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Objective In the past few years,F-18-fluorocholine PET/CT has been established as a promising imaging technique for preoperative localization of parathyroid adenomas, but the optimal time point to start PET/CT acquisition after tracer injection is yet unknown. The aim of the present study was to assess the optimal time frame to acquire the PET/CT images and to evaluate the ability of dynamic imaging to differentiate parathyroid adenomas from active lymph nodes, a common cause for false-positive scan results. Patients and methods Patients with primary hyperparathyroidism who had undergone a dynamic(18)F-fluorocholine PET/CT positive for parathyroid disease and who subsequently underwent successful parathyroidectomy were retrospectively included in this study. On the 20 minutes dynamic images, standardized uptake value measurements were acquired per 1 minute frame for the parathyroid adenoma, the thyroid gland, blood pool activity, and, if present, lymph node activity. Results A total of 101 patients were included in this study. Time-activity curves showed a decrease of activity in parathyroid and thyroid glands, with faster wash-out from the thyroid gland and on average a stable, lower activity in lymph nodes. Blood pool activity was particularly present in the first 2 minutes. Differentiation of a parathyroid adenoma from active lymph nodes was best before 5 minutes, but no definitive cutoff value could be determined. Differentiation of a parathyroid adenoma from the thyroid gland was best after 10 minutes. Conclusion Dynamic imaging starting at the early time point of 2 minutes after injection of(18)F-fluorocholine is useful for characterization of hyperfunctioning parathyroid glands.

AIM Evaluation of major adverse cardiovascular events (MACE) in women referred for NH3-PET/CT in relation to scan outcome and pharmacological stress ECG (PxECG) results. PATIENTS AND METHODS Six hundred twenty-four women, referred for NH3-PET/CT between 2012 and 2016, were included. Demographic data and MACE during follow-up (407 ± 207 days) were retrieved from electronic patient charts. NH3-PET/CT was scored as either normal or abnormal. PxECG was scored as negative, non-diagnostic or positive. PxECG was compared with NH3-PET/CT and related to MACE. RESULTS The NH3-PET/CT was normal in 482/624 (77%) and abnormal in 142/624 (23%). PxECG was negative in 234/624 (38%), non-diagnostic in 365/624 (58%) and positive in 25/624 (4%). NH3-PET/CT was normal in 87, 71 and 72% with normal, nondiagnostic and positive PxECG, respectively. 41/624(7%) experienced a MACE, 38 with abnormal NH3-PET/CT versus three with normal NH3-PET/CT (P < 0.001). MACE occurred in 5/234 (0.9%), 31/365 (8%) and 5/25 (20%) with normal, non-diagnostic and positive PxECG, respectively (P < 0.001). No MACEs were seen in 204 with both normal PxECG and NH3-PET/CT versus 5/30(17%) with normal PxECG but abnormal NH3-PET/. No MACE occurred in 3/260(1%) with non-diagnostic PxECG and normal NH3-PET/CT versus 28/105(27%) with non-diagnostic PxECG and abnormal NH3-PET/CT. 0/18 with positive PxECG and normal NH3-PET/CT showed MACE versus 5/7(71%) with a positive PxECG and abnormal NH3-PET/CT. CONCLUSION Normal NH3-PET/CT is most prevalent in women with normal PxECG. The occurrence of MACE during follow-up is more frequently related to an abnormal NH3-PET/CT than to PxECG. Furthermore, in women with positive PxECG but normal NH3-PET/CT no MACE are to be expected.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

An 81-year-old woman was evaluated for a stroke. CT showed no intracranial abnormalities but diffuse patchy aspect of the neurocranium. An MRI and F-NA PET/CT were performed to differentiate between metastases, Paget disease, hyperostosis frontalis interna, and primary malignancy. MRI yielded no additional findings. F-NA PET/CT showed diffusely increased uptake in the skull and 4 spots with intense uptake. No other suspicious skeletal foci were seen elsewhere. Low-dose CT showed no sign of malignancy elsewhere. Image findings together with elevated serum alkaline phosphatase levels, slightly increased calcium levels, and normal phosphorus levels were interpreted as pathognomic for monostotic Paget.

In dialogue, speakers tend to adapt their speech to the speech of their interlocutor. Adapting speech production to preceding speech input may be particularly relevant for second language (L2) speakers interacting with native (L1) speakers, as adaptation may facilitate L2 learning. Here we asked whether Dutch-English bilinguals adapt pronunciation of the English phonemes /ae/ and coda /b/ when reading aloud sentences after exposure to native English speech. Additionally, we tested whether social context (presence or absence of a native English confederate) and time lag between perception and production of the phoneme affected adaptation. Participants produced more English-like target words that ended in word-final /b/ after exposure to target phonemes produced by a native speaker, but the participants did not change their production of the phoneme /ae/ after exposure to native /ae/. The native English speaking confederate did not show consistent changes in speech production after exposure to target phonemes produced by L2 speakers. These findings are in line with Gambi and Pickering's simulation theory of phonetic imitation (Gambi & Pickering, 2013). (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Purpose: To analyze the results of endovascular repair of common iliac artery (CIA) aneurysms without preemptive coil embolization of the internal iliac artery (IIA). Materials and Methods: Between January 2010 and July 2016, 79 patients (mean age 74.3±8.4 years; 76 men) underwent endovascular repair extending into the external iliac artery owing to a CIA aneurysm. The procedure was performed for a ruptured aneurysm in 22 (28%) patients. Eighty-one IIAs were intentionally covered. The median CIA diameter was 37 mm (range 20–90). The primary outcomes were the occurrence of type II endoleaks and the incidence of buttock claudication. Results: Five (6%) patients died within 30 days (4 with ruptured aneurysms and 1 elective case). Two type II endoleaks originating from a covered IIA were recorded; one required an endovascular intervention because of aneurysm growth. The other patient died of a rupture based on an additional type III endoleak. Mean follow-up was 37.6±26.3 months. Nineteen (26%) patients required a secondary intervention. Buttock claudication was reported in 21 (28%) of 74 patients and persisted after 1 year in 7. No severe ischemic complications as a result of IIA coverage were recorded, and no revascularization was required during follow-up. Conclusion: Treatment of CIA aneurysms by overstenting the IIA without preemptive coil embolization is safe and has a low risk of type II endoleak and aneurysm growth. Persisting buttock claudication is rare.

