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Few cases of programmed death-ligand 1 inhibitor-induced scleroderma have been reported and their clinical features remain unpublished. Optimal management is, therefore, unknown and an autoantibody association has yet to be identified. We present the case of a female in her 60s who developed skin thickening after starting atezolizumab for metastatic non-small cell lung cancer. Skin biopsy 7 months after symptom onset showed histological changes consistent with scleroderma. Anti-PM/SCL-75 antibody was positive. Atezolizumab was discontinued and treatment was started with mycophenolate mofetil. After 5 months, she experienced mild improvement in skin thickening. Earlier identification of this complication may limit morbidity in this disease process, which otherwise has limited treatment options. In suspected cases, obtaining scleroderma-associated autoantibodies may help with earlier diagnosis.

Rationale: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored. Objectives: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes. Methods: Patients with bronchiectasis have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. The primary outcome was 5-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at 1, 2, and 3-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables. Results: Among the 1,771 patients (median age, 67 yr; 63.4% female) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significantly higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both 3-year (23 [22.8%] vs. 83 [8.5%], respectively; P,0.01) and 5-year (26 [35.1%] vs. 116 [15.9%], respectively; P,0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations because of severe exacerbations (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.20-2.79; P=0.01) after 1-year followup, as well as increased 3-year (OR, 3.06; 95% CI, 1.74-5.39; P,0.01) and 5-year (OR, 2.46; 95% CI, 1.39-4.37; P,0.01) mortality. Conclusions: Platelets represent a cheap and easy-to-evaluate biomarker, and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations because of exacerbations, poor quality of life, and mortality in adults with bronchiectasis.

Impaired semantic knowledge is a characteristic feature of some forms of frontotemporal dementia (FTD), particularly the sporadic disorder semantic dementia. Less is known about semantic cognition in the genetic forms of FTD caused by mutations in the genes MAPT, C9orf72, and GRN. We developed a modified version of the Camel and Cactus Test (mCCT) to investigate the presence of semantic difficulties in a large genetic FTD cohort from the Genetic FTD Initiative (GENFI) study. Six-hundred-forty-four participants were tested with the mCCT including 67 MAPT mutation carriers (15 symptomatic, and 52 in the presymptomatic period), 165 GRN mutation carriers (33 symptomatic, 132 presymptomatic), and 164 C9orf72 mutation carriers (56 symptomatic, 108 presymptomatic) and 248 mutation-negative members of FTD families who acted as a control group. The presymptomatic mutation carriers were further split into those early and late in the presymptomatic period (more than vs. within 10 years of expected symptom onset). Groups were compared using a linear regression model, adjusting for age and education, with bootstrapping. Performance on the mCCT had a weak negative correlation with age (rho = −0.20) and a weak positive correlation with education (rho = 0.13), with an overall abnormal score (below the 5th percentile of the control population) being below 27 out of a total of 32. All three of the symptomatic mutation groups scored significantly lower than controls: MAPT mean 22.3 (standard deviation 8.0), GRN 24.4 (7.2), C9orf72 23.6 (6.5) and controls 30.2 (1.6). However, in the presymptomatic groups, only the late MAPT and late C9orf72 mutation groups scored lower than controls (28.8 (2.2) and 28.9 (2.5) respectively). Performance on the mCCT correlated strongly with temporal lobe volume in the symptomatic MAPT mutation group (rho > 0.80). In the C9orf72 group, mCCT score correlated with both bilateral temporal lobe volume (rho > 0.31) and bilateral frontal lobe volume (rho > 0.29), whilst in the GRN group mCCT score correlated only with left frontal lobe volume (rho = 0.48). This study provides evidence for presymptomatic impaired semantic knowledge in genetic FTD. The different neuroanatomical associations of the mCCT score may represent distinct cognitive processes causing deficits in different groups: loss of core semantic knowledge associated with temporal lobe atrophy (particularly in the MAPT group), and impaired executive control of semantic information associated with frontal lobe atrophy. Further studies will be helpful to address the longitudinal change in mCCT performance and the exact time at which presymptomatic impairment occurs.

The availability of direct-acting antivirals (DAAs) sparked efforts to eliminate hepatitis C virus (HCV) in Australia. We evaluated whether an educational intervention of a 1-h discussion among staff using audit and feedback data from the MedicineInsight GP programme would improve DAA uptake. Of 296 eligible general practices in MedicineInsight, 11% opted out. Randomization stratified by practice caseload allocated 130 practices to the intervention arm and 129 to control. The primary outcome was the number of patients started on DAAs over 6 months using the negative binomial regression model adjusted for DAA prescription history and clustering by practice. Data for analysis were available for 78% of practices, which included 101 practices and 2469 DAA-naive patients with confirmed/possible HCV in the intervention arm, and 100 practices and 2466 patients in the control arm. At baseline, 49.5% of practices had prescribed ≥1 DAA in the past year; 18.9% of HCV patients had already been treated with DAAs; the mean age of DAA-naive HCV patients was 43 years old, and 57% were men. Over 6 months, 43 patients in the intervention arm and 36 in the control arm started DAAs (adjusted IRR 1.19; 95% CI 0.67-2.11, p = 0.55). In the first 3 months, 27 vs 16 patients started DAAs (adjusted IRR 1.77, 0.88-3.58; p = 0.111). Few patients were started on DAAs, and a facilitated discussion in HCV management did not lead to a significant increase. Alternative measures, such as incentivizing GP initiations or patients, are suggested to address remaining barriers to DAA uptake in Australian primary care. Australian New Zealand Clinical Trial Registry (ANZCTR) Registration Number: ACTRN12619000508178p.

Australia was one of the first countries with unrestricted access to government subsidized direct-acting antiviral (DAA) therapy for adults with chronic hepatitis C virus. This study assessed real-world DAA treatment outcomes across a diverse range of Australian clinical services and evaluated factors associated with successful treatment and loss to follow-up. Real-world Effectiveness of Antiviral therapy in Chronic Hepatitis C (REACH-C) consisted a national observational cohort of 96 clinical services including specialist clinics and less traditional settings such as general practice. Data were obtained on consecutive individuals who commenced DAAs from March 2016 to June 2019. Effectiveness was assessed by sustained virological response ≥12 weeks following treatment (SVR) using intention-to-treat (ITT) and per-protocol (PP) analyses. Within REACH-C, 10,843 individuals initiated DAAs (male 69%; ≥50 years 52%; cirrhosis 22%). SVR data were available in 85% (9,174 of 10,843). SVR was 81% (8,750 of 10,843) by ITT and 95% (8,750 of 9,174) by PP. High SVR (≥92%) was observed across all service types and participant characteristics. Male gender (adjusted odds ratio [aOR] 0.56, 95% confidence interval [CI] 0.43-0.72), cirrhosis (aOR 0.52, 95% CI 0.41-0.64), recent injecting drug use (IDU; aOR 0.64, 95% CI 0.46-0.91) and previous DAA treatment (aOR 0.50, 95% CI 0.28-0.90) decreased the likelihood of achieving SVR. Multiple factors modified the likelihood of loss to follow-up including IDU ± opioid agonist therapy (OAT; IDU only: aOR 1.75, 95% CI 1.44-2.11; IDU + OAT: aOR 1.39, 95% CI 1.11-1.74; OAT only, aOR 1.36; 95% CI 1.13-1.68) and age (aOR 0.97, 95% CI 0.97-0.98). Conclusion: Treatment response was high in a diverse population and through a broad range of services following universal access to DAA therapy. Loss to follow-up presents a real-world challenge. Younger people who inject drugs were more likely to disengage from care, requiring innovative strategies to retain them in follow-up.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare, and relatively new, form of chronic pancreatitis. The management of AIP can vary considerably among different centres in daily clinical practice. OBJECTIVES: The aim of this study is to present a picture of epidemiological, clinical characteristics, outcomes, and the real-life practice in terms of management in several academic and non-academic centres in Italy. METHODS: Data on the clinical presentation, diagnostic work-up, treatments, frequency of relapses, and long-term outcomes were retrospectively collected in a cohort of AIP patients diagnosed at 14 centres in Italy. RESULTS: One hundred and six patients were classified as type 1 AIP, 48 as type 2 AIP, and 19 as not otherwise specified. Epidemiological, clinical, radiological, and serological characteristics, and relapses were similar to those previously reported for different types of AIP. Endoscopic cytohistology was available in 46.2% of cases, and diagnostic for AIP in only 35.2%. Steroid trial to aid diagnosis was administered in 43.3% cases, and effective in 93.3%. Steroid therapy was used in 70.5% of cases, and effective in 92.6% of patients. Maintenance therapy with low dose of steroid (MST) was prescribed in 25.4% of cases at a mean dose of 5 (±1.4) mg/die, and median time of MST was 60 days. Immunosuppressive drugs were rarely used (10.9%), and rituximab in 1.7%. Faecal elastase-1 was evaluated in only 31.2% of patients, and was pathological in 59.2%. CONCLUSIONS: In this cohort of AIP patients, diagnosis and classification for subtype was frequently possible, confirming the different characteristics of AIP1 and AIP2 previously reported. Nevertheless, we observed a low use of histology and steroid trial for a diagnosis of AIP. Steroid treatment was the most used therapy in our cohort. Immunosuppressants and rituximab were rarely used. The evaluation of exocrine pancreatic insufficiency is underemployed considering its high prevalence.

OBJECTIVE The aim of this study was to review the use of patient-controlled analgesia (PCA) in sickle cell disease (SCD) for pediatric patients with vaso-occlusive crisis (VOC) in our institution and to compare the effect of early vs late PCA start on pain relief and LOS. METHODS This retrospective study included all pediatric patients treated with PCA for a severe VOC from 2010 to 2016. “Early-PCA” was defined as start of PCA within 48 hours of arrival. Time to reach adequate analgesia was defined as the time to reach 2 consecutive pain scores less than 5/10 at 4-hour interval. RESULTS During the study period, 46 patients presented 87 episodes of VOC treated with PCA. Sixty-three patients with VOC were treated with Early-PCA and 24 with Late-PCA. Both groups were comparable except for median pain score at admission; the Early-PCA group had higher scores: 9.0/10 vs 7.0/10. Time to reach adequate analgesia could be evaluated only in a subset of patients (n = 32) but was shorter in the Early-PCA group with a median difference of 41.0 hours (95% CI −82.0 to −6.0). Early-PCA was associated with a median reduction in LOS of 3.4 days (95% CI −4.9 to −1.9). There was no difference between the 2 groups in terms of side effects and occurrence of acute chest syndrome during hospitalization. CONCLUSIONS In this study, a reduced time to reach adequate analgesia and LOS was noted in the Early-PCA group for severe VOC. A prospective study is required to confirm these results.

Background Studies comparing dipeptidyl peptidase-4 inhibitors (DPP4Is) to sulfonylureas (SUs) are unavailable for frail older adults, especially nursing home (NH) residents. We examined the effects of DPP4Is versus SUs on severe adverse glycemic events, cardiovascular events, and death among NH residents. Methods We conducted a national retrospective cohort study of long-stay NH residents aged ≥65 years using 2008-2010 national US Minimum Data Set clinical assessment data and linked Medicare claims. Exposure was new DPP4I versus new SU use assessed via Medicare Part D drug claims. One-year outcomes were severe hypoglycemia, severe hyperglycemia, acute myocardial infarction (AMI), heart failure (HF), major adverse cardiovascular events plus HF (MACE+HF), and death. We compared outcomes after propensity score matching using Cox proportional hazards regression models. Results The cohort (N = 2016) had a mean (SD) age of 81 (8.1) years and was 72% female. Compared with SU users, DPP4I users had a lower 1-year rate of severe hypoglycemic events (HR = 0.57, 95% CI 0.34-0.94), but statistically similar rates of severe hyperglycemic events (HR = 0.94, 95% CI 0.52-1.72), AMI (HR = 0.76, 95% CI 0.44-1.30), HF (HR = 1.01, 95% CI 0.79-1.30), MACE+HF (HR = 0.90, 95% CI 0.72-1.12), and death (HR = 0.97, 95% CI 0.86-1.10). Conclusions DPP4Is should be a preferred treatment option over SUs for NH residents and other frail older adults given the importance of avoiding hypoglycemia.

Background People who inject drugs are at greater risk of hepatitis C virus (HCV) infection and hospitalization, yet admissions are not utilized for HCV treatment initiation. We aimed to assess the extent to which people with HCV notification, including those with evidence of recent drug dependence, are hospitalized while eligible for direct-acting antiviral (DAA) therapy, and treatment uptake according to hospitalization in the DAA era. Methods We conducted a longitudinal, population-based cohort study of people living with HCV in the DAA era (March 2016–December 2018) through analysis of linked databases in New South Wales, Australia. Kaplan-Meier estimates were used to report HCV treatment uptake by frequency, length, and cause-specific hospitalization. Results Among 57 467 people, 14 938 (26%) had evidence of recent drug dependence, 50% (n = 7506) of whom were hospitalized while DAA eligible. Incidence of selected cause-specific hospitalization was highest for mental health-related (15.84 per 100 person-years [PY]), drug-related (15.20 per 100 PY), and injection-related infectious disease (9.15 per 100 PY) hospitalizations, and lowest for alcohol use disorder (4.58 per 100 PY) and liver-related (3.13 per 100 PY). In total, 65% (n = 4898) of those who were hospitalized had been admitted ≥2 times, and 46% (n = 3437) were hospitalized ≥7 days. By the end of 2018, DAA therapy was lowest for those hospitalized ≥2 times, for ≥7 days, and those whose first admission was for injection-related infectious disease, mental health disorders, and drug-related complications. Conclusions Among people who have evidence of recent drug dependence, frequent hospitalization—particularly mental health, drug, and alcohol admissions—presents an opportunity for engagement in HCV care.

