Which Method of Fall Ascertainment Captures the Most Falls in Prefrail and Frail Seniors?

There is no consensus on the most reliable method of ascertaining falls among the elderly. Therefore, we investigated which method captured the most falls among prefrail and frail seniors from 2 randomized controlled trials conducted in Zurich, Switzerland: an 18-month trial (2009-2010) including 200 community-dwelling prefrail seniors with a prior fall and a 12-month trial (2005-2008) including 173 frail seniors with acute hip fracture. Both trials included the same methods of fall ascertainment: monthly active asking, daily self-report diary entries, and a call-in hotline. We compared numbers of falls reported and estimated overall and positive percent agreement between methods. Prefrail seniors reported 499 falls (fall rate = 2.5/year) and frail seniors reported 205 falls (fall rate = 1.4/year). Most falls (81% of falls in prefrail seniors and 78% in frail seniors) were reported via active asking. Among prefrail seniors, diaries captured an additional 19% of falls, while the hotline added none. Among frail seniors, the hotline added 16% of falls, while diaries added 6%. The positive percent agreement between active asking and diary entries was 100% among prefrail seniors and 88% among frail seniors. While monthly active asking captures most falls in both groups, this method alone missed 19% of falls in prefrail seniors and 22% in frail seniors. Thus, a combination of active asking and diaries for prefrail seniors and a combination of active asking and a hotline for frail seniors is warranted.

Compositional and toxicological analysis of a GM potato line with reduced α-solanine content--a 90-day feeding study in the Syrian Golden hamster.

Steroidal glycoalkaloids (GAs) are toxins, produced by plants of the Solanaceae family. The potato plant (Solanum tuberosum L.) and its tubers predominantly contain the two GAs α-chaconine and α-solanine. These compounds are believed to act in synergy, and the degree of toxicity may therefore depend on their ratio in the potato. To determine the influence of α-solanine: α-chaconine ratio in potatoes on toxicity, a GM potato line (SGT 9-2) with reduced α-solanine content, and the parental control line (Desirée wild-type) having a traditional α-solanine: α-chaconine ratio were (1) studied for compositional similarity by analysing for a range of potato constituents, and (2) used in a 90-day feeding trial with the Syrian Golden hamster to study differential toxicity. The animal feeding study used diets with up to 60% freeze-dried potato powder from either line. Whilst data indicated some compositional differences between the GM line and its wildtype control these did not raise concerns related to nutritional value or safety. Results of the feeding trials showed a low number of significant differences between potato lines with different α-solanine: α-chaconine ratio but none were considered to raise safety concerns with regard to human (or animal) consumption.

Toxicity testing in the 21st century: a vision and a strategy.

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

Risk assessment of mixtures of pesticides. Current approaches and future strategies.

The risk assessment of pesticide residues in food is based on toxicological evaluation of the single compounds and no internationally accepted procedure exists for evaluation of cumulative exposure to multiple residues of pesticides in crops, except for a few groups of pesticides sharing a group ADI. However, several attempts have been suggested during the last decade. This paper gives an overview of the various approaches. It is of paramount importance to consider whether there will be either no interaction or interaction between the compounds in the mixture. When there are no interactions several approaches are available for the risk assessment of mixtures of pesticides. However, no single simple approach is available to judge upon potential interactions at the low doses that humans are exposed to from pesticide residues in food. In these cases, PBTK models could be useful as tools to assess combined tissue doses and to help predict potential interactions including thresholds for such effects. This would improve the quality of the risk assessment.

[Diagnosis of delirium]. / Diagnostik des Delirs.

Delirium is a clinical diagnosis, which is based on observed disturbances of consciousness and cognitive dysfunction. Associated neuropsychiatric and psychomotoric symptoms are common. Many elderly delirious patients are hypoactive, manifesting a passive demeanor, reduced activity and, in extreme cases, stupor and coma. Delirium has an acute onset and a fluctuating course. It is usually reversible. It is crucial to examine cognitive functions among elderly hospitalized patients, since advanced age and preexisting dementia are important risk factors for the development of delirium. In patients with suspected delirium there should follow a further diagnostic approach with specific tests, such as the Confusion Assessment Method (CAM), a diagnostic tool which has a high sensitivity and specifity. Delirium often develops during the course of hospitalization, so repeated screening and cognitive testing is needed. Predisposing factors need to be identified and treated. The cause of delirium is often multifactorial and heterogeneous. Symptoms might be subtle, and clinicians frequently under-recognize delirium, so that it is often diagnosed late in its course. Especially in the elderly delirium can be the only symptom of an acute and severe illness. The typical clinical findings of this illness can be missing. The clinical examination and careful use of diagnostic tools is therefore essential in the identification and treatment of delirium.

