Herpes Simplex Virus-1 ICP27 Nuclear Export Signal Mutants Exhibit Cell Type-Dependent Deficits in Replication and ICP4 Expression.

Herpes simplex virus type-1 (HSV-1) protein ICP27 is an essential immediate early (IE) protein that promotes the expression of viral early (E) and late (L) genes via multiple mechanisms. Our understanding of this complex regulatory protein has been greatly enhanced by the characterization of HSV-1 mutants bearing engineered alterations in the ICP27 gene. However, much of this analysis has been performed in interferon-deficient Vero monkey cells. Here, we assessed the replication of a panel of ICP27 mutants in several other cell types. Our analysis shows that mutants lacking ICP27's amino (N)-terminal nuclear export signal (NES) display a striking cell type-dependent growth phenotype, i.e., they grow semi-permissively in Vero and some other cells but are tightly blocked for replication in primary human fibroblasts and multiple human cell lines. This tight growth defect correlates with a failure of these mutants to replicate viral DNA. We also report that HSV-1 NES mutants are deficient in expressing the IE protein ICP4 at early times postinfection. Analysis of viral RNA levels suggests that this phenotype is due, at least in part, to a defect in the export of ICP4 mRNA to the cytoplasm. In combination, our results (i) show that ICP27's NES is critically important for HSV-1 replication in many human cells, and (ii) suggest that ICP27 plays a heretofore unappreciated role in the expression of ICP4. IMPORTANCE HSV-1 IE proteins drive productive HSV-1 replication. The major paradigm of IE gene induction, developed over many years, involves the parallel activation of the five IE genes by the viral tegument protein VP16, which recruits the host RNA polymerase II (RNAP II) to the IE gene promoters. Here, we provide evidence that ICP27 can enhance ICP4 expression early in infection. Because ICP4 is required for transcription of viral E and L genes, this finding may be relevant to understanding how HSV-1 enters and exits the latent state in neurons.

Widespread remodeling of the m6A RNA-modification landscape by a viral regulator of RNA processing and export.

N6-methyladenosine (m6A) is the most abundant internal messenger RNA (mRNA) modification, contributing to the processing, stability, and function of methylated RNAs. Methylation occurs in the nucleus during pre-mRNA synthesis and requires a core methyltransferase complex consisting of METTL3, METTL14, and WTAP. During herpes simplex virus (HSV-1) infection, cellular gene expression is profoundly suppressed, allowing the virus to monopolize the host transcription and translation apparatus and antagonize antiviral responses. The extent to which HSV-1 uses or manipulates the m6A pathway is not known. Here, we show that, in primary fibroblasts, HSV-1 orchestrates a striking redistribution of the nuclear m6A machinery that progresses through the infection cycle. METTL3 and METTL14 are dispersed into the cytoplasm, whereas WTAP remains nuclear. Other regulatory subunits of the methyltransferase complex, along with the nuclear m6A-modified RNA binding protein YTHDC1 and nuclear demethylase ALKBH5, are similarly redistributed. These changes require ICP27, a viral regulator of host mRNA processing that mediates the nucleocytoplasmic export of viral late mRNAs. Viral gene expression is initially reduced by small interfering RNA (siRNA)-mediated inactivation of the m6A methyltransferase but becomes less impacted as the infection advances. Redistribution of the nuclear m6A machinery is accompanied by a wide-scale reduction in the installation of m6A and other RNA modifications on both host and viral mRNAs. These results reveal a far-reaching mechanism by which HSV-1 subverts host gene expression to favor viral replication.

The effect of the endoscopic device Endocuff™/Endocuff vision™ on quality standards in colonoscopy: A systematic review and meta-analysis of randomized trials.

