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Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules, including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor and vitamin D’s anti-cancer effects, the role of vitamin-D-regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aims to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of eighty-nine human studies identified twenty-five miRNAs found dysregulated in more than one NAFLD study. In contrast, only seventeen studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integration of the data suggests seven vitamin-D-modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.
The paper presents the error characteristics of a vehicle dynamic model (VDM)-based integration architecture for fixed-wing unmanned aerial vehicles. Global navigation satellite system (GNSS) and inertial measurement unit measurements are fused in an extended Kalman filter (EKF) which uses the VDM as the main process model. Control inputs from the autopilot system are used to drive the navigation solution. Using a predefined trajectory with segments of both high and low dynamics and a variable wind profile, Monte Carlo simulations reveal a degrading performance in varying periods of GNSS outage lasting 10 s, 20 s, 30 s, 60 s and 90 s, respectively. These are followed by periods of re-acquisition where the navigation solution recovers. With a GNSS outage lasting less than 60 s, the position error gradually grows to a maximum of 8⋅4 m while attitude errors in roll and pitch remain bounded, as opposed to an inertial navigation system (INS)/GNSS approach in which the navigation solution degrades rapidly. The model-based approach shows improved navigation performance even with parameter uncertainties over a conventional INS/GNSS integration approach.
Background: Hand hygiene (HH) has long been a focus in the prevention of healthcare-associated infections. The limitations of direct observation, including small sample size (often 20–100 observations per month) and the Hawthorne effect, have cast doubt on the accuracy of reported compliance rates. As a result, hospitals are exploring the use of automated HH monitoring systems (AHHMS) to overcome the limitations of direct observation and to provide a more robust and realistic estimation of HH behaviors. Methods: Data analyzed in this study were captured utilizing a group-based AHHMS installed in a number of North American hospitals. Emergency departments, overflow units, and units with <1 year of data were excluded from the study. The final analysis included data from 58 inpatient units in 10 hospitals. Alcohol-based hand rub and soap dispenses HH events (HHEs) and room entries and exits (HH opportunities (HHOs) were used to calculate unit-level compliance rates. Statistical analysis was performed on the annual number of dispenses and opportunities using a mixed effects Poisson regression with random effects for facility, unit, and year, and fixed effects for unit type. Interactions were not included in the model based on interaction plots and significance tests. Poisson assumptions were verified with Pearson residual plots. Results: Over the study period, 222.7 million HHOs and 99 million HHEs were captured in the data set. There were an average of 18.7 beds per unit. The average number of HHOs per unit per day was 3,528, and the average number of HHEs per unit per day was 1,572. The overall median compliance rate was 35.2 (95% CI, 31.5%–39.3%). Unit-to-unit comparisons revealed some significant differences: compliance rates for medical-surgical units were 12.6% higher than for intensive care units (P < .0001). Conclusions: This is the largest HH data set ever reported. The results illustrate the magnitude of HHOs captured (3,528 per unit per day) by an AHHMS compared to that possible through direct observation. It has been previously suggested that direct observation samples between 0.5% to 1.7% of all HHOs. In healthcare, it is unprecedented for a patient safety activity that occurs as frequently as HH to not be accurately monitored and reported, especially with HH compliance as low as it is in this multiyear, multicenter study. Furthermore, hospitals relying on direct observation alone are likely insufficiently allocating and deploying valuable resources for improvement efforts based on the scant information obtained. AHHMSs have the potential to introduce a new era in HH improvement.
Funding: GOJO Industries, Inc., provided support for this study.
Disclosures: Lori D. Moore and James W. Arbogast report salary from GOJO.