Objectives: We hypothesize that three-dimensional (3D) geometric analyses in weight bearing CT-images of the foot and ankle are more reproducible compared to two-dimensional (2D) analyses. Therefore, we compared 2D and 3D analyses on bones of weight-bearing and non weight-bearing cone-beam CT images of healthy volunteers. Methods: Twenty healthy volunteers (10 male, 10 female, mean age 37.5 years) underwent weight-bearing and non weight-bearing cone-beam CT imaging of both feet. Clinically relevant height and angle measurements were performed in 2D and 3D (for example: cuboid height, calcaneal pitch, talo-calcaneal angle, Meary's angle, intermetatarsal angle). Three-dimensional measurements were obtained using automated software. Intra-observer and inter-observer agreement were evaluated for all 2D measurements. Results: Overall intraclass correlation coefficients (ICC's) were higher than 0.750 for most 2D measurements, ranging from 0.352 to 0.995. Calcaneal pitch, angle between the first metatarsal (MT1) and proximal phalange 1, between the fifth metatarsal (MT5) and the calcaneus and heights of the sesamoid bones, navicular, cuboid and talus decreased during weight-bearing in both 2D and 3D results (p < 0.01). Meary's angle was not statistically different in 2D (p = 0.627) and 3D (p = 0.765). Higher coefficients of variation in 2D geometric analysis parameters (0.27 versus 0.16) indicate that 3D analyses are more precise compared to 2D (p < 0.01). Results of left and right feet are comparable for 2D and 3D analyses. Conclusion: Although 2D and 3D geometrical analyses are fundamentally different, automated 3D analyses are more reproducible and precise compared to 2D analyses. In addition, 3D evaluation better demonstrates differences in bone configurations between weight-bearing and non weight-bearing conditions, which may be of value to demonstrate pathology.

Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, R t, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the R t of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, R t fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Purpose To investigate whether diabetes knowledge and health literacy impact glycemic control after 1 year of intermittently scanned continuous glucose monitoring (isCGM) in people with type 1 diabetes ≥ 16 years. Methods In this prospective real-world cohort study, we assessed diabetes knowledge using a new 10-item questionnaire [Patient Education and Knowledge (PEAK)] and health literacy using the validated 6-item Newest-Vital Sign-D (NVS-D) questionnaire. Primary endpoint was association between PEAK score and change in hemoglobin A1c (HbA1c). Secondary endpoints were link between NVS-D score and change in HbA1c and that between time spent in/above/below range and PEAK/NVS-D scores. Results 851 subjects were consecutively recruited between July 2016 and July 2018. Median PEAK score was 8 (range: 0-10), and median NVS-D score was 6 (range 0-6). HbA1c evolved from 7.9% (7.8%-8.0%), 63 (62-64) mmol/mol, at start to 7.7% (7.6%-7.7%), 61 (60-61) mmol/mol (P Conclusions isCGM reduced time in hypoglycemia, and HbA1c evolved favorably. Our findings suggest that diabetes and health literacy affect glucometrics, emphasizing the importance of education.

Identifying drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and quantifying population immunity is crucial to prepare for future epidemics. We performed a serial cross-sectional serosurvey throughout the first pandemic wave among patients from the largest health board in Scotland. Screening of 7480 patient serum samples showed a weekly seroprevalence ranging from 0.10% to 8.23% in primary and 0.21% to 17.44% in secondary care, respectively. Neutralization assays showed that highly neutralizing antibodies developed in about half of individuals who tested positive with enzyme-linked immunosorbent assay, mainly among secondary care patients. We estimated the individual probability of SARS-CoV-2 exposure and quantified associated risk factors. We show that secondary care patients, male patients, and 45–64-year-olds exhibit a higher probability of being seropositive. The identification of risk factors and the differences in virus neutralization activity between patient populations provided insights into the patterns of virus exposure during the first pandemic wave and shed light on what to expect in future waves.

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques., Inhibition of the metabolic enzyme ATP-citrate lyase can attenuate atherosclerosis by preventing dyslipidemia and potentially also by reducing macrophage-mediated inflammation. Here, the authors show that specific targeting of ACLY in macrophages results in more stable atherosclerotic plaques.

A 57 year old woman with a history of liver cirrhosis and ascites presented with serous exudate spontaneously leaking from a ruptured umbilical hernia, also known as Flood syndrome. This syndrome is a rare complication of decompensated liver cirrhosis and is associated with high mortality. In this specific case, there was also omentum protruding through the umbilical hernia which limited the outflow of ascites. Patient was successfully treated with antibiotics and consecutive open primary hernia repair without mesh implantation.

Research on error monitoring suggests that bilingual Dutch–English speakers are slower to correct some speech errors in their second language (L2) as opposed to their first language (L1). But which component of self-monitoring is slowed down in L2, error detection or interruption and repair of the error? This study charted the time course of monitoring in monolingual English speakers and bilingual Dutch–English speakers in language production and language comprehension, with the aim of pinpointing the component(s) of monitoring that cause an L2 disadvantage. First, we asked whether phonological errors are interrupted more slowly in L2. An analysis of data from three speech error elicitation experiments indeed showed that Dutch–English bilinguals were slower to stop speaking after an error had been detected in their L2 (English) than in their L1 (Dutch), at least for interrupted errors. A similar L2 disadvantage was found when comparing the L2 of Dutch–English bilinguals to the L1 of English monolinguals. Second, monolingual English speakers and bilingual Dutch–English speakers performed a picture naming task, a production monitoring task, and a comprehension monitoring task. Bilingual English speakers were slower in naming pictures in their L2 than monolingual English speakers. However, the production monitoring task and comprehension monitoring task yielded comparable response latencies between monolinguals in their L1 and bilinguals in their L2, indicating that monitoring processes in L2 are not generally slower. We suggest that interruption and repair are planned concurrently and that the difficulty of repairing in L2 triggers a slow-down in L2 interruption.

Background The diagnosis of infected hip prosthesis is frequently not straightforward yet very important as it changes treatment. Purpose To retrospectively investigate the added value of 18F-FDG PET/CT to conventional tests including radiography, erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) testing, and joint aspiration, in diagnosing infected hip prosthesis. Material and Methods Seventy-eight hip prostheses of 78 patients (55% men; mean age = 66.5 years; age range = 30–85 years) with non-specific clinical presentation, i.e. no abscess or sinus tract communicating with the joint space at clinical examination, were analyzed. Cultures of intra-articular fluid and peri-implant tissues after revision surgery or clinical follow-up ≥6 months served as gold standard. Areas under the receiver operating characteristic curves (AUCs) of radiography, ESR/CRP testing, aspiration culture, and white blood cell (WBC) count without and with the addition of 18F-FDG PET/CT were compared. Results The addition of 18F-FDG PET/CT increased AUCs: for radiography with 0.212, P = 0.001; for ESR/CRP testing with 0.076, P = 0.072; for aspiration culture with 0.126, P = 0.032; and for aspiration WBC count with 0.191, P = 0.035. Conclusion This study shows that 18F-FDG PET/CT adds to individual conventional tests in diagnosing infected hip prosthesis. It may improve the preoperative planning and should therefore be considered in the diagnostic work-up. Future studies should define the exact place of 18F-FDG PET/CT in the diagnostic work-up of periprosthetic joint infection.