Background and Aim The primary objective of this study was to determine whether the characteristics of patients prescribed direct acting antiviral (DAA) medicines have changed since initial listing of the medicines on the Australian Pharmaceutical Benefits Scheme (PBS). Methods A cross‐sectional study was conducted using data from MedicineInsight, an Australian database of general practice electronic health records, from March 2016 to August 2018. We compared sociodemographic, comorbidity, and clinical characteristics of patients aged at least 18 years who were prescribed at least one DAA in the first 4 months of PBS listing in 2016 with those prescribed at least one DAA in 2018. Results There were 2251 eligible adult patients prescribed a DAA during the study period, 62% were men and 59% were aged 50 years and older. Patients prescribed DAA medicines initially were older (aged ≥50 years: 67.9% vs 49.3%; P 1 (20.4% vs 8.9%; P, Despite evidence of decreasing uptake of direct acting antiviral (DAA) medicines across Australia, there has been broadened uptake among younger age groups and those residing in regional/remote and socioeconomically disadvantaged areas since 2016. Although uptake of DAA medicines in some population subgroups appears to have improved, continuous efforts to improve uptake across the Australian population are essential.

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Aim: Recent studies suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically inherited condition causing hemolytic anemia, may be a risk factor for cardiovascular disease (CVD). We aimed to perform a retrospective case–control study in Sardinia taking advantage from clinical records of patients undergoing upper digestive endoscopy and screened for H. pylori infection. Methods: A total of 9,604 patients with a known G6PD status and a complete clinical history, encompassing CVD, and leading CVD risk factors, including H. pylori infection, undergoing upper endoscopy between 2002 and 2017 were enrolled in this study. Results: Multivariate logistic regression analysis confirmed an increased CVD risk in subjects with G6PD deficiency [odd ratio (OR), 3.24; 95% confidence interval (CI) 2.44–4.30] after adjusting for potential confounders and effect modifiers, including H. pylori infection. Cardiovascular risk was similar in subjects with and without G6PD deficiency before age 60 (OR, 1.26; 95% CI 0.78–2.04, P =0.562), whereas it increased after age 60 in the former group (OR, 3.05; 95% CI 2.22–4.19, P ＜0.0001) especially in males (OR 3.67; 95% CI 2.19–6.14) compared with females (OR, 2.96; 95% CI 1.89–4.64) by sex-specific logistic regression analysis. Conclusion: The risk of CVD was greater in G6PD-deficient subjects after age 60, both in males and females, than those with normal enzyme activity, after adjusting for conventional CVD risk factors and H. pylori infection. The reduction of important protective mechanisms against oxidative stress in the elderly might explain the study findings.

Background No long-term maintenance therapy has been tested in patients with seborrheic dermatitis (SD). Objective We sought to compare the efficacy and tolerance of tacrolimus 0.1% ointment versus ciclopiroxolamine 1% cream as maintenance therapy for severe SD. Methods This double-blind randomized controlled study was conducted from 2014 to 2017 in 5 Dermatology Departments and 15 dermatology practices in France. Consecutive patients with severe and chronic facial SD were included. Patients were initially treated with desonide 0.05% cream twice daily for 7 days. Patients cleared after this open phase were randomized to receive tacrolimus 0.1% or ciclopiroxolamine 1% cream 2 times a week 24 weeks. The primary endpoint was disease-free-duration, defined as the time from randomization to first relapse. Results One hundred fourteen patients were randomized (tacrolimus, n = 57; ciclopiroxolamine, n = 57). Twelve patients relapsed in the tacrolimus group after a median delay of 91.5 days (range 15-195 days) versus 23 patients in the ciclopiroxolamine group (median delay, 27 days [range 13-201 days]). Comparison of disease-free duration curves showed that patients in the tacrolimus group had a longer duration of complete remission than those in the ciclopiroxolamine group (P = .018), corresponding to a hazard ratio of relapse of 0.44 (95% confidence interval 0.22-0.89; P = .022). Limitations The theoretical sample size was not reached. Conclusion Tacrolimus 0.1% is more effective than ciclopiroxolamine 1% as maintenance therapy for patients with facial SD.

Amyloid-β (Aβ) PET imaging has now been available for over 15 years. The ability to detect Aβ in vivo has greatly improved the clinical and research landscape of Alzheimer's disease (AD) and other neurodegenerative conditions. Aβ imaging provides very reliable, accurate, and reproducible measurements of regional and global Aβ burden in the brain. It has proved invaluable in anti-Aβ therapy trials, and is now recognized as a powerful diagnostic tool. The appropriate use of Aβ PET, when combined with comprehensive clinical evaluation by a dementia-trained specialist, can improve the accuracy of a clinical diagnosis of AD and substantially alter management. It can assist in differentiating AD from other neurodegenerative conditions, often by its ability to rule out the presence of Aβ. When combined with tau imaging, further increase in specificity for the diagnosis of AD can be achieved. The integration of Aβ PET, in conjunction with biomarkers of tau, neurodegeneration and neuroinflammation, into large, longitudinal, observational cohort studies continues to increase our understanding of the development of AD. Its incorporation into clinical trials has been pivotal in defining the most effective anti-Aβ biological therapies and optimal dosing so that effective disease modifying therapy now appears imminent. Aβ deposition is a gradual and protracted process, permitting a wide treatment window for anti-Aβ therapies and Aβ PET has made trials in this preclinical AD period feasible. Continuing improvement in Aβ tracer target to background ratio is allowing trials in earlier AD that tailor drug dosage to Aβ level. The quest to standardize quantification and define universally applicable thresholds for all Aβ tracers has produced the Centiloid method. Centiloid values that correlate well with neuropathologic findings and prognosis have been identified. Rapid cloud-based automated individual scan analysis is now possible and does not require MRI. Challenges remain, particularly around cross camera standardized uptake value ratio variation that need to be addressed. This review will compare available Aβ radiotracers, discuss approaches to quantification, as well as the clinical and research applications of Aβ PET.

Background 123I-Metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy is a useful technique to differentiate Parkinson's disease (PD) from atypical parkinsonisms, since it is generally abnormal in PD and normal in the latter. Reduction of myocardial MIBG uptake is a supportive feature in the latest PD diagnostic criteria. Objectives To explore the clinical contribution of myocardial scintigraphy in discriminating different forms of parkinsonisms, especially when atypical features are present. Methods Forty-one patients with parkinsonism underwent a 123I-MIBG myocardial scintigraphy in our Movement Disorders Center. Disease evolution was reviewed by applying the latest disease criteria for PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), as appropriate. Three diagnostic times were defined: T1 (before scintigraphy execution), T2 (immediately after the exam) and T3 (two years later). Early and delayed heart/mediastinum (H/M) ratios and washout rate (WR) were analyzed. Results Myocardial scintigraphy showed impaired MIBG uptake in 12 out of 15 patients with a definite PD diagnosis, while normal uptake was found in 20 of 26 patients with no-PD. Early and delayed H/M ratios were significantly lower in PD compared to overall no-PD patients and MSA patients. 123I-MIBG myocardial scintigraphy was abnormal in all PD patients with dysautonomia. After 123I-MIBG myocardial scintigraphy (T2), in 9 patients (22%) an improvement of diagnostic accuracy was reached. Conclusions Diagnostic accuracy of myocardial scintigraphy in distinguishing PD from atypical parkinsonism was suboptimal. Nevertheless, this study confirmed the relevance of 123I-MIBG myocardial scintigraphy for the discrimination of PD from atypical parkinsonism, especially when dysautonomic symptoms are present.

Cardiovascular disorders (CVD) are highly prevalent and the leading cause of death worldwide. Atherosclerosis is responsible for most cases of CVD. The plaque formation and subsequent thrombosis in atherosclerosis constitute an ongoing process that is influenced by numerous risk factors such as hypertension, diabetes, dyslipidemia, obesity, smoking, inflammation, and sedentary lifestyle. Among the various risk and protective factors, the role of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common inborn enzyme disorder across populations, is still debated. For decades, it has been considered a protective factor against the development of CVD. However, in the recent years, growing scientific evidence has suggested that this inherited condition may act as a CVD risk factor. The role of G6PD deficiency in the atherogenic process has been investigated using in vitro or ex vivo cellular models, animal models, and epidemiological studies in human cohorts of variable size and across different ethnic groups, with conflicting results. In this review, the impact of G6PD deficiency on CVD was critically reconsidered, taking into account the most recent acquisitions on molecular and biochemical mechanisms, namely, antioxidative mechanisms, glutathione recycling, and nitric oxide production, as well as their mutual interactions, which may be impaired by the enzyme defect in the context of the pentose phosphate pathway. Overall, current evidence supports the notion that G6PD downregulation may favor the onset and evolution of atheroma in subjects at risk of CVD. Given the relatively high frequency of this enzyme deficiency in several regions of the world, this finding might be of practical importance to tailor surveillance guidelines and facilitate risk stratification.

Background: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer’s disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Objective: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Methods: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. Results: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= –0.269, p = 0.03). Conclusion: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

Background [18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Methods A total of 2770 [18F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD). Results Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region. Conclusions Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

International audience; PURPOSE: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients. METHODS: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy. RESULTS: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months). CONCLUSIONS: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.

Purpose: To assess the role of complete blood cell count (CBC) dimensional indices and CBC-derived measures in non-arteritic anterior ischemic optic neuropathy (NA-AION). Methods: In this retrospective case-control survey, 37 newly diagnosed NA-AION patients and 37 sex- and age-matched cataract controls were enrolled in 2017-2018. On the same day of NA-AION diagnosis, a blood sample was collected and CBC was determined using an automatic blood counter. CBC dimensional indices, such as mean platelet volume (MPV) and red cell distribution width (RDW), and CBC-combined indices, including neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells - neutrophils)], and platelet/lymphocyte ratio (PLR), were evaluated. Erythrocyte sedimentation rate (ESR) was also measured. Results: Mean platelet count, median MPV, RDW, NLR, and dNLR were 221±48 x 109/L, 8.2 fL (IQR=7.6-8.9), 13% (IQR=12-14.5), 2.50 (IQR=1.77-3.06), and 1.73 (IQR=1.31-2.07) in NA-AION patients and 248±56 x 109/L, 7.60 fL (IQR=7.05-8.25), 12% (IQR=11.6-13), 1.95 (IQR=1.43-2.49) and 1.36 (IQR=1.07-1.69) in controls. NA-AION patients showed significantly lower platelet count (p=0.03) and significantly higher median values of MPV (p=0.01), RDW (p=0.015), NLR (p=0.03), and dNLR (p=0.01). Multivariate logistic regression models disclosed a significant correlation only between higher levels of RDW and NA-AION (p≤0.05). The attributable risk of the association between NA-AION and RDW was 33%. Conclusions: Results suggest that RDW may be somehow involved in the pathogenesis of NA-AION. However, high-quality cohort studies are warranted to confirm whether, or not, an altered RDW may be considered a potential biomarker of this vascular disorder affecting the optic nerve.

Background & Aims Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking. Methods REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early. Results The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4–89.0) in the short arm and 86/95, 90.5% (95% CI 82.7–95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8–95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0–99.7; difference -8.3%, p = 0.025). Conclusions In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy. Lay summary In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. ClinicalTrials.gov Identifier NCT02625909 .

Background & Aims High HCV treatment uptake among people at most risk of transmission is essential to achieve elimination. We aimed to characterise subpopulations of people with HCV based on drug dependence, to estimate direct-acting antiviral (DAA) uptake in an unrestricted treatment era, and to evaluate factors associated with treatment uptake among people with recent drug dependence. Methods HCV notifications in New South Wales, Australia (1995-2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, HIV notifications, deaths, and prescription databases. Drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT, with indicators in 2016-2018 considered recent. Records were weighted to account for spontaneous clearance. Logistic regression was used to analyse factors associated with treatment uptake among those with recent drug dependence. Results 57,467 people were estimated to have chronic HCV throughout the DAA era. Treatment uptake was highest among those with recent (47%), compared to those with distant (38%), and no (33%) drug dependence. Among those with recent drug dependence, treatment was more likely among those with HIV (adjusted odds ratio [aOR] 1.71; 95% CI 1.24–2.36), recent incarceration (aOR 1.10; 95% CI 1.01–1.19), and history of alcohol use disorder (aOR 1.22; 95% CI 1.13–1.31). Treatment was less likely among women (aOR 0.78; 95% CI 0.72–0.84), patients of Indigenous ethnicity (aOR 0.75; 95% CI 0.69–0.81), foreign-born individuals (aOR 0.86; 95% CI 0.78–0.96), those with outer-metropolitan notifications (aOR 0.90; 95% CI 0.82–0.98), HBV coinfection (aOR 0.69; 95% CI 0.59–0.80), and >1 recent hospitalisation (aOR: 0.91; 95% CI 0.84–0.98). Conclusions These data provide evidence of high DAA uptake among people with recent drug dependence, including those who are incarcerated. Enhancing this encouraging initial uptake among high-risk populations will be essential to achieve HCV elimination. Lay summary To facilitate HCV elimination, those at highest risk of infection and transmission are a treatment priority. This study shows the successes of Australia's universal provision of DAA therapy in reducing the barriers to treatment which have historically persisted among people who inject drugs. Despite higher DAA therapy uptake among those with recent drug dependence, gaps remain. Strategies which aim to reduce marginalisation and increase treatment uptake to ensure equitable HCV elimination must be advanced.

Background Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. The incidence of GC varies between countries according to exposure to different risk factors. Hypothyroidism has been suggested as a potential GC risk factor. In Sardinia, Italy, the prevalence of endemic goiter is high and GC mortality is unevenly distributed. This ecological study aimed to investigate GC mortality and its relationship with hypothyroidism, adjusting for potential confounders. Methods The spatial association between GC mortality and goiter (a proxy of hypothyroidism), diet, stature and pastoralism (a proxy of Helicobacter pylori infection), available at the aggregated level, was modelled in the island's 377 municipalities, separately by sex, using geographically weighted regression (GWR). Results The GC standardized mortality ratio ranged from 0.0 to 10.4 across municipalities. A hotspot of GC mortality was detected in the central mountainous area of Sardinia among males, positively associated with goiter (GWR estimate 0.213 ± 0.122), and the practice of sheep‒rearing (GWR estimate 0.127 ± 0.080), whereas a negative association with the diet score (GWR estimate 0.032 ± 0.034), and null for stature were found. No significant associations were found in females. Conclusion Within the limitations of ecological studies goiter prevalence was an independent predictor of GC mortality in males.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.

The risk of thyroid disorders (TDs) in inflammatory bowel disease (IBD) is still controversial. The aim of this retrospective, single-center, case-control study was to explore the association between clinically relevant functional TDs and IBD.Consecutive individuals for a total of 313 IBD patients [90 Crohn's disease (CD); 223 ulcerative colitis (UC)], and 833 individuals undergoing colonoscopy for screening without IBD were collected. In the study, subject's information on thyroid status were retrieved. Thyroid disorders were classified, according to the functional status, as hypothyroidism or hyperthyroidism. Patients with TDs (cases) were compared with 941 without (controls) according to IBD exposure. Unadjusted and adjusted odds ratios (ORs) and their 95% confidence interval (CI) were calculated.Clinically relevant TDs were detected in 205 (17,9%) patients and the prevalence was significantly lower in IBD patients compared with subjects without (8.3% vs 12.9%;Overall, in our study, the risk of TDs was lower in IBD patients. To assess routinely hormones and/or thyroid gland imaging in the absence of clinical signs or symptoms seems unnecessary in IBD patients, at least in our geographic area.

Summary Background Limited empirical evidence exists for the effectiveness of hepatitis C virus (HCV) treatment-as-prevention. The Surveillance and Treatment of Prisoners with hepatitis C (SToP-C) study aimed to assess the effect of HCV treatment-as-prevention in the prison setting. Methods SToP-C was a prospective study, including a before-and-after analysis, within a cohort of people incarcerated in two maximum-security prisons (male) and two medium-security prisons (one male, one female) in New South Wales, Australia. All prison inmates aged at least 18 years were eligible for enrolment. After HCV testing, participants were monitored for risk behaviours and HCV infection, among three sub-populations: uninfected (HCV antibody-negative); previously infected (HCV antibody-positive, HCV RNA-negative); and infected (HCV antibody and HCV RNA-positive). Uninfected participants were followed up every 3–6 months to detect HCV primary infection and previously infected participants were followed up every 3–6 months to detect re-infection. Participants with HCV infection were assessed for treatment, initially standard-of-care treatment (administered by prison health services) from 2014 to mid-2017, then direct-acting antiviral (DAA) treatment scale-up from mid-2017 onwards (12 weeks of sofosbuvir plus velpatasvir, administered through SToP-C). Participants were followed up until study closure in November, 2019. The primary study outcome was HCV incidence before and after DAA treatment scale-up among participants at risk of HCV primary infection or re-infection. This study is registered with ClinicalTrials.gov, NCT02064049. Findings Between Oct 30, 2014, and Sept 30, 2019, 3691 participants were enrolled in the SToP-C study. 719 (19%) participants had detectable HCV RNA, 2240 (61%) were at risk of primary HCV infection, and 725 (20%) were at risk of re-infection at baseline. DAA treatment was initiated in 349 (70%) of 499 eligible participants during the treatment scale-up period. The HCV incidence analysis comprised 1643 participants at risk of HCV infection or re-infection during longitudinal follow-up (median age 33 years [IQR 27–42]; 1350 [82%] male). 487 (30%) of 1643 participants reported injecting drugs in prison. HCV incidence decreased from 8·31 per 100 person-years in the pre-treatment scale-up period to 4·35 per 100 person-years in the post-treatment scale-up period (incidence rate ratio [IRR] 0·52 [95% CI 0·36–0·78]; p=0·0007). The incidence of primary infection decreased from 6·64 per 100 person-years in the pre-treatment scale-up period to 2·85 per 100 person-years in the post-treatment scale-up period (IRR 0·43 [95% CI 0·25–0·74]; p=0·0019), whereas the incidence of re-infection decreased from 12·36 per 100 person-years to 7·27 per 100 person-years (0·59 [0·35–1·00]; p=0·050). Among participants reporting injecting drugs during their current imprisonment, the incidence of primary infection decreased from 39·08 per 100 person-years in the pre-treatment scale-up period to 14·03 per 100 person-years in the post-treatment scale-up period (IRR 0·36 [95% CI 0·16–0·80]; p=0·0091), and the incidence of re-infection decreased from 15·26 per 100 person-years to 9·34 per 100 person-years (0·61 [0·34–1·09]; p=0·093). The adjusted analysis (adjusted for age, Indigenous Australian ethnicity, duration of stay in prison, previous imprisonment, injecting drug use status, and prison site) indicated a significant reduction in the risk of HCV infection between the pre-DAA treatment scale-up and post-DAA treatment scale-up periods (adjusted hazard ratio 0·50 [95% CI 0·33–0·76]; p=0·0014). Interpretation DAA treatment scale-up was associated with reduced HCV incidence in prison, indicative of a beneficial effect of HCV treatment-as-prevention in this setting. These findings support broad DAA treatment scale-up within incarcerated populations. Funding Australian National Health and Medical Research Council Partnership Project Grant and Gilead Sciences.

Background: Obstructive sleep apnea (OSA) has been linked to an increase risk of dementia. Few studies have cross-sectionally examined whether clinically-confirmed OSA is associated with a higher brain amyloid burden. Objective: The aim of this study was to compare brain amyloid burden in individuals with untreated OSA and healthy controls, and explore associations between amyloid burden and polysomnographic and subjective measures of sleep, demographics, and mood. Methods: Thirty-four individuals with OSA (mean age 57.5±4.1 y; 19 males) and 12 controls (mean age 58.5±4.2 y; 6 males) underwent a clinical polysomnogram and a 11C-PiB positron emission tomography (PET) scan to quantify amyloid burden. Results: Amyloid burden was elevated in the OSA group relative to controls, and was significantly higher in those with severe OSA relative to mild/moderate OSA. Correlation analyses indicated that higher amyloid burden was associated with a higher Non-REM apnea hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep, when controlling for age. Conclusion: Severe OSA is associated with a modest elevation of brain amyloid, the significance of which should be further investigated to explore the implications for dementia risk.

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5-77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6-70.3); however, noncarriers reached the threshold later at age 78 (76.1-84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.

Pulmonary involvement in Sjogren syndrome (SS) could manifest as cystic lung disease (CLD). CLD in SS includes lymphocytic interstitial pneumonia (LIP) and pulmonary amyloidosis. Differential diagnosis usually requires surgical lung biopsy, whereas CT-guided percutaneous fine needle aspiration biopsy (CT-FNAB) has not yet explored. We describe the case of a 63-year-old never smoker Caucasian female with a SS diagnosis who displayed a newly detected diffuse CLD at high-resolution computed tomography, though totally asymptomatic. Given the favorable location of one big lesion at the superior left lobe, a CT-FNAB was proposed instead of a more invasive SLB. At histology examination a diagnosis of pulmonary nodular AL kappa amyloidosis in the context of SS was established. In conclusion, CT-FNAB might represent an alternative and less invasive diagnostic procedure than SLB in the differential diagnosis of CLD, even if further research is needed. Moreover, this case presents an unusual association between SS and pulmonary nodular AL kappa amyloidosis, with pulmonary nodules and cysts without systemic manifestations.

Introduction: We describe an outbreak of hepatitis A among men who have sex with men (MSM) which evolved in Sassari (Italy), between January 2017 and December 2018, close to a contextual of large concurrent hepatitis A outbreak reported in Europe and recently, in Italy. Methodology: HAV RNA detection and molecular characterization was performed from serum samples and/or stool by RT - PCR of VP1/2A junction region that ranges from nt. 2,873 to nt. 3,376. The phylogenetic correlation of the circulating hepatitis A strains was assessed by sequencing method according to the HAVNET protocol. Results: 10 Acute Hepatitis A virus (AHA)-positive cases, 8 of which were among men who have sex with men (MSM) were identified. All patients were tested at the time of hospitalization for the presence of anti-HIV antibodies, only two MSM resulted co-infected by HIV. No differences were observed in median age (37 years vs. 41 years, P-value = 0.14), severity or duration of hospitalization between seropositive and HIV-negative men. Phylogenetic analysis was conducted in 2 cases and revealed two distinct sequences of genotype IA linking to clusters recognized in MSM in other European countries in 2016. Conclusion: Our study reported a recent increase of notified hepatitis A cases attributable to cases in the European interconnectedness of MSM in Sassari, a small locality. Hepatitis A vaccination for MSM in Sardinia region is recommended; however, our data emphasize the need of hepatitis A screening and vaccination not only for MSM with occasional partners but also for those in monogamous relationships.

The World Health Organization has set ambitious viral hepatitis elimination targets; however, difficulties in identifying and engaging patients remain. The emergency visit is an opportunity for enhanced linkage to care (LTC). We assessed the effectiveness of an automated Emergency Department (ED) screening service in identifying patients with hepatitis C (HCV) and achieving LTC. A retrospective evaluation was undertaken, analysing the first 5000 patients screened through an automatic Australian service termed 'Screening Emergency Admissions at Risk of Chronic Hepatitis' (SEARCH). Screening was performed for those recommended in the Australian national testing policy, specifically overseas born (OB) and Aboriginal or Torres Strait Islanders (ATSI). Healthcare worker education, patient information materials and opt-out informed consent were used to test sera already collected for biochemistry assays. 5000 of 5801 (86.2%) consecutive eligible patients were screened (OB: 4778, ATSI: 222) from 14 093 ED presentations. HCV antibody was positive in 181 patients (3.6%); 51 (1.0%) were HCV RNA positive. Of 51 HCV RNA-positive patients, 12 were new diagnoses, 32 were 're-diagnoses' (aware but lost to follow-up [LTFU]), and 7 were previously known but treatment contraindicated. LTC was successful in 38 viraemic patients (7 deceased, 4 LTFU, 1 treatment ineligible and 1 declined). Of RNA-negative patients, 75 were previously treated and 49 had presumed spontaneous clearance. Opt-out consent was acceptable to all patients and staff involved. ED screening can lead to additional diagnosing and 're-diagnosing' of HCV, with high rates of LTC. Opt-out consent and automation removed major obstacles to testing.

Summary Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. Introduction Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. Methods Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. Results At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs − 0.8% (0.43%) with PBO/ALN (P

People with Hepatitis C Who Inject Drugs To reduce the burden of HCV, it will be important to expand harm reduction for people who inject drugs. One model comes from Australia, where high treatment...

Background Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population. Methods 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30–70 years old), HbA1c of 6.5–10%, CKD Stage 1–3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value Results A double positive CD34/CD184 cell count had a statistically significant increase (p Conclusions In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015

The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward.

Supplemental Digital Content is available in the text., Hypertensive pregnancy is associated with increased maternal cardiovascular risk in later life. A range of cardiovascular adaptations after pregnancy have been reported to partly explain this risk. We used multimodality imaging to identify whether, by midlife, any pregnancy-associated phenotypes were still identifiable and to what extent they could be explained by blood pressure. Participants were identified by review of hospital maternity records 5 to 10 years after pregnancy and invited to a single visit for detailed cardiovascular imaging phenotyping. One hundred seventy-three women (age, 42±5 years, 70 after normotensive and 103 after hypertensive pregnancy) underwent magnetic resonance imaging of the heart and aorta, echocardiography, and vascular assessment, including capillaroscopy. Women with a history of hypertensive pregnancy had a distinct cardiac geometry with higher left ventricular mass index (49.9±7.1 versus 46.0±6.5 g/m2; P=0.001) and ejection fraction (65.6±5.4% versus 63.7±4.3%; P=0.03) but lower global longitudinal strain (−18.31±4.46% versus −19.94±3.59%; P=0.02). Left atrial volume index was also increased (40.4±9.2 versus 37.3±7.3 mL/m2; P=0.03) and E:A reduced (1.34±0.35 versus 1.52±0.45; P=0.003). Aortic compliance (0.240±0.053 versus 0.258±0.063; P=0.046) and functional capillary density (105.4±23.0 versus 115.2±20.9 capillaries/mm2; P=0.01) were reduced. Only differences in functional capillary density, left ventricular mass, and atrial volume indices remained after adjustment for blood pressure (P

