Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound

The accumulation of amyloid beta (Aβ) in Alzheimer’s disease is caused by an imbalance of production and clearance, which leads to increased soluble Aβ species and extracellular plaque formation in the brain. Multiple Aβ-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Aβ, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Aβ physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a γ-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Aβ (β- and γ-secretase) is that precursors of Aβ may accumulate and cause a rapid increase in Aβ production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable isotope labeling, and dose-dependently reduced newly generated CNS Aβ. In contrast to systemic Aβ metabolism, CNS Aβ production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Aβ, including C-terminal truncated forms of Aβ: 1–14, 1–15 and 1–16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during γ-secretase inhibition

Adherence to Cancer Prevention Guidelines in 18 African Countries

Background Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. Methods Data on adults 18 years and older were obtained from the 2002–2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. Results Across all countries, adherence to the guidelines among adults was high for smoking (72%–99%) and alcohol (85%–100%), but low for body weight (1.8%–78%), physical activity (3.4%–84%) and nutrition (1.4%–61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). Conclusions The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition

A systematic review of primary care models for non-communicable disease interventions in Sub-Saharan Africa

Background Chronic diseases, primarily cardiovascular disease, respiratory disease, diabetes and cancer, are the leading cause of death and disability worldwide. In sub-Saharan Africa (SSA), where communicable disease prevalence still outweighs that of non-communicable disease (NCDs), rates of NCDs are rapidly rising and evidence for primary healthcare approaches for these emerging NCDs is needed. Methods A systematic review and evidence synthesis of primary care approaches for chronic disease in SSA. Quantitative and qualitative primary research studies were included that focused on priority NCDs interventions. The method used was best-fit framework synthesis. Results Three conceptual models of care for NCDs in low- and middle-income countries were identified and used to develop an a priori framework for the synthesis. The literature search for relevant primary research studies generated 3759 unique citations of which 12 satisfied the inclusion criteria. Eleven studies were quantitative and one used mixed methods. Three higher-level themes of screening, prevention and management of disease were derived. This synthesis permitted the development of a new evidence-based conceptual model of care for priority NCDs in SSA. Conclusions For this review there was a near-consensus that passive rather than active case-finding approaches are suitable in resource-poor settings. Modifying risk factors among existing patients through advice on diet and lifestyle was a common element of healthcare approaches. The priorities for disease management in primary care were identified as: availability of essential diagnostic tools and medications at local primary healthcare clinics and the use of standardized protocols for diagnosis, treatment, monitoring and referral to specialist care

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

David J. Betz, Civil-Military Relations in Russia and Eastern Europe, RoutledgeCurzon Contemporary Russia and Eastern Europe Series 2, London and New York: RoutledgeCurzon, 2004. ix + 203 pages.

This meticulously-researched and well-written book provides a wealth of detailed information and analysis about the development of civil-military relations during the 1990s in four post-Communist countries: Poland, Hungary, Russia and Ukraine. David Betz is interested primarily at the civilian side of the civil-military relationship, and throughout the book he poses questions (and suggests answers) about the nature and extent of civilian control of the armed forces and the reasons why civil-m..