Objective Determination of the accuracy of sodium fluorine-18-fluoride (F-NaF) PET/computed tomography (CT) for the evaluation of bone metastases, and the impact on patient management in breast cancer patients. Patients and methods Patients with breast cancer, referred for F-NaF PET/CT between February 2014 and June 2016, were included in a database. Baseline characteristics, clinical indication, definitive diagnosis according to follow-up data, as well as changes in patient management were recorded. Follow-up was performed during a period of at least 6 months using histopathologic, medical imaging, biochemical, and clinical data. Results A total of 118 patients were included in the study. Indications for F-NaF PET/CT included primary staging (12%), follow-up (31%), bone pain (52%), abnormal laboratory findings (5%), and evaluation of equivocal osseous lesions on other imaging modalities (3%). Bone metastases were found in 42%, whereas 53% of the scans were negative and 5% yielded equivocal results. Correlation with the reference standard yielded a sensitivity of 0.96, a specificity of 0.91, a positive predictive value of 0.89, a negative predictive value of 0.97, and an accuracy of 0.93. In 25% of the patients, the scan results led to alterations in patient management. F-NaF PET/CT for the evaluation of bone pain showed no explanation in 29%, benign pathology in 66%, and bone metastases in 5%. Conclusion In the present cohort of patients with breast cancer, F-NaF PET/CT detected bone metastases in 42% with an accuracy of 0.93. The scan results led to a change in patient management in 25%. In the evaluation of bone pain, an explanation for pain was found in 71% of the scans.

A 78-year-old woman with chest pain and a history of pacemaker implantation for arrhythmia underwent myocardial perfusion imaging by means of N-NH3 cardiac PET/CT. N-NH3 cardiac PET showed no signs of ischemia or infarction. Incidentally, a nodule with increased N-NH3 activity was observed in the right breast. Histopathologic examination revealed invasive ductal carcinoma.

OBJECTIVE In 2016, nationwide reimbursement of intermittently scanned continuous glucose monitoring (isCGM) for people living with type 1 diabetes treated in specialist diabetes centers was introduced in Belgium. We undertook a 12-month prospective observational multicenter real-world study to investigate impact of isCGM on quality of life and glycemic control. RESEARCH DESIGN AND METHODS Between July 2016 and July 2018, 1,913 adults with type 1 diabetes were consecutively recruited in three specialist diabetes centers. Demographic, metabolic, and quality of life data were collected at baseline, 6 months, and 12 months of standardized clinical follow-up. The primary end point was evolution of quality of life from baseline to 12 months. Secondary outcome measures were, among others, change in HbA1c, time spent in different glycemic ranges, occurrence of acute diabetes complications, and work absenteeism. RESULTS General and diabetes-specific quality of life was high at baseline and remained stable, whereas treatment satisfaction improved (P < 0.0001). Admissions for severe hypoglycemia and/or ketoacidosis were rare in the year before study (n = 63 out of 1,913; 3.3%), but decreased further to 2.2% (n = 37 out of 1,711; P = 0.031). During the study, fewer people reported severe hypoglycemic events (n = 280 out of 1,913 [14.6%] vs. n = 134 out of 1,711 [7.8%]; P < 0.0001) or hypoglycemic comas (n = 52 out of 1,913 [2.7%] vs. n = 18 out of 1,711 [1.1%]; P = 0.001) while maintaining HbA1c levels. Fewer people were absent from work (n = 111 out of 1,913 [5.8%] vs. n = 49 out of 1,711 [2.9%]; P < 0.0001). Time spent in hypoglycemia significantly decreased in parallel with less time in range and more time in hyperglycemia. Eleven percent (n = 210) of participants experienced skin reactions, leading to stopping of isCGM in 22 participants (1%). CONCLUSIONS Nationwide unrestricted reimbursement of isCGM in people with type 1 diabetes treated in specialist diabetes centers results in higher treatment satisfaction, less severe hypoglycemia, and less work absenteeism, while maintaining quality of life and HbA1c.

OBJECTIVE. Cannabis and alcohol use are correlated behaviors among youth. It is not known whether discontinuation of cannabis use is associated with changes in alcohol use. This study assessed alcohol use in youth before, during, and after four weeks of paid cannabis abstinence. METHODS. Healthy, non-treatment seeking, cannabis users (n=160), aged 14-25 years, 84% of whom used alcohol in the last month, were enrolled for a 4-week study with a 2-4 week follow-up. Participants were randomly assigned to four weeks of either biochemically-verified cannabis abstinence achieved through a contingency management framework (CB-Abst) or monitoring with no abstinence requirement (CB-Mon). Participants were assessed at baseline and approximately 4, 6, 10, 17, 24, and 31 days after enrollment. A follow-up visit with no cannabis abstinence requirement for CB-Abst was conducted after 2-4 weeks. RESULTS. Sixty percent of individuals assigned to the CB-Abst condition increased in frequency and quantity of alcohol consumption during the 4-week period of incentivized cannabis abstinence. As a whole, CB-Abst increased by a mean of 0.6 drinking days and 0.2 drinks per day in the initial week of abstinence (p’s0.53). There was no change in drinking frequency or quantity during the 4-week monitoring or follow-up periods among CB-Mon. CONCLUSIONS. On average, four weeks of incentivized (i.e., paid) cannabis abstinence among non-treatment seeking youth was associated with increased frequency and amount of alcohol use in week 1 that was sustained over 4 weeks and resolved with resumption of cannabis use. However, there was notable variability in individual-level response, with 60% increasing in alcohol use and 23% actually decreasing in alcohol use during cannabis abstinence. Findings suggest that increased alcohol use during cannabis abstinence among youth merits further study to determine whether this behavior occurs among treatment seeking youth and its clinical significance.

