Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Mepolizumab in children and adolescents with severe eosinophilic asthma not eligible for omalizumab: a single Center experience.

BACKGROUND: Mepolizumab is an anti-interleukin-5 monoclonal antibody shown to reduce asthma exacerbations in adults and adolescents with severe eosinophilic asthma. AIM: To assess the impact of mepolizumab on children and adolescents over 12 months by examining steroid usage, asthma-related hospitalizations, Asthma Control Test (ACT) scores, fractional exhaled nitric oxide concentration (FeNO), forced expiratory volume in 1 s (FEV1), mid expiratory flow (FEF25-75%), and blood eosinophil count. METHODS: Retrospective analysis performed between October 2015 and December 2022. Data was reviewed 12 months before and after commencing mepolizumab. Mepolizumab was offered if the patient had severe eosinophilic asthma and were unresponsive to or ineligible for omalizumab. RESULTS: Sixteen participants (age 7-17, 8 males, 8 females) received subcutaneous mepolizumab monthly with no serious adverse reactions. Incidence of hospital admissions fell significantly (IRR 0.33, p = 0.007). Among the 11 patients receiving daily oral corticosteroids, 3 were weaned off daily oral steroids and 3 patients' daily dose was significantly reduced (mean Δ-0.095 ± 0.071 mg/kg, p = 0.0012). Eosinophil count was decreased (mean Δ-0.85 x 109/L, p < 0.001). There was no significant change in mean overall steroid burden per patient (mean Δ-1445.63 ± 1603.18 mg, p = 0.10), ACT scores (mean Δ2.88 ± 6.71, p = 0.17), FEV1 z-scores (mean Δ-0.99 ± 1.88, p = 0.053), FEF25-75% z-scores (mean Δ-0.65 ± 1.61, p = 0.13), FeNO (mean Δ-20.09 ± 80.86, p = 0.34), or number of courses of oral steroids given for asthma attacks (IRR 0.71, p = 0.09). CONCLUSION: Among children and adolescents with severe eosinophilic asthma ineligible for or not responsive to omalizumab, mepolizumab therapy exhibited significant reduction in rate of asthma-related hospitalizations and significant decrease in daily steroid dosage.

Deep intronic 9q21.11 polymorphism contributes to atopic dermatitis risk through methylation regulated expression of tight junction protein 2.

BACKGROUND AND OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory itchy skin condition. Genomic- and epigenetic wide association studies provide insights into the genetic susceptibility and potential underlying disease pathogenesis. This study sought to functionally characterise an AD-associated single nucleotide polymorphism (SNP) located deep intronic of the tight junction protein 2 (TJP2) gene (9q21.11 locus), identified through a genome-wide association study (GWAS). METHODS: The association between the 9q21.11 locus (rs7872806) and AD was identified through a GWAS of 956 cases and 723 controls. TJP2 expression in peripheral blood mononuclear cells (PBMCs) was assessed against the rs7872806 genotypes. Allele-specific methylation was evaluated at CpG sites 10kb up- and down-stream of the 9q21.11 locus. Effects of DNA methylation on TJP2 expression was validated via in vitro methylation and 5-aza-2'-deoxycytidine-induced transcriptional activation studies. Trans-epidermal water loss measurements were used to determine skin barrier function. RESULTS: The major allele of rs7872806 was determined to increase AD risk by 2.64-fold (adjusted p-value=2.40 x 10-18, OR=0.38), associated with increased methylation levels at cg13920460 site (p<0.001) and lower TJP2 expression in PBMCs (Pearson's p=1.09 x 10-6, Pearson's R=-0.313, p<0.001). Methylation inhibition by 5-aza-2'-deoxycytidine increased TJP2 promoter activity by up to 85%. Elimination of the cg13920460 methylation site increased expression by approximately 25%. The rs7872806 major allele was also found to be associated with increased trans-epidermal water loss (p<0.001). CONCLUSION: Epigenetic influence at CpG site cg13920460 is associated with rs7872806 located deep intronic at 9q21.11. The SNP confers susceptibility to AD through altering TJP2 expression and promoting trans-epidermal water loss.

Liver disease among patients with psoriasis: the Malaysian Psoriasis Registry.

