Additive scales in degenerative disease - calculation of effect sizes and clinical judgment

<p>Abstract</p> <p>Background</p> <p>The therapeutic efficacy of an intervention is often assessed in clinical trials by scales measuring multiple diverse activities that are added to produce a cumulative global score. Medical communities and health care systems subsequently use these data to calculate pooled effect sizes to compare treatments. This is done because major doubt has been cast over the clinical relevance of statistically significant findings relying on <it>p </it>values with the potential to report chance findings. Hence in an aim to overcome this pooling the results of clinical studies into a meta-analyses with a statistical calculus has been assumed to be a more definitive way of deciding of efficacy.</p> <p>Methods</p> <p>We simulate the therapeutic effects as measured with additive scales in patient cohorts with different disease severity and assess the limitations of an effect size calculation of additive scales which are proven mathematically.</p> <p>Results</p> <p>We demonstrate that the major problem, which cannot be overcome by current numerical methods, is the complex nature and neurobiological foundation of clinical psychiatric endpoints in particular and additive scales in general. This is particularly relevant for endpoints used in dementia research. 'Cognition' is composed of functions such as memory, attention, orientation and many more. These individual functions decline in varied and non-linear ways. Here we demonstrate that with progressive diseases cumulative values from multidimensional scales are subject to distortion by the limitations of the additive scale. The non-linearity of the decline of function impedes the calculation of effect sizes based on cumulative values from these multidimensional scales.</p> <p>Conclusions</p> <p>Statistical analysis needs to be guided by boundaries of the biological condition. Alternatively, we suggest a different approach avoiding the error imposed by over-analysis of cumulative global scores from additive scales.</p

How predictive is the MMSE for cognitive performance after stroke?

Cognitive deficits are commonly observed in stroke patients. Neuropsychological testing is time-consuming and not easy to administer after hospital discharge. Standardised screening measures are desirable. The Mini-Mental State Examination (MMSE) is the test most widely applied to screen for cognitive deficits. Despite its broad use, its predictive characteristics after stroke have not been exhaustively investigated. The aim of this study was to determine whether the MMSE is able to adequately screen for cognitive impairment and dementia after stroke and whether or not the MMSE can predict further deterioration or recovery in cognitive function over time. To this end, we studied 194 first-ever stroke patients without pre-stroke cognitive deterioration who underwent MMSEs and neuropsychological test batteries at 1, 6, 12, and 24 months after stroke. The MMSE score 1 month after stroke predicted cognitive functioning at later follow-up visits. It could not predict deterioration or improvement in cognitive functioning over time. The cut-off score in the screening for 1 cognitive disturbed domain was 27/28 with a sensitivity of 0.72. The cut-off score in the screening for at least 4 impaired domains and dementia were 26/27 and 23/24 with a sensitivity of 0.82 and 0.96, respectively. The results indicated that the MMSE has modest qualities in screening for mild cognitive disturbances and is adequate in screening for moderate cognitive deficits or dementia in stroke patients 1 month after stroke. Poor performance on the MMSE is predictive for cognitive impairment in the long term. However, it cannot be used to predict further cognitive deterioration or improvement over time

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension

BACKGROUND: Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. METHODS AND RESULTS: Four hundred seventy‐seven patients with mild‐to‐moderate Alzheimer disease were randomized to the calcium‐channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH‐related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow‐up visits. Mean age of the study population was 72.2±8.2 years and mean Mini‐Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by −7.8/−3.9 mm Hg for nilvadipine and by −0.4/−0.8 mm Hg for placebo (P<0.001). Across the 78‐week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8–1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH‐related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. CONCLUSIONS: This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild‐to‐moderate Alzheimer disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340

Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1null (Prop1-/-) and the Ames dwarf (Prop1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells

Clinical preference for factors in treatment of&nbsp;geriatric depression

Matthias W Riepe Mental Health and Geriatric Psychiatry, Psychiatry II, Ulm&nbsp;University, Ulm, Germany Abstract: Little is known about symptom preferences of clinical psychiatrists in the treatment of geriatric depression and preferences for avoiding adverse drug effects. Participants (board-certified psychiatrists) were recruited prior to a lecture on geriatric depression during a continuing education program. An analytic hierarchy process was performed and participants were asked for pairwise comparison of criteria guiding them in appraising therapeutic efficacy, and in avoiding toxicity and adverse events. Of the 61 participants from the continuing education program, 42 (69%) returned their data sheet. Avoidance of cardiotoxicity was regarded as more important than avoidance of hepatotoxicity or hematotoxicity. Concerning adverse events, highest preference was given to avoidance of falls and drug interactions, followed by avoidance of sedation, weight change, and impairment of sexual function. The most important preferences for appraisal of therapeutic efficacy were suicidality over ability to concentrate and sleep. Clinical psychiatrists have a hierarchy of preferences for treatment goals and avoidance of adverse events and toxicity. This raises the question for future research whether these preferences cause differences in prescription patterns in clinical practice even though a multitude of antidepressants are similarly effective when judged with instruments used in clinical trials. Keywords: depressive disorder, symptoms, analytic hierarchy process, toxicity, adverse events, symptom