Purpose: To evaluate the differences in technical outcomes and secondary interventions between elective endovascular aneurysm repair (el-EVAR) procedures and those for ruptured aneurysms (r-EVAR). Methods: Of the 906 patients treated with primary EVAR from September 1998 until July 2012, 43 cases were excluded owing to the use of first-generation stent-grafts. Among the remaining 863 patients, 773 (89.6%) patients (mean age 72 years; 697 men) with asymptomatic or symptomatic abdominal aortic aneurysms (AAAs) were assigned to the el-EVAR group; 90 (10.4%) patients (mean age 73 years; 73 men) were assigned to the r-EVAR group based on blood outside the aortic wall on preoperative imaging. The primary study outcome was technical success; secondary endpoints, including freedom from secondary interventions and late survival, were examined with Kaplan-Meier analyses. Results: At baseline, r-EVAR patients had larger aneurysms on average (p

Hendra virus (HeV) continues to cause fatal infection in horses and threaten infection in close-contact humans in eastern Australia. Species of Pteropus bats (flying-foxes) are the natural reservoir of the virus. We caught and sampled flying-foxes from a multispecies roost in southeast Queensland, Australia on eight occasions between June 2013 and June 2014. The effects of sample date, species, sex, age class, body condition score (BCS), pregnancy and lactation on HeV antibody prevalence, log-transformed median fluorescent intensity (lnMFI) values and HeV RNA status were assessed using unbalanced generalised linear models. A total of 1968 flying-foxes were sampled, comprising 1012 Pteropus alecto, 742 P. poliocephalus and 214 P. scapulatus. Sample date, species and age class were each statistically associated with HeV RNA status, antibody status and lnMFI values; BCS was statistically associated with HeV RNA status and antibody status. The findings support immunologically naïve sub-adult P. alecto playing an important role in maintaining HeV infection at a population level. The biological significance of the association between BCS and HeV RNA status, and BCS and HeV antibody status, is less clear and warrants further investigation. Contrary to previous studies, we found no direct association between HeV infection and pregnancy or lactation. The findings in P. poliocephalus suggest that HeV exposure in this species may not result in systemic infection and virus excretion, or alternatively, may reflect assay cross-reactivity with another (unidentified) henipavirus.

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5-50mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 minutes (when peak effects were expected), and at 200 minutes after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) concentration significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 minutes after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.

Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA. Cancer Immunol Res; 4(2); 146–56. ©2015 AACR.

Rationale: Pulmonary sarcoidosis is classically defined by T-helper (Th) cell type 1 inflammation (e.g., IFN-gamma production by CD4(+) effector T cells). Recently, IL-17A-secreting cells have been found in lung lavage, invoking Th17 immunity in sarcoidosis. Studies also identified IL-17A-secreting cells that expressed IFN-gamma, but their abundance as a percentage of total CD4(+) cells was either low or undetermined. Objectives: Based on evidence that Th17 cells can be polarized to Th17.1 cells to produce only IFN-gamma, our goal was to determine whether Th17.1 cells are a prominent source of IFN-gamma in sarcoidosis. Methods: We developed a single-cell approach to define and isolate major Th-cell subsets using combinations of chemokine receptors and fluorescence-activated cell sorting. We subsequently confirmed the accuracy of subset enrichment by measuring cytokine production. Measurements and Main Results: Discrimination between Th17 and Th17.1 cells revealed very high percentages of Th17.1 cells in lung lavage in sarcoidosis compared with controls in two separate cohorts. No differences in Th17 or Th1 lavage cells were found compared with controls. Lung lavage Th17.1-cell percentages were also higher than Th1-cell percentages, and approximately 60% of Th17.1-enriched cells produced only IFN-gamma. Conclusions: Combined use of surface markers and functional assays to study CD4(+) T cells in sarcoidosis revealed a marked expansion of Th17.1 cells that only produce IFN-gamma. These results suggest that Th17.1 cells could be misclassified as Th1 cells and may be the predominant producer of IFN-gamma in pulmonary sarcoidosis, challenging the Th1 paradigm of pathogenesis.

The major treatment effect of prednisone on FVC is reached within 2 to 3 weeks in newly treated sarcoidosis patientshttp://ow.ly/3A3E30h5ZuT

The lung-draining mediastinal lymph nodes (MLNs) are currently widely used to diagnose sarcoidosis. We previously reported that T-helper (Th) 17.1 cells are responsible for the exaggerated interferon-γ production in sarcoidosis lungs. In this study, we aimed to investigate 1) whether Th17.1 cells are also increased in the MLNs of sarcoidosis patients and 2) whether frequencies of the Th17.1 cells at diagnosis may correlate with disease progression.MLN cells from treatment-naive pulmonary sarcoidosis patients (n=17) and healthy controls (n=22) and peripheral blood mononuclear cells (n=34) and bronchoalveolar lavage fluid (BALF) (n=36) from sarcoidosis patients were examined for CD4+ T-cell subset proportions using flow cytometry.Higher proportions of Th17.1 cells were detected in sarcoidosis MLNs than in control MLNs. Higher Th17.1 cell proportions were found in sarcoidosis BALF compared with MLNs and peripheral blood. Furthermore, BALF Th17.1 cell proportions were significantly higher in patients developing chronic disease than in patients undergoing resolution within 2 years of clinical follow-up.These data suggest that Th17.1 cell proportions in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and could serve as a new therapeutic target.

Prednisone is used as first-line therapy for pulmonary sarcoidosis. What dosing strategy has the best balance between effect and side-effects is largely unknown. We analyzed change in forced vital capacity (FVC) and weight during different prednisone doses used in daily practice for treatment naïve pulmonary sarcoidosis patients.Multilevel models were used to describe FVC and weight change over time. Correlations were calculated using linear regression models.Fifty-four patients were included. FVC changed over time (p 0.001), with an average increase of 9.6% predicted (95% CI: 7.2 to 12.1) at 12 months. Weight changed significantly over time (p 0.001), with an average increase of 4.3 kg (95% CI: 3.0 to 5.6) at 12 months. Although FVC and weight changed significantly over time, there was little correlation between prednisone dose and FVC change, while weight increase correlated significantly with cumulative prednisone dose at 24 months. In patients treated with a high cumulative prednisone dose, baseline FVC was on average lower (p = 0.001) compared to low dose treated patients, while no significant differences were observed in need for second/third-line therapy or number of exacerbations. A strategy leading to a low cumulative dose at 12 months was defined by rapid dose tapering to 10 mg/day within 3.5 months.These results suggest that prednisone therapy aimed at improving or preserving FVC in newly- treated pulmonary sarcoidosis can often be reduced in dose, using a treatment regimen that is characterized by early dose tapering.

