Evaluation of a novel immunoassay to detect p-Tau Thr127 in the CSF to distinguish Alzheimer disease from other dementias

OBJECTIVE: To investigate whether p-tau T217 assay in cerebrospinal fluid (CSF) can distinguish Alzheimer's disease from other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from three cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy subjects (n = 44). RESULTS: The p-tau T217 assay (cut-off 242 pg/ml) identified AD subjects with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, 88% specificity compared favorably with p-tau T181 ELISA (52 pg/ml) showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, 97% sensitivity. The assay distinguished AD patients from age-matched healthy subjects (cut-off 163 pg/ml, sensitivity 98%, specificity 93%) similarly to p-tau T181 ELISA (cut-off 60 pg/ml, 96% sensitivity and 86% specificity). In AD patients, we found a strong correlation between p-tau T217-tau and p-tau T181, t-tau and Aβ40 but not with Aβ42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggests that the new p-tau T217 assay has a potential as an AD diagnostic test in the clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes AD from other dementias and healthy controls

The personal experience of parenting a child with Juvenile Huntington’s Disease: perceptions across Europe

The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington’s disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington’s disease; living with the disease; other people’s knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Foot orthoses: how much customisation is necessary?

The relative merit of customised versus prefabricated foot orthoses continues to be the subject of passionate debate among foot health professionals. Although there is currently insufficient evidence to reach definitive conclusions, a growing body of research literature suggests that prefabricated foot orthoses may produce equivalent clinical outcomes to customised foot orthoses for some conditions. Consensus guidelines for the prescription of customised foot orthoses need to be developed so that the hypothesised benefits of these devices can be thoroughly evaluated

Standardisation of intestinal ultrasound scoring in clinical trials for luminal Crohn's disease

Background: Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn’s disease (CD). However, there is no widely accepted luminal disease activity index. / Aims: To identify appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials. / Methods: An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1-9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting. / Results: A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions. / Conclusions: The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed

Purinergic signaling microenvironments: An introduction

The common theme of this introductory article and the minireviews that follow in this special issue is the concept of microenvironments within tissues and surrounding cells that would be ideal signaling venues for a biologically active purinergic ligand. Collectively, the editors/authors and the other contributing authors agree that nucleotides and nucleosides would be most potent within a confined system. A talented cadre of purinergics has been solicited to discuss purinergic signaling in his or her favorite microenvironment within a given organ or tissue. We are gratified by the large number of original articles that also have successfully navigated the peer review process and are part of this special issue. These concepts are not simply purinergic, but the idea of maximal potency in a tissue microenvironment and surrounding specialized cells within a tissue pertains to any autacoid or paracrine agonist

Multi-task learning for subthalamic nucleus identification in deep brain stimulation

Deep brain stimulation (DBS) of Subthalamic nucleus (STN) is the most successful treatment for advanced Parkinson’s disease. Localization of the STN through Microelectrode recordings (MER) is a key step during the surgery. However, it is a complex task even for a skilled neurosurgeon. Different researchers have developed methodologies for processing and classification of MER signals to locate the STN. Previous works employ the classical paradigm of supervised classification, assuming independence between patients. The aim of this paper is to introduce a patient-dependent learning scenario, where the predictive ability for STN identification at the level of a particular patient, can be used to improve the accuracy for STN identification in other patients. Our inspiration is the multi-task learning framework, that has been receiving increasing interest within the machine learning community in the last few years. To this end, we employ the multi-task Gaussian processes framework that exhibits state of the art performance in multi-task learning problems. In our context, we assume that each patient undergoing DBS is a different task, and we refer to the method as multi-patient learning. We show that the multi-patient learning framework improves the accuracy in the identification of STN in a range from 4.1 to 7.7%, compared to the usual patient-independent setup, for two different datasets. Given that MER are non stationary and noisy signals. Traditional approaches in machine learning fail to recognize accurately the STN during DBS. By contrast in our proposed method, we properly exploit correlations between patients with similar diseases, obtaining an additional information. This information allows to improve the accuracy not only for locating STN for DBS but also for other biomedical signal classification problems

Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance

Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aro- matic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol sub- stituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logRe- sistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications

Drug-Eluting Stents in Patients with Chronic Kidney Disease: A Prospective Registry Study

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with adverse outcomes after percutaneous coronary intervention (PCI). There are limited data on the effectiveness of drug-eluting stents (DES) in patients with CKD. METHODOLOGY/PRINCIPAL FINDINGS: Of 3,752 consecutive patients enrolled in the Guthrie PCI Registry between 2001 and 2006, 436 patients with CKD - defined as a creatinine clearance <60 mL/min - were included in this study. Patients who received DES were compared to those who received bare metal stents (BMS). Patients were followed for a mean duration of 3 years after the index PCI to determine the prognostic impact of stent type. Study end-points were all-cause death, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and the composite of major adverse cardiovascular events (MACE), defined as death, MI or TVR. Patients receiving DES in our study, by virtue of physician selection, had more stable coronary artery disease and had lower baseline risk of thrombotic or restenotic events. Kaplan-Meier estimates of proportions of patients reaching the end-points were significantly lower for DES vs. BMS for all-cause death (p = 0.0008), TVR (p = 0.029) and MACE (p = 0.0015), but not MI (p = 0.945) or ST (p = 0.88). Multivariable analysis with propensity adjustment demonstrated that DES implantation was an independent predictor of lower rates of all-cause death (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.92), TVR (HR 0.50, 95% CI 0.27-0.94) and MACE (HR 0.62, 95% CI 0.41-0.94). CONCLUSIONS: In a contemporary PCI registry, selective use of DES in patients with CKD was safe and effective in the long term, with lower risk of all-cause death, TVR and MACE and similar risk of MI and ST as compared with BMS. The mortality benefit may be a result of selection bias and residual confounding, or represent a true finding; a hypothesis that warrants clarification by randomized clinical trials

HIV-Neutralizing Activity of Cationic Polypeptides in Cervicovaginal Secretions of Women in HIV-Serodiscordant Relationships

HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules