United States Department of Veterans Affairs

One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

Microbiology Society journals contain high-quality research papers and topical review articles. We are a not-for-profit publisher and we support and invest in the microbiology community, to the benefit of everyone. This supports our principal goal to develop, expand and strengthen the networks available to our members so that they can generate new knowledge about microbes and ensure that it is shared with other communities.

No abstract available for this article.

Communities have the potential to function effectively and adapt successfully in the aftermath of disasters. Drawing upon literatures in several disciplines, we present a theory of resilience that encompasses contemporary understandings of stress, adaptation, wellness, and resource dynamics. Community resilience is a process linking a network of adaptive capacities (resources with dynamic attributes) to adaptation after a disturbance or adversity. Community adaptation is manifest in population wellness, defined as high and non-disparate levels of mental and behavioral health, functioning, and quality of life. Community resilience emerges from four primary sets of adaptive capacities--Economic Development, Social Capital, Information and Communication, and Community Competence--that together provide a strategy for disaster readiness. To build collective resilience, communities must reduce risk and resource inequities, engage local people in mitigation, create organizational linkages, boost and protect social supports, and plan for not having a plan, which requires flexibility, decision-making skills, and trusted sources of information that function in the face of unknowns.

BACKGROUND: Although numerous studies suggest that there is an inverse relation between hospital volume of surgical procedures and surgical mortality, the relative importance of hospital volume in various surgical procedures is disputed. METHODS: Using information from the national Medicare claims data base and the Nationwide Inpatient Sample, we examined the mortality associated with six different types of cardiovascular procedures and eight types of major cancer resections between 1994 and 1999 (total number of procedures, 2.5 million). Regression techniques were used to describe relations between hospital volume (total number of procedures performed per year) and mortality (in-hospital or within 30 days), with adjustment for characteristics of the patients. RESULTS: Mortality decreased as volume increased for all 14 types of procedures, but the relative importance of volume varied markedly according to the type of procedure. Absolute differences in adjusted mortality rates between very-low-volume hospitals and very-high-volume hospitals ranged from over 12 percent (for pancreatic resection, 16.3 percent vs. 3.8 percent) to only 0.2 percent (for carotid endarterectomy, 1.7 percent vs. 1.5 percent). The absolute differences in adjusted mortality rates between very-low-volume hospitals and very-high-volume hospitals were greater than 5 percent for esophagectomy and pneumonectomy, 2 to 5 percent for gastrectomy, cystectomy, repair of a nonruptured abdominal aneurysm, and replacement of an aortic or mitral valve, and less than 2 percent for coronary-artery bypass grafting, lower-extremity bypass, colectomy, lobectomy, and nephrectomy. CONCLUSIONS: In the absence of other information about the quality of surgery at the hospitals near them, Medicare patients undergoing selected cardiovascular or cancer procedures can significantly reduce their risk of operative death by selecting a high-volume hospital.

A Histology Activity Index has been developed which generates a numerical score for liver biopsy specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. Under code, three pathologists and three hepatologists evaluated 14 liver biopsy specimens obtained from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between severity of liver biopsy lesions as judged by conventional histological descriptions and Histology Activity Index scores. Significant differences in Histology Activity Index score occurred in only 2 or 28 duplicate scorings of biopsy specimens by two observers. This system provides definitive endpoints for statistical analysis of serial changes in liver histology and offers an alternative to the use of conventional pathological descriptions in following the natural history and treatment responses of asymptomatic chronic active hepatitis.

OBJECTIVE: To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. METHODS: Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. CONCLUSIONS: There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

Abstract The development of a bone‐bonding calcia‐phosposilicate glass‐ceramic is discussed. A theoretical model to explain the interfacial bonding is based upon in‐vitro studies of glass‐ceramic solubility in interfacial hydroxyapatite crystallization mechanisms, compared with in‐vivo rat femur implant histology and ultrastructure results.