Technology and interest for use of automated hand hygiene monitoring systems (AHHMS) as a tool to help improve healthcare personnel hand hygiene has been advancing for the last decade. Emerging evidence indicates that the use of AHHMS plus complementary strategies improves hand hygiene (HH) performance rates and outcomes (eg, healthcare-associated infections). The WHO HH guideline “Multimodal Strategy” teaches the importance of multiple components as necessary to build and sustain HH compliance. Few published data compare the impact of different complementary behavioral strategies in combination with AHHMS on results. Methods: We utilized data from 1 AHHMS that records alcohol-based hand rub and soap dispensing and room entries and exits to provide group HH performance rates. Data were collected from 58 units in 10 hospitals in North America from July 2014 through August 2019. Hospitals were stratified into 4 categories based on their approach to hospital-initiated unit-level interventions and AHHMS vendor support (Table 1). Baseline data were defined for each unit as the initial 1–2 months of execution, before complementary strategies were initiated. Statistical analysis was performed on the annual number of dispenses and opportunities with a mixed-effects Poisson regression with random effects for facility, unit and year and fixed effects for intervention type and unit type. Interactions were not included in the model based on interaction plots and significance tests. Poisson assumptions were verified with Pearson residual plots. Results: HH performance rates overall and compared to the baseline are shown in Table 2. More than 8 million opportunities were achieved in all 58 units combined. An intervention strategy with multiple complementary components (ie, clinical support provided by the AHHMS vendor plus hospital-initiated unit level interventions) yielded significantly better HH performance than all other categories (>20% increase, P < .00001). Somewhat surprisingly, vendor clinical support or hospital-initiated, unit-level interventions alone with the AHHMS yielded a slight decrease in HH performance relative to AHHMS only (P < .00001). Conclusions: AHHMS is a useful tool in understanding HH performance and identifying unit-based initiatives that need attention. Implementation of an AHHMS by itself or with limited complementary behavior-change strategies does not drive improvement. Support provided by the vendor and hospital-initiated, complementary strategies were not sufficient additions to the AHHMS individually, but in combination they resulted in the greatest improvements in HH performance. These findings illustrate the value of a partnership between the hospital and the AHHMS vendor.
Funding: GOJO Industries, Inc., provided support for this study.
Disclosures: James W. Arbogast, Lori D. Moore and Megan DiGiorgio report salary from GOJO Industries.
Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation.
The Nutrition Society's 1st Annual Nutrition and Cancer Networking Conference brought together scientists from the fields of Nutrition, Epidemiology, Public Health, Medical Oncology and Surgery with representatives of the public, cancer survivors and cancer charities. Speakers representing these different groups presented the challenges to collaboration, how the needs of patients and the public can be met, and the most promising routes for future research. The conference programme promoted debate on these issues to highlight current gaps in understanding and barriers to generating and implementing evidence-based nutrition advice. The main conclusions were that the fundamental biology of how nutrition influences the complex cancer risk profiles of diverse populations needs to be better understood. Individual and population level genetics interact with the environment over a lifespan to dictate cancer risk. Large charities and government have a role to play in diminishing our current potently obesogenic environment and exploiting nutrition to reduce cancer deaths. Understanding how best to communicate, advise and support individuals wishing to make dietary and lifestyle changes, can reduce cancer risk, enhance recovery and improve the lives of those living with and beyond cancer.
This study integrated an experimental medicine approach and a randomized cross-over clinical trial design following CONSORT recommendations to evaluate a cognitive training (CT) intervention for attention deficit hyperactivity disorder (ADHD). The experimental medicine approach was adopted because of documented pathophysiological heterogeneity within the diagnosis of ADHD. The cross-over design was adopted to provide the intervention for all participants and make maximum use of data.
Children (n = 93, mean age 7.3 +/− 1.1 years) with or sub-threshold for ADHD were randomly assigned to CT exercises over 15 weeks, before or after 15 weeks of treatment-as-usual (TAU). Fifteen dropped out of the CT/TAU group and 12 out of the TAU/CT group, leaving 66 for cross-over analysis. Seven in the CT/TAU group completed CT before dropping out making 73 available for experimental medicine analyses. Attention, response inhibition, and working memory were assessed before and after CT and TAU.
Children were more likely to improve with CT than TAU (27/66 v. 13/66, McNemar p = 0.02). Consistent with the experimental medicine hypotheses, responders improved on all tests of executive function (p = 0.009–0.01) while non-responders improved on none (p = 0.27–0.81). The degree of clinical improvement was predicted by baseline and change scores in focused attention and working memory (p = 0.008). The response rate was higher in inattentive and combined subtypes than hyperactive-impulsive subtype (p = 0.003).
Targeting cognitive dysfunction decreases clinical symptoms in proportion to improvement in cognition. Inattentive and combined subtypes were more likely to respond, consistent with targeted pathology and clinically relevant heterogeneity within ADHD.
Healthcare personnel who perform invasive procedures and are living with HIV or hepatitis B have been required to self-notify the NC state health department since 1992. State coordinated review of HCP utilizes a panel of experts to evaluate transmission risk and recommend infection prevention measures. We describe how this practice balances HCP privacy and patient safety and health.
Activated hepatic stellate cells (HSCs) are a key contributor to liver fibrosis and drive the progression to advanced disease for many liver conditions, including non-alcoholic fatty liver disease. Previous studies suggest vitamin D may reduce inflammatory and pro-fibrogenic activity of HSCs in vitro. However, the mechanisms underpinning the effects of vitamin D in HSCs are not fully understood. The overall aim of these experiments was to mimic a lipid loading model on immortalised HSCs to test their responses to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). Two different human immortalised cell lines: HepG2, hepatocellular carcinoma cells, and LX-2, hepatic stellate cells; were cultured using standard methods. Cell viability in different treatment vehicles (2% DMSO and/or 0.1% ethanol) under serum free conditions was measured by MTT assay after 6 and 24 h. Cells were cultured with increasing concentrations of fatty acids (0–500μM, 1:1 oleic acid: palmitic acid) or vitamin D. Nile red, a neutral lipophilic fluorescent dye, was used to measure total intracellular lipid and quantified relative to vehicle. CYP24A1 mRNA expression was measured by qPCR in response to 1000nM 1α,25(OH)2D3 treatment in both cell lines for 24 h using TaqMan® gene expression assays and normalised to 18S rRNA. Cell viability in response to vehicle was examined at 6 h and 24 h to determine the optimal experimental time points. Whereas, HepG2 cells remained unaffected at 24 h in response to either or both vehicles combined (n = 4; combined vehicles, P = 0.3187), LX-2 cells showed reduced viability even at 6 h (n = 5; combined vehicles, P = 0.0050). Fatty acid treatment led to intracellular lipid accumulation in both cell lines. In response to 500μM fatty acid treatment, intracellular lipid increased by 1.7-fold in LX-2 cells at 6 h (n = 5, P = 0.00174) and 3.9-fold in HepG2 cells after 24 h (n = 4, P = 0.00184). Notably, CYP24A1 mRNA expression was markedly induced by vitamin D treatment in LX-2 cells (136 ± 7.64-fold, n = 3, P = 0.0010) in comparison to HepG2 cells (22 ± 0.78-fold, n = 3, P < 0.0001). In summary, the cell viability data suggested optimal time points for both fatty acid and vitamin D treatments may be 6 h for LX-2 cells, and 24 h for HepG2 cells. While intracellular lipid accumulation differed between the cell lines in response to fatty acid treatment, both cell lines produced a dose-dependent increase in intracellular lipid. Lastly, CYP24A1 mRNA expression confirmed the responsiveness of both cell types to vitamin D treatment. Ongoing experiments are examining microRNA expression in HSCs in response to both vitamin D and lipid loading.
Beyond safety considerations for other patients and staff in the immediate vicinity, those practising in the field of infectious diseases, microbiology and virology must have proficient knowledge, skills and behaviour relating to the public health considerations of communicable disease control. Practitioners must be able to describe the public health issues relating to communicable diseases and to specific infections (incubation periods, transmission routes, vaccinations available, need for mandatory notification), as well as understand basic epidemiological methods and the functions of health protection and environmental health teams.