AIM: The adenoma detection rate (ADR) is an important quality measure, with a high ADR reflecting high-quality colonoscopy. This systematic review and meta-analysis aimed to assess the effects of Endocuff™/Endocuff Vision™-assisted colonoscopy (EAC) versus standard colonoscopy (SC) on ADR and other clinical, patient and resource-use outcomes. METHOD: MEDLINE, EMBASE, Web of Science, Scopus and the Cochrane Central Register of Controlled Trials were searched for full papers reporting randomized studies comparing EAC with SC. The primary outcome was ADR. Secondary outcomes comprised key polyp/adenoma detection, procedure-related, patient-related and health economic measures. Random effects meta-analyses provided pooled estimates of outcomes [risk ratio (RR) or mean difference (MD), with 95% confidence intervals (CI)]. RESULTS: Twelve parallel-group randomized controlled trials (RCTs) and three crossover RCTs with data on 9140 patients were included. EAC significantly increased the ADR (RR 1.18, 95% CI 1.09-1.29), mean adenomas per procedure (MAP) (MD 0.19, 95% CI 0.06-0.33), polyp detection rate (PDR) (RR 1.20, 95% CI 1.10-1.30) and mean polyps per procedure (MPP) (MD 0.39, 95% CI 0.14-0.63) versus SC. EAC significantly increased segmental PDR versus SC in the sigmoid (RR 2.02, 95% CI 1.64-2.49), transverse (RR 1.63, 95% CI 1.09-2.42), ascending (RR 1.74, 95% CI 1.26-2.41) and caecal segments (RR 1.91, 95% CI 1.29-2.82). Procedure-related variables did not differ between arms. There were insufficient data for meta-analysis of health economic or patient-centred outcomes. CONCLUSIONS: EAC increased ADR, MAP, PDR and MPP versus SC without detrimental effects on procedure measures. Cost-effectiveness and patient experience data are lacking and would be valuable to inform practice recommendations.

A qualitative interview study applying the COM-B model to explore how hospital-based trainers implement antimicrobial stewardship education and training in UK hospital-based care.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health threat caused by the inappropriate use of antimicrobials in healthcare and other settings. Antimicrobial stewardship (AMS) is a broad multi-component health services intervention that promotes and monitors the judicious use of antimicrobials to preserve their future effectiveness. A main component of AMS is education and training (E&T). However, there are often discrepancies in how such interventions are implemented and delivered in hospital-based care. The aim of this study was to explore the factors influencing the implementation of AMS E&T in UK hospitals. METHODS: Semi-structured interviews were carried out with AMS E&T trainers in UK hospitals. The interview schedule was developed using the Capability, Opportunity, Motivation = Behaviour (COM-B) model. Participants were identified via professional networks and social media. Interviews were analysed using inductive thematic analysis, followed by deductive analysis using the COM-B model as a framework. RESULTS: A total of 34 participants (26 antimicrobial pharmacists, 3 nurses, 1 advanced clinical practitioner, 2 infectious disease consultants, 1 microbiologist and 1 clinical scientist). responsible for designing, implementing and evaluating AMS E&T in UK hospitals (five from Northern Ireland, four from Wales, two from Scotland and 23 from England) took part in virtual interviews. Key themes were: (1) The organisational context, including system-level barriers to AMS included competing organisational targets (Reflective motivation and physical opportunity) and the impact of the COVID-19 pandemic on activity (Physical opportunity); (2) Healthcare professionals' roles and the wider multi-disciplinary team, such that AMS roles were defined and addressed poorly in E&T (Social opportunity); and (3) The individual perception of the need for AMS E&T in hospital-based care, manifest in a perceived lack of conviction of the wider threat of AMR and the resulting need for AMS E&T (Reflective motivation). CONCLUSION: This study has identified factors influencing implementation of AMS E&T in UK hospitals and further identified where implemented, AMS E&T did not address real-world challenges. Current AMS E&T needs to be optimised to elicit practice change, with recommendations including training and engaging the wider work-force and drawing upon theoretically-informed intervention development frameworks to inform AMS E&T to better target AMS behaviour change.

An empirical analysis of American Passenger's willingness to fly in commercial airplanes after vaccination against COVID-19.

Although several studies have explored the effects of the pandemic on aviation, little remains known about whether members of the public are willing to fly again after they have been vaccinated. The current study uses the Health Belief Model (HBM) to fill this missing gap by manipulating the following variables: 1) whether or not the participant is vaccinated; 2) whether or not airlines require that all passengers and crew receive vaccinations; 3) length of flight; 4) destination; and 5) the number of passengers. The data from 678 participants revealed that willingness to fly is much higher if the participants themselves have been vaccinated, if the airlines require all passengers to be vaccinated, if the flight is short, if the destination is domestic, and if the number of passengers is low. These findings did not appear to differ as a function of flying business versus pleasure. We discuss the practical implications of these data as airlines struggle to bring back their customer base.

