Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor—Rationale and Design of the IMAD Pilot Study

Background: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer’s clinical syndrome within a one-year follow-up period. Methods: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19–26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months. Conclusion: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer’s clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters

The true and the fake: archaeometric investigations on two Bronze Age solid-hilted swords from East Flanders (Belgium)

International audienc

Efficiently Reducing Corrections Costs in Wisconsin: Applying the Washington State Model

The authors examine evidence-based programs that can reduce crime and lower corrections costs in Wisconsin. Their cost-benefit analysis identifies nine combinations of prison population reduction and reinvestment of subsequent savings into programs that reduce crime. Decreasing the average daily prison population by 10 percent (2,248 prisoners) and reinvesting 100 percent of the savings was the option with the highest estimated societal savings

Nitrous oxide in the northern Gulf of Aqaba and the central Red Sea

Nitrous oxide (N2O) is a climate-relevant atmospheric trace gas. It is produced as an intermediate of the nitrogen cycle. The open and coastal oceans are major sources of atmospheric N2O. However, its oceanic distribution is still largely unknown. Here we present the first measurements of the water column distribution of N2O in the Gulf of Aqaba and the Red Sea. Samples for N2O depth profiles were collected at the time-series site Station A in the northern Gulf of Aqaba (June and September 2003, and February 2004) and at several stations in the central Red Sea (October 2014, January and August 2016). Additionally, we measured N2O concentrations in brine pool samples collected in the northern and central Red Sea (January 2005 and August 2016). In the Gulf of Aqaba, N2O surface concentrations ranged from 6 to 8 nmol L−1 (97–111% saturation) and were close to the equilibrium with the overlying atmosphere. A pronounced temporal variability of the N2O water column distribution was observed. We suggest that this variability is a reflection of the interplay between N2O production by nitrification and its consumption by N2 fixation in the layers below 150 m during summer. N2O surface concentrations and saturations in the central Red Sea basin ranged from 2 to 9 nmol L−1 (43–155% saturation). A pronounced temporal variability with significant supersaturation in October 2014 and undersaturation in January and August 2016 was observed in the surface layer. In October 2014, N2O in the water column seemed to result from production via nitrification. Low N2O water column concentrations in January and August 2016 indicated a significant removal of N2O. We speculate that either in-situ consumption or remote loss processes of N2O such as denitrification in coastal regions were responsible for this difference. Strong meso- and submesoscale processes might have transported the coastal signals across the Red Sea. In addition, enhanced N2O concentrations of up to 39 nmol L−1 were found at the seawater-brine pool interfaces which point to an N2O production via nitrification and/or denitrification at low O2 concentrations. Our results indicate that the Red Sea and the Gulf of Aqaba are unique natural laboratories for the study of N2O production and consumption pathways under extreme conditions in one of the warmest and most saline region of the global oceans

Agreement between Self- and Clinician-Collected Specimen Results for Detection and Typing of High-Risk Human Papillomavirus in Specimens from Women in Gugulethu, South Africa▿

We assessed the agreement in detection of high-risk human papillomavirus (HPV), as well as specific HPV types, between self- and clinician-obtained specimens for 450 women over 18 years of age attending a community health center in Gugulethu, South Africa. Both self-collected swabs and tampons had high agreement with clinician-obtained brushes when the Roche Reverse Line Blot Assay (RLBA) was used (for swabs, 86% concordance, with a kappa statistic [κ] of 0.71; for tampons, 89% concordance, with κ of 0.75). Agreement was lower, although still fair, with the Digene Hybrid Capture 2 test (HC2), with κ higher for swabs than for tampons (for swabs, 81% concordance, with κ of 0.61; for tampons, 82% concordance, with κ of 0.55). Low-risk HPV types were nearly two times more common in self-collected specimens than in clinician-collected specimens tested by RLBA. All 15 women diagnosed with high-grade lesions by cytology tested positive for high-risk HPV with clinician-collected specimens tested by RLBA and HC2, while 11 out of 15 tested positive with self-collected specimens by HC2 and 5 out of 6 tested positive by RLBA. Self-collected specimens can provide valid specimens for HPV testing using nucleic acid amplification tests, although a few cytological abnormalities may be missed

