The UK Biobank resource with deep phenotyping and genomic data.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

Contemporary Concise Review 2022: Sleep.

COVID-19 AND SLEEP: The COVID-19 pandemic is associated with an increase in insomnia and impaired sleep quality Health care workers are particularly susceptible and improved with cognitive behavioural therapy for insomnia (CBT-I) Long COVID has significant effects on sleep OSA impacts on the severity of acute COVID-19 illness OBSTRUCTIVE SLEEP APNOEA: Large trials of clinically representative patients confirm the cardiovascular benefits of CPAP treatment in OSA CPAP may improve long-term cognitive outcomes in OSA, but further research is needed Racial disparities in OSA prevalence and mortality risk are becoming evident Periodic evaluation of OSA risk in pregnancy is important as timing may be key for intervention to prevent or treat cardiovascular risk factors INSOMNIA: Comorbid insomnia and obstructive sleep apnoea (COMISA) can frequently co-exist and the combined negative effects of both may be deleterious, particularly to cardiovascular health There is evidence for effectiveness with novel orexin receptor antagonists.

Barriers to sleep in acute hospital settings.

OBJECTIVE: This study aimed to examine the environmental and operational factors that disrupt sleep in the acute, non-ICU hospital setting. DESIGN, SETTING AND PARTICIPANTS: This was a prospective study of adult patients admitted to an acute tertiary hospital ward (shared versus single room) and sleep laboratory (single room conducive to sleep). MAIN OUTCOME MEASURES: This study measured ambient light (lux) and sound (dB), number of operational interruptions, and questionnaires assessing sleep and mental health. RESULTS: Sixty patients were enrolled, 20 in a double bedroom located close to the nursing station ('shared ward'), 20 in a single bedroom located distant to the nursing station ('single ward') and 20 attending the sleep laboratory for overnight polysomnography ('sleep laboratory'). Sleep was disturbed in 45% of patients in the shared and single ward groups (Pittsburgh Sleep Quality Index > 5). Light levels were appropriately low across all 3 locations. Sound levels (significant effect of room F(1.38) = 6.452, p = 0.015) and operational interruptions (shared ward 5.6 ± 2.5, single ward 6.2 ± 2.9, sleep laboratory 2.7 ± 2.1 per night, p < 0.05 wards compared to sleep laboratory) were higher in the shared and single ward group compared to the sleep laboratory but not compared to each other. Noise was rated as the greatest environmental disturbance by 70% of ward patients compared to 10% in the sleep laboratory. CONCLUSION: Higher noise levels and frequent operational interruptions are potential barriers to sleep and recovery on an acute medical ward which are not ameliorated by being in a single bedroom located distant to the nursing station.

Engineering the Low Coordinated Pt Single Atom to Achieve the Superior Electrocatalytic Performance toward Oxygen Reduction.

Configuring metal single-atom catalysts (SACs) with high electrocatalytic activity and stability is one efficient strategy in achieving the cost-competitive catalyst for fuel cells' applications. Herein, the atomic layer deposition (ALD) strategy for synthesis of Pt SACs on the metal-organic framework (MOF)-derived N-doped carbon (NC) is proposed. Through adjusting the ALD exposure time of the Pt precursor, the size-controlled Pt catalysts, from Pt single atoms to subclusters and nanoparticles, are prepared on MOF-NC support. X-ray absorption fine structure spectra determine the increased electron vacancy in Pt SACs and indicate the Pt-N coordination in the as-prepared Pt SACs. Benefiting from the low-coordination environment and anchoring interaction between Pt atoms and nitrogen-doping sites from MOF-NC support, the Pt SACs deliver an enhanced activity and stability with 6.5 times higher mass activity than that of Pt nanoparticle catalysts in boosting the oxygen reduction reaction (ORR). Density functional theory calculations indicate that Pt single atoms prefer to be anchored by the pyridinic N-doped carbon sites. Importantly, it is revealed that the electronic structure of Pt SAs can be adjusted by adsorption of hydroxyl and oxygen, which greatly lowers free energy change for the rate-determining step and enhances the activity of Pt SACs toward the ORR.

Bovine viral diarrhea virus compromises Neutrophil's functions in strain dependent manner.

