Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

The Critical Role of Biomarkers for Drug Development Targeting the Biology of Aging.

Alzheimer's disease is a devastating neurodegenerative disorder that poses a significant societal burden. Approval of anti-amyloid antibody therapies is a significant milestone for treatment that was enabled by the inclusion of biomarkers. The use of biomarkers in clinical trials for Alzheimer's disease has enabled selective participant recruitment, improved treatment monitoring, and supported more rigorous trial designs. This review discusses emerging biomarkers associated with the biology of aging and their application in Alzheimer's disease clinical trials. Aging is the primary risk factor for sporadic Alzheimer's disease and is associated with biological processes implicated in disease development and progression. Novel therapies targeting these underlying biological aging processes are currently undergoing clinical development. Biomarkers that capture the biology of aging are integral to accelerating the development of these therapies. Current progress in biomarker development demonstrates efforts to capture the full spectrum of aging biology. Further work is needed to expand the range of biomarkers that enable comprehensive assessment of brain pathology and aid in prognosis, diagnosis, and measuring treatment response. Establishing a comprehensive arsenal of biomarkers will support strategic decision making and increase the likelihood of positive clinical trials and drug registration for the next generation of Alzheimer's disease drugs targeting the biology of aging.

Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.

Background: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. Patients and methods: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. Results: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. Conclusion: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer.

Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m2 and subsequent doses 250 mg/m2, weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m2, Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848.

Reduced peripheral activity leading to hepato-preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes.

AIMS: Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes. MATERIALS AND METHODS: This was a randomized, open-label, four-period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d-[3-3 H] glucose. RESULTS: Following correction for equivalent human insulin concentrations (EHIC), low-dose GL infusion resulted in similar EGP at the end of the clamp compared to low-dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC-corrected GDR/EGP at the end of the clamp was 1.72-fold greater for GL than BIL following low-dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. CONCLUSIONS: Compared with GL, BIL restored the hepato-peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.

A new species of the genus Acria Stephens, 1834 (Lepidoptera: Depressariidae: Acriinae) from India.

A new species, Acria meyricki sp. nov. (Lepidoptera: Depressariidae: Acriinae) occurring on oil palm, is described from India. The status and nomenclature of the genus is reviewed and an annotated checklist of species is given. A key to the seven species known so far from the Indian subcontinent is provided.

Whose transplant function fails after ureteral revision following kidney transplantation?

BACKGROUND: Kidney transplantation is associated with ureteral complications in about 5% of cases. While many reasons for ureteral complications are known, it is currently unknown whether transplant outcomes are affected by operative revision of the transplanted ureter. In a retrospective analysis, we compared patients with versus without loss of transplant function after operative revision for a ureteral complication. PATIENTS AND METHODS: Between 1997 and 2005, a total of 43 ureteral complications occurred in 636 patients (6.8%) after kidney transplantation. Thirty-one of 43 patients underwent open operative revision of the transplant ureter. One patient died from suicide. The remaining 30 patients were analyzed for clinical parameters and transplant outcome. RESULTS: At median 5-year follow-up, 18/30 patients (60%) had functioning transplants and 12/30 (40%) had returned to dialysis. Various parameters such as number of mismatches, ischemia times, number of previous transplantations, and interval from transplantation to occurrence of ureteral complication as well as posttransplant and postrevision serum creatinine values showed no influence on transplant outcomes. CONCLUSIONS: In our retrospective analysis, transplant outcome was not affected by specific parameters associated with operative revision of the transplant ureter.

Superresolution and noise filtering using moving least squares.

An irregularly spaced sampling raster formed from a sequence of low-resolution frames is the input to an image sequence superresolution algorithm whose output is the set of image intensity values at the desired high-resolution image grid. The method of moving least squares (MLS) in polynomial space has proved to be useful in filtering the noise and approximating scattered data by minimizing a weighted mean-square error norm, but introducing blur in the process. Starting with the continuous version of the MLS, an explicit expression for the filter bandwidth is obtained as a function of the polynomial order of approximation and the standard deviation (scale) of the Gaussian weight function. A discrete implementation of the MLS is performed on images and the effect of choice of the two dependent parameters, scale and order, on noise filtering and reduction of blur introduced during the MLS process is studied.

Landmine detection and classification with complex-valued hybrid neural network using scattering parameters dataset.

Neural networks have been applied to landmine detection from data generated by different kinds of sensors. Real-valued neural networks have been used for detecting landmines from scattering parameters measured by ground penetrating radar (GPR) after disregarding phase information. This paper presents results using complex-valued neural networks, capable of phase-sensitive detection followed by classification. A two-layer hybrid neural network structure incorporating both supervised and unsupervised learning is proposed to detect and then classify the types of landmines. Tests are also reported on a benchmark data.

High resolution image formation from low resolution frames using Delaunay triangulation.

An algorithm based on spatial tessellation and approximation of each triangle patch in the Delaunay (1934) triangulation (with smoothness constraints) by a bivariate polynomial is advanced to construct a high resolution (HR) high quality image from a set of low resolution (LR) frames. The high resolution algorithm is accompanied by a site-insertion algorithm for update of the initial HR image with the availability of more LR frames till the desired image quality is attained. This algorithm, followed by post filtering, is suitable for real-time image sequence processing because of the fast expected (average) time construction of Delaunay triangulation and the local update feature.

Crystallization and preliminary X-ray crystallographic studies of recombinant human betaine-homocysteine S-methyltransferase.

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes a reaction essential for regulation of methionine and homocysteine metabolism and the catabolism of choline in mammalian tissues. Human recombinant BHMT (MW = 45 kDa) has been crystallized by the hanging-drop vapor-diffusion method at 294 K using ethylene glycol as the precipitant. The crystals belong to the monoclinic space group C2, with unit-cell parameters a = 109.190, b = 91.319, c = 88.661 A, beta = 122.044 degrees, and diffract to 2.9 A resolution on a local rotating-anode X-ray source. Rotation-function analysis and the Matthews coefficient, V(M) = 2.46 A(3) Da(-1), are consistent with a dimer in the asymmetric unit, suggesting that the active enzyme is a tetramer with 222 symmetry.

Vector quantization of neural networks.

The problem of vector quantizing the parameters of a neural network is addressed, followed by a discussion of different algorithms applicable for quantizer design. Optimal, as well as several suboptimal quantization schemes are described. Simulations involving nonlinear prediction of speech signals are presented to compare the performance of different quantization techniques. Performance evaluation conducted uncover the tradeoffs in implementational complexity. Among the three examined suboptimal quantization schemes, it is shown that the multistage quantizer offers the best tradeoff between complexity and performance.

Carcinoid tumor of the gallbladder: report of a case.

We report herein the rare case of a 40-year-old woman with a 10-year history of dull abdominal pain, in whom a carcinoid tumor of the gallbladder was confirmed by postoperative histological findings. A review of the world literature revealed that only 22 other such cases have been documented, all of which were diagnosed by incidental findings at the time of surgery or at post mortem. Although these patients may present with liver metastasis, rarely do they manifest with features of a carcinoid syndrome. The rarity of this entity prompted us to present our patient's case report, followed by a brief review of the literature on the previous 22 cases.

Case report: ultrasound demonstration of traumatic fracture of the pancreas with pancreatic duct disruption.

Fracture of the pancreas is a rare injury caused by blunt abdominal trauma. Abdominal CT is probably the best modality for the detection of this uncommon injury. Ultrasonography is excellent for demonstrating an accompanying pseudocyst, but it is otherwise considered less effective than CT in the evaluation of pancreatic trauma. We report a case where we were able to demonstrate a fracture through the body of the pancreas along with disruption of the pancreatic duct, using a conventional ultrasound scanner.