BACKGROUND: Therapeutic options may be limited for patients with psoriasis who have concomitant liver disease (PsL). OBJECTIVES: We aimed to report the frequency of liver disease among patients with psoriasis, and describe the clinical features, treatment modalities and quality of life. METHODS: This was a multicentre cross-sectional study of patients with psoriasis notified to the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. RESULTS: Of 21 735 patients with psoriasis, 174 (0.8%) had liver disease. The three most common liver diseases were viral hepatitis (62.1%), fatty liver (14.4%) and liver cirrhosis (10.9%). The male-to-female ratio was 3.8 : 1. Mean age (SD) of onset of psoriasis was higher in those with liver disease vs. those without [37.25 years (13.47) vs. 33.26 years (16.96), P < 0.001]. Patients with PsL, compared with those without liver disease, had a higher rate of dyslipidaemia (27.5% vs. 16.4%, P < 0.001), hypertension (33.9% vs. 23.7%, P = 0.002), diabetes mellitus (22.4% vs. 15.9%, P = 0.021) and HIV infection (5.3% vs. 0.4%, P < 0.001). Those with PsL were also more likely than those without liver disease to have severe disease [body surface area > 10% and/or Dermatology Life Quality Index (DLQI) > 10] (59.3% vs. 49.9%, P = 0.027), psoriatic arthropathy (21.1% vs. 13.0%, P = 0.002) and nail involvement (78.2% vs. 56.1%, P < 0.001). Also significantly higher in the group with PsL were the use of phototherapy (8.4% vs. 2.6%, P < 0.001), acitretin (7.3% vs. 2.8%, P < 0.001) and ciclosporin (3.0% vs. 0.7%, P < 0.001). Mean DLQI was similar in both groups [9.69 (7.20) vs. 9.62 (6.75), P = 0.88]. CONCLUSIONS: The frequency of patients with PsL in the MPR was 0.8%. Patients with PsL were more likely to be male, had a higher rate of comorbidities, severe disease, and nail and joint involvement than those without liver disease.

Long-Term Exposure to AIR Pollution and COVID-19 Mortality and Morbidity in DENmark: Who Is Most Susceptible? (AIRCODEN).

INTRODUCTION: Early ecological studies have suggested a link between air pollution and Coronavirus Diseases 2019 (COVID-19); however, the evidence from individual-level prospective cohort studies is still sparse. Here, we have examined, in a general population, whether long-term exposure to air pollution is associated with the risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19, resulting in hospitalization or death and who is most susceptible. We also examined whether long-term exposure to air pollution is associated with hospitalization or death due to COVID-19 in those who have tested positive for SARS-CoV-2. METHODS: We included all Danish residents 30 years or older who resided in Denmark on March 1, 2020. and followed them in the National COVID-19 Surveillance System until first positive test (incidence), COVID-19 hospitalization, or death until April 26, 2021. We estimated mean levels of nitrogen dioxide (NO2), particulate matter with an aerodynamic diameter <2.5 µm (PM2.5), black carbon (BC), and ozone (O3) at cohort participants' residence in 2019 by the Danish Eulerian Hemispheric Model/Urban Background Model. We used Cox proportional hazard models to estimate the associations of air pollutants with COVID-19 incidence, hospitalization, and mortality adjusting for age, sex, and socioeconomic status (SES) at the individual and area levels. We examined effect modification by age, sex, SES (education, income, wealth, employment), and comorbidities with cardiovascular disease, respiratory disease, acute lower respiratory infections, diabetes, lung cancer, and dementia. We used logistic regression to examine association of air pollutants with COVID-19-related hospitalization or death among SARS-CoV-2 positive patients, adjusting for age, sex, individual- and area-level SES. RESULTS: Of 3,721,810 people, 138,742 were infected, 11,270 hospitalized, and 2,557 died from COVID-19 during 14 months of follow-up. We detected strong positive associations with COVID-19 incidence, with hazard ratio (HR) and 95% confidence interval (CI) of 1.10 (CI: 1.05-1.14) per 0.5-µg/m3 increase in PM2.5 and 1.18 (CI: 1.14-1.23) per 3.6-µg/m3 increase in NO2. For COVID-19 hospitalizations and for COVID-19 deaths, corresponding HRs and 95% CIs were 1.09 (CI: 1.01-1.17) and 1.19 (CI: 1.12-1.27), respectively for PM2.5, and 1.23 (CI: 1.04-1.44) and 1.18 (CI: 1.03-1.34), respectively for NO2. We also found strong positive and statistically significant associations with BC and negative associations with O3. Associations were strongest in those aged 65 years old or older, participants with the lowest SES, and patients with chronic cardiovascular, respiratory, metabolic, lung cancer, and neurodegenerative disease. Among 138,742 individuals who have tested positive for SARS-Cov-2, we detected positive association with COVID-19 hospitalizations (N = 11,270) with odds ratio and 95% CI of 1.04 (CI: 1.01- 1.08) per 0.5-µg/m3 increase in PM2.5 and 1.06 (CI: 1.01-1.12) per 3.6-µg/m3 increase in NO2, but no association with PM with an aerodynamic diameter <10 µm (PM10), BC, or O3, and no association between any of the pollutants and COVID-19 mortality (N = 2,557). CONCLUSIONS: This large nationwide study provides strong new evidence in support of association between long-term exposure to air pollution and COVID-19.

