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BackgroundGallbladder disease in people is frequently associated with disorders of lipid metabolism and metabolic syndrome. A recently emergent gallbladder disease of dogs, referred to as mucocele formation, is characterized by secretion of abnormal mucus by the gallbladder epithelium and is similarly associated with hyperlipidemia, endocrinopathy, and metabolic dysfunction. The cause of gallbladder mucocele formation in dogs is unknown.MethodsA prospective case-controlled study was conducted to gain insight into disease pathogenesis by characterization of plasma lipid abnormalities in 18 dogs with gallbladder mucocele formation and 18 age and breed matched control dogs using direct infusion mass spectrometry for complex plasma lipid analysis. This analysis was complemented by histochemical and ultrastructural examination of gallbladder mucosa from dogs with gallbladder mucocele formation and control dogs for evidence of altered lipid homeostasis of the gallbladder epithelium.ResultsGallbladder mucocele formation in dogs carried a unique lipidomic signature of increased lipogenesis impacting 50% of lipid classes, 36% of esterified fatty acid species, and 11% of complex lipid species. Broad enrichment of complex lipids with palmitoleic acid (16:1) and decreased abundance within complex lipids of presumptive omega-3 fatty acids eicosapentaenoic (20:5) and docosahexaenoic (22:6) was significant. Severe lipidosis of gallbladder epithelium pinpoints the gallbladder as involved causally or consequently in abnormal lipid metabolism.ConclusionOur study supports a primary increase in lipogenesis in dogs with mucocele formation and abnormal gallbladder lipid metabolism in disease pathogenesis.

IntroductionResearch suggests that general practice can play an important role in managing long COVID. However, studies investigating the perspectives of general practitioners (GPs) and patients are lacking and knowledge regarding optimal long COVID care in general practice is therefore limited.AimTo investigate GPs' and patients' perspectives on the topic of long COVID and its management in general practice.MethodsBrief questionnaires (GP n = 11, Patient n = 7) and in-depth semi-structured interviews (GP n = 10, Patient n = 7) were conducted with GPs and patients from Irish general practices during July 2022-January 2023. Interviews were conducted via telephone and audio recordings were transcribed. A phenomenological analysis involving reflexive thematic analysis and constant comparison techniques was adopted.ResultsAnalysis of interviews with GPs (male = 7, female = 3; median age = 50yrs (IQR = 39.5-56)) and patients (males = 2, female = 5; median age = 58yrs (IQR = 45-62yrs) generated four themes. These were (1) Complex presentations (2) the value of standardising care, (3) choosing the right path, and (4) supportive and collaborative doctor-patient relationships. Strong agreement was observed among GPs and patients regarding the need for holistic and integrated multidisciplinary care. Supportive and collaborative doctor-patient relationships were largely well received by GPs and patients also. GPs strongly endorsed standardising long COVID care operations.ConclusionGPs and patients indicated that structured, integrated, and collaborative care can help optimise long COVID management in general practice. GPs are advised to incorporate these elements into their long COVID care practices going forward. Future research examining stakeholder's perspectives using larger and longitudinal samples is advised to enhance the generalisability of evidence in this area.

PurposeSavouring interventions aim to amplify the intensity and duration of positive feelings and positive affect. Research has shown that the potential benefits of savouring include the promotion of psychological well-being and diminution of negative affective states. Savouring strategies may be particularly useful amongst clinical populations in changing biobehavioural processes which can strengthen an individual's propensity to exert control over how to develop, intensify and promote psychological well-being, while simultaneously mitigating negative affective states. This paper outlines a protocol for a systematic review that will be used to identify, critically appraise and synthesise findings of studies examining the effectiveness of savouring interventions in adult clinical populations. Savouring interventions will be defined broadly, operationalised as any savouring strategy focusing on past, present or future events or experiences whereby participants are instructed to attend to and amplify positive affect relating to same. The goal of our review is to include the extent of the literature on this topic and contribute to the overall evidence to support savouring interventions.MethodsThis protocol is carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols Guidelines. The protocol has been registered with PROSPERO (CRD42023404857). The databases PsycINFO, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Scopus will be searched alongside a search of grey literature. An examination of the first 200 papers on Google Scholar will also be done to identify relevant papers. Studies describing randomised controlled trials evaluating the effects of savouring interventions as described within this article on adult clinical populations will be included in the review. Outcomes will include well-being, quality of life, depression, anxiety or stress. Study selection and data extraction will be completed by three independent reviewers to reduce risk of bias. Interrater percentage agreement and interrater reliability will be reported on same. The quality of studies will be assessed using criteria based on the Cochrane Collaboration's tool for assessing risk of bias and the Jadad scale. A narrative synthesis with tables of study characteristics will be provided. Separate considerations of the three time perspectives of savouring interventions (past-focused, present-focused, and future-focused) will also be described.ConclusionsThis systematic review will provide important clinical insights into the potential efficacy of savouring interventions when working with adult clinical samples.

Inattentional blindness refers to when people fail to notice obvious and unexpected events when their attention is elsewhere. Existing research suggests that inattentional blindness is a poorly understood concept that violates the beliefs that are commonly held by the public about vision and attention. Given that legal cases may involve individuals who may have experienced inattentional blindness, it is important to understand the beliefs legal populations and members of the community have about inattentional blindness, and their general familiarity and experience with the concept. Australian police officers (n = 94) and lawyers (n = 98), along with psychology students (n = 99) and community members (n = 100) completed a survey where they: a) stated whether an individual would have noticed an event in six legal vignettes, b) rated whether factors would make an individual more, less, or just as likely to notice an unexpected event, c) reported their familiarity with and personal experiences of inattentional blindness, and d) indicated whether they believed individuals could make themselves more likely to notice unexpected events. Respondents in all populations frequently responded "yes" to detecting the unexpected event in most legal vignettes. They also held misconceptions about some factors (expertise and threat) that would influence the noticing of unexpected events. Additionally, personal experiences with inattentional blindness were commonly reported. Finally, respondents provided strategies for what individuals can do to make themselves more likely to notice of unexpected events, despite a lack of evidence to support them. Overall, these findings provide direction for where education and training could be targeted to address misconceptions about inattentional blindness held by legal populations, which may lead to improved decision-making in legal settings.