[Drug-induced delirium]. / Medikamentenassoziiertes Delirium.

Drugs have been strongly associated with the development of delirium, and they are one of the most easily reversible triggers. In addition to polypharmacy, physiological changes with aging including pharmacokinetic and pharmacodynamic changes as well as medical co-morbidities can increase the susceptibility to a drug induced delirium. Since it is widely accepted that delirium represents reversible impairment of cerebral oxidative metabolism and neurotransmission [37], it is not surprising that any drug interfering with the function, the supply or the use of substrates for neurotransmitter metabolism can cause delirium. Drugs with anticholinergic activity, especially those with muscarine receptor activity, constitute a considerable risk-group. Many different classes of drugs can induce delirium, but several studies have shown that it all comes down to the so-called anticholinergic burden, which becomes greater with each medication someone takes. In the elderly, polypharmacy and anticholinergic toxicity is common. Dementia, e.g. Alzheimer's disease, and, to a lesser extent, other chronic brain pathologies, predispose, through reduced integrity of the blood-brain barrier function, additionally to the development of delirium. Misinterpretation of an adverse drug reaction as another medical condition may lead to the prescription of additional medications with their own potential to cause side effects. To reduce the morbidity and mortality associated with drug induced delirium and also to prevent it, patients' medications should be closely monitored. Wherever possible, drugs with anticholinergic effects should be avoided in elderly patients, particularly in those suffering from dementia.

Outcomes after spinal stenosis surgery by type of surgery in adults aged 60 years and older.

AIMS OF THE STUDY: Mobility disability due to spinal stenosis is common in the senior population and often surgery is warranted for patients with severe symptoms and neurological dysfunction. However, although current clinical guidelines recommend stabilisation surgery in addition to decompression in patients with spinal stenosis and instability due to degenerative spondylolisthesis, the relationship between outcomes and the specific type of surgery have not been well studied. We therefore assessed the postoperative recovery timeline for 12 months and compared patient-reported outcomes dependent on the extent of decompression and additional stabilisation among seniors undergoing spinal stenosis surgery. METHODS: We investigated 457 patients (mean age 76.0 ± 10.7 years, 58% women) from a consecutive cohort prior to spinal stenosis surgery. Follow-up was at 3 or 6months and at 12 months postoperatively. At each visit, pain, neurological dysfunction and disability were assessed using the North American Spine Society questionnaire. Repeated-measures analysis compared outcomes by type of surgery adjusting for baseline symptoms, gender, age, number of comorbidities, centre and year of surgery. RESULTS: Most improvement occurred within the first 3 to 6 months with little or no further improvement at 12 months. Over 12 months and in adjusted models, patients receiving one-segment versus multi-segment decompression experienced significantly greater reduction of pain (−49.2% vs −41.9%, p = 0.013) and neurological dysfunction (−37.1% vs −25.9%, p <0.0001), but only borderline greater reduction of disability (−32.7% vs −28.2%, p = 0.051). Moreover, reduction in pain and neurological function did not differ with or without additional stabilisation and extend of decompression. However, patients who received one-segment (−28.9%) or multi-segment (−28.3%) stabilisation experienced significantly less reduction in disability after surgery compared with those who were not stabilised (−34.1%, p <0.043). CONCLUSIONS: Among senior patients undergoing spinal stenosis surgery, recovery was largely complete by 3 to 6 months after surgery and differed little by type of surgery independently of symptoms prior to surgery and other covariates. However we could document a trend toward more improvement in particularly neurological dysfunction and disability with less invasive surgery.

Prediction of Emergency Department Re-Visits in Older Patients by the Identification of Senior at Risk (ISAR) Screening.