A new clinically accessible measure of balance, functional reach (FR), is the difference between arm's length and maximal forward reach, using a fixed base of support. The purposes of this study were to (a) establish FR as a measure of the margin of stability versus the laboratory measure, center of pressure excursion (COPE); (b) test reliability and precision, and (c) determine factors that influence FR, including age and anthropometrics. We evaluated FR in 128 volunteers (age 21-87 years). FR was determined with a precise electronic device and a simple clinical apparatus (yardstick). FR correlates with COPE (Pearson r = .71) and is precise (coefficient of variation = 2.5%) and stable (intraclass correlation coefficient across days = .81). Age and height influence FR. FR is portable, inexpensive, reliable, precise, and a reasonable clinical approximator of the margin of stability. FR may be useful for detecting balance impairment, change in balance performance over time, and in the design of modified environments for impaired older persons.

Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of biological functions. Details of its biochemistry, however, remain poorly understood. The broader chemistry of nitrogen monoxide (NO) involves a redox array of species with distinctive properties and reactivities: NO+ (nitrosonium), NO., and NO- (nitroxyl anion). The integration of this chemistry with current perspectives of NO biology illuminates many aspects of NO biochemistry, including the enzymatic mechanism of synthesis, the mode of transport and targeting in biological systems, the means by which its toxicity is mitigated, and the function-regulating interaction with target proteins.

Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NF kappa B. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

ABSTRACT The Stanford Sleepiness Scale (SSS) is a self‐rating scale which is used to quantify progressive steps in sleepiness. The present study investigated whether the SSS cross‐validates with performance on mental tasks and whether the SSS demonstrates changes in sleepiness with sleep loss. Five college student S s were given a brief test of memory and the Wilkinson Addition Test in 2 test sessions and The Wilkinson Vigilance Test in 2 other sessions spaced throughout a 16‐hr day for 6 days. S s made SSS ratings every 15 min during their waking activities. On night 4, S s underwent all night sleep deprivation. On all other nights, S s were allowed only 8 hrs in bed. Mean SSS ratings correlated r = .68 with performance on the Wilkinson Tests. Discrete SSS ratings correlated r = .47 with performance on the memory test. Moreover, mean baseline SSS ratings were found to be significantly lower than corresponding ratings of the deprivation period.

OBJECTIVES: To estimate the magnitude of small meaningful and substantial individual change in physical performance measures and evaluate their responsiveness. DESIGN: Secondary data analyses using distribution- and anchor-based methods to determine meaningful change. SETTING: Secondary analysis of data from an observational study and clinical trials of community-dwelling older people and subacute stroke survivors. PARTICIPANTS: Older adults with mobility disabilities in a strength training trial (n=100), subacute stroke survivors in an intervention trial (n=100), and a prospective cohort of community-dwelling older people (n=492). MEASUREMENTS: Gait speed, Short Physical Performance Battery (SPPB), 6-minute-walk distance (6MWD), and self-reported mobility. RESULTS: Most small meaningful change estimates ranged from 0.04 to 0.06 m/s for gait speed, 0.27 to 0.55 points for SPPB, and 19 to 22 m for 6MWD. Most substantial change estimates ranged from 0.08 to 0.14 m/s for gait speed, 0.99 to 1.34 points for SPPB, and 47 to 49 m for 6MWD. Based on responsiveness indices, per-group sample sizes for clinical trials ranged from 13 to 42 for substantial change and 71 to 161 for small meaningful change. CONCLUSION: Best initial estimates of small meaningful change are near 0.05 m/s for gait speed, 0.5 points for SPPB, and 20 m for 6MWD and of substantial change are near 0.10 m/s for gait speed, 1.0 point for SPPB, and 50 m for 6MWD. For clinical use, substantial change in these measures and small change in gait speed and 6MWD, but not SPPB, are detectable. For research use, these measures yield feasible sample sizes for detecting meaningful change.

Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)

A bstract : A Cumulative Illness Rating Scale, designed to meet the need for a brief, comprehensive and reliable instrument for assessing physical impairment, has been developed and tested. The scale format provides for 13 relatively independent areas grouped under body systems. Ratings are made on a 5‐point “degree of severity” scale, ranging from “none” to “extremely severe.” Findings, in terms of reliability and validity, reflect statistical significance at the P < .01 level. As a rapid assessment technique which is objective and easily quantified, the scale is well suited to a variety of research uses.

As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.

We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.

Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.