Objective(s) To evaluate changes in injecting and sexual risk behaviours, and hepatitis C virus (HCV) reinfection incidence among people with HIV/HCV coinfection following unrestricted access to direct-acting antiviral therapy in Australia. Design Prospective observational cohort study (2014-2018). Methods Among people enrolled in the Control and Elimination of HCV from HIV-infected individuals within Australia study, changes in injecting and sexual behaviour were evaluated, including injecting drug use (IDU) in the last 6 months and last month, frequency of IDU and equipment sharing, condom-less anal intercourse with casual male partner(s), and group sex. HCV reinfection incidence was evaluated with follow-up through May 2018. Results Overall, 272 HIV/HCV antibody-positive participants [median age; 50 years, 96% male, 83% identified as gay and bisexual men (GBM)] had behavioural data at enrolment and follow-up (median 2.91 years) available for analysis. The proportion reporting IDU in the last 6 months remained stable from enrolment (35%) to follow-up (39%). Among GBM, the proportion reporting condom-less anal intercourse with casual partner(s) at enrolment (48%) and follow-up (46%) was also similar. Reinfection was detected in five individuals (all GBM) during total follow-up of 474 person-years for an overall incidence of 1.05 per 100 person-years (95% confidence interval, 0.44-2.53). Conclusion No change was observed in levels of injecting or sexual risk behaviour for HCV infection following unrestricted access to direct-acting antiviral therapy in an Australian HIV/HCV cohort. Incidence of HCV reinfection was low potentially reflecting high levels of treatment coverage within this population. Continued screening and rapid retreatment of reinfection will be required to maintain progress towards elimination.

Homeostatic and hedonic pathways distinctly interact to control food intake. Dysregulations of circuitries controlling hedonic feeding may disrupt homeostatic mechanisms and lead to eating disorders. The anorexigenic peptides nucleobindin-2 (NUCB2)/nesfatin-1 may be involved in the interaction of these pathways. The endogenous levels of this peptide are regulated by the feeding state, with reduced levels following fasting and normalized by refeeding. The fasting state is associated with biochemical and behavioral adaptations ultimately leading to enhanced sensitization of reward circuitries towards food reward. Although NUCB2/nesfatin-1 is expressed in reward-related brain areas, its role in regulating motivation and preference for nutrients has not yet been investigated. We here report that both dopamine and GABA neurons express NUCB2/nesfatin-1 in the VTA. Ex vivo electrophysiological recordings show that nesfatin-1 hyperpolarizes dopamine, but not GABA, neurons of the VTA by inducing an outward potassium current. In vivo, central administration of nesfatin-1 reduces motivation for food reward in a high-effort condition, sucrose intake and preference. We next adopted a 2-bottle choice procedure, whereby the reward value of sucrose was compared with that of a reference stimulus (sucralose + optogenetic stimulation of VTA dopamine neurons) and found that nesfatin-1 fully abolishes the fasting-induced increase in the reward value of sucrose. These findings indicate that nesfatin-1 reduces energy intake by negatively modulating dopaminergic neuron activity and, in turn, hedonic aspects of food intake. Since nesfatin-1´s actions are preserved in conditions of leptin resistance, the present findings render the NUCB2/nesfatin-1 system an appealing target for the development of novel therapeutical treatments towards obesity.

Background and aims Among treatment-naive individuals with chronic hepatitis C viral (HCV) infection and without cirrhosis, glecaprevir/pibrentasvir for 8 weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir/pibrentasvir for 6 weeks in people with acute and recent HCV infection. Approach and results In this open-label, single-arm, multicenter, international pilot study, adults with recent HCV (duration of infection 10 × upper limit of normal) or anti-HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months of enrollment and evidence of prior spontaneous or treatment-induced clearance. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Thirty men (median age 43 years, 90% men who have sex with men) received treatment, of whom 77% (n = 23) were human immunodeficiency virus-positive, 47% (n = 14) had ever injected drugs, and 13% (n = 4) had HCV reinfection. The majority had HCV genotype 1 (83%, n = 25), followed by genotype 4 (10%, n = 3) and genotype 3 (7%, n = 2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention-to-treat and per-protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse, and there were two cases of nonvirological failure (death, n = 1; loss to follow-up, n = 1). No treatment-related serious adverse events were seen. Conclusions Glecaprevir/pibrentasvir for 6 weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened-duration pan-genotypic therapy in this setting.

Colorectal cancer (CRC) is common across countries in males and females. Most cases originate from adenomas harboring high grade dysplasia. Among risk factors, weight excess has been suggested to positively influence dysplasia progression. In this study, the relationship between dysplasia grade of adenomas and body mass index (BMI) categories was analyzed.This was a retrospective case-control study. A total of 4745 charts (59.8% females) from patients undergoing colonoscopy were collected. Data regarding age, sex, smoking habits, occupation, residence, personal history of CRC, personal history of polyps and BMI were retrieved. Adenomas with high-grade dysplasia were labeled as advanced.They were 970 (20.4%) subjects with adenomas (cases: mean age 64.67 ± 11.35 years) and 3775 without (controls: mean age 56.43 ± 16.56 years). As expected, adenomas were significantly associated with overweight or obesity. After adjusting for all covariates the presence of advanced adenoma was significantly associated with age, male sex, smoking habits, personal history of CRC, overweight (OR = 1.298, IC 95% 1.092-1.697) and obesity (OR = 1.780, IC 95% 1.260-2.515).Our findings support the protective effect a normal weight against advanced adenomas. Reduction of BMI value should be pursued in healthy programs.

Introduction: Inadequate diet, whether due to excess or insufficient calories and nutrients, results in health risk situations as well as inadequate nutritional profile. The presence of nutritional deficiencies is more visible in women and, therefore, is more likely to reflect the risks of such deficiencies. Knowing the profile of the nutritional status of the female population of Maranhão, Brazil, which provide evidence of the nutritional status of their families, may support the creation of specific actions to combat eating problems and, consequently, improve their health. Objective: To evaluate the nutritional profile and its relationship with social determinants in a population of women attended by the program of Family Health Strategy in Maranhão. Methods: Cross-sectional study with 989 women aged 15 to 49 years, carried out during July to September 2010. Socioeconomic data were collected through a questionnaire, in addition it was applied of the Brazilian Food Insecurity Scale to know the level of food insecurity. Body mass index (BMI) and hip and waist circumference measurements were obtained to verify the nutritional profile. The variables were analyzed for frequencies, distribution and central tendency. Bivariate analysis was performed as to the associations between socioeconomic variables and BMI. The Spearman correlation coefficient was used between the food safety score and the BMI, adopting a significance level of 5%. Multivariate linear regression analysis was performed. Results: It was found a relationship between the BMI classification with some social determinants such as age, family income and food insecurity. There is a high prevalence of women at nutritional risk, especially for overweight and obesity, as well as the presence of thinness and short stature. Conclusion: Socioeconomic factors have a significant association with women's Body Mass Index indicating that there is an important relationship between age-matched maternal Body Mass Index and food insecurity.