The "Identification of Seniors at Risk" (ISAR) screening is a tool to identify seniors at risk of adverse outcomes. We investigated whether seniors with a positive ISAR screening have an increased risk of Emergency Department (ED) re-visits and health-service costs. In a pilot project, we enrolled 96 ED patients (≥70 years) who received an ISAR screening in the ED. We compared the rate of ED re-visits and in-hospital costs between ISAR positive (≥2 pts) and ISAR negative (<2 pts) patients. In some patients, a geriatrician performed a single Geriatric Consultation (GC) during the ED stay to assess older patients' needs.32% of the study population had an unplanned ED re-visit (31 of 96). Fifty patients were ISAR positive (52%) and showed an increased risk of ED re-visits compared with ISAR negative patients (dds ratio (OR) 6.8, 95% confidence interval (CI) 2.2-21.0, p = 0.001). The positive ISAR screening tool fairly predicted ED re-visits in seniors (area under the curve (AUC) 0.711). A single GC during the ED stay did not reduce the risk of unplanned ED re-visits in ISAR positive patients (p = 0.80) ISAR positive patients with GC did not have higher in-hospital costs than ISAR negative patients without GC. Based on these findings, we aim to establish a comprehensive outpatient geriatric assessment program to identify relevant risk factors for ED re-visits and to recommend preventive strategies in ISAR positive ED seniors.

Association between Caregiver Role and Short- and Long-Term Functional Recovery after Hip Fracture: A Prospective Study.

OBJECTIVES: After a hip fracture, 50% of senior patients are left with permanent functional decline and 30% lose their autonomy. The aim of this prospective study was to evaluate whether seniors who are in a caregiver role have better functional recovery after hip fracture compared with noncaregivers. DESIGN: Prospective observational study. SETTING: A total of 107 Swiss patients with acute hip fracture age 65 years and older (84% women; 83.0 ± 6.9 years; 87% community-dwelling). MEASUREMENTS: At baseline, participants were asked if they were caregivers for a person, a pet, or a plant. Lower-extremity mobility was measured using the Timed Up and Go (TUG) test at baseline during acute care (day 1-12 after hip fracture surgery) and at 6 and 12 months follow-up. Subjective physical functioning (SPF) was rated for prefracture values and at 6 and 12 months follow-up using the Short Form 36 Health Survey questionnaire. Differences in TUG performance or SPF between caregivers and noncaregivers at 6 and 12 months were assessed using multivariable repeated-measures analysis adjusted for age, sex, body mass index, Charlson comorbidity index, Mini-Mental State Examination, living condition, baseline TUG, and treatment (vitamin D, home exercise program as part of the original trial). RESULTS: At baseline, adjusted TUG performance was better in caregivers of any kind compared with noncaregivers (40.9 vs 84.4 seconds, P < .0001). At 6 months, and after adjustment for baseline TUG performance and other covariates, TUG was better in caregivers of any kind (-6.4 seconds, P = .007) and caregivers of plants (-6.6 seconds, P = .003) compared with noncaregivers. At 12 months, only caregivers of persons had better TUG performance compared with noncaregivers (-7.3 seconds, P = .009). Moreover, at 12 months, SPF was better in caregivers of persons (58.9 vs 45.6, P = .01) and caregivers of any kind (50.8 vs 39.3, P = .02) compared with noncaregivers. CONCLUSIONS: Senior hip fracture patients who have a caregiver role of any kind, and especially of plants, had better short-term recovery after hip fracture assessed with the TUG. For long-term recovery, senior hip fracture patients who are caregivers for other persons appeared to have a significant benefit. These benefits were independent of baseline function and all other covariates.

Statin Use and 25-Hydroxyvitamin D Blood Level Response to Vitamin D Treatment of Older Adults.