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Effects of Primary Biliary Cholangitis on Quality of Life and Health Care Costs in the United Kingdom.

BACKGROUND & AIMS: There have been few high-quality studies of the costs, preference-based health-related quality of life (HRQoL) and cost effectiveness of treatments for primary biliary cholangitis (PBC). We aimed to estimate the marginal effects of PBC complications and symptoms, accounting for treatment, on HRQoL and the annual cost of health care in the United Kingdom (UK). These are essential components for evaluation of cost effectiveness and this information will aid in evaluation of new treatments. METHODS: Questionnaires were mailed to 4583 participants in the UK-PBC research cohort and data were collected on HRQoL and use of the National Health Service (NHS) in the UK from 2015 through 2016. HRQoL was measured using the EQ-5D-5L instrument. The annual cost of resource use was calculated using unit costs obtained from NHS sources. We performed econometric analyses to determine the effects of treatment, symptoms, complications, liver transplantation status, and patient characteristics on HRQoL and annual costs. RESULTS: In an analysis of data from 2240 participants (over 10% of all UK PBC patients), we found that PBC symptoms have a considerable effect on HRQoL. Ursodeoxycholic acid therapy was associated with significantly higher HRQoL regardless of response status. Having had a liver transplant and ascites were also independently associated with reduced HRQoL. Having had a liver transplant (US$4294) and esophageal varices (US$3401) were the factors with the two greatest mean annual costs to the NHS. Symptoms were not independently associated with cost but were associated with reduction in HRQoL for patients, indicating the lack of effective treatments for PBC symptoms. CONCLUSIONS: In an analysis of data from 2240 participants in the UK PBC, we found that HRQoL and cost estimates provide greater insight into the relative importance of PBC-related symptoms and complications. These findings provide estimates for health technology assessments of new treatments for PBC.

RNAIndel: discovering somatic coding indels from tumor RNA-Seq data.

MOTIVATION: Reliable identification of expressed somatic insertions/deletions (indels) is an unmet need due to artifacts generated in PCR-based RNA-Seq library preparation and the lack of normal RNA-Seq data, presenting analytical challenges for discovery of somatic indels in tumor transcriptome. RESULTS: We present RNAIndel, a tool for predicting somatic, germline and artifact indels from tumor RNA-Seq data. RNAIndel leverages features derived from indel sequence context and biological effect in a machine-learning framework. Except for tumor samples with microsatellite instability, RNAIndel robustly predicts 88-100% of somatic indels in five diverse test datasets of pediatric and adult cancers, even recovering subclonal (VAF range 0.01-0.15) driver indels missed by targeted deep-sequencing, outperforming the current best-practice for RNA-Seq variant calling which had 57% sensitivity but with 14 times more false positives. AVAILABILITY AND IMPLEMENTATION: RNAIndel is freely available at https://github.com/stjude/RNAIndel. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Secondary transfer of emergency stroke patients eligible for mechanical thrombectomy by air in rural England: economic evaluation and considerations.

BACKGROUND: Mechanical thrombectomy (MT) is a time-sensitive emergency procedure for patients who had ischaemic stroke leading to improved health outcomes. Health systems need to ensure that MT is delivered to as many patients as quickly as possible. Using decision modelling, we aimed to evaluate the cost-effectiveness of secondary transfer by helicopter emergency medical services (HEMS) compared with ground emergency medical services (GEMS) of rural patients eligible for MT in England. METHODS: The model consisted of (1) a short-run decision tree with two branches, representing secondary transfer transportation strategies and (2) a long-run Markov model for a theoretical population of rural patients with a confirmed ischaemic stroke. Strategies were compared by lifetime costs: quality-adjusted life years (QALYs), incremental cost per QALY gained and net monetary benefit. Sensitivity and scenario analyses explored uncertainty around parameter values. RESULTS: We used the base case of early-presenting (<6 hours to arterial puncture) patient aged 75 years who had stroke to compare HEMS and GEMS. This produced an incremental cost-effectiveness ratio (ICER) of £28 027 when a 60 min reduction in travel time was assumed. Scenario analyses showed the importance of the reduction in travel time and futile transfers in lowering ICERs. For late presenting (>6 hours to arterial puncture), ground transportation is the dominant strategy. CONCLUSION: Our model indicates that using HEMS to transfer patients who had stroke eligible for MT from remote hospitals in England may be cost-effective when: travel time is reduced by at least 60 min compared with GEMS, and a £30 000/QALY threshold is used for decision-making. However, several other logistic considerations may impact on the use of air transportation.

HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression.

Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS-STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.

Are there socio-economic inequalities in utilization of predictive biomarker tests and biological and precision therapies for cancer? A systematic review and meta-analysis.

BACKGROUND: Novel biological and precision therapies and their associated predictive biomarker tests offer opportunities for increased tumor response, reduced adverse effects, and improved survival. This systematic review determined if there are socio-economic inequalities in utilization of predictive biomarker tests and/or biological and precision cancer therapies. METHODS: MEDLINE, Embase, Scopus, CINAHL, Web of Science, PubMed, and PsycINFO were searched for peer-reviewed studies, published in English between January 1998 and December 2019. Observational studies reporting utilization data for predictive biomarker tests and/or cancer biological and precision therapies by a measure of socio-economic status (SES) were eligible. Data was extracted from eligible studies. A modified ISPOR checklist for retrospective database studies was used to assess study quality. Meta-analyses were undertaken using a random-effects model, with sub-group analyses by cancer site and drug class. Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each study. Pooled utilization ORs for low versus high socio-economic groups were calculated for test and therapy receipt. RESULTS: Among 10,722 citations screened, 62 papers (58 studies; 8 test utilization studies, 37 therapy utilization studies, 3 studies on testing and therapy, 10 studies without denominator populations or which only reported mean socio-economic status) met the inclusion criteria. Studies reported on 7 cancers, 5 predictive biomarkers tests, and 11 biological and precision therapies. Thirty-eight studies (including 1,036,125 patients) were eligible for inclusion in meta-analyses. Low socio-economic status was associated with modestly lower predictive biomarker test utilization (OR 0.86, 95% CI 0.71-1.05; 10 studies) and significantly lower biological and precision therapy utilization (OR 0.83, 95% CI 0.75-0.91; 30 studies). Associations with therapy utilization were stronger in lung cancer (OR 0.71, 95% CI 0.51-1.00; 6 studies), than breast cancer (OR 0.93, 95% CI 0.78-1.10; 8 studies). The mean study quality score was 6.9/10. CONCLUSIONS: These novel results indicate that there are socio-economic inequalities in predictive biomarker tests and biological and precision therapy utilization. This requires further investigation to prevent differences in outcomes due to inequalities in treatment with biological and precision therapies.

A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits.

An integral part of the antiviral innate immune response is the APOBEC3 family of single-stranded DNA cytosine deaminases, which inhibits virus replication through deamination-dependent and -independent activities. Viruses have evolved mechanisms to counteract these enzymes, such as HIV-1 Vif-mediated formation of a ubiquitin ligase to degrade virus-restrictive APOBEC3 enzymes. A new example is Epstein-Barr virus (EBV) ribonucleotide reductase (RNR)-mediated inhibition of cellular APOBEC3B (A3B). The large subunit of the viral RNR, BORF2, causes A3B relocalization from the nucleus to cytoplasmic bodies and thereby protects viral DNA during lytic replication. Here, we use coimmunoprecipitation and immunofluorescence microscopy approaches to ask whether this mechanism is shared with the closely related gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) and the more distantly related alphaherpesvirus herpes simplex virus 1 (HSV-1). The large RNR subunit of KSHV, open reading frame 61 (ORF61), coprecipitated multiple APOBEC3s, including A3B and APOBEC3A (A3A). KSHV ORF61 also caused relocalization of these two enzymes to perinuclear bodies (A3B) and to oblong cytoplasmic structures (A3A). The large RNR subunit of HSV-1, ICP6, also coprecipitated A3B and A3A and was sufficient to promote the relocalization of these enzymes from nuclear to cytoplasmic compartments. HSV-1 infection caused similar relocalization phenotypes that required ICP6. However, unlike the infectivity defects previously reported for BORF2-null EBV, ICP6 mutant HSV-1 showed normal growth rates and plaque phenotypes. Combined, these results indicate that both gamma- and alphaherpesviruses use a conserved RNR-dependent mechanism to relocalize A3B and A3A and furthermore suggest that HSV-1 possesses at least one additional mechanism to neutralize these antiviral enzymes.IMPORTANCE The APOBEC3 family of DNA cytosine deaminases constitutes a vital innate immune defense against a range of different viruses. A novel counterrestriction mechanism has recently been uncovered for the gammaherpesvirus EBV, in which a subunit of the viral protein known to produce DNA building blocks (ribonucleotide reductase) causes A3B to relocalize from the nucleus to the cytosol. Here, we extend these observations with A3B to include a closely related gammaherpesvirus, KSHV, and a more distantly related alphaherpesvirus, HSV-1. These different viral ribonucleotide reductases also caused relocalization of A3A, which is 92% identical to A3B. These studies are important because they suggest a conserved mechanism of APOBEC3 evasion by large double-stranded DNA herpesviruses. Strategies to block this host-pathogen interaction may be effective for treating infections caused by these herpesviruses.