The cornerstone of practice for practitioners in infectious diseases, microbiology and virology is the ability to diagnose and manage important clinical syndromes where infection is in the differential diagnosis. Practitioners must hold a detailed knowledge (covering the epidemiology, clinical presentation, relevant investigations and management and prognosis) of both community-acquired and healthcare-associated infections. This knowledge must cover infections in all body compartments and those causing systemic infections (such as blood-borne viruses). This must incorporate patients presenting from the community, and infections which develop among those already undergoing healthcare treatment for other conditions. In this latter group, infections among surgical patients and those colonised and infected with multi-drug-resistant organisms must be able to be managed with confidence. Similarly, common clinical infection syndromes presenting among patients returning from travel abroad must be able to be recognised, investigated appropriately and treated promptly. Practitioners must also be able to manage infections among special populations, including itinerant populations, those who may misuse drugs or alcohol, those at the extremes of age or who are pregnant and immunocompromised individuals. Specific to immunocompromised individuals, this should encompass both those with primary and with secondary immunocompromise.
In a clinical setting, practising infectious diseases medicine must incorporate knowledge, skills and behaviour to prevent onward spread of communicable diseases to other patients and to members of staff. The mode of transmission of communicable diseases must be understood, and practitioners must be able to interrupt their onward transmission. This includes the use of personal protective equipment for clinical interactions; from the types of equipment available, to their indication and the legislation surrounding their use (including Health and Safety at work). This also includes the use of isolation facilities; the indications for side rooms, negative pressure ventilation rooms; and when and how to arrange transfer to high-consequence infectious diseases units.
Patients living with human immunodeficiency virus (HIV) have particular health needs relating to their diagnosis, the opportunistic infections which can affect them, and the chronic disease management of their condition which is impacted by the disease process itself and the medication used to control it. Practitioners working with patients living with human immunodeficiency virus must hold knowledge of the pathophysiology and natural history of the disease, the therapeutic options available for virological control and the likely complication from HIV and the medications. Practitioners must be able to safely monitor and interpret the test results of patients living with human immunodeficiency virus. They must also be able to advise on strategies to decrease onwards transmission of HIV, including pre-and post-exposure prophylaxis. Practitioners managing patients living with human immunodeficiency virus must be able to identify and treat the opportunistic infections which may arise.
An essential resource for practitioners in infectious diseases and microbiology, studying for the new FRCPath Part 1 infection examination accredited by the Royal College of Pathologists, and trainees sitting the membership exams of the Royal College of Physicians. Including over 300 multiple choice questions in an exam-style Q&A format, this guide provides an invaluable revision platform for domestic and international trainees alike, with scope to present infection-based support for other medical specialties, where infection forms a core component, including intensive care. Authored by leading specialists in infectious diseases and microbiology, this invaluable training guide is the first of its kind to cover both undergraduate and postgraduate material in infectious diseases. Mapping directly from the FRCPath and RCP infection curricula, students are able to explore areas of curriculum to gain knowledge and optimise decision-making skills, under pressure.
The nature of infectious diseases means that they are not bound by political or social boundaries. Practitioners in infectious diseases, microbiology and virology must, therefore, be competent in the recognition and management of imported infections and be aware of mechanisms to identify prevalent infections in different geographical areas. Practitioners must also be able to recognise problems of non-communicable diseases among immigrants from low- and middle-income settings. Practitioners in infectious diseases must also be competent in giving pre-travel medical advice including vaccination against communicable diseases and prophylaxis (both physical and chemical).
Microbial and host cellular biology and interactions dictate the breadth of clinical infection practice, from colonisation to invasion to infection. Understanding the classifications used for bacteria, viruses, fungi and parasites aids clinical and laboratory diagnosis and ultimately patient management. Understanding the common host responses to infective agents at the cellular level enables appropriate clinical management both with direct acting anti-infectives and other supportive therapy.
A basic understanding of the mechanism of action and indication for antimicrobials is held by most prescribers. The key properties of different classes of antimicrobials, their anticipated side effects and the spectrum of activity against different pathogens is inherent in most undergraduate and post-graduate medical curricula. Practitioners in the fields of infectious diseases, microbiology and virology must have a firm grasp of this knowledge, and should be able to apply it to patients with bacterial, viral, fungal or parasitic infections. They must be able to integrate this knowledge with the pharmacokinetic properties of the antimicrobials, and should be able to adapt this in differing patient populations including those with renal impairment or on renal replacement therapy and those with allergies or other host factors.