This research focusses on low mood as a generic category in everyday social interactions, outside the clinical realm and among non-patients. We examine if and how a clinical depression label and treatment are employed when low mood occurs in everyday life, which enables us to analyze the extent and content of medicalization and brings to the fore the interactional mechanisms and cultural concerns that potentially drive medicalization. The analysis is based on 316 observations of everyday life in the Netherlands. We observed and recorded interactions in which low mood was spontaneously expressed.Our paper shows that the clinical depression label resonates widely even if low mood is not fully medicalized. People de-medicalize low mood, and low mood can be un-medicalized. Our analysis thus suggests that dominance is not achieved, which nuances Horwitz and Wakefield's claim that the clinical category of depression has come to encompass all forms of low mood. Moreover, uncertainties about the meaning of low mood and about the depression label remain pragmatic concerns of everyday life.The cultural norm of happiness and active citizenship are very prominent in everyday life across medicalized and un-medicalized interactions. These norms thus seem to be a necessary but insufficient condition for medicalization. While pragmatic concerns do not seem to trigger medicalization either, one specific type of concern is consistently related to medicalization: relational conflicts.In sum, the cultural construction of low mood is not dominated by a single medical approach; however, it mirrors the diversity and uncertainties within and around the medical field.

Background Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. Methods Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. Results Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. Conclusion Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.

Background Endovascular aneurysm repair of aortoiliac or iliac aneurysms is often performed with stent graft coverage of the origin of the hypogastric artery (HA) to ensure adequate distal seal. It is considered common practice to perform adjunctive coiling of the HA to prevent a type II endoleak. Our objective was to question the necessity of pre-emptive coiling by comparing the outcomes of HA coverage with and without prior coil embolization. Methods Data from the Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE), which prospectively enrolled 1263 endovascular aneurysm repair patients between March 2009 and April 2011 from multiple centers worldwide, were used for this study. We identified patients in whom the Endurant stent graft (Medtronic Vascular, Santa Rosa, Calif) covered one or both HAs and grouped them into cases in which prior HA embolization—coils or plugs—was performed (CE) and cases in which HA embolization was not performed (NE). The occurrence of covered HA-related endoleak and secondary interventions were compared between groups. Results In 197 patients, 225 HAs were covered. Ninety-one HAs were covered after coil embolization (CE group), and 134 HAs were covered without prior coil embolization (NE group). Both groups were similar at baseline and had comparable length of follow-up to last image (665.2 ± 321.7 days for CE patients; 641.6 ± 327.6 days for NE patients; P = .464). Importantly, both groups showed equivalent iliac morphology concerning common iliac artery proximal, mid, and distal dimensions and tortuosity, making them suitable for comparative analysis. During follow-up, HA-related endoleaks were sparse and occurred equally often in both groups (CE 5.5% vs NE 3.0%; P = .346). Secondary intervention to resolve an HA-related endoleak was performed twice in the CE group and three times in the NE group. Late non-HA-related endoleaks occurred more often in the CE group compared with the NE group, (25.0% vs 15.0%; P = .080). Secondary interventions for other reasons than HA-related endoleaks occurred in 7.5% of NE cases and 15.4% of CE cases ( P = .057), mostly for occlusions in the ipsilateral iliac limb. During follow-up, 19 NE patients and 9 CE patients died, which is not significantly different ( P = .225), and no deaths were related directly or indirectly to HA coverage. Also, no reports of gluteal necrosis and bowel ischemia were made. Conclusions This study shows that HA coverage with the Endurant endograft without prior coil embolization does not increase the incidence of endoleak or related secondary interventions. These findings together with the already available evidence suggest that omission of coil embolization may be a more resource-effective strategy whenever HA coverage is required.

Objective Lifelong yearly surveillance is advised after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms. This follow-up requires a substantial amount of health care resources. The aim of this paper was to assess the occurrence of stent graft-related complications and secondary interventions during a minimum 10-year follow-up after elective EVAR. Methods Patients who were treated in a high-volume endovascular center in The Netherlands with the Talent infrarenal stent graft (Medtronic Vascular, Santa Rosa, Calif) between June 1999 and February 2005 were included. Patients with previous aortic surgery or emergency interventions were excluded. Our primary outcome was clinical success up to 10 years. Secondary end points were technical success and survival. Results A total of 149 patients were included; 91.9% were male. The mean age was 70.2 ± 7.8 years. A stent graft was implanted in 98% of patients; technical success was achieved in 89.9%. Clinical success after 30 days, 1 year, 5 years, and 10 years was 81.1%, 74.3%, 70.3%, and 65.5%, respectively. In 30 patients (20.7%), a secondary intervention was required; 80.0% of first secondary interventions occurred within the first 5 years. Six late conversions were necessary because of stent graft infection (2), migration (2), or persisting endoleak (2). The 5- and 10-year overall survival rates were 55.2% and 38.6%, respectively. Conclusions The risk of EVAR-related complication is highest in the first 5 years. Consequently, the main focus should be on that period; further follow-up must not be neglected, as complications occur up to 10 years after treatment.

Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NPs induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-α in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.

Dendritic cells are potential targets in allergy therapy as they, under the influence of their microenvironment, regulate T-cell responses. Histamine has been shown to promote Th2 polarization by dendritic cells. However, neither the mechanism nor the functionality of the different histamine receptors in this process has been fully elucidated. The aim of the present study was to identify factors involved in histamine-mediated dendritic cell activation as well as to study dendritic cell expression of histamine H(1) and H(4) receptors and their influence on allergen-specific T-cell responses in grass pollen allergy. Assessment of dendritic cell gene regulation by histamine using mRNA microarrays demonstrated that histamine alters many immunoregulatory genes of which the majority are novel in this context. Additionally, immunocytochemical stainings showed protein expression of histamine H(1) and H(4) receptors on dendritic cells from healthy and allergic donors. Furthermore, histamine H(1) and H(4) receptor antagonists (pyrilamine/N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyridin-2-ylethane-1,2-diamine and JNJ7777120/1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine, respectively) were shown to influence histamine-induced dendritic cell maturation. Interestingly, JNJ7777120 inhibited dendritic cells' capacity to induce allergen-specific T-cell proliferation. In conclusion, H(4) receptor antagonism suppressed DC-induced, allergen-specific T-cell responses in humans and might thus inhibit allergic responses. This finding indicates that the H(4) receptor is a potential treatment target in human allergic conditions.