Nitrous oxide in the northern Gulf of Aqaba and the central Red Sea

Nitrous oxide (N2O) is a climate-relevant atmospheric trace gas. It is produced as an intermediate of the nitrogen cycle. The open and coastal oceans are major sources of atmospheric N2O. However, its oceanic distribution is still largely unknown. Here we present the first measurements of the water column distribution of N2O in the Gulf of Aqaba and the Red Sea. Samples for N2O depth profiles were collected at the time-series site Station A in the northern Gulf of Aqaba (June and September 2003, and February 2004) and at several stations in the central Red Sea (October 2014, January and August 2016). Additionally, we measured N2O concentrations in brine pool samples collected in the northern and central Red Sea (January 2005 and August 2016). In the Gulf of Aqaba, N2O surface concentrations ranged from 6 to 8 nmol L−1 (97–111% saturation) and were close to the equilibrium with the overlying atmosphere. A pronounced temporal variability of the N2O water column distribution was observed. We suggest that this variability is a reflection of the interplay between N2O production by nitrification and its consumption by N2 fixation in the layers below 150 m during summer. N2O surface concentrations and saturations in the central Red Sea basin ranged from 2 to 9 nmol L−1 (43–155% saturation). A pronounced temporal variability with significant supersaturation in October 2014 and undersaturation in January and August 2016 was observed in the surface layer. In October 2014, N2O in the water column seemed to result from production via nitrification. Low N2O water column concentrations in January and August 2016 indicated a significant removal of N2O. We speculate that either in-situ consumption or remote loss processes of N2O such as denitrification in coastal regions were responsible for this difference. Strong meso- and submesoscale processes might have transported the coastal signals into the central Red Sea. In addition, enhanced N2O concentrations of up to 39 nmol L−1 were found at the seawater-brine pool interfaces which point to an N2O production via nitrification and/or denitrification at low O2 concentrations. Our results indicate that the Red Sea and the Gulf of Aqaba are unique natural laboratories for the study of N2O production and consumption pathways under extreme conditions in one of the warmest and most saline regions of the global ocean

Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients

Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression. Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.3, Cyfra 21-1, HE4, NSE, proGRP and SCCA) using electrochemiluminescence immunoassays. Biomarker concentration changes were compared with the outcome of CT-scans during therapy. The median difference of the concentration of ctDNA, CA125 and Cyfra21-1 was significantly lower in patients with partial response (PR) compared to patients with progressive disease (PD) on the first evaluation CT-scan (P<0.001, P=0.042 and P=0.020, respectively). A substantial agreement between ctDNA or CA125 response and radiographic response was observed (k=0.692 and k=0.792, respectively). The median difference of the concentration of ctDNA and Cyfra21-1 was also significantly lower in PR patients compared to PD patients at the last CT-scan during therapy (P<0.001 and P=0.026, respectively). An almost perfect agreement between ctDNA and radiographic response (k=0.827) and a moderate agreement between Cyfra21-1 response and radiographic response was observed (k=0.553). Serial testing of the concentration of ctDNA, Cyfra21-1, and possibly CA125 could be a useful added tool for monitoring therapy response and early detection of disease progression in lung cancer patients

Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer

Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis. This prospective, multicenter study establishes the diagnostic value of ctDNA analysis by droplet digital PCR (ctDNA-ddPCR) in patients with primary lung cancer. CtDNA from 458 primary lung cancer patients was analyzed using a panel of multiplex ddPCRs for EGFR (Ex19Del, G719S, L858R, L861Q and S768I) , KRAS G12/G13 and BRAF V600 mutations. For 142 of 175 advanced stage non-squamous NSCLC patients tDNA-NGS results were available to compare to ctDNA-ddPCR. tDNA-NGS identified 98 mutations, of which ctDNA-ddPCR found 53 mutations (54%), including 32 of 45 (71%) targetable driver mutations. In 2 of these 142 patients,a mutation was found by ctDNA-ddPCR only. In 33 advanced stage patients lacking tDNA-NGS results, ctDNA-ddPCR detected 15 additional mutations, of which 7 targetable. Overall, ctDNA-ddPCR detected 70 mutations and tDNA-NGS 98 mutations in 175 advanced NSCLC patients. Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies