Independent study demonstrates amyloid probability score accurately indicates amyloid pathology

BACKGROUND: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD PURPOSE: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. METHODS: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. RESULTS: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive. INTERPRETATION: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired

Preoperative Exercise during Neoadjuvant Therapy for Pancreatic Cancer: A Pilot Study

Exercise improves cancer treatment outcomes including health-related quality of life and physical functioning. Patients with pancreatic cancer are generally older adults, and frailty and cachexia are prevalent. Chemotherapy and chemoradiation are increasingly administered prior to pancreatic cancer surgery, and sarcopenia has been shown to accompany these therapies. Preoperative exercise may improve health, well-being, and perioperative outcomes among patients undergoing preoperative therapy for pancreatic cancer. The purpose of this pilot study was to determine the feasibility of exercise in this context. Feasibility was defined as patients completing, on average, 60% of recommended weekly exercise minutes. Twenty patients (M=64 years old, SD=9.9; 42% female) enrolled in a home-based exercise program during preoperative therapy (chemotherapy and/or chemoradiation and preoperative “rest”, M=21.2 weeks total, SD=16.4). Exercise recommendations included moderate-intensity walking for 20-30 minutes/day on ≥3 days/week and moderate-intensity resistance exercises for 30-45 minutes/day on ≥2 days/week. Exercise recommendations (120 minutes of moderate-intensity activity/week) were based on American College of Sports Medicine and American Cancer Society recommendations (150 minutes of moderate-intensity activity/week), but reduced due to patients’ older age and concurrent preoperative therapy. Resistance exercises targeted upper body, lower body, and abdominal muscles, and patients were instructed to perform 3 sets of 8-12 repetitions of multiple exercises for each region during each session. Patients received Yamax Digiwalker pedometers, graded resistance tube sets, and booklets and DVDs with instructions and safety tips. Research staff provided detailed instructions and resistance exercise demonstrations at enrollment and monitored and encouraged adherence with biweekly phone calls. Patients recorded minutes of walking and resistance exercise in daily logs. On average, patients reported 73.9 minutes of walking (\u3e100% of recommendation, SD=72.4) and 43.1 minutes of resistance exercise per week (71.8% of recommendation, SD=39.0). Patients reported the most walking during chemoradiation (M=94.7 minutes/week, SD=104.3), followed by preoperative “rest” (M=77.4 minutes/week, SD=80.4), and chemotherapy (M=70.8 minutes/week, SD=75.2). Patients reported the most resistance exercise during the preoperative “rest” period (M=51.6 minutes/week, SD=52.3), followed by chemoradiation (M=38.0 minutes/week, SD=36.8), and chemotherapy (M=31.1 minutes/week, SD=38.1). Walking and resistance exercise are feasible for patients undergoing preoperative therapy for pancreatic cancer. Varying levels of fatigue and treatment-related side effects may affect exercise during different treatment phases

Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies

<p>Abstract</p> <p>Background</p> <p>The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent <it>in vitro </it>studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models.</p> <p>Methods</p> <p>Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN.</p> <p>Results</p> <p>Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers.</p> <p>Conclusions</p> <p>Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer.</p> <p>Trial Registration</p> <p><b>Trial registration: Study A</b>: NCT 0075647. <b>Study B</b>: NCT00640978</p

A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: Findings from a multi cohort validity analysis

BACKGROUND: The development of blood-based biomarker tests that are accurate and robust for Alzheimer\u27s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. METHODS: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. RESULTS: Plasma Aβ42/40 ratio was significantly (p \u3c 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. CONCLUSIONS: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer\u27s disease; and may enhance the efficiency of enrolling participants into Alzheimer\u27s disease drug trials

Peningkatan Prestasi Belajar CAD Mahasiswa Teknik Otomotif Non-Reguler FT UNY melalui Pembuatan “Pohon Kata” Perintah dalam Program AutoCAD

Penelitian ini bertujuan meningkatkan prestasi belajar mata kuliah Computer Aided Design (CAD) mahasiswa prodi Teknik Otomotif Non-Reguler yang dinyatakan dalam bentuk rerata nilai akhir semester yang berasal dari komponen nilai tugas harian, nilai ujian tengah semester dan nilai ujian akhir semester. Penelitian quasi-eksperimen ini terdiri dari tahapan penelitian diawali dengan penyusunan materi pembelajaran sejumlah pokok bahasan tertentu dalam satu job sheet (lembar kerja), dilanjutkan dengan pembuatan bantuan “Pohon Kata” perintah dalam Auto CAD kepada kelas eksperimen yang ditentukan secara random dari dua kelas peserta kuliah Auto CAD pada Semester Genap 2008/2009. Kedua kelas diamati prestasinya, baik kecepatan penyelesaiannya maupun kualitas kebenaran gambarnya. Prestasi belajar kedua kelas juga diukur melalui pemberian ujian tengah semester dan ujian akhir semester. Setelah data prestasi kedua kelas terkumpul dilanjutkan dengan analisis statistik melalui uji beda (t-test) setelah sebelumnya dilakukan uji persyaratan analisis yang ternyata dapat dipenuhi. Hasil penelitian ini disimpulkan bahwa: prestasi belajar CAD mahasiswa pada kelas yang diberi perlakuan strategi pembelajaran menggunakan “Pohon Kata” perintah dalam Program Auto CAD lebih baik dibanding prestasi belajar CAD mahasiswa pada kelas yang tidak diberi perlakuan (75,41>70,89), dengan demikian pembelajaran CAD menggunakan media “Pohon Kata” perintah dalam Program Auto CAD dapat meningkatkan prestasi belajar mahasiswa Teknik Otomotif Program Non-Reguler

Potential and Actual Terrestrial Rabies Exposures in People and Domestic Animals, Upstate South Carolina, 1994–2004: A Surveillance Study

<p>Abstract</p> <p>Background</p> <p>Although there has been a reduction of rabies in pets and domestic animals during recent decades in the United States, rabies remains enzootic among bats and several species of terrestrial wildlife. Spillover transmission of wildlife rabies to domestic animals therefore remains a public health threat</p> <p>Methods</p> <p>Retrospective analysis of surveillance data of reported animal incidents (bites, scratches, mucous membrane contacts) from South Carolina, 1995 to 2003, was performed to assess risk factors of potential rabies exposures among human and animal victims.</p> <p>Results</p> <p>Dogs and cats contributed the majority (66.7% and 26.4%, respectively) of all reported incidents, with stray dogs and cats contributing 9.0% and 15.1 respectively. Current rabies vaccination status of dogs and cats (40.2% and 13.8%, respectively) were below World Health Organization recommended levels. Owned cats were half as likely to be vaccinated for rabies as dogs (OR 0.53, 95% CI 0.48, 0.58). Animal victims were primarily exposed to wildlife (83.0%), of which 27.5% were rabid. Almost 90% of confirmed rabies exposures were due to wildlife. Skunks had the highest prevalence of rabies among species of exposure animals (63.2%). Among rabid domestic animals, stray cats were the most commonly reported (47.4%).</p> <p>Conclusion</p> <p>While the majority of reported potential rabies exposures are associated with dog and cat incidents, most rabies exposures derive from rabid wildlife. Stray cats were most frequently rabid among domestic animals. Our results underscore the need for improvement of wildlife rabies control and the reduction of interactions of domestic animals, including cats, with wildlife.</p

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Assessing the diagnostic accuracy of the identification of hyperkinetic disorders following the introduction of government guidelines in England

<p>Abstract</p> <p>Background</p> <p>Previous studies have suggested that both underdiagnosis and overdiagnosis routinely occur in ADHD and hyperkinesis (hyperkinetic disorders). England has introduced governmental guidelines for these disorders' detection and treatment, but there has been no study on clinical diagnostic accuracy under such a regime.</p> <p>Methods</p> <p>All open cases in three Child and Adolescent Mental Health Services (CAMHS) in the South East of England were assessed for accuracy in the detection of hyperkinetic disorders, using a two-stage process employing the Strengths and Difficulties Questionnaire (SDQ) for screening, with the cut-off between "unlikely" and "possible" as the threshold for identification, and the Development And Well-Being Assessment (DAWBA) as a valid and reliable standard.</p> <p>Results</p> <p>502 cases were collected. Their mean age 11 years (std dev 3 y); 59% were clinically diagnosed as having a hyperkinetic disorder including ADHD. Clinicians had missed two diagnoses of hyperkinesis and six of ADHD. The only 'false positive' case was one that had become asymptomatic on appropriate treatment.</p> <p>Conclusion</p> <p>The identification of children with hyperkinetic disorders by three ordinary English CAMHS teams appears now to be generally consistent with that of a validated, standardised assessment. It seems likely that this reflects the impact of Governmental guidelines, which could therefore be an appropriate tool to ensure consistent accurate diagnosis internationally.</p

Rassenschande, genocide and the reproductive Jewish body: examining the use of rape and sexualized violence against Jewish women during the Holocaust

Rape and sexual violence against Jewish women is a relatively unexplored area of investigation. This article adds to the scant literature on this topic. It asks: how and why did women's reproductive bodies (gender), combined with their status as Jews (race), make them particularly vulnerable during the Holocaust? The law against Rassenschande (racial defilement) prohibited sexual relations between Aryans and non-Aryans. Yet, Jewish women were raped by German men. Providing a more nuanced account than is provided by the dehumanization thesis, this article argues that women were targeted precisely because of their Jewishness and their reproductive capabilities. In addition, this piece proposes that the genocidal attack on women's bodies in the form of rape (subsequently leading to the murder of impregnated women) and sexualized violence (forced abortions and forced sterilizations) must be interpreted as an attack on an essentialized group: woman-as-Jew