Autopilots in the Operating Room: Safe Use of Automated Medical Technology.

Automated medical technology is becoming an integral part of routine anesthetic practice. Automated technologies can improve patient safety, but may create new workflows with potentially surprising adverse consequences and cognitive errors that must be addressed before these technologies are adopted into clinical practice. Industries such as aviation and nuclear power have developed techniques to mitigate the unintended consequences of automation, including automation bias, skill loss, and system failures. In order to maximize the benefits of automated technology, clinicians should receive training in human-system interaction including topics such as vigilance, management of system failures, and maintaining manual skills. Medical device manufacturers now evaluate usability of equipment using the principles of human performance and should be encouraged to develop comprehensive training materials that describe possible system failures. Additional research in human-system interaction can improve the ways in which automated medical devices communicate with clinicians. These steps will ensure that medical practitioners can effectively use these new devices while being ready to assume manual control when necessary and prepare us for a future that includes automated health care.

Male energy reserves, mate-searching activities, and reproductive success: alternative resource use strategies in a presumed capital breeder.

Sexual selection studies often focus on morphological traits that are important only in the later stages of mate acquisition. Comparatively little is known about traits that lead to mate acquisition, such as mate-searching activities. We experimentally manipulated body condition (i.e., the energy reserves) in male puff adders (Bitis arietans) prior to the mating season using supplemental feeding in the field, and used radio-telemetry and DNA paternity analyses to characterize the relationships between male energy reserves, mating activities, and reproductive success. We found that male mobility is a strongly sexually selected trait because males that travelled further in search of females have higher female encounter rates and reproductive success. However, supplemental feeding did not have a significant effect on mating activities or reproductive success, because control snakes compensated by foraging more often during the mating season. The time invested in foraging by control snakes did not come at the costs of decreased mating activities or opportunity compared to fed snakes, because the latter spent the spare time resting. Our experimental field research directly demonstrates the link between male mobility and reproductive success, identifying the ultimate mechanism leading to the evolution of prolonged male mate-searching activities in snakes, and indicates that male puff adders, presumed capital breeders, adjust their breeding tactics according to resource availability.

Correction to: Male energy reserves, mate-searching activities, and reproductive success: alternative resource use strategies in a presumed capital breeder.

The authors would like to correct the error in table 4 which was incorrectly published in original version. Correct version of Table 4 is updated here.

Avoidance and aggregation create consistent egg distribution patterns of congeneric caddisflies across spatially variable oviposition landscapes.

Amongst oviparous animals, the spatial distribution of individuals is often set initially by where females lay eggs, with potential implications for populations and species coexistence. Do the spatial arrangements of oviposition sites or female behaviours determine spatial patterns of eggs? The consequences of spatial patterns may be context independent if strong behaviours drive patterns; context dependent if the local environment dominates. We tested these ideas using a guild of stream-dwelling caddisflies that oviposit on emergent rocks, focussing on genera with contrasting behaviours. In naturally occurring oviposition landscapes (riffles with emergent rocks), we surveyed the spatial arrangement and environmental characteristics of all emergent rocks, identified and enumerated egg masses on each. Multiple riffles were surveyed to test for spatially invariant patterns and behaviours. In landscapes, we tested for spatial clumping of oviposition sites exploited by each species and for segregation of congeneric species. At oviposition sites, we characterised the frequency distributions of egg masses and tested for species associations. Genus-specific behaviours produced different spatial patterns of egg masses in the same landscapes. Congregative behaviour of Ulmerochorema spp. at landscape scales and an aggregative response at preferred oviposition sites led to clumped patterns, local aggregation and species overlap. In contrast, avoidance behaviours by congeners of Apsilochorema resulted in no or weak clumping, and species segregation in some landscapes. Spatial patterns were consistent across riffles that varied in area and oviposition site density. These results suggest that quite different oviposition behaviours may be context independent, and the consequences of spatial patterns may be spatially invariant also.