Climate change is already impacting coastal communities, and ongoing and future shifts in fisheries species productivity from climate change have implications for the livelihoods and cultures of coastal communities. Harvested marine species in the California Current Large Marine Ecosystem support U.S. West Coast communities economically, socially, and culturally. Ecological vulnerability assessments exist for individual species in the California Current but ecological and human vulnerability are linked and vulnerability is expected to vary by community. Here, we present automatable, reproducible methods for assessing the vulnerability of U.S. West Coast fishing dependent communities to climate change within a social-ecological vulnerability framework. We first assessed the ecological risk of marine resources, on which fishing communities rely, to 50 years of climate change projections. We then combined this with the adaptive capacity of fishing communities, based on social indicators, to assess the potential ability of communities to cope with future changes. Specific communities (particularly in Washington state) were determined to be at risk to climate change mainly due to economic reliance on at risk marine fisheries species, like salmon, hake, or sea urchins. But, due to higher social adaptive capacity, these communities were often not found to be the most vulnerable overall. Conversely, certain communities that were not the most at risk, ecologically and economically, ranked in the category of highly vulnerable communities due to low adaptive capacity based on social indicators (particularly in Southern California). Certain communities were both ecologically at risk due to catch composition and socially vulnerable (low adaptive capacity) leading to the highest tier of vulnerability. The integration of climatic, ecological, economic, and societal data reveals that factors underlying vulnerability are variable across fishing communities on the U.S West Coast, and suggests the need to develop a variety of well-aligned strategies to adapt to the ecological impacts of climate change.

To date studies have not investigated the culture-independent microbiome of bile from dogs, a species where aseptic collection of bile under ultrasound guidance is somewhat routine. Despite frequent collection of bile for culture-based diagnosis of bacterial cholecystitis, it is unknown whether bile from healthy dogs harbors uncultivable bacteria or a core microbiota. The answer to this question is critical to understanding the pathogenesis of biliary infection and as a baseline to exploration of other biliary diseases in dogs where uncultivable bacteria could play a pathogenic role. A pressing example of such a disease would be gallbladder mucocele formation in dogs. This prevalent and deadly condition is characterized by excessive secretion of abnormal mucus by the gallbladder epithelium that can eventually lead to rupture of the gallbladder or obstruction of bile flow. The cause of mucocele formation is unknown as is whether uncultivable, and therefore unrecognized, bacteria play any systematic role in pathogenesis. In this study we applied next-generation 16S rRNA gene sequencing to identify the culture-negative bacterial community of gallbladder bile from healthy dogs and gallbladder mucus from dogs with mucocele formation. Integral to our study was the use of 2 separate DNA isolations on each sample using different extraction methods and sequencing of negative control samples enabling recognition and curation of contaminating sequences. Microbiota findings were validated by simultaneous culture-based identification, cytological examination of bile, and fluorescence in-situ hybridization (FISH) performed on gallbladder mucosa. Using culture-dependent, cytological, FISH, and 16S rRNA sequencing approaches, results of our study do not support existence of a core microbiome in the bile of healthy dogs or gallbladder mucus from dogs with mucocele formation. Our findings further document how contaminating sequences can significantly contribute to the results of sequencing analysis when performed on samples with low bacterial biomass.

IntroductionGlobal interest has increased in improving the quality and increasing the number of graduates from surgical training programmes in countries with limited resources. Needs assessment of stakeholders in the training programmes represent the backbone of such process. The aim of this study was to assess the surgical training in Sudan from trainees' perspective in order to inform training delivery.MethodsWe adopted mixed methods design using focus group discussion for qualitative data collection and questionnaire survey for quantitative data. NVivo 20 Pro was used to organize qualitative data and SPSS 24.0 was used for quantitative data analysis.ResultsThematic analysis of qualitative data identified three themes. Trainees were overall satisfied that they will make good surgeons after completion of the programme. They identified case volume and collaborations with colleagues as the main strengths of the programme and lacking clear objectives for each year of training and academic activities as the main weaknesses. They suggested motivation of trainers and utilization of online resources and meeting platforms as solutions to improve supervision and academic activities during training.ConclusionThe gaps in training and their suggested solutions highlighted by trainees in this study should form the base for reforming the surgical training in Sudan and countries with similar circumstances.

ObjectiveTo investigate the association between denture wearing and airflow limitation in men in Northern Ireland enrolled in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study.MethodsA case-control design was used to study partially dentate men. Cases were men aged 58-72 years who were confirmed as denture wearers. Controls were never denture wearers who were matched by age (± 1 month) and smoking habit to the cases. The men had a periodontal assessment and completed a questionnaire detailing their medical history, dental history and behaviours, social circumstances, demographic background and tobacco use. Physical examination and spirometry measurements of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were also undertaken. Spirometry data for edentulous men who wore complete dentures were compared with that recorded for the partially dentate men studied.ResultsThere were 353 cases who were partially dentate and were confirmed denture wearers. They were matched for age and smoking habit to never denture wearer controls. The cases had an FEV1 that was on average 140 ml lower than the controls, p = 0.0013 and a 4% reduction in percent predicted FEV1, p = 0.0022. Application of the GOLD criteria indicated that 61 (17.3%) of the cases had moderate to severe airflow limitation compared with 33 (9.3%) of controls, p = 0.0051. Fully adjusted multivariable analysis showed that partially dentate men who were denture wearers were significantly more likely (p = 0.01) to have moderate to severe airflow reduction with an adjusted odds ratio (OR) of 2.37 (95% confidence intervals 1.23-4.55). In the 153 edentulous men studied moderate to severe airflow limitation was recorded in 44 (28.4%), which was significantly higher than in the partially dentate denture wearers (p = 0.017), and the men who had never worn a denture (pConclusionDenture wearing was associated with an increased risk of moderate to severe airflow limitation in the cohort of middle-aged Western European men studied.

BackgroundDirect access to diagnostic imaging in General Practice provides an avenue to reduce referrals to hospital-based specialities and emergency departments, and to ensure timely diagnosis. Enhanced GP access to radiology imaging could potentially reduce hospital referrals, hospital admissions, enhance patient care, and improve disease outcomes. This scoping review aims to demonstrate the value of direct access to diagnostic imaging in General Practice and how it has impacted on healthcare delivery and patient care.MethodsA search was conducted of 'PubMed', 'Cochrane Library', 'Embase' and 'Google Scholar' for papers published between 2012-2022 using Arksey and O'Malley's scoping review framework. The search process was guided by the PRISMA extension for Scoping Reviews checklist (PRISMA-ScR).ResultsTwenty-three papers were included. The studies spanned numerous geographical locations (most commonly UK, Denmark, and Netherlands), encompassing several study designs (most commonly cohort studies, randomised controlled trials and observational studies), and a range of populations and sample sizes. Key outcomes reported included the level of access to imaging serves, the feasibility and cost effectiveness of direct access interventions, GP and patient satisfaction with direct access initiatives, and intervention related scan waiting times and referral process.ConclusionDirect access to imaging for GPs can have many benefits for healthcare service delivery, patient care, and the wider healthcare ecosystem. GP focused direct access initiatives should therefore be considered as a desirable and viable health policy directive. Further research is needed to more closely examine the impacts that access to imaging studies have on health system operations, especially those in General Practice. Research examining the impacts of access to multiple imaging modalities is also warranted.