Bovine viral diarrhea virus (BVDV) infection is a major problem that results in economically important diseases of the cattle industry worldwide. The two major consequences of this disease are persistent infection and immune dysfunction. A number of studies have been done to determine the underline mechanisms of BVDV-induced immune dysfunction, in particular targeting antigen-presenting cells, T- and B- cells and cytokine gene expression. However, little research has focused Eon the effect of BVDV on neutrophils. Neutrophils are one of the predominant leukocytes circulating in blood and are considered the first line of defense in the innate immune system along with macrophages. Neutrophils not only eliminate the invading bacteria but also activate innate as well as adaptive immune responses. Therefore, compromised neutrophil function would affect both arms of immune system and caused immune suppression. In the current study, we used virus strains from both BVDV-1 and BVDV-2 species. Including a highly virulent non-cytopathic type 2a BVDV (ncp BVDV2a-1373), moderately virulent non-cytopathic type 2a (ncp BVDV2a 28508-5), and a pair of non-cytopathic type 1b BVDV (ncp BVDV1b TGAN) and cytopathic type 1b BVDV (cp BVDV1b TGAC) strain isolated from a case of mucosal disease. The highly virulent ncp BVDV2a-1373 significantly increased neutrophil apoptosis. However, none of the other BVDV strains affected neutrophil viability. All BVDV strains used significantly reduced CD18 and L-selectin expression on neutrophils as well as their oxidative burst and neutrophil extracellular traps (NET) activity. Cp BVDV significantly reduced neutrophil's phagocytic activity but ncp BVDV did not have any effect on it. On the other hand, ncp BVDV significantly increased neutrophil's CD14 expression and chemotactic activity while cp BVDV did not show any effect either on neutrophil's CD14 expression or on chemotactic activity. In conclusion, BVDV affected neutrophils variability and functional activity in strain dependent manner. Results of the current study will further help in understanding the pathophysiology of different BVDV strains.

Clinician and patient barriers to the recognition of insomnia in family practice: a narrative summary of reported literature analysed using the theoretical domains framework.

BACKGROUND: Insomnia is a common sleep complaint, with 10% of adults in the general population experiencing insomnia disorder, defined as lasting longer than three months in DSM-5. Up to 50% of patients attending family practice experience insomnia, however despite this, symptoms of insomnia are not often screened for, or discussed within this setting. We aimed to examine barriers to the assessment and diagnosis of insomnia in family practice from both the clinician and patient perspective. METHODS: The present article identified research that has examined barriers to assessing insomnia from the clinician's and the client's perspectives following MEDLINE and Google Scholar searches, and then classified these barriers using the theoretical domains framework. RESULTS: The most common barriers from the clinician's perspective were related to Knowledge, Skills, and the Environmental Context. From the patient perspective, barriers identified included their Beliefs about the consequences of Insomnia, Social Influences, and Behavioural Regulation of Symptoms. CONCLUSIONS: Utilising this theoretical framework, we discuss options for bridging the gap between the identification and subsequent management of insomnia within the family practice setting. To assist clinicians and those in community health care to overcome the Knowledge and Skills barriers identified, this article provides existing relevant clinical criteria that can be utilised to make a valid diagnosis of insomnia.

The 2016 Melbourne thunderstorm asthma epidemic: Risk factors for severe attacks requiring hospital admission.

BACKGROUND: The world's most catastrophic and deadly thunderstorm asthma epidemic struck Melbourne, Australia, on November 21, 2016. OBJECTIVE: Among thunderstorm-affected patients presenting to emergency rooms (ERs), we investigated risk factors predicting severe attacks requiring admission to hospital. METHODS: Thunderstorm-affected patients were identified from ER records at the eight major Melbourne health services and interviewed by telephone. Risk factors for hospital admission were analyzed. RESULTS: We interviewed 1435/2248 (64%) of thunderstorm-affected patients, of whom 164 (11.4%) required hospital admission. Overall, rhinitis was present in 87%, and current asthma was present in 28%. Odds for hospital admission were higher with increasing age (odds ratio 1.010, 95% CI 1.002, 1.019) and among individuals with current asthma (adjusted odds ratio [aOR] 1.87, 95% CI 1.26, 2.78). Prior hospitalization for asthma in the previous 12 months further increased the odds for hospital admission (aOR 3.16, 95% CI 1.63, 6.12). Among patients of Asian ethnicity, the odds for hospital admission were lower than for non-Asian patients (aOR 0.59, 95% CI 0.38, 0.94), but higher if born in Australia (OR = 5.42, 95% CI 1.56, 18.83). CONCLUSIONS: In epidemic thunderstorm asthma patients who presented to the ER, higher odds for hospital admission among patients with known asthma were further amplified by recent asthma admission, highlighting the vulnerability conferred by suboptimal disease control. Odds for hospital admission were lower in Asian patients born overseas, but higher in Asian patients born locally, than in non-Asian patients; these observations suggest susceptibility to severe thunderstorm asthma may be enhanced by gene-environment interactions.