OBJECTIVES: To determine whether statin use alters response of 25-hydroxyvitamin D (25(OH)D) level to vitamin D treatment. DESIGN: Pooled analysis. SETTING: Three double-blind randomized controlled trials that tested different doses of vitamin D. PARTICIPANTS: Participants of three trials (N = 646; mean age 76.3 ± 8.4, 65% female). MEASUREMENTS: In all three trials, 25(OH)D status and statin use were assessed repeatedly over time (baseline, 6 and 12 months). Repeated-measures analysis was used to compare 25(OH)D response to vitamin D treatment at baseline and 6 and 12 months of statin users and nonusers, controlling for age, sex, body mass index, Charlson Comorbidity Index, vitamin D dose, trial, and season. RESULTS: At baseline, 17.5% were statin users, and 65% were vitamin D deficient (25(OH)D < 20 ng/mL). Baseline 25(OH)D levels did not differ significantly between groups at baseline (18.8 for statin users, 17.2 ng/mL for nonusers, P = .07), but according to the longitudinal analyses, the total increase over 12 months in 25(OH)D concentration was significantly lower in statin users (13.1 ng/L) than nonusers (15.9 ng/mL; 21.4% difference; P = .009). CONCLUSION: Of persons aged 60 and older at high risk of vitamin D deficiency, statin users had a 21.4% smaller increase in 25(OH)D serum concentrations over time than nonusers, independent of vitamin D dose and other covariates.

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial.

IMPORTANCE: Vitamin D deficiency has been associated with poor physical performance. OBJECTIVE: To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline. DESIGN, SETTING, AND PARTICIPANTS: One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. INTERVENTIONS: Three study groups with monthly treatments, including a low-dose control group receiving 24,000 IU of vitamin D3 (24,000 IU group), a group receiving 60,000 IU of vitamin D3 (60,000 IU group), and a group receiving 24,000 IU of vitamin D3 plus 300 µg of calcifediol (24,000 IU plus calcifediol group). MAIN OUTCOMES AND MEASURES: The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index. RESULTS: The study cohort comprised 200 participants (men and women ≥ 70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60,000 IU and 24,000 IU plus calcifediol were more likely than 24,000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60,000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24,000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24,000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60,000 IU group (mean, 1.47) and the 24,000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24,000 IU group (mean, 0.94) (P = .09). CONCLUSIONS AND RELEVANCE: Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01017354.

The combination of 1alpha,25(OH2)-vitamin D3, calcium and acetylsalicylic acid affects azoxymethane-induced aberrant crypt foci and colorectal tumours in rats.

Effects of 1alpha,25(OH)(2)-vitamin D(3) and acetylsalicylic acid at various dietary levels of calcium (CaCO(3)) on development of aberrant crypt foci (ACF) and tumours in colon were examined in groups of 16 male F344 rats initiated with azoxymethane and observed for 16 weeks. Calcium was the most potent modulator of ACF development. The total number of ACF increased with low calcium and decreased with high calcium. The number of large ACF decreased with any addition of calcium, acetylsalicylic acid and 1alpha,25(OH)(2)-vitamin D(3). High levels of calcium alone or in combination with 1alpha,25(OH)(2)-vitamin D(3) increased the incidence of tumour-bearing animals. 1alpha,25(OH)(2)-vitamin D(3) and acetylsalicylic acid at 5,000 ppm calcium increased the incidence as well.

Testing and assessment strategies, including alternative and new approaches.

The object of toxicological testing is to predict possible adverse effect in humans when exposed to chemicals whether used as industrial chemicals, pharmaceuticals or pesticides. Animal models are predominantly used in identifying potential hazards of chemicals. The use of laboratory animals raises ethical concern. However, irrespective of animal welfare it is an important aspect of the discipline of toxicology that the primary object is human health. The ideal testing and assessment strategy is simple to use all the available test methods and preferably more in laboratory animal species from which we get as many data as possible in order to obtain the most extensive database for the toxicological evaluation of a chemical. Consequently, the society has decided that certain group of chemicals should be tested accordingly. However, realising that, this idea is not obtainable in practice because there are more than 100000 chemicals which are potential for human exposure, so the development of alternative testing and assessment strategies has taken place in the recent years. The toxicological evaluation should enable the society to cope with the simultaneous requirement of many chemicals for different uses and of the absence of health problems involved with their use. Thus, the regulatory toxicology is a cocktail of science and pragmatism added a crucial concern for animal welfare. Test methods are most often used in a testing sequence as bricks in a testing strategy. The main key driving forces for introducing assessment and testing strategies e.g. using a limited number of tests and/or alternative test methods are: (a) animal welfare considerations; (b) new scientific knowledge i.e. introducing tests for new endpoints and tests for better understanding of mode of action; and (c) lack of testing capacity/reduction of required resources economically as well as time wise.