IntroductionAngiogenin-1 (Ang1) and angiogenin-4 (Ang4) are 14-kDa ribonucleases with potent angiogenic and antimicrobial properties. The role of Ang1 and Ang4 in chronic colitis and colitis-associated cancer has not been previously studied.MethodsWild-type (WT) and angiogenin-1 knock-out (Ang1-KO) C57BL/6 mice were given azoxymethane, a colon carcinogen, 2 days in advance of three cycles of 3.5% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded, a colonoscopy was performed after each DSS treatment, and mice were euthanized (colitis, recovery, cancer) with tissue evaluated by histopathology. Ang1, Ang4, TNF-α, Il-1F062, IL-6, IL-10, IL-23, IL-33 mRNA levels were analyzed by RT-PCR.ResultsAng1-KO mice exhibited more severe colitis compared to WT mice during both the acute (PConclusionsIn a mouse model of colitis-associated cancer, Ang1-KO mice develop more severe colitis, but fewer tumors compared to WT mice. Ang1 levels correlate with the severity of colitis and the development of colitis-associated cancer, while Ang4 was upregulated during both colitis and cancer. Ang1 and Ang4 play important regulatory roles in the response to chronic colitis and the development of colitis-associated cancer and may serve as novel therapeutic targets.

Three-dimensional (3D) cell culture models can help bridge the gap between in vitro cell cultures and in vivo responses by more accurately simulating the natural in vivo environment, shape, tissue stiffness, stressors, gradients and cellular response while avoiding the costs and ethical concerns associated with animal models. The inclusion of the third dimension in 3D cell culture influences the spatial organization of cell surface receptors that interact with other cells and imposes physical restrictions on cells in compared to Two-dimensional (2D) cell cultures. Spheroids' distinctive cyto-architecture mimics in vivo cellular structure, gene expression, metabolism, proliferation, oxygenation, nutrition absorption, waste excretion, and drug uptake while preserving cell-extracellular matrix (ECM) connections and communication, hence influencing molecular processes and cellular phenotypes. This protocol describes the in vitro generation of tumourspheroids using the low attachment plate, hanging drop plate, and cellusponge natural scaffold based methods. The expected results from these protocols confirmed the ability of all these methods to create uniform tumourspheres.

Introduction: Research suggests that general practice can play an important role in managing long COVID. However, studies investigating the perspectives of general practitioners (GPs) and patients are lacking and knowledge regarding optimal long COVID care in general practice is therefore limited. Aim: To investigate GPs' and patients' perspectives on the topic of long COVID and its management in general practice. Methods: Brief questionnaires (GP n = 11, Patient n = 7) and in-depth semi-structured interviews (GP n = 10, Patient n = 7) were conducted with GPs and patients from Irish general practices during July 2022-January 2023. Interviews were conducted via telephone and audio recordings were transcribed. A phenomenological analysis involving reflexive thematic analysis and constant comparison techniques was adopted. Results: Analysis of interviews with GPs (male = 7, female = 3; median age = 50yrs (IQR = 39.5–56)) and patients (males = 2, female = 5; median age = 58yrs (IQR = 45-62yrs) generated four themes. These were (1) Complex presentations (2) the value of standardising care, (3) choosing the right path, and (4) supportive and collaborative doctor-patient relationships. Strong agreement was observed among GPs and patients regarding the need for holistic and integrated multidisciplinary care. Supportive and collaborative doctor-patient relationships were largely well received by GPs and patients also. GPs strongly endorsed standardising long COVID care operations. Conclusion: GPs and patients indicated that structured, integrated, and collaborative care can help optimise long COVID management in general practice. GPs are advised to incorporate these elements into their long COVID care practices going forward. Future research examining stakeholder's perspectives using larger and longitudinal samples is advised to enhance the generalisability of evidence in this area. [ABSTRACT FROM AUTHOR]

Background: Gallbladder disease in people is frequently associated with disorders of lipid metabolism and metabolic syndrome. A recently emergent gallbladder disease of dogs, referred to as mucocele formation, is characterized by secretion of abnormal mucus by the gallbladder epithelium and is similarly associated with hyperlipidemia, endocrinopathy, and metabolic dysfunction. The cause of gallbladder mucocele formation in dogs is unknown. Methods: A prospective case-controlled study was conducted to gain insight into disease pathogenesis by characterization of plasma lipid abnormalities in 18 dogs with gallbladder mucocele formation and 18 age and breed matched control dogs using direct infusion mass spectrometry for complex plasma lipid analysis. This analysis was complemented by histochemical and ultrastructural examination of gallbladder mucosa from dogs with gallbladder mucocele formation and control dogs for evidence of altered lipid homeostasis of the gallbladder epithelium. Results: Gallbladder mucocele formation in dogs carried a unique lipidomic signature of increased lipogenesis impacting 50% of lipid classes, 36% of esterified fatty acid species, and 11% of complex lipid species. Broad enrichment of complex lipids with palmitoleic acid (16:1) and decreased abundance within complex lipids of presumptive omega-3 fatty acids eicosapentaenoic (20:5) and docosahexaenoic (22:6) was significant. Severe lipidosis of gallbladder epithelium pinpoints the gallbladder as involved causally or consequently in abnormal lipid metabolism. Conclusion: Our study supports a primary increase in lipogenesis in dogs with mucocele formation and abnormal gallbladder lipid metabolism in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Prescription of PCSK9-inhibitors has increased in recent years but not much is known about its off-target effects. PCSK9-expression is evident in non-hepatic tissues, notably the brain, and genetic variation in the PCSK9 locus has recently been shown to be associated with mood disorder-related traits. We investigated whether PCSK9 inhibition, proxied by a genetic reduction in expression of PCSK9 mRNA, might have a causal adverse effect on mood disorder-related traits. We used genetic variants in the PCSK9 locus associated with reduced PCSK9 expression (eQTLs) in the European population from GTEx v8 and examined the effect on PCSK9 protein levels and three mood disorder-related traits (major depressive disorder, mood instability, and neuroticism), using summary statistics from the largest European ancestry genome-wide association studies. We conducted summary-based Mendelian randomization analyses to estimate the causal effects, and attempted replication using data from eQTLGen, Brain-eMETA, and the CAGE consortium. We found that genetically reduced PCSK9 gene-expression levels were significantly associated with reduced PCSK9 protein levels but not with increased risk of mood disorder-related traits. Further investigation of nearby genes demonstrated that reduced USP24 gene-expression levels was significantly associated with increased risk of mood instability (p-value range = 5.2x10-5-0.03), and neuroticism score (p-value range = 2.9x10-5-0.02), but not with PCSK9 protein levels. Our results suggest that genetic variation in this region acts on mood disorders through a PCSK9-independent pathway, and therefore PCSK9-inhibitors are unlikely to have an adverse impact on mood disorder-related traits.