Our previous screening of a Glossina morsitans morsitans λgt11 salivary gland expression library with serum of a tsetse fly exposed rabbit identified a cDNA encoding Tsetse Antigen5 (TAg5, 28.9 kDa), a homologue of Antigen5 sting venom allergens. Recombinant TAg5 was produced in Sf9 cells in order to assess its immunogenic properties in humans. Plasma from a patient that previously exhibited anaphylactic reactions against tsetse fly bites contained circulating anti-TAg5 and anti-saliva IgEs. In a significant proportion of plasma samples of African individuals, TAg5 and saliva binding IgEs (respectively 56 and 65%) can be detected. Saliva, harvested from flies that were subjected to TAg5-specific RNA interference (RNAi), displayed significantly reduced IgE binding potential. Allergenic properties of TAg5 and tsetse fly saliva were further illustrated in immunized mice, using an immediate cutaneous hypersensitivity and passive cutaneous anaphylaxis assay. Collectively, TAg5 was illustrated to be a tsetse fly salivary allergen, demonstrating that Antigen5-related proteins are represented as functional allergens not only in stinging but also in blood feeding insects. Abstract: Our previous screening of a Glossma morsitans; morsitans lambda gt11 salivary gland expression library with serum of a tsetse fly exposed rabbit identified a cDNA encoding Tsetse Antigen5 (TAg5, 28.9 kDa), a homologue of Antigen5 sting venom allergens. Recombinant TAg5 was produced in Sf9 cells in order to assess its immunogenic properties in humans. Plasma from a patient that previously exhibited anaphylactic reactions against tsetse fly bites contained circulating anti-TAg5 and anti-saliva IgEs. In a significant proportion of plasma samples of African individuals, TAg5 and saliva binding IgEs (respectively 56 and 65%) can be detected. Saliva, harvested from flies that were subjected to TAg5-specific RNA interference (RNAi), displayed significantly reduced IgE binding potential. Allergenic properties of TAg5 and tsetse fly saliva were further illustrated in immunized mice, using an immediate cutaneous hypersensitivity and passive cutaneous anaphylaxis assay. Collectively, TAg5 was illustrated to be a tsetse fly salivary allergen, demonstrating that Antigen5-related proteins are represented as functional allergens not only in stinging but also in blood feeding insects. (C) 2009 Elsevier Ltd. All rights reserved.

Contains fulltext : 81934.pdf (Publisher’s version ) (Closed access) CONTEXT: Liquid-based cytology has been developed as an alternative for conventional cervical cytology. Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy. OBJECTIVE: To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN). DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized controlled trial involving 89,784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40,562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008. INTERVENTION: Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). MAIN OUTCOME MEASURES: Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). RESULTS: The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. CONCLUSION: This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1032.

Basophils are emerging as immunoregulatory cells capable of interacting with their environment not only via their characteristic IgE-mediated activation, but also in an IgE-independent manner. Basophils are known to express and respond to stimulation via TLR2, TLR4, DC-SIGN and DCIR, but whether basophils also express other C-type lectin receptors (CLRs) is largely unknown. In this study, we investigate the CLR expression profile of human basophils using multicolour flow cytometry. As FcRs as well as some CLRs are associated with allergen recognition and shown to be involved in subsequent immune responses, the expression of CLRs and FcRs on peripheral blood basophils, as well as their frequency, was monitored for 1 year in subjects undergoing subcutaneous allergen-specific immunotherapy (AIT). Here, we show that human basophils express CLECSF14, DEC205, Dectin-1, Dectin-2 and MRC2. Furthermore, we demonstrate that the frequencies of basophils expressing the allergy-associated CLRs Dectin-1 and Dectin-2 were significantly reduced after 1 year and 8 weeks of AIT, respectively. In contrast, the frequency of basophils positive for FcγRII, as well as the fraction of total basophils, significantly increased after 1 year of AIT. The herein demonstrated expression of various CLRs on basophils, and their altered CLR and FcR expression profile upon AIT, suggest yet unexplored ways by which basophils can interact with antigens and may point to novel immunoregulatory functions targeted through AIT.

Allergen-specific immunotherapy (AIT) induces tolerance and shifts the Th2 response towards a regulatory T-cell profile. The underlying mechanisms are not fully understood, but dendritic cells (DC) play a vital role as key regulators of T-cell responses. DCs interact with allergens via Fc receptors (FcRs) and via certain C-type lectin receptors (CLRs), including CD209/DC-SIGN, CD206/MR and Dectin-2/CLEC6A. In this study, the effect of AIT on the frequencies as well as the FcR and CLR expression profiles of human DC subsets was assessed. PBMC was isolated from peripheral blood from seven allergic donors before and after 8 weeks and 1 year of subcutaneous AIT, as well as from six non-allergic individuals. Cells were stained with antibodies against DC subset-specific markers and a panel of FcRs and CLRs and analyzed by flow cytometry. After 1 year of AIT, the frequency of CD123+ DCs was increased and a larger proportion expressed FceRI. Furthermore, the expression of CD206 and Dectin-2 was reduced on CD141+ DCs after 1 year of treatment and CD206 as well as Dectin-1 was additionally down regulated in CD1c+ DCs. Interestingly, levels of DNGR1/CLEC9A on CD141+ DCs were increased by AIT, reaching levels similar to cells isolated from non-allergic controls. The modifications in phenotype and occurrence of specific DC subsets observed during AIT suggest an altered capacity of DC subsets to interact with allergens, which can be part of the mechanisms by which AIT induces allergen tolerance.

In cases of complex reconstructive surgery of the innominate bone, it is difficult to draw up a good surgical plan; manual planning of a 3D reconstruction is highly demanding and time-consuming. This paper presents and validates methodology to automatically generate 3D correction proposals for reconstructive surgery of the innominate bone, and illustrates its use with clinical applications.The developed Matlab methodology starts from CT-based outer surface representations of the patient's bone, which allow straightforward mirror and matching implementations for automated reconstruction procedures. The validation on 9 cadavers was two-fold: the geometrical deviations of the intact original with respect to the reconstructed surface meshes were assessed, and the characteristics of both original and reconstructed acetabular cup regions were determined.Eighteen healthy and thus, it was assumed, spherical acetabula were automatically reconstructed with mean accuracies of 3.2 +/- 2.2 mm, 0.1 +/- 1.0 mm and 3.8 +/- 2.9 degrees for the hip joint centerpoint, joint radius and cup orientation, respectively. As a demonstration, a triflange cup acetabular implant was rapidly designed, starting from the correction proposal.A highly automated, computer-aided approach to surgical planning for pelvic bone defects was developed and sample applications demonstrated. Validation results for healthy acetabula were superior to those obtained in real surgery. The generated virtual correction proposals can be used as targets in surgical planning and cup navigation applications, or in the design of customized implants with complex shapes.