There is substantial evidence linking disturbed gastrointestinal motility to inflammation. Thus, it is not surprising that abnormalities of gastrointestinal motility play a role in inflammatory bowel disease (IBD), affecting patient outcomes. We performed a review of the literature to investigate the relationship between abnormal gut motility and IBD. With an extensive literature search, we retrieved the pertinent articles linking disturbed gut motility to IBD in various anatomical districts. The evidence in the literature suggests that abnormal gastrointestinal motility plays a role in the clinical setting of IBD and may confuse the clinical picture. Abnormal gut motility may be important in the clinical setting of IBD. However, additional data obtained with modern techniques (e.g., magnetic resonance imaging) are needed to individuate in a more precise manner gastrointestinal motor dysfunctions, to understand the nature of clinical manifestations and properly tailor the treatment of patients.

BACKGROUND Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection is highly curative and tolerable. Among patients with hepatocellular carcinoma (HCC), optimal timing of DAA therapy remains unclear. Data on efficacy of DAA therapy in patients with HCC would inform this decision-making. AIM To evaluate response to DAA therapy among patients diagnosed with HCV infection and HCC. METHODS Bibliographic databases and conference abstracts were searched. Meta-analysis was conducted to pool sustained virologic response (SVR) estimates. RESULTS Fifty-six studies with 5522 patients with HCV and HCC were included. Overall SVR was 88.3% (95% CI 86.1-90.4). Twenty-seven studies included patients with prior or present HCC (n = 3126) and patients without HCC (n = 49 138), in which SVR was 88.2% (95% CI 85.0-91.4) and 92.4% (95% CI 91.1-93.7) among patients with and without HCC, respectively (odds ratio: 0.54, 95% CI 0.43-0.68, P

Background There is no systematic evidence review of the long-term results of surgical pulmonary valve replacement (PVR) dedicated to adults with repaired tetralogy of Fallot (rTOF) and pulmonary regurgitation. Methods Our primary objective was to determine whether PVR reduced long-term mortality in adults with rTOF compared with conservative therapy. Secondary objectives were to determine the postoperative incidence rate of death, the changes in functional capacity and in right ventricular (RV) volumes and ejection fraction after PVR, and the postoperative incidence rate of sustained ventricular arrhythmias. A systematic search of multiple databases for studies was conducted without limits. Results No eligible randomized controlled trial or cohort study compared outcomes of PVR and conservative therapy in adults with rTOF. We selected 10 cohort studies (total 657 patients) reporting secondary outcomes. After PVR, the pooled incidence rate of death was 1% per year (95% confidence interval [CI] 0-1% per year) and the pooled incidence rate of sustained ventricular arrhythmias was 1% per year (95% CI 1%-2% per year). PVR improved symptoms (odds ratio for postoperative New York Heart Association functional class > II 0.08, 95% CI 0.03-0.24). Indexed RV end-diastolic (−61.29 mL/m2, −43.64 to −78.94 mL/m2) and end-systolic (−37.20 mL/m2, −25.58 to −48.82 mL/m2) volumes decreased after PVR, but RV ejection fraction did not change (0.19%, −2.36% to 2.74%). The effect of PVR on RV volumes remained constant regardless of functional status. Conclusion Studies comparing PVR and conservative therapy exclusively in adults with rTOF are lacking. After PVR, the incidence rates of death and ventricular tachycardia are both 1 per 100 patient-years. Pooled analyses demonstrated an improved functional status and a reduction in RV volumes.

Neonatal diarrhea remains the primary cause of mortality in dairy calves around the world, and optimal treatment protocols are needed. The main goals of therapy are to restore hydration and electrolyte concentrations, correct strong ion (metabolic) acidemia, and provide nutritional support. Administration of oral electrolyte solutions (OES) has long been the primary method used to treat neonatal diarrhea in humans and calves because OES are capable of addressing each of the primary goals of therapy. In calves with moderate dehydration, we hypothesized that oral electrolytes would be as good as or better than small volumes of intravenous (IV) or subcutaneous (SC) fluids. Therefore, the main goal of this study was to compare the ability of a commercially available oral electrolyte solution (OES) administered alone or in combination with hypertonic saline with small volumes of IV or SC fluid therapy to resuscitate calves with diarrhea. Thirty-three Holstein calves from 5 to 14 d of age were utilized in this clinical trial. Diarrhea and dehydration were induced by adding sucrose to the milk replacer. In addition, hydrochlorothiazide and spironolactone were given orally and furosemide intramuscularly. Depression status, clinical hydration scores, fecal consistency, and body weight were recorded at regular intervals. Treatment began when calves had severe diarrhea and had a decrease in plasma volume of at least 10%. Calves were randomly assigned to 1 of 4 treatment groups of 8 to 9 calves per group: (1) OES; (2) OES with hypertonic saline (4 mL/kg, IV); (3) IV fluids (lactated Ringer's, 2 L); or (4) SC fluids (lactated Ringer's, 2 L). Treatments were given at 0 and 12 h. Changes in plasma volume, blood pH, electrolyte levels, and physical examination scores were determined before therapy and again at 1, 2, 4, 8, and 12 h after each treatment. All 4 treatments were ultimately successful in improving hydration as well as increasing blood pH; however, animals in both groups that received OES had much faster resuscitation than those in either the IV or SC fluid group. In conclusion, oral electrolyte products remain the gold standard for resuscitating diarrheic calves with moderate dehydration and acidemia and will likely perform better than small volumes of IV lactated Ringer's solution. Subcutaneous fluids by themselves are a poor treatment option and should be only be used as supportive therapy following the initial correction of hypovolemia and metabolic acidosis.

Purpose Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear. Methods Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [18F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Results The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.

The case highlights the value of contrast echocardiography in raising clinical suspicion of malignancy, allowing a diagnostic work‐up and the treatment of the primitive heart tumors., >The case highlights the value of contrast echocardiography in raising clinical suspicion of malignancy, allowing a diagnostic work‐up and the treatment of the primitive heart tumors. ​