Mindfulness-based therapy for smoking cessation and mental health: a randomised controlled trial.

INTRODUCTION: Effective smoking cessation programmes are essential for assisting smokers in quitting, indirectly lowering mortality and morbidity associated with smoking. Numerous studies have indicated positive outcomes when using mindfulness treatment (MT) to treat psychological or behavioural health issues. Although to date, no study has looked at the effectiveness of online MT for quitting smoking while addressing mental health, particularly among the Asian population. Therefore, this study compares the efficiency of online MT to traditional counselling therapy (CT) in aiding smoking cessation programmes while also addressing mental health. MATERIALS AND METHODS: A randomised control study with a two-group, single-blind design and baseline evaluation was selected. Social media sites were used to advertise for participants, who were then admitted after meeting the requirements. Participants who met the eligibility requirements were randomly split into two groups. Each group received a total of three sessions of online therapy (MT or CT), once every two weeks, as well as one phone call per week as reinforcement. At the beginning and end of the intervention, participants completed questionnaires (1st week and 5th week). Generalized Estimating Equation (GEE) statistical analysis was used to analyse all the variables. RESULTS: The MT group experienced a statistically significant decrease in cigarette consumption (ß: -3.50, 95% Wald CI: - 4.62, -2.39) compared to the CT group over time. Furthermore, the MT group demonstrated significant improvements in their scores for the AAQ-2, anxiety, stress, depression and mindfulness compared to the CT group. CONCLUSION: Online MT is more successful at assisting smokers in lowering their daily cigarette intake and supporting their mental health during the smoking cessation process. Further longitudinal comparisons of the effectiveness of online MT should be undertaken using online platforms in future studies.

Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies.

OBJECTIVE: Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis. METHODS: Ovid Medline, Embase and CINAHL were searched between inception and June 2021 using MeSH terms and key words to identify studies examining the association between metformin use and outcome measures related to osteoarthritis. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. This systematic review is registered on PROSPERO (CRD42021261052 and CRD42021261060). RESULTS: Fifteen (10 pre-clinical and 5 human) studies were included. Most studies (10 pre-clinical and 3 human) assessed the effect of metformin using knee osteoarthritis models. In pre-clinical studies, metformin was assessed for the effect on structural outcomes (n = 10); immunomodulation (n = 5); pain (n = 4); and molecular pathways of its effect in osteoarthritis (n = 7). For human studies, metformin was evaluated for the effect on structural progression (n = 3); pain (n = 1); and immunomodulation (n = 1). Overall, pre-clinical studies consistently showed metformin having a chondroprotective, immunomodulatory and analgesic effect in osteoarthritis, predominantly mediated by adenosine monophosphate-activated protein kinase activation. Evidence from human studies, although limited, was consistent with findings in pre-clinical studies. CONCLUSION: We found consistent evidence across pre-clinical and human studies to support a favourable effect of metformin on chondroprotection, immunomodulation and pain reduction in knee osteoarthritis. Further high-quality clinical trials are needed to confirm these findings as metformin could be a novel therapeutic drug for the treatment of osteoarthritis.

Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women.

Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. INTRODUCTION: Selective estrogen receptor modulators may be an alternative to bisphosphonates for treating rebound resorption after discontinuing denosumab. This study aimed to investigate the effects of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. METHODS: This retrospective observational study included 61 patients who received 12-month follow-up raloxifene therapy after denosumab discontinuation. The primary endpoint was the bone mineral density change. The secondary endpoints were the changes in bone turnover markers and the incidence of new vertebral fractures. RESULTS: Raloxifene administration for 12 months after denosumab discontinuation resulted in a significantly lower bone mineral density at all sites compared to the level at 6 months after the last denosumab treatment (lumbar spine, - 5.48%; femoral neck, - 2.95%; total hip, - 3.52%; all, p < 0.001). The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Marked increases in the bone turnover markers from baseline were noted after switching to raloxifene. However, no new vertebral fractures occurred during raloxifene treatment. CONCLUSIONS: Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. Therefore, raloxifene administered sequentially after denosumab discontinuation was not effective in preventing rebound phenomenon.

Lytic to temperate switching of viral communities.

Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.

Typicality modulates the visual awareness of objects.

In the present study, we assessed whether typicality can influence the visual awareness of objects. Participants tracked moving images of objects and counted how often members of one category bounced off the edges of the display. On the last trial, an unexpected object moved across the display. In our first two experiments, this object could belong to the same category as the tracked or untracked objects. While participants were more likely to notice atypical members of the untracked category, this pattern of results reversed when participants tracked atypical objects. In our last two experiments, the unexpected object could belong to the same category as the tracked objects or a new category of objects. In this case, participants were more likely to notice typical members of both the tracked category and the new category. Together, these findings suggest that typicality can modulate the visual awareness of objects.

Diagnosis and treatment of nail melanoma: a review of the clinicopathologic, dermoscopic, and genetic characteristics.

Nail melanoma (NM) is an important differential diagnosis in patients with longitudinal melanonychia. However, diagnosis is often challenging as it is difficult to differentiate from other pigmented nail disorders. The main challenge for diagnosis is obtaining adequate nail matrix biopsy specimens for histopathological assessment. Furthermore, the histopathological changes in the early stages of NM are subtle and contribute to a delay in diagnosis and care. Therefore, the integration of clinical and histopathological analyses is essential. Clinical and dermoscopic features, such as a broadened width of asymmetric bands in an irregular pattern, with multicolour pigmentation, periungual pigmentation, and continuous growth, are features that support the diagnosis of NM. The essential histological features that must be assessed are cellular morphology, architectural features, melanocyte density, and inflammatory changes. The reported mutations in NMs were BRAF (0-43%), NRAS (0-31%), KIT (0-50%), NF1 (0-50%), and GNAQ (0-25%). Surgery is the primary treatment for NM. The recommended treatment for in situ or minimally invasive NM is functional surgery, but cases with suspected bone invasion should be treated with amputation. Targeted therapy and immunotherapy are indicated for advanced stages of NM. This review summarizes the updated guidelines for the diagnosis and treatment of NM.

Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

Public sentiment on the global outbreak of monkeypox: an unsupervised machine learning analysis of 352,182 twitter posts.

OBJECTIVES: This study aimed to study the public's sentiments on the current monkeypox outbreaks via an unsupervised machine learning analysis of social media posts. STUDY DESIGN: This was an exploratory analysis of tweets sentiments. METHODS: We extracted original tweets containing the terms 'monkeypox', 'monkey pox' or 'monkey_pox' and posted them in the English language from 6 May 2022 (first case detected in the United Kingdom) to 23 July 2022 (when World Health Organization declared Monkeypox to be a global health emergency). Retweets and duplicate tweets were excluded from study. Bidirectional Encoder Representations from Transformers (BERT) Named Entity Recognition. This was followed by topic modelling (specifically BERTopic) and manual thematic analysis by the study team, with independent reviews of the topic labels and themes. RESULTS: Based on topic modelling and thematic analysis of a total of 352,182 Twitter posts, we derived five topics clustered into three major themes related to the public discourse on the ongoing outbreaks. These include concerns of safety, stigmatisation of minority communities, and a general lack of faith in public institutions. The public sentiments underscore growing (and existing) partisanship, personal health worries in relation to the evolving situation, as well as concerns of the media's portrayal of lesbian, gay, bisexual, transgender and queer and minority communities, which might further stigmatise these groups. CONCLUSIONS: Monkeypox is an emerging infectious disease of public concern. Our study has highlighted important societal issues, including misinformation, political mistrust and anti-gay stigma that should be sensitively considered when designing public health policies to contain the ongoing outbreaks.