Pteropid bats or flying-foxes (Chiroptera: Pteropodidae) are the natural host of Hendra virus (HeV) which sporadically causes fatal disease in horses and humans in eastern Australia. While there is strong evidence that urine is an important infectious medium that likely drives bat to bat transmission and bat to horse transmission, there is uncertainty about the relative importance of alternative routes of excretion such as nasal and oral secretions, and faeces. Identifying the potential routes of HeV excretion in flying-foxes is important to effectively mitigate equine exposure risk at the bat-horse interface, and in determining transmission rates in host-pathogen models. The aim of this study was to identify the major routes of HeV excretion in naturally infected flying-foxes, and secondarily, to identify between-species variation in excretion prevalence. A total of 2840 flying-foxes from three of the four Australian mainland species (Pteropus alecto, P. poliocephalus and P. scapulatus) were captured and sampled at multiple roost locations in the eastern states of Queensland and New South Wales between 2012 and 2014. A range of biological samples (urine and serum, and urogenital, nasal, oral and rectal swabs) were collected from anaesthetized bats, and tested for HeV RNA using a qRT-PCR assay targeting the M gene. Forty-two P. alecto (n = 1410) had HeV RNA detected in at least one sample, and yielded a total of 78 positive samples, at an overall detection rate of 1.76% across all samples tested in this species (78/4436). The rate of detection, and the amount of viral RNA, was highest in urine samples (>serum, packed haemocytes >faecal >nasal >oral), identifying urine as the most plausible source of infection for flying-foxes and for horses. Detection in a urine sample was more efficient than detection in urogenital swabs, identifying the former as the preferred diagnostic sample. The detection of HeV RNA in serum is consistent with haematogenous spread, and with hypothesised latency and recrudesence in flying-foxes. There were no detections in P. poliocephalus (n = 1168 animals; n = 2958 samples) or P. scapulatus (n = 262 animals; n = 985 samples), suggesting (consistent with other recent studies) that these species are epidemiologically less important than P. alecto in HeV infection dynamics. The study is unprecedented in terms of the individual animal approach, the large sample size, and the use of a molecular assay to directly determine infection status. These features provide a high level of confidence in the veracity of our findings, and a sound basis from which to more precisely target equine risk mitigation strategies.

Purpose: To examine outcomes of endovascular aortic aneurysm repair (EVAR) using general, regional, or local anesthesia. Methods: From March 2009 to April 2011, patients were enrolled from 79 sites in 30 countries worldwide and treated with an Endurant Stent Graft System. Data were compared among 3 groups based on the method of anesthesia: general anesthesia (GA) was used in 785 (62%) patients, regional anesthesia (RA) in 331 (27%) patients, and local anesthesia (LA) in 145 (11%) patients. Multivariate logistic regression analysis was performed to adjust for possible confounding factors; outcomes are presented as the odds ratio and 95% confidence interval. Results: There were intercontinental differences in the distribution of type of anesthesia used for EVAR. Higher ASA (American Society of Anesthesiologists) classification was associated with predominant use of GA. Procedure time was reduced in LA (80.4±40.0 minutes) compared with RA (94.2±41.6 min, adjusted p =0.001) and GA (105.3±46.0 minutes, adjusted p

This study aimed to compare perioperative and postoperative outcomes after endovascular repair of abdominal aortic aneurysms (AAAs) in patients with various neck morphologic features.Data from the Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE) were used for the analyses. Patients were categorized into three different groups according to proximal aortic neck anatomy: regular (REG), intermediate (INT), and challenging (CHA). REG was defined as AAAs with a proximal neck ≥15 mm combined with a suprarenal angulation (α) ≤45 degrees and an infrarenal neck angulation (ß) ≤60 degrees. INT was defined as AAAs with a proximal neck of 10 to 15 mm combined with α ≤45 degrees and ß ≤60 degrees or with a proximal neck of15 mm combined with α ≤60 degrees and ß = 60 to 75 degrees or α = 45 to 60 degrees and ß ≤75 degrees. CHA was defined as infrarenal necks that exceed at least one of the three defining factors.Overall, 925 patients (75.9%) had REG anatomy, 189 patients (15.5%) had INT anatomy, and 104 patients (8.5%) had CHA anatomy. Patient demographics and risk factors were similar. There was a significant difference in AAA diameter between the REG and CHA groups (59.4 mm vs 65.2 mm; P.001). Technical success was similar among groups (REG 99.1% vs INT 99.5% vs CHA 97.1%). There were no differences in mortality or the need for secondary procedures within 30 days or at 1 year. A significantly higher rate of type I endoleaks within 30 days was seen in CHA compared with REG (adjusted odds ratio, 0.15; 95% confidence interval, 0.05-0.46) and INT (adjusted odds ratio, 0.08; 95% confidence interval, 0.01-0.70), but there was no difference at 1-year follow-up.This real-world, global experience shows promising results and indicates that endovascular AAA repair with the Endurant stent graft (Medtronic Vascular, Santa Rosa, Calif) is safe and effective in patients with challenging aortic neck anatomy. However, long-term follow-up of patients is required to confirm results.

Objective A ruptured abdominal aortic aneurysm (RAAA) is associated with a high mortality rate. If cardiopulmonary resuscitation (CPR) is required before surgical repair, mortality rates are said to approach 100%. The aim of this multicenter, retrospective study was to study outcome in RAAA patients who required CPR before a surgical (endovascular or open) repair (CPR group). RAAA patients who did not need CPR served as controls (non-CPR group). Methods Over a 5-year time period, demographic and clinical characteristics and specifics of preoperative CPR if necessary were studied in all patients who were treated for a RAAA in three large, nonacademic hospitals. Results A total of 199 consecutive RAAA patients were available for analysis; 176 patients were surgically treated. Thirteen of these 176 patients (7.4%) needed CPR, and 163 (92.6%) did not. A 38.5% (5 of 13) survival rate was observed in the CPR group. Thirty-day mortality was almost three times greater in the CPR group compared with the non-CPR group (61.5% vs 22.7%; P = .005). Both CPR patients who received endovascular aortic repair survived. In contrast, survival in 11 CPR patients who underwent open RAAA repair was 27% (3 of 11; P = .128). A trend for higher Hardman index was found in patients who received CPR compared with patients who did not receive CPR ( P = .052). The 30-day mortality in patients with a 0, 1, 2, or 3 Hardman index was 16.1%, 31.0%, 37.9%, and 33.3%, respectively ( P = .093). Conclusions An RAAA that requires preoperative CPR is not necessarily a lethal combination. Patient selection must be tailored before surgery is denied.