BackgroundInternational migration has increased during the past years and little is known about the mortality of young adult immigrants and refugees that came to Sweden as children. This study aimed to investigate 1) the risk of all-cause and cause-specific mortality in young accompanied and unaccompanied refugees and non-refugee immigrants compared to Swedish born individuals; and 2) to determine the role of educational level and migrations-related factors in these associations.MethodsThis register linkage study is based on 682,358 individuals (633,167 Swedish-born, 2,163 unaccompanied and 25,658 accompanied refugees and 21,370 non-refugee immigrants) 19-25 years old, who resided in Sweden 31.12.2004. Outcomes were all-cause mortality and mortality due to suicide and external causes. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models with a maximum follow-up to 2016.ResultsAfter adjusting for covariates, all-cause mortality was significantly lower in non-refugee immigrants (aHR 0.70, 95% CI 0.59-0.84) and refugees (aHR 0.76, 95% CI 0.65-0.88) compared to Swedish-born individuals. The same direction of association was observed for mortality due to suicide and external causes. No differences between accompanied and unaccompanied refugees were found. Risk estimates for all migrant groups varied with educational level, duration of residency, age at arrival and country of birth. Further, the mortality risk of migrants arriving in Sweden before the age of 6 years did not significantly differ from the risk of their Swedish-born peers. Low education was a considerable risk factor.ConclusionIn general, young adult refugees and non-refugee immigrants have a lower risk of all-cause and cause-specific mortality than Swedish-born individuals. The identified migrant groups with higher mortality risk need specific attention.

BackgroundElevations of high-sensitivity cardiac troponin (hs-cTn) concentrations not related to type 1 myocardial infarction are common in chest pain patients presenting to emergency departments. The discrimination of these patients from those with type 1 myocardial infarction (MI) is challenging and resource-consuming. We aimed to investigate whether the hs-cTn I/T ratio might provide diagnostic and prognostic increment in this context.MethodsWe calculated the hs-cTn I/T ratio in 888 chest pain patients having hs-cTnI (Abbott Laboratories) or hs-cTnT (Roche Diagnostics) concentrations above the respective 99th percentile at 2 hours from presentation. All patients were followed for one year regarding mortality.ResultsThe median hs-cTn I/T ratio was 3.45 (25th, 75th percentiles 1.80-6.59) in type 1 MI patients (n = 408 ☯46.0%]), 1.18 (0.81-1.90) in type 2 MI patients (n = 56 ☯6.3%]) and 0.67 (0.39-1.12) in patients without MI. The hs-cTn I/T ratio provided good discrimination of type 1 MI from no type 1 MI (area under the receiver-operator characteristic curve 0.89 ☯95% confidence interval 0.86-0.91]), of type 1 MI from type 2 MI (area under the curve 0.81 ☯95% confidence interval 0.74-0.87]), and was associated with type 1 MI in adjusted analyses. The hs-cTn I/T ratio provided no consistent prognostic value.ConclusionsThe hs-cTn I/T ratio appears to be useful for early diagnosis of type 1 MI and its discrimination from type 2 MI in chest pain patients presenting with elevated hs-cTn. Differences in hs-cTn I/T ratio values may reflect variations in hs-cTn release mechanisms in response to different types of myocardial injury.

Reconstructing the evolution, diversity, and paleobiogeography of North America’s Late Cretaceous dinosaur assemblages require spatiotemporally contiguous data; however, there remains a spatial and temporal disparity in dinosaur data on the continent. The rarity of vertebrate-bearing sedimentary deposits representing Turonian–Santonian ecosystems, and the relatively sparse record of dinosaurs from the eastern portion of the continent, present persistent challenges for studies of North American dinosaur evolution. Here we describe an assemblage of ornithomimosaurian materials from the Santonian Eutaw Formation of Mississippi. Morphological data coupled with osteohistological growth markers suggest the presence of two taxa of different body sizes, including one of the largest ornithomimosaurians known worldwide. The regression predicts a femoral circumference and a body mass of the Eutaw individuals similar to or greater than that of large-bodied ornithomimosaurs, Beishanlong grandis, and Gallimimus bullatus. The paleoosteohistology of MMNS VP-6332 demonstrates that the individual was at least ten years of age (similar to B. grandis [~375 kg, 13–14 years old at death]). Additional pedal elements share some intriguing features with ornithomimosaurs, yet suggest a larger-body size closer to Deinocheirus mirificus. The presence of a large-bodied ornithomimosaur in this region during this time is consistent with the relatively recent discoveries of early-diverging, large-bodied ornithomimosaurs from mid-Cretaceous strata of Laurasia (Arkansaurus fridayi and B. grandis). The smaller Eutaw taxon is represented by a tibia preserving seven growth cycles, with osteohistological indicators of decreasing growth, yet belongs to an individual approaching somatic maturity, suggesting the co-existence of medium- and large-bodied ornithomimosaur taxa during the Late Cretaceous Santonian of North America. The Eutaw ornithomimosaur materials provide key information on the diversity and distribution of North American ornithomimosaurs and Appalachian dinosaurs and fit with broader evidence of multiple cohabiting species of ornithomimosaurian dinosaurs in Late Cretaceous ecosystems of Laurasia.

Since first identified in 1879, plasma, the fourth state of matter, has been developed and utilised in many fields. Nonthermal atmospheric plasma, also known as cold plasma, can be applied to liquids, where plasma reactive species such as reactive Oxygen and Nitrogen species and their effects can be retained and mediated through plasma-activated liquids (PAL). In the medical field, PAL is considered promising for wound treatment, sterilisation and cancer therapy due to its rich and relatively long-lived reactive species components. This study sought to identify any potential antagonistic effect between antioxidative intracellularly accumulated platinum nanoparticles (PtNPs) and PAL. We found that PAL can significantly reduce the viability of glioblastoma U-251MG cells. This did not involve measurable ROS influx but instead lead to lipid damage on the plasma membrane of cells exposed to PAL. Although the intracellular antioxidative PtNPs showed no protective effect against PAL, this study contributes to further understanding of principle cell killing routes of PAL and discovery of potential PAL-related therapy and methods to inhibit side effects.