Comparison of fracture risk between type 1 and type 2 diabetes: a comprehensive real-world data.

Population-based cohort study of 6,548,784 Korean subjects demonstrates that the risk of fracture was higher in patients with diabetes than in nondiabetic subjects. Furthermore, patients with type 1 diabetes were associated with a higher risk of fracture than patients with type 2 diabetes for all measurement sites. INTRODUCTION: Diabetes mellitus is associated with increased fracture risk. Although the pathophysiologic effect on bone metabolism differs according to the type of diabetes, a higher risk of fracture in patients with diabetes than in nondiabetic patients has been consistently demonstrated. Considering the ever-increasing number of patients with diabetes, we aimed to provide updated information on whether this phenomenon remains valid in real-world settings by using large-scale population datasets. METHODS: We conducted a retrospective longitudinal study using data from the Korean National Health Insurance Service dataset of preventive health check-ups between January 2009 and December 2016. The hazard ratios were calculated for any fracture, vertebral fracture, and hip fracture and were analyzed according to the presence and type of diabetes. Among 10,585,818 subjects, 6,548,784 were eligible for the analysis (2418 patients with type 1 diabetes mellitus [T1DM] and 506,208 patients with type 2 diabetes mellitus [T2DM]). RESULTS: The mean follow-up duration (in years) was 7.0 ± 1.3 for subjects without diabetes, 6.4 ± 2.0 for those with T1DM, and 6.7 ± 1.7 for T2DM. Patients with T1DM had a higher incidence rate for all types of fractures per 1000 person-years. The fully adjusted hazard ratios (HRs) for any fracture, vertebral fracture, and hip fracture were higher in T1DM than in T2DM (1.37 [95% confidence interval (CI): 1.23-1.52] for any fracture, 1.33 [95% CI: 1.09-1.63] for vertebral fracture, and 1.99 [95% CI: 1.56-2.53] for hip fracture). CONCLUSIONS: In this large-scale population analysis, diabetes was associated with a higher risk of all types of fractures. Patients with T1DM had a higher risk of fracture than those with T2DM for all measurement sites, and hip fractures had the highest risk. Therefore, fracture prevention training for patients with diabetes is advisable.

Global Microscopic Description of Nucleon-Nucleus Scattering with Quantified Uncertainties.

We develop for the first time a microscopic global nucleon-nucleus optical potential with quantified uncertainties suitable for analyzing nuclear reaction experiments at next-generation rare-isotope beam facilities. Within the improved local density approximation and without any adjustable parameters, we begin by computing proton-nucleus and neutron-nucleus optical potentials from a set of five nuclear forces from chiral effective field theory for 1800 target nuclei in the mass range 12≤A≤242 for energies between 0 MeV

When polymyositis meets Graves' disease: A rare case report.

Polymyositis is rarely associated with Graves' disease. A 22- year-old woman was admitted for progressively worsening proximal muscle weakness of both upper and lower extremities. One month prior to admission, she was diagnosed with thyrotoxicosis and prescribed carbimazole 10mg twice daily. Neurological examination confirmed proximal myopathy and blood investigations revealed marked elevation of muscle enzymes, particularly creatine kinase. Electromyography demonstrated myopathic changes while right quadriceps muscle biopsy showed only traces of inflammatory myopathy. She was treated with pulsed intravenous methylprednisolone followed by tapering doses of oral prednisolone, which was eventually down-titrated to 5mg daily during subsequent clinic visits. The initial clinical improvement that she exhibited did not persist despite being rendered euthyroid. She was readmitted approximately one year later with the same complaint. A second course of intravenous methylprednisolone brought about clinical improvement as well as reduction of creatine kinase levels. A diagnosis of polymyositis was then made, for which she was managed with oral prednisolone 20mg daily in combination with gradual up-titration of azathioprine. She continued to show clinical and biochemical improvements during follow-ups. Polymyositis should be considered in the diagnostic workup of proximal myopathy in a patient with Graves' disease, especially in the setting of markedly raised muscle enzymes.

