Translating the Biology of Aging into New Therapeutics for Alzheimer's Disease: Senolytics.

The recent FDA-approval for amyloid lowering therapies reflects an unwavering commitment from the Alzheimer's disease (AD) research community to identify treatments for this leading cause of dementia. The clinical benefits achieved by reducing amyloid, though modest, provide evidence that disease modification is possible. Expanding the same tenacity to interventions targeting upstream drivers of AD pathogenesis could significantly impact the disease course. Advanced age is the greatest risk factor for developing AD. Interventions targeting biological aging offer the possibility of disrupting a foundational cause of AD. Senescent cells accumulate with age and contribute to inflammation and age-related diseases like AD. Senolytic drugs that clear senescent cells improve healthy aging, halt AD disease progression in animal models and are undergoing clinical testing. This review explores the biology of aging, the role of senescent cells in AD pathology, and various senotherapeutic approaches such as senolytics, dampening the SASP (senescence associated secretory phenotype), senescence pathway inhibition, vaccines, and prodrugs. We highlight ongoing clinical trials evaluating the safety and efficacy of the most advanced senolytic approach, dasatinib and quercetin (D+Q), including an ongoing Phase II senolytic trial supported by the Alzheimer's Drug Discovery Foundation (ADDF). Challenges in the field of senotherapy for AD, including target engagement and biomarker development, are addressed. Ultimately, this research pursuit may lead to an effective treatment for AD and provide the field with another disease-modifying therapy to be used, alone or in combination, with other emerging treatment options.

Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.

Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).

The burden of healthcare-associated Clostridium difficile infection in a non-metropolitan setting.

OBJECTIVE: Healthcare-associated Clostridium difficile infection (HCA-CDI) remains a major cause of morbidity and mortality in industrialized countries. However, few data exist on the burden of HCA-CDI in multi-site non-metropolitan settings. This study examined the introduction of an antimicrobial stewardship programme (ASP) in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs. METHODS: A comparative before-and-after intervention study of patients aged ≥16 years with HCA-CDI from December 2010 to April 2016 across the nine hospitals of a non-metropolitan health district in New South Wales, Australia was undertaken. The intervention comprised a multi-site ASP supported by a clinical decision support system, with subsequent introduction of email feedback of HCA-CDI cases to admitting medical officers. MAIN OUTCOME MEASURES: HCA-CDI rates, comparative LOS and hospital costs, prior use of antimicrobials and proton pump inhibitors, and appropriateness of CDI treatment. RESULTS: HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-days pre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-intervention (P=0.24). Median LOS (17 vs six days; P<0.01) and hospital costs (AU$19,222 vs $7861; P<0.01) were significantly greater for HCA-CDI cases (N=91) than for matched controls (N=172). Half of the patients with severe HCA-CDI (4/8) did not receive initial appropriate treatment (oral vancomycin). CONCLUSIONS: HCA-CDI placed a significant burden on the regional and rural health service through increased LOS and hospital costs. Interventions targeting HCA-CDI could be employed to consolidate the effects of ASPs.

Vascular access devices: perspectives on designs, complications, and management.

The use of vascular access devices in hospitalized and home care patients has expanded rapidly in the past decade. New designs, materials, insertion techniques, and protocols for care related to vascular access devices have emerged. Complications associated with them, however, have remained a persistent problem. Septicemia, thrombosis, and occlusion are three of the more serious complications that can lead to the need for removal of the device. These complications are reviewed and areas for future research are identified.

High tech home care: surviving and prospering in a changing environment.

Managed care plans are expanding rapidly into new marketplaces. Reimbursement for home infusion therapy, including parenteral and enteral nutrition, is significantly affected under managed care, especially when capitated payment mechanisms are used. Home care companies have experienced downsizing, mergers, acquisitions, and fierce competition in the managed care environment. Clinicians who are entering the home care setting may find that, in addition to clinical expertise, their marketability depends on a set of new skills and abilities in order to prosper in this new environment.

Nutritional support in home care.

Nutritional support was among the first of the high-tech therapies to make the transition from hospital to home. Growth in high-tech home care accelerated in the mid-1980s, following establishment of the prospective payment system. Rapid growth in home care continues amid acquisitions and mergers of home care companies. The HPN and HEN populations have both enlarged and evolved with time, and the current populations mirror changes in health care demographics--showing the largest increases in services to the elderly. Changes have occurred in the types of venous and enteral access devices, infusion systems, parenteral and enteral products, and infusion schedules used by HPN and HEN patients. As therapies have caused less disruption in patients' lifestyles and as services have become more widely available, adaptation to HPN and HEN has become somewhat less difficult. However, patients still report concerns over finances, respite services, and symptoms management. Nurses have a primary role in the preparation of patients for home nutritional support and in the provision of home care services. Nursing research can illuminate the unique contribution of nurses to safe, cost effective, and high quality home nutritional support.

Issues in the management of percutaneous central venous catheters. Single and multiple lumens.

In this era of high technology and extensive parenteral therapies, multiple-lumen CVCs seem to be among the many devices needed to provide appropriate care to hospitalized patients. All CVCs, regardless of their benefit, create substantial risks for mechanical and septic complications. Antibacterial solutions that are bonded to the catheter and longer-acting skin antiseptics offer preliminary evidence that CVC sepsis rates can be reduced. The advances in CVC design, materials, and coatings are intended to be a supplement to--not a substitute for--meticulous care of CVCs.