BackgroundAs prevalence of multimorbidity and polypharmacy rise, health care systems must respond to these challenges. Data is needed from general practice regarding the impact of age, number of chronic illnesses and medications on specific metrics of healthcare utilisation.MethodsThis was a retrospective study of general practices in a university-affiliated education and research network, consisting of 72 practices. Records from a random sample of 100 patients aged 50 years and over who attended each participating practice in the previous two years were analysed. Through manual record searching, data were collected on patient demographics, number of chronic illnesses and medications, numbers of attendances to the general practitioner (GP), practice nurse, home visits and referrals to a hospital doctor. Attendance and referral rates were expressed per person-years for each demographic variable and the ratio of attendance to referral rate was also calculated.ResultsOf the 72 practices invited to participate, 68 (94%) accepted, providing complete data on a total of 6603 patients' records and 89,667 consultations with the GP or practice nurse; 50.1% of patients had been referred to hospital in the previous two years. The attendance rate to general practice was 4.94 per person per year and the referral rate to the hospital was 0.6 per person per year, giving a ratio of over eight attendances for every referral. Increasing age, number of chronic illnesses and number of medications were associated with increased attendance rates to the GP and practice nurse and home visits but did not significantly increase the ratio of attendance to referral rate.DiscussionAs age, morbidity and number of medications rise, so too do all types of consultations in general practice. However, the rate of referral remains relatively stable. General practice must be supported to provide person centred care to an ageing population with rising rates of multi-morbidity and polypharmacy.

Climate change is already impacting coastal communities, and ongoing and future shifts in fisheries species productivity from climate change have implications for the livelihoods and cultures of coastal communities. Harvested marine species in the California Current Large Marine Ecosystem support U.S. West Coast communities economically, socially, and culturally. Ecological vulnerability assessments exist for individual species in the California Current but ecological and human vulnerability are linked and vulnerability is expected to vary by community. Here, we present automatable, reproducible methods for assessing the vulnerability of U.S. West Coast fishing dependent communities to climate change within a social-ecological vulnerability framework. We first assessed the ecological risk of marine resources, on which fishing communities rely, to 50 years of climate change projections. We then combined this with the adaptive capacity of fishing communities, based on social indicators, to assess the potential ability of communities to cope with future changes. Specific communities (particularly in Washington state) were determined to be at risk to climate change mainly due to economic reliance on at risk marine fisheries species, like salmon, hake, or sea urchins. But, due to higher social adaptive capacity, these communities were often not found to be the most vulnerable overall. Conversely, certain communities that were not the most at risk, ecologically and economically, ranked in the category of highly vulnerable communities due to low adaptive capacity based on social indicators (particularly in Southern California). Certain communities were both ecologically at risk due to catch composition and socially vulnerable (low adaptive capacity) leading to the highest tier of vulnerability. The integration of climatic, ecological, economic, and societal data reveals that factors underlying vulnerability are variable across fishing communities on the U.S West Coast, and suggests the need to develop a variety of well-aligned strategies to adapt to the ecological impacts of climate change.

Profiling the adaptive immune repertoire using next generation sequencing (NGS) has become common in human medicine, showing promise in characterizing clonal expansion of B cell clones through analysis of B cell receptors (BCRs) in patients with lymphoid malignancies. In contrast, most work evaluating BCR repertoires in dogs has employed traditional PCR-based approaches analyzing the IGH locus only. The objectives of this study were to: (1) describe a novel NGS protocol to evaluate canine BCRs; (2) develop a bioinformatics pipeline for processing canine BCR sequencing data; and (3) apply these methods to derive insights into BCR repertoires of healthy dogs and dogs undergoing treatment for B-cell lymphoma. RNA from peripheral blood mononuclear cells of healthy dogs (n = 25) and dogs newly diagnosed with intermediate-to-large B-cell lymphoma (n = 18) with intent to pursue chemotherapy was isolated, converted into cDNA and sequenced by NGS. The BCR repertoires were identified and quantified using a novel analysis pipeline. The IGK repertoires of the healthy dogs were far less diverse compared to IGL which, as with IGH, was highly diverse. Strong biases at key positions within the CDR3 sequence were identified within the healthy dog BCR repertoire. For a subset of the dogs with B-cell lymphoma, clonal expansion of specific IGH sequences pre-treatment and reduction post-treatment was observed. The degree of expansion and reduction correlated with the clinical outcome in this subset. Future studies employing these techniques may improve disease monitoring, provide earlier recognition of disease progression, and ultimately lead to more targeted therapeutics.

Ischemic heart disease (IHD) has been linked to exposures to airborne particles with an aerodynamic diameter

ObjectiveMindfulness-based cognitive therapy (MBCT) includes a combination of focused attention (FA) and open monitoring (OM) meditation practices. The aim of this study was to assess both short- and long-term between- and within-group differences in affective disturbance among FA, OM and their combination (MBCT) in the context of a randomized controlled trial.MethodOne hundred and four participants with mild to severe depression and anxiety were randomized into one of three 8-week interventions: MBCT (n = 32), FA (n = 36) and OM (n = 36). Outcome measures included the Inventory of Depressive Symptomatology (IDS), and the Depression Anxiety Stress Scales (DASS). Mixed effects regression models were used to assess differential treatment effects during treatment, post-treatment (8 weeks) and long-term (20 weeks). The Reliable Change Index (RCI) was used to translate statistical findings into clinically meaningful improvements or deteriorations.ResultsAll treatments demonstrated medium to large improvements (ds = 0.42-1.65) for almost all outcomes. While all treatments were largely comparable in their effects at post-treatment (week 8), the treatments showed meaningful differences in rapidity of response and pattern of deteriorations. FA showed the fastest rate of improvement and the fewest deteriorations on stress, anxiety and depression during treatment, but a loss of treatment-related gains and lasting deteriorations in depression at week 20. OM showed the slowest rate of improvement and lost treatment-related gains for anxiety, resulting in higher anxiety in OM at week 20 than MBCT (d = 0.40) and FA (d = 0.36), though these differences did not reach statistical significance after correcting for multiple comparisons (p's = .06). MBCT and OM showed deteriorations in stress, anxiety and depression at multiple timepoints during treatment, with lasting deteriorations in stress and depression. MBCT showed the most favorable pattern for long-term treatment of depression.ConclusionsFA, OM and MBCT show different patterns of response for different dimensions of affective disturbance.Trial registrationThis trial is registered at (v NCT01831362); www.clinicaltrials.gov.