Role of contrast-enhanced ultrasound in the evaluation of post-liver transplant vasculature.

Liver transplantation is a frequently used treatment for patients with end-stage liver disease and ultrasound is often the first-line imaging technique for detection of vascular complications after liver transplant. Although colour Doppler ultrasound is a good screening method for evaluation of post-liver transplant vasculature, it has limitations in evaluating small-calibre vessels and vessels in close proximity. Contrast-enhanced ultrasound (CEUS) has been proposed to overcome these limitations by improving visualisation of post-liver transplant vasculature and reducing the number of false-positive cases, which necessitate unnecessary additional investigations such as computed tomography or angiography. Liver transplant anatomy and the wide array of post-transplant imaging findings on colour Doppler have already been well described but literature on the use of CEUS and its image interpretation remain scarce. This review aims to discuss the indications for CEUS after liver transplant, to demonstrate CEUS technique and familiarise readers with the imaging appearances of post-transplant vascular complications on CEUS.

Notch1 inactivation promotes invasion and metastasis of nasopharyngeal carcinoma cells partly through Slug activation.

Nasopharyngeal carcinoma (NPC) is a rare form of the head and neck cancer of the epithelial lining of the nasopharynx and exhibits the highest metastatic rate among head and neck cancers. Underlying mechanisms of metastasis remain largely unknown. Here, we explored whether Notch1 affects the invasion and metastasis of NPC cells. In vitro migration and invasion capacities were evaluated after the knockdown of Notch1 expression in NPC cells. To investigate the role of Notch1 in in vivo metastasis, we examined the metastatic ability to the lungs following administration of cancer cells via mouse tail vein. The expression of epithelial-mesenchymal transition (EMT) markers associated with Notch1-mediated metastasis was investigated, and their roles in metastasis and relationship with Notch1 expression were investigated. Suppression of Notch1 expression increased the ability of NPC cells to invade Matrigel in vitro. Knockdown of Notch1 expression in NPC cells resulted in extensive lung metastasis in a mouse model and increased the mRNA expression of Slug in NPC cells. Slug-specific RNA interference resulted in the loss of the metastatic and invasion capacities in Notch1-suppressed NPC cells. These findings show that Notch1 has a significant suppressive role in the regulation of metastasis in NPCs, suggestive of its prudent use in clinical trials.

Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV).

BACKGROUND: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. OBJECTIVES: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. RESULTS: The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

Molecular detection of porcine Enterocytozoon bieneusi infection in Peninsular Malaysia and epidemiological risk factors associated with potentially zoonotic genotypes.

Enterocytozoon bieneusi is an emerging opportunistic pathogen infecting humans, and both domestic and wild pigs are known to harbour zoonotic genotypes. There remains a paucity of information on the prevalence and epidemiology of this enteropathogen in Southeast Asia. The present study was undertaken to determine the molecular prevalence and risk factors associated with E. bieneusi infection among commercially farmed pigs in Malaysia. Faecal samples were collected from 450 pigs from 15 different farms and subjected to nested PCR amplification of the ribosomal internal transcribed spacer (ITS) gene of E. bieneusi. Phylogenetic analysis involved 28 nucleotide sequences of the ITS region of E. bieneusi. An interviewer-administered questionnaire provided information on the animal hosts, farm management systems and environmental factors and was statistically analysed to determine the risk factors for infection. The prevalence of E. bieneusi infection was relatively high (40.7%). The highest prevalence (51.3%) was recorded among the piglets, while the adults showed the lowest level of infection (31.3%). Multivariate analysis indicated that age of the pigs, distance of the farm from human settlement and farm management system were significant risk factors of infection. Three genotypes (EbpA, EbpC and Henan-III) detected among the pigs are potentially zoonotic. The high prevalence of E. bieneusi among locally reared pigs, the presence of zoonotic genotypes and the spatial distribution of pig farms and human settlements warrant further investigation on the possibility of zoonotic transmission.