Assessing the impact of diet, exercise and the combination of the two as a treatment for OSA: A systematic review and meta-analysis.

This study aimed to provide an updated systematic review and meta-analysis of randomized controlled trials (RCT) investigating the effectiveness of lifestyle interventions on weight loss and the impact on the severity of obstructive sleep apnoea (OSA). A systematic search of five databases between 1980 and May 2018 was used to identify all RCT which employed a lifestyle intervention (i.e. diet-only, exercise-only or combination of the two) aiming to reduce the severity of OSA (assessed using the apnoea-hypopnoea index (AHI)). Random-effects meta-analyses followed by meta-regression were conducted. Ten RCT involving 702 participants (Intervention group: n = 354; Control group: n = 348) were assessed in two meta-analyses. The weighted mean difference in AHI (-8.09 events/h, 95% CI: -11.94 to -4.25) and body mass index (BMI, -2.41 kg/m2 , 95% CI: -4.09 to -0.73) both significantly favoured lifestyle interventions over control arms. Subgroup analyses demonstrated that all interventions were associated with reductions in the AHI, but only the diet-only interventions were associated with a significant reduction in BMI. No association was found between the reduction in AHI or BMI and the length of the intervention, or with baseline AHI and BMI levels. All lifestyle interventions investigated appear effective for improving OSA severity and should be an essential component of treatment for OSA. Future research should be directed towards identifying subgroups likely to reap greater treatment benefits as well as other therapeutic benefits provided by these interventions.

A magnetic resonance and electrochemical study of the role of polymer mobility in supporting hydrogen transport in perfluorosulfonic acid membranes.

Perfluorosulfonic acid (PFSA) materials have been used in polymer electrolyte membrane fuel cells (PEMFCs) as electrolyte materials due to their mechanical durability and high proton conductivity. To understand the fundamental chemistry at a molecular level in material performance properties, we have developed and validated method for evaluating local dynamics using 19F double-quantum solid-state nuclear magnetic resonance (ssNMR) spectroscopy. The local dynamics information can be separated and analyzed in terms of fluorine interactions with respect to the different temperatures and hydration levels. The polymer side chain is proven to be more locally mobile which is reflected by the lower apparent dipolar coupling constant (Dapp) compared to the backbone. This observation agrees with the micro-phase separation morphology evolution. In the current study, different types of PFSA materials were explored and compared. The dynamics investigation of the PFSA materials has been conducted at various conditions. In operando membrane performance analyses were performed in parallel at Ballard Power Systems. PFSA membranes were prepared into membrane electrode assemblies (MEAs), with catalyst layers and gas diffusion layers. From the cyclic voltammetry measurements, the H2 crossover values were extracted. These data reveal a strong correlation between the proton conductivity and the site-specific PFSA side chain local dynamics. Moreover, a correlation was drawn between increasing side chain mobility (lower Dapp), and increased H2 permeability. The link between the fundamental dynamics study and this key PFSA performance analysis provides insight into proton transport mechanisms.

Models of care for non-invasive ventilation in the Acute COPD Comparison of three Tertiary hospitals (ACT3) study.

BACKGROUND AND OBJECTIVE: Non-invasive ventilation (NIV) improves clinical outcomes in hypercapnic acute exacerbations of COPD (AECOPD), but the optimal model of care remains unknown. METHODS: We conducted a prospective observational non-inferiority study comparing three models of NIV care: general ward (Ward) (1:4 nurse to patient ratio, thrice weekly consultant ward round), a high dependency unit (HDU) (1:2 ratio, twice daily ward round) and an intensive care unit (ICU) (1:1 ratio, twice daily ward round) model in three similar teaching tertiary hospitals. Changes in arterial blood gases (ABG) and clinical outcomes were compared and corrected for differences in AECOPD severity (Blood urea > 9 mmol/L, Altered mental status (Glasgow coma scale (GCS) < 14), Pulse > 109 bpm, age > 65 (BAP-65)) and co-morbidities. An economic analysis was also undertaken. RESULTS: There was no significant difference in age (70 ± 10 years), forced expiratory volume in 1 s (FEV1 ) (0.84 ± 0.35 L), initial pH (7.29 ± 0.08), partial pressure of CO2 in arterial blood (PaCO2 ) (72 ± 22 mm Hg) or BAP-65 scores (2.9 ± 1.01) across the three models. The Ward achieved an increase in pH (0.12 ± 0.07) and a decrease in PaCO2 (12 ± 18 mm Hg) that was equivalent to HDU and ICU. However, the Ward treated more patients (38 vs 28 vs 15, P < 0.001), for a longer duration in the first 24 h (12.3 ± 4.8 vs 7.9 ± 4.1 vs 8.4 ± 5.3 h, P < 0.05) and was more cost-effective per treatment day ($AUD 1231 ± 382 vs 1745 ± 2673 vs 2386 ± 1120, P < 0.05) than HDU and ICU. ICU had a longer hospital stay (9 ± 11 vs 7 ± 7 vs 13 ± 28 days, P < 0.002) compared with the Ward and HDU. There was no significant difference in intubation rate or survival. CONCLUSION: In acute hypercapnic Chronic obstructive pulmonary disease (COPD) patients, the Ward model of NIV care achieved equivalent clinical outcomes, whilst being more cost-effective than HDU or ICU models.