BackgroundDeprivation can perpetuate across generations; however, the causative pathways are not well understood. Directed acyclic graphs (DAG) with mediation analysis can help elucidate and quantify complex pathways in order to identify modifiable factors at which to target interventions.Methods and findingsWe linked ten Scotland-wide databases (six health and four education) to produce a cohort of 217,226 pupils who attended Scottish schools between 2009 and 2013. The DAG comprised 23 potential mediators of the association between area deprivation at birth and subsequent offspring 'not in education, employment or training' status, covering maternal, antenatal, perinatal and child health, school engagement, and educational factors. Analyses were performed using modified g-computation. Deprivation at birth was associated with a 7.3% increase in offspring 'not in education, employment or training'. The principal mediators of this association were smoking during pregnancy (natural indirect effect of 0·016, 95% CI 0·013, 0·019) and school absences (natural indirect effect of 0·021, 95% CI 0·018, 0·024), explaining 22% and 30% of the total effect respectively. The proportion of the association potentially eliminated by addressing these factors was 19% (controlled direct effect when set to non-smoker 0·058; 95% CI 0·053, 0·063) for smoking during pregnancy and 38% (controlled direct effect when set to no absences 0·043; 95% CI 0·037, 0·049) for school absences.ConclusionsCombining a DAG with mediation analysis helped disentangle a complex public health problem and quantified the modifiable factors of maternal smoking and school absence that could be targeted for intervention. This study also demonstrates the general utility of DAGs in understanding complex public health problems.

Gaze-tracking techniques have advanced our understanding of visual attention and decision making during walking and athletic events, but little is known about how vision influences behavior during running over common, natural obstacles. This study tested hypotheses about whether runners regularly collect visual information and pre-plan obstacle clearance (feedforward control), make improvisational adjustments (online control), or some combination of both. In this study, the gaze profiles of 5 male and 5 female runners, fitted with a telemetric gaze-tracking device, were used to identify the frequency of fixations on an obstacle during a run. Overall, participants fixated on the obstacle 2.4 times during the run, with the last fixation occurring on average between 40% and 80% of the run, suggesting runners potentially shifted from a feedforward planning strategy to an online control strategy during the late portions of the running trial. A negative association was observed between runner velocity and average number of fixations. Consistent with previous studies on visual strategies used during walking, our results indicate that visual attentiveness is part of an important feedforward strategy for runners allowing them to safely approach an obstacle. Thus, visual obstacle attention is a key factor in the navigation of complex, natural landscapes while running.

Lignin is the second most abundant carbon polymer on earth and despite having more fuel value than cellulose, it currently is considered a waste byproduct in many industrial lignocellulose applications. Valorization of lignin relies on effective and green methods of de-lignification, with a growing interest in the use of microbes. Here we investigate the physiology and molecular response of the novel facultative anaerobic bacterium, Tolumonas lignolytica BRL6-1, to lignin under anoxic conditions. Physiological and biochemical changes were compared between cells grown anaerobically in either lignin-amended or unamended conditions. In the presence of lignin, BRL6-1 accumulates higher biomass and has a shorter lag phase compared to unamended conditions, and 14% of the proteins determined to be significantly higher in abundance by log2 fold-change of 2 or greater were related to Fe(II) transport in late logarithmic phase. Ferrozine assays of the supernatant confirmed that Fe(III) was bound to lignin and reduced to Fe(II) only in the presence of BRL6-1, suggesting redox activity by the cells. LC-MS/MS analysis of the secretome showed an extra band at 20 kDa in lignin-amended conditions. Protein sequencing of this band identified a protein of unknown function with homology to enzymes in the radical SAM superfamily. Expression of this protein in lignin-amended conditions suggests its role in radical formation. From our findings, we suggest that BRL6-1 is using a protein in the radical SAM superfamily to interact with the Fe(III) bound to lignin and reducing it to Fe(II) for cellular use, increasing BRL6-1 yield under lignin-amended conditions. This interaction potentially generates organic free radicals and causes a radical cascade which could modify and depolymerize lignin. Further research should clarify the extent to which this mechanism is similar to previously described aerobic chelator-mediated Fenton chemistry or radical producing lignolytic enzymes, such as lignin peroxidases, but under anoxic conditions.

Offshore wind farms are a crucial component for the improvement of renewable energy in the United States. The Bureau of Ocean Energy Management (BOEM) designated ~170 km2 of shelf area for wind energy development off the coast of Maryland, USA. In order to understand potential environmental impacts of wind turbine installation on the benthic ecosystem within the designated area, we conducted a study to visually characterize bottom habitats and epibenthic communities in the Mid-Atlantic Outer Continental Shelf blocks of the Maryland wind energy area. Seven 5 km long transects were sampled using a towed camera sled with a downward-facing digital camera that captured images at 5 frames·s-1s. Additional small-mesh beam trawling was also conducted at selected locations complementary for species identification. Image data were analyzed using two image selection methods, random and systematic (i.e. video frames were selected at various intervals). For both methods, estimates of community diversity (Hill's N2) stabilized with sample sizes ranging from 316 to 398 frames. Our results allowed us to define distinct epibenthic communities and bottom habitats that are associated with offshore wind energy sites and to develop a sampling technique for digital images that can be applied to other research programs.

Morphological characterization and multi-locus DNA sequence analysis of fungal isolates obtained from 32 clinical cases of equine fungal keratitis (FK) was performed to identify species and determine associations with antifungal susceptibility, response to therapy and clinical outcome. Two species of Aspergillus (A. flavus and A. fumigatus) and three species of Fusarium (F. falciforme, F. keratoplasticum, and F. proliferatum) were the most common fungi isolated and identified from FK horses. Most (91%) equine FK Fusarium nested within the Fusarium solani species complex (FSSC) with nine genetically diverse strains/lineages, while 83% of equine FK Aspergillus nested within the A. flavus clade with three genetically diverse lineages. Fungal species and evolutionary lineage were not associated with clinical outcome. However, species of equine FK Fusarium were more likely (p = 0.045) to be associated with stromal keratitis. Species of Aspergillus were more susceptible to voriconazole and terbinafine than species of Fusarium, while species of Fusarium were more susceptible to thiabendazole than species of Aspergillus. At the species level, A. fumigatus and A. flavus were more susceptible to voriconazole and terbinafine than F. falciforme. Natamycin susceptibility was higher for F. falciforme and A. fumigatus compared to A. flavus. Furthermore, F. falciforme was more susceptible to thiabendazole than A. flavus and A. fumigatus. These observed associations of antifungal sensitivity to natamycin, terbinafine, and thiabendazole demonstrate the importance of fungal identification to the species rather than genus level. The results of this study suggest that treatment of equine FK with antifungal agents requires accurate fungal species identification.

