamination, as well as addressing the time consuming nature of LCM.

PurposeInclusion of animals in emergency contingency planning is not yet common practice in many countries. The purpose of this paper is to assess the need for and viability of such inclusion in Latin America.Design/methodology/approachThe study surveyed 1,882 pet owners in urban areas in Colombia, Costa Rica and Mexico to evaluate perceptions of pet owners with regard to their animals in emergencies.FindingsOverall 74.5 percent (confidence interval 72.5‐76.5) said they would take their animals if evacuated. Only 16 percent (14.5‐17.8) would leave their animals behind. Regular vaccination was carried out by 70.5 percent of owners (68.0‐72.5): from 63.6 percent (60.8‐66.2 percent) in Mexico to 87.5 percent (84.3‐90.0) in Colombia. People in lower socio‐economic levels were less likely to take animals to the vet, or to vaccinate or identify them, and more likely to leave their animal behind during evacuation.Practical implicationsResults indicate both the need and the likely success of an animal contingency planning process in urban areas of Latin America.Originality/valueThis is the first survey of its kind concerning disaster preparedness for pets in developing countries, and counters the common perception that in such countries owners are less attached to their pets and that inclusion of animals in emergency contingency planning is not important.

Purpose A pilot study was conducted to determine the 2-year clinical performance of a new bioactive dental cement (Ceramir CB 13 patients were available for the 2-year recall examination. Restorations at 2-year recall examination included 17 single-unit, full-coverage crown restorations, four 3-unit FPDs comprising 8 abutments, and one 2-unit splint. No retentive failures or sensitivity were recorded at 2-year recall. Marginal integrities of all restorations/abutments at 2 years were rated in the "alpha" category. Average VAS score for tooth sensitivity decreased from 7.63 mm at baseline to 0.44 mm at 6-month recall, 0.20 mm at 1-year recall, and 0.00 mm at 2-year recall. The average gingival index score for gingival inflammation decreased from 0.56 at baseline to 0.11 at 6-month recall, then 0.16 at 1-year recall, and 0.21 at 2-year recall. Conclusions Two-year recall data yielded no loss of retention, no secondary caries, no marginal discolorations, and no subjective sensitivity. All restorations rated "alpha" for marginal integrity at the 2-year recall. After periodic recalls up to 2 years, the new bioactive cement tested thus far has performed favorably as a luting agent for permanent cementation.

Crime suspects in the USA are typically questioned in a two-step process aimed, first, at behavioural lie detection during a pre-interrogation interview, followed by the elicitation of a confession during the interrogation itself (in Great Britain, the practice of investigative interviewing does not make this sharp distinction). Research conducted on the first step shows that police investigators often target innocent people for interrogation because of erroneous but confident judgments of deception. Research on the second step shows that innocent people are sometimes induced to confess to crimes they did not commit as a function of certain dispositional vulnerabilities or the use of overly persuasive interrogation tactics. Citing recent studies, this paper proposes that laboratory paradigms be used to help build more diagnostic models of interrogation. Substantively, we suggest that the British PEACE approach to investigative interviewing may provide a potentially effective alternative to the classic American interrogation. As a matter of policy, we suggest that the videotaping of entire interrogations from a balanced camera perspective is necessary to improve the fact finding accuracy of judges and juries who must evaluate confession evidence in court.