Effect of Obstructive Sleep Apnea Treatment on Renal Function in Patients with Cardiovascular Disease.

RATIONALE: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes. OBJECTIVES: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease. METHODS: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit. MEASUREMENTS AND MAIN RESULTS: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m2), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m2/yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings. CONCLUSIONS: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT00738179).

Low accuracy and confidence in chest radiograph interpretation amongst junior doctors and medical students.

Accurate chest X-ray (CXR) interpretation is an essential skill in clinical practice. Previous studies have shown poor accuracy and confidence rates (CR) of CXR interpretation by junior doctors and medical students. We presented 10 chest radiographs via an online questionnaire to Australian medical students and junior doctors, who were asked to identify the radiographic abnormality from a list of 15 options and to rate their confidence for each answer. Of 67 complete responses, junior doctors achieved a mean score of 57.6% and medical students 56.1%, with CR of 67 versus 58% respectively. There was a significant positive relationship between accuracy and CR among junior doctors (Pearson's coefficient + 0.798, P = 0.006) and students (Pearson's coefficient + 0.716, P = 0.020). This study identified similarities in strength and weakness in CXR interpretation between medical students and junior doctors. There was a positive association between test scores and self-rated confidence scores.

Electronic health records and online medical records: an asset or a liability under current conditions?

Objective The aim of the present study was to audit the current use of medical records to determine completeness and concordance with other sources of medical information. Methods Medical records for 40 patients from each of five Melbourne major metropolitan hospitals were randomly selected (n=200). A quantitative audit was performed for detailed patient information and medical record keeping, as well as data collection, storage and utilisation. Using each hospital's current online clinical database, scanned files and paperwork available for each patient audited, the reviewers sourced as much relevant information as possible within a 30-min time allocation from both the record and the discharge summary. Results Of all medical records audited, 82% contained medical and surgical history, allergy information and patient demographics. All audited discharge summaries lacked at least one of the following: demographics, medication allergies, medical and surgical history, medications and adverse drug event information. Only 49% of records audited showed evidence the discharge summary was sent outside the institution. Conclusions The quality of medical data captured and information management is variable across hospitals. It is recommended that medical history documentation guidelines and standardised discharge summaries be implemented in Australian healthcare services. What is known about this topic? Australia has a complex health system, the government has approved funding to develop a universal online electronic medical record system and is currently trialling this in an opt-out style in the Napean Blue Mountains (NSW) and in Northern Queensland. The system was originally named the personally controlled electronic health record but has since been changed to MyHealth Record (2016). In Victoria, there exists a wide range of electronic health records used to varying degrees, with some hospitals still relying on paper-based records and many using scanned medical records. This causes inefficiencies in the recall of patient information and can potentially lead to incidences of adverse drug events. What does this paper add? This paper supports the concept of a shared medical record system using 200 audited patient records across five Victorian metropolitan hospitals, comparing the current information systems in place for healthcare practitioners to retrieve data. This research identifies the degree of concordance between these sources of information and in doing so, areas for improvement. What are the implications for practitioners? Implications of this research are the improvements in the quality, storage and accessibility of medical data in Australian healthcare systems. This is a relevant issue in the current Australian environment where no guidelines exist across the board in medical history documentation or in the distribution of discharge summaries to other healthcare providers (general practitioners, etc).

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.

BACKGROUND AND PURPOSE: The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. RESULTS: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. CONCLUSIONS: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.

The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.

Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.

Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.

The effect of bovine viral diarrhea virus (BVDV) strains on bovine monocyte-derived dendritic cells (Mo-DC) phenotype and capacity to produce BVDV.

BACKGROUND: Dendritic cells (DC) are important antigen presentation cells that monitor, process, and present antigen to T cells. Viruses that infect DC can have a devastating impact on the immune system. In this study, the ability of bovine viral diarrhea virus (BVDV) to replicate and produce infectious virus in monocyte-derived dendritic cells (Mo-DC) and monocytes was studied. The study also examined the effect of BVDV infection on Mo-DC expression of cell surface markers, including MHCI, MHCII, and CD86, which are critical for DC function in immune response. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from bovine blood through gradient centrifugation. The adherent monocytes were isolated from PBMCs and differentiated into Mo-DC using bovine recombinant interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GMCSF). To determine the effect of BVDV on Mo-DC, four strains of BVDV were used including the severe acute non-cytopathic (ncp) BVDV2a-1373; moderate acute ncp BVDV2a 28508-5; and a homologous virus pair [i.e., cytopathic (cp) BVDV1b TGAC and ncp BVDV1b TGAN]. The Cooper strain of bovine herpesvirus 1 (BHV1) was used as the control virus. Mo-DC were infected with one of the BVDV strains or BHV-1 and were subsequently examined for virus replication, virus production, and the effect on MHCI, MHCII, and CD86 expression. RESULTS: The ability of monocytes to produce infectious virus reduced as monocytes differentiated to Mo-DC, and was completely lost at 120 hours of maturation. Interestingly, viral RNA increased throughout the course of infection in Mo-DC, and the viral non-structural (NS5A) and envelope (E2) proteins were expressed. The ncp strains of BVDV down-regulated while cp strain up-regulated the expression of the MHCI, MHCII, and CD86 on Mo-DC. CONCLUSIONS: The study revealed that the ability of Mo-DC to produce infectious virus was reduced with its differentiation from monocytes to Mo-DC. The inability to produce infectious virus may be due to a hindrance of virus packaging or release mechanisms. Additionally, the study demonstrated that ncp BVDV down-regulated and cp BVDV up-regulated the expression of Mo-DC cell surface markers MHCI, MHCII, and CD86, which are important in the mounting of immune responses.

Role of phosphatidylinositol 3-kinase (PI3K) and Akt1 kinase in porcine reproductive and respiratory syndrome virus (PRRSV) replication.

We have previously reported that inhibition of phosphatidylinositol 3-kinase (PI3K) reduces porcine reproductive and respiratory syndrome (PRRSV) replication. Here, we further investigate the mechanism by which PI3K inhibition affects virus replication and the role of Akt1 kinase in virus replication. We found that PI3K inhibition reduced viral gene transcription by approximately 1.5-fold. Accordingly, viral protein synthesis was significantly reduced by PI3K inhibition. Interestingly, cells overexpressing the dominant negative mutant Akt1 exhibited a significant reduction in viral gene transcription compared to cells overexpressing the constitutively active Akt1. Viral protein synthesis was also enhanced in cells overexpressing the constitutively active Akt1. Overall, our data show that both PI3K and Akt1 play a role in viral gene expression, leading to an increase in virus replication.

The skin, a novel niche for recirculating B cells.

B cells infiltrate the skin in many chronic inflammatory diseases caused by autoimmunity or infection. Despite potential contribution to disease, skin-associated B cells remain poorly characterized. Using an ovine model of granulomatous skin inflammation, we demonstrate that B cells increase in the skin and skin-draining afferent lymph during inflammation. Surprisingly, skin B cells are a heterogeneous population that is distinct from lymph node B cells, with more large lymphocytes as well as B-1-like B cells that coexpress high levels of IgM and CD11b. Skin B cells have increased MHC class II, CD1, and CD80/86 expression compared with lymph node B cells, suggesting that they are well-suited for T cell activation at the site of inflammation. Furthermore, we show that skin accumulation of B cells and Ab-secreting cells during inflammation increases local Ab titers, which could augment host defense and autoimmunity. Although skin B cells express typical skin-homing receptors, such as E-selectin ligand and α-4 and ß-1 integrins, they are unresponsive to ligands for chemokine receptors associated with T cell homing into skin. Instead, skin B cells migrate toward the cutaneously expressed CCR6 ligand CCL20. Our data support a model in which B cells use CCR6-CCL20 to recirculate through the skin, fulfilling a novel role in skin immunity and inflammation.