Gallbladder mucocele formation is an emerging disease in dogs characterized by increased secretion of condensed granules of gel-forming mucin by the gallbladder epithelium and formation of an abnormally thick mucus that can culminate in obstruction of the bile duct or rupture of the gallbladder. The disease is associated with a high morbidity and mortality and its pathogenesis is unknown. Affected dogs have a significantly increased likelihood of concurrent diagnosis of hyperadrenocorticism, hypothyroidism, and hyperlipidemia. Whether these endocrinopathies represent coincidental primary disease processes that exacerbate gallbladder mucocele formation in predisposed dogs or reflect a concurrent disruption of endocrine and lipid metabolism is unclear. In this study, we investigated a hypothesis that dogs with gallbladder mucocele formation would have a high prevalence of occult and atypical abnormalities in adrenal cortical and thyroid gland function that would suggest the presence of endocrine disruption and provide deeper insight into disease pathogenesis. We performed a case-control study of dogs with and without ultrasonographic diagnosis of gallbladder mucocele formation and profiled adrenal cortical function using a quantitative mass spectrometry-based assay of serum adrenal-origin steroids before and after administration of synthetic cosyntropin. We simultaneously profiled serum thyroid hormone concentrations and evaluated iodine sufficiency by measurement of urine iodine:creatinine ratios (UICR). The studies were complemented by histological examination of archival thyroid tissue and measurements of thyroid gland organic iodine from dogs with gallbladder mucocele formation and control dogs. Dogs with gallbladder mucocele formation demonstrated an exaggerated cortisol response to adrenal stimulation with cosyntropin. A prevalence of 10% of dogs with gallbladder mucocele formation met laboratory-based criteria for suspect or definitive diagnosis of hyperadrenocorticism. A significantly greater number of dogs with gallbladder mucocele formation had basal serum dehydroepiandrosterone (DHEAS) increases compared to control dogs. A high percentage of dogs with gallbladder mucocele formation (26%) met laboratory-based criteria for diagnosis of hypothyroidism, but lacked detection of anti-thyroglobulin antibodies. Dogs with gallbladder mucocele formation had significantly higher UICRs than control dogs. Examination of thyroid tissue from an unrelated group of dogs with gallbladder mucocele formation did not demonstrate histological evidence of thyroiditis or significant differences in content of organic iodine. These findings suggest that dogs with gallbladder mucocele formation have a greater capacity for cortisol synthesis and pinpoint DHEAS elevations as a potential clue to the underlying pathogenesis of the disease. A high prevalence of thyroid dysfunction with absent evidence for autoimmune thyroiditis suggest a disrupted thyroid hormone metabolism in dogs with gallbladder mucocele formation although an influence of non-thyroidal illness cannot be excluded. High UICR in dogs with gallbladder mucocele formation is of undetermined significance, but of interest for further study.

A common feature of preclinical animal experiments is repeated measurement of the outcome, e.g., body weight measured in mice pups weekly for 20 weeks. Separate time point analysis or repeated measures analysis approaches can be used to analyze such data. Each approach requires assumptions about the underlying data and violations of these assumptions have implications for estimation of precision, and type I and type II error rates. Given the ethical responsibilities to maximize valid results obtained from animals used in research, our objective was to evaluate approaches to reporting repeated measures design used by investigators and to assess how assumptions about variation in the outcome over time impact type I and II error rates and precision of estimates. We assessed the reporting of repeated measures designs of 58 studies in preclinical animal experiments. We used simulation modelling to evaluate three approaches to statistical analysis of repeated measurement data. In particular, we assessed the impact of (a) repeated measure analysis assuming that the outcome had non-constant variation at all time points (heterogeneous variance) (b) repeated measure analysis assuming constant variation in the outcome (homogeneous variance), (c) separate ANOVA at individual time point in repeated measures designs. The evaluation of the three model fitting was based on comparing the p-values distributions, the type I and type II error rates and by implication, the shrinkage or inflation of standard error estimates from 1000 simulated dataset. Of 58 studies with repeated measures design, three provided a rationale for repeated measurement and 23 studies reported using a repeated-measures analysis approach. Of the 35 studies that did not use repeated-measures analysis, fourteen studies used only two time points to calculate weight change which potentially means collected data was not fully utilized. Other studies reported only select time points (n = 12) raising the issue of selective reporting. Simulation studies showed that an incorrect assumption about the variance structure resulted in modified error rates and precision estimates. The reporting of the validity of assumptions for repeated measurement data is very poor. The homogeneous variation assumption, which is often invalid for body weight measurements, should be confirmed prior to conducting the repeated-measures analysis using homogeneous covariance structure and adjusting the analysis using corrections or model specifications if this is not met.

Bees and the pollination services they deliver are beneficial to both food crop production, and for reproduction of many wild plant species. Bee decline has stimulated widespread interest in assessing hazards and risks to bees from the environment in which they live. While there is increasing knowledge on how the use of broad-spectrum insecticides in agricultural systems may impact bees, little is known about effects of other pesticides (or plant protection products; PPPs) such as herbicides and fungicides, which are used more widely than insecticides at a global scale. We adopted a systematic approach to review existing research on the potential impacts of fungicides and herbicides on bees, with the aim of identifying research approaches and determining knowledge gaps. While acknowledging that herbicide use can affect forage availability for bees, this review focussed on the potential impacts these compounds could have directly on bees themselves. We found that most studies have been carried out in Europe and the USA, and investigated effects on honeybees. Furthermore, certain effects, such as those on mortality, are well represented in the literature in comparison to others, such as sub-lethal effects. More studies have been carried out in the lab than in the field, and the impacts of oral exposure to herbicides and fungicides have been investigated more frequently than contact exposure. We suggest a number of areas for further research to improve the knowledge base on potential effects. This will allow better assessment of risks to bees from herbicides and fungicides, which is important to inform future management decisions around the sustainable use of PPPs.

High levels of undiagnosed and untreated HCV infection exist in prison populations globally. Prisons are a key location to identify, treat and prevent HCV infection among people who inject drugs (PWID). Understanding prisoners' lived experiences of the HCV continuum of care informs how HCV care can be effectively delivered to this marginalised and high-risk population. This study aimed to explore Irish prisoners' experience of prison and community-based HCV care. We conducted one-to-one interviews with 25 male prisoners with chronic HCV infection. Data collection and analysis was informed by grounded theory. The mean age of participants and first incarceration was 39.5 and 18.3 years respectively. The mean number of incarcerations was eight. The following themes were identified: medical and social factors influencing engagement (fear of treatment and lack of knowledge, HCV relevance and competing priorities), adverse impact of HCV on health and wellness, positive experience of prison life and health care and the transformative clinical and non-clinical changes associated with HCV treatment and cure. Findings suggest that prison release was associated with multiple stressors including homelessness and drug dependence which quickly eroded the health benefits gained during incarceration. The study generated a substantive theory of the need to increase the importance of HCV care among the routine competing priorities associated with the lives of PWID. HCV infected prisoners often lead complex lives and understanding their journeys through the HCV continuum can inform the development of meaningful HCV care pathways. Many challenges exist to optimising HCV treatment uptake in this group and incarceration is an opportunity to successfully engage HCV infected prisoners who underutilise and are underserved by community-based medical services. Support and linkage to care on release is essential to optimising HCV management.