Pancreatic insufficiency cystic fibrosis (CF) patients receive vitamin E supplementation according to CF-specific recommendations in order to prevent deficiencies. It has been suggested that higher serum α-tocopherol levels could have protective effects on pulmonary function (PF) in patients with CF. Whether current recommendations are indeed optimal for preventing deficiency and whether vitamin E has therapeutic benefits are subjects of debate. Therefore, we studied vitamin E intake as well as the long-term effects of vitamin E intake, the coefficient of fat absorption (CFA) and IgG on α-tocopherol levels. We also examined the long-term effects of serum α-tocopherol and serum IgG on forced expiratory volume in 1 s expressed as percentage of predicted (FEV1% pred.) in paediatric CF patients during a 7-year follow-up period. We found that CF patients failed to meet the CF-specific vitamin E recommendations, but serum α-tocopherol below the 2·5th percentile was found in only twenty-three of the 1022 measurements (2 %). Furthermore, no clear effect of vitamin E intake or the CFA on serum α-tocopherol was found (both P≥ 0·103). FEV1% pred. was longitudinally inversely associated with age (PP= 0·003), but it was not related to serum α-tocopherol levels. We concluded that in the present large sample of children and adolescents with CF, vitamin E intake was lower than recommended, but serum α-tocopherol deficiency was rare. We found no evidence that higher serum α-tocopherol levels had protective effects on PF. Adjustment of the recommendations to the real-life intake of these patients may be considered.

As the world population ages, the prevalence of osteoporosis and the incidence of hip fractures will increase dramatically, being responsible for an increase of the health expenditure. On the other hand, there is the inescapable fact of scarcity creating the necessity of making difficult choices with regard to the allocation of human resources. So the question remains: should we carry on investing an important part of our health expenditure for the treatment of hip fractures in elderly people? To answer this statement, we compared 384 hip fracture patients of 70 years and older treated in our department between 1978 and 1983 with 1102 patients treated between 1998 and 2003. Both groups had a prospective follow-up of at least one year. There were no statistically significant differences: mortality rate 24% vs. 23%; good functional outcome 82% vs. 73%; and home going rate 60% vs. 66%. The factors influencing these results were studied. So we can conclude: The number of hip fractures treated nowadays has increased compared with twenty years ago; There is no significant improvement in mortality, nor in quality of life; Age is not a contraindication for hip fracture surgery.

Objective Sustained external chest compressions during cardiocerebral resuscitation (CCR) are physically demanding. It might be hypothesized that a high cardiopulmonary exercise capacity and/or muscle strength delays the development of physical fatigue and, consequently, preserves CCR quality. We intended to assess the impact of cardiopulmonary exercise capacity and muscle strength on CCR quality. Methods Fifteen healthcare professionals (10 men and five women, mean age 34± 9 years) performed a 15-min hands-on CCR session on an adult training manikin. CCR compression depth (from which CCR quality was calculated) and frequency were monitored. During CCR we assessed serial blood lactate concentrations, and provided continuous heart rate monitoring. Relationships were examined between participant characteristics, peak cardiopulmonary exercise capacity, ventilatory threshold, maximal muscle strength, muscle strength endurance and CCR quality. Results Significant univariate correlations were found between 15-min CCR quality and body height (r =0.53), ventilatory threshold (r =0.67), peak oxygen uptake capacity (r =0.54), peak cycling power output (r= 0.54), and maximal isometric elbow extension strength (r= 0.55) (P < 0.05). CCR quality was significantly lower in females, when compared with males (P < 0.05). Within different timeframes, CCR quality was mainly related to the ventilatory threshold up to the first 5 min (P < 0.05), whereas CCR quality was mainly related to maximal isometric elbow extension strength after 5 min (P

In situ modification of antigen-presenting cells garnered interest in cancer immunotherapy. Therefore, we developed APC-targeted lentiviral vectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL-12 is a potent mediator of antitumor immunity, we evaluated whether this proinflammatory cytokine could enhance antitumor immunity of an APC-targeted LV-based vaccine. Therefore, we compared subcutaneous administration of broad tropism LVs (VSV-G-LV) with APC-targeted LVs (DC2.1-LV)-encoding enhanced GFP and ovalbumin, or IL-12 and ovalbumin in mice. We show that codelivery of IL-12 by VSV-G-LVs or DC2.1-LVs augments CD4(+) or CD8(+) T-cell proliferation, respectively. Furthermore, we demonstrate that codelivery of IL-12 enhances the CD4(+) TH 1 profile irrespective of its delivery mode, while an increase in cytotoxic and therapeutic CD8(+) T cells was only induced upon VSV-G-LV injection. While codelivery of IL-12 by DC2.1-LVs did not enhance CD8(+) T-cell performance, it increased expression of inhibitory checkpoint markers Lag3, Tim3, and PD-1. Finally, the discrepancy between CD4(+) T-cell stimulation with and without functional CD8(+) T-cell stimulation by VSV-G- and DC2.1-LVs is partly explained by the observation that IL-12 relieves CD8(+) T cells from CD4(+) T-cell help, implying that a T(H)1 profile is of minor importance for antitumor immunotherapy if IL-12 is exogenously delivered.

Background Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis. Methods Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC). Results In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO+ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs. Conclusion In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.

Item does not contain fulltext OBJECTIVE: Since chronic Q fever often develops insidiously, and symptoms are not always recognized at an early stage, complications are often present at the time of diagnosis. We describe complications associated with vascular chronic Q fever as found in the largest cohort of chronic Q fever patients so far. METHODS: Patients with proven or probable chronic Q fever with a focus of infection in an aortic aneurysm or vascular graft were included in this study, using the Dutch national chronic Q fever database. RESULTS: A total of 122 patients were diagnosed with vascular chronic Q fever between April 2008 and June 2012. The infection affected a vascular graft in 62 patients (50.8%) and an aneurysm in 53 patients (43.7%). Seven patients (5.7%) had a different vascular focus. Thirty-six patients (29.5%) presented with acute complications, and 35 of these patients (97.2%) underwent surgery. Following diagnosis and start of antibiotic treatment, 26 patients (21.3%) presented with a variety of complications requiring surgical treatment during a mean follow-up of 14.1 +/- 9.1 months. The overall mortality rate was 23.7%. Among these patients, mortality was associated with chronic Q fever in 18 patients (62.1%). CONCLUSIONS: The management of vascular infections with C. burnetii tends to be complicated. Diagnosis is often difficult due to asymptomatic presentation. Patients undergo challenging surgical corrections and long-term antibiotic treatment. Complication rates and mortality are high in this patient cohort.