A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

Acute toxicity of high doses of the glycoalkaloids, alpha-solanine and alpha-chaconine, in the Syrian Golden hamster.

Sprouted, stressed, or spoiled potato tubers have reportedly led to human acute intoxication, coma, and death when consumed in high amounts. These effects have been attributed to glycoalkaloids (GAs), primarily alpha-solanine and alpha-chaconine, naturally present in all potatoes. The level of GAs in potato tubers has previously been shown to increase substantially as a result of improper handling and postharvest storage. A short-term study was performed to investigate the dose-response profile of alpha-solanine and alpha-chaconine alone or in combination, administered daily by oral gavage to Syrian Golden hamsters. Daily doses of 100 mg of alpha-solanine [kg body weight (BW)] (-1) induced death in two of four hamsters within 4 days, when administered by gavage to female Syrian hamsters. Doses of 100 mg of alpha-chaconine alone or alpha-solanine and alpha-chaconine combined in a ratio of 1:2.5, in doses of 75 or 100 mg (kg BW) (-1), induced death in one of four hamsters within the same period. Animals dosed with alpha-solanine alone or in combination with alpha-chaconine suffered from fluid-filled and dilated small intestines. The GA administration had no effect on acetyl cholinesterase (AChE) or butyryl cholinesterase (BuChE) activity in plasma or brain. Liquid chromatography-mass spectrometry-based metabolomics showed that there was a specific accumulation of alpha-chaconine in the liver tissues. In addition, metabolomics gave direct evidence of glycolytic metabolism of the GA with the beta 1, beta 2, and gamma-GAs detected in the urine and, to a lesser extent, the feces. Doses from 75 mg (kg BW) (-1) of alpha-chaconine, alpha-solanine, or the two compounds combined were potentially lethal within 4-5 days in the Syrian Golden hamster. However, the cause of death in these studies could not be established. No synergistic effects of alpha-solanine combined with alpha-chaconine were evident.

Carbohydrate digestibility predicts colon carcinogenesis in azoxymethane-treated rats.

The purpose of this study was to compare the effect of carbohydrate structure and digestibility on azoxymethane (AOM)-induced colon carcinogenesis. Five groups of male Fischer 344 rats each comprising 30 animals were injected with AOM and fed a high-fat diet with 15% of various carbohydrates. The carbohydrate sources used were sucrose, cornstarch (a linear starch, reference group), potato starch (a branched starch), a short-chained oligofructose (Raftilose), and a long-chained inulin-type fructan (Raftiline). An interim sacrifice was performed after 9 wk to investigate markers of carbohydrate digestibility, including caecal fermentation (caecum weight and pH) and glucose and lipid metabolism [glucose, fructoseamine, HbA1c, triglycerides, and insulin-like growth factor (IGF) 1]. In addition potential early predictors of carcinogenicity [cell proliferation and aberrant crypt foci (ACF)] at 9 wk and their correlation to colon cancer risk after 32 wk were investigated. Tumor incidence was significantly reduced in animals fed oligofructose, and the number of tumors per animal was significantly reduced in animals fed inulin and oligofructose at 32 wk after AOM induction compared to the reference group fed sucrose. Increased caecum weight and decreased caecal pH were seen in groups fed oligofructose, inulin, and potato starch. Plasma triglyceride was decreased in rats fed oligofructose and inulin. Cell proliferation was increased in the proximal colon of rats fed sucrose, oligofructose, and inulin, and the number of cells per crypt decreased in rats fed oligofructose and inulin. The total number of ACF's was unaffected by treatment, and the size and multiplicity of ACF was unrelated to tumor development. It was concluded that less digestible carbohydrates with an early effect on caecum fermentation and plasma triglyceride decreased subsequent tumor incidence and multiplicity. This was unrelated to ACF, cell proliferation, and other markers of glucose and lipid metabolism.