BACKGROUND:Rhythmic Auditory Stimulation (RAS) is an effective technique to improve gait and reduce freezing episodes for Persons with Parkinson's Disease (PwPD). The BeatHealth system, which comprises a mobile application, gait sensors, and a website, exploits the potential of the RAS technique. This paper describes the tools used for co-designing and evaluating the system and discusses the results and conclusions. METHODS:Personas, interviews, use cases, and ethnographic observations were used to define the functional requirements of the system. Low fidelity prototypes were created for iterative and incremental evaluation with end-users. Field trials were also performed with the final system. The process followed a user centered design methodology defined for this project with the aim of building a useful, usable, and easy-to-use system. RESULTS:Functional requirements of the system were produced as a result of the initial exploration phase. Building upon these, mock-ups for the BeatHealth system were created. The mobile application was iterated twice, with the second version of it achieving a rating of 75 when assessed by participants through the System Usability Scale (SUS). After another iteration field trials were performed and the mobile application was rated with an average 78.6 using SUS. Participants rated two website mock-ups, one for health professionals and another for end-users, as good except from minor issues related to visual design (e.g. font size), which were resolved in the final version. CONCLUSION:The high ratings obtained in the evaluation of the BeatHealth system demonstrate the benefit of applying a user centered design methodology which involves stakeholders from the very beginning. Other important lessons were learned through the process of design and development of the system, such as the importance of motivational aspects, the techniques which work best, and the extra care that has to be taken when evaluating non-functional mock-ups with end users.

Mucocele formation is characterized by secretion of abnormally thick mucus by the gallbladder epithelium of dogs that may cause obstruction of the bile duct or rupture of the gallbladder. The disease is increasingly recognized and is associated with a high morbidity and mortality. The cause of gallbladder mucocele formation in dogs is unknown. There is a strong breed predisposition and affected dogs have a high incidence of concurrent endocrinopathy or hyperlipidemia. These observations suggest a significant influence of both genetic and metabolic factors on disease pathogenesis. In this study, we investigated a theory that mucocele formation is associated with a syndrome of metabolic disruption. We surmised that a global, untargeted metabolomics approach could provide unique insight into the systemic pathogenesis of gallbladder mucocele formation and identify specific compounds as candidate biomarkers or treatment targets. Moreover, concurrent examination of the serum and hepatic duct bile metabolome would enable the construction of mechanism-based theories or identification of specific compounds responsible for altered function of the gallbladder epithelium. Abnormalities observed in dogs with gallbladder mucocele formation, including a 33-fold decrease in serum adenosine 5'-monophosphate (AMP), lower quantities of precursors required for synthesis of energy transporting nucleotides, and increases in citric acid cycle intermediates, suggest excess metabolic energy and a carbon surplus. Altered quantities of compounds involved in protein translation and RNA turnover, together with accumulation of gamma-glutamylated and N-acetylated amino acids in serum suggest abnormal regulation of protein and amino acid metabolism. Increases in lathosterol and 7α-hydroxycholesterol suggest a primary increase in cholesterol synthesis and diversion to bile acid formation. A number of specific biomarker compounds were identified for their ability to distinguish between control dogs and those that formed a gallbladder mucocele. Particularly noteworthy was a significant decrease in quantity of biologically active compounds that stimulate biliary ductal fluid secretion including adenosine, cAMP, taurolithocholic acid, and taurocholic acid. These findings support the presence of significant metabolic disruption in dogs with mucocele formation. A targeted, quantitative analysis of the identified serum biomarkers is warranted to determine their utility for diagnosis of this disease. Finally, repletion of compounds whose biological activity normally promotes biliary ductal secretion should be examined for any therapeutic impact for resolution or prevention of mucocele formation.

Systematic reviews are increasingly using data from preclinical animal experiments in evidence networks. Further, there are ever-increasing efforts to automate aspects of the systematic review process. When assessing systematic bias and unit-of-analysis errors in preclinical experiments, it is critical to understand the study design elements employed by investigators. Such information can also inform prioritization of automation efforts that allow the identification of the most common issues. The aim of this study was to identify the design elements used by investigators in preclinical research in order to inform unique aspects of assessment of bias and error in preclinical research. Using 100 preclinical experiments each related to brain trauma and toxicology, we assessed design elements described by the investigators. We evaluated Methods and Materials sections of reports for descriptions of the following design elements: 1) use of comparison group, 2) unit of allocation of the interventions to study units, 3) arrangement of factors, 4) method of factor allocation to study units, 5) concealment of the factors during allocation and outcome assessment, 6) independence of study units, and 7) nature of factors. Many investigators reported using design elements that suggested the potential for unit-of-analysis errors, i.e., descriptions of repeated measurements of the outcome (94/200) and descriptions of potential for pseudo-replication (99/200). Use of complex factor arrangements was common, with 112 experiments using some form of factorial design (complete, incomplete or split-plot-like). In the toxicology dataset, 20 of the 100 experiments appeared to use a split-plot-like design, although no investigators used this term. The common use of repeated measures and factorial designs means understanding bias and error in preclinical experimental design might require greater expertise than simple parallel designs. Similarly, use of complex factor arrangements creates novel challenges for accurate automation of data extraction and bias and error assessment in preclinical experiments.

Intracranial electrodes are a vital component of implantable neurodevices, both for acute diagnostics and chronic treatment with open and closed-loop neuromodulation. Their performance is hampered by acute implantation trauma and chronic inflammation in response to implanted materials and mechanical mismatch between stiff synthetic electrodes and pulsating, natural soft host neural tissue. Flexible electronics based on thin polymer films patterned with microscale conductive features can help alleviate the mechanically induced trauma; however, this strategy alone does not mitigate inflammation at the device-tissue interface. In this study, we propose a biomimetic approach that integrates microscale extracellular matrix (ECM) coatings on microfabricated flexible subdural microelectrodes. Taking advantage of a high-throughput process employing micro-transfer molding and excimer laser micromachining, we fabricate multi-channel subdural microelectrodes primarily composed of ECM protein material and demonstrate that the electrochemical and mechanical properties match those of standard, uncoated controls. In vivo ECoG recordings in rodent brain confirm that the ECM microelectrode coatings and the protein interface do not alter signal fidelity. Astrogliotic, foreign body reaction to ECM coated devices is reduced, compared to uncoated controls, at 7 and 30 days, after subdural implantation in rat somatosensory cortex. We propose microfabricated, flexible, biomimetic electrodes as a new strategy to reduce inflammation at the device-tissue interface and improve the long-term stability of implantable subdural electrodes.