The Impact of Autoimmune Hepatitis and Its Treatment on Health Utility.

Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health-related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient-reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK-AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) and clinical data forms. The EQ-5D-5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ-5D-5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. CONCLUSION: Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid-free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH. (Hepatology 2018; 00:000-000).

Patient Perceptions of New Robotic Technologies in Clinical Restorative Dentistry.

Patient perception research has failed to focus on burgeoning technology within the dental field. Specifically, researchers have yet to focus on developing robotic technologies which are being utilized by dentists to help perform certain procedures with added precision and route mapping. The current study attempts to fill the gap created by a lack of intersection between dental technology research, consumer perceptions research, and automation research. The current research takes a two-study approach, with study 1 investigating if gender or price of the procedure affects willingness to undergo a robotic dental procedure. Study 2 further investigates this phenomenon, identifying ten separate types of dental procedures (ranging from minimally invasive to extremely invasive) to further understand consumer perceptions. Results indicate that females are less willing to undergo a robotic dental procedure, and that participants in general are more willing to undergo a procedure if it is half price than if it full price. Willingness is influenced by gender and the type of procedure being performed - participants were less willing to undergo invasive procedures such as gum surgery than noninvasive procedures such as teeth whitening. These results, and their theoretical and practical significance are discussed.

Interventions to increase attendance for diabetic retinopathy screening.

BACKGROUND: Despite evidence supporting the effectiveness of diabetic retinopathy screening (DRS) in reducing the risk of sight loss, attendance for screening is consistently below recommended levels. OBJECTIVES: The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.Secondary objectives were:To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, Web of Science, ProQuest Family Health, OpenGrey, the ISRCTN, ClinicalTrials.gov, and the WHO ICTRP to identify randomised controlled trials (RCTs) that were designed to improve attendance for DRS or were evaluating general quality improvement (QI) strategies for diabetes care and reported the effect of the intervention on DRS attendance. We searched the resources on 13 February 2017. We did not use any date or language restrictions in the searches. SELECTION CRITERIA: We included RCTs that compared any QI intervention to usual care or a more intensive (stepped) intervention versus a less intensive intervention. DATA COLLECTION AND ANALYSIS: We coded the QI strategy using a modification of the taxonomy developed by Cochrane Effective Practice and Organisation of Care (EPOC) and BCTs using the BCT Taxonomy version 1 (BCTTv1). We used Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social capital (PROGRESS) elements to describe the characteristics of participants in the included studies that could have an impact on equity of access to health services.Two review authors independently extracted data. One review author entered the data into Review Manager 5 and a second review author checked them. Two review authors independently assessed risks of bias in the included studies and extracted data. We rated certainty of evidence using GRADE. MAIN RESULTS: We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs 'goal setting (outcome)' (RD 0.26, 95% CI 0.16 to 0.36) and 'feedback on outcomes of behaviour' (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and 'restructuring the social environment' (RD 0.19, 95% CI 0.12 to 0.26) and 'credible source' (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).Fourteen studies reporting any QI intervention compared to usual care included economic outcomes. However, only five of these were full economic evaluations. Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.With the exception of gender and ethnicity, the characteristics of participants were poorly described in terms of PROGRESS elements. Seventeen studies (25.8%) were conducted in disadvantaged populations. No studies were carried out in low- or middle-income countries. AUTHORS' CONCLUSIONS: The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care. This is a significant finding, due to the additional benefits of general QI interventions in terms of improving glycaemic control, vascular risk management and screening for other microvascular complications. It is likely that further (but smaller) improvements in DRS attendance can also be achieved by increasing the intensity of a particular QI component or adding further components.

The Type and Impact of Evidence Review Group Exploratory Analyses in the NICE Single Technology Appraisal Process.

BACKGROUND: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. OBJECTIVES: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. METHODS: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. RESULTS: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category "Matters of judgment," which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. CONCLUSIONS: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision-making process.