Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

A risk adjusted cost-effectiveness analysis of alternative models of nurse involvement in obesity management in primary care.

OBJECTIVE: Controlled evaluations are subject to uncertainty regarding their replication in the real world, particularly around systems of service provision. Using routinely collected data, we undertook a risk adjusted cost-effectiveness (RAC-E) analysis of alternative applied models of primary health care for the management of obese adult patients. Models were based on the reported level of involvement of practice nurses (registered or enrolled nurses working in general practice) in the provision of clinical-based activities. DESIGN AND METHODS: Linked, routinely collected clinical data describing clinical outcomes (weight, BMI, and obesity-related complications) and resource use (primary care, pharmaceutical, and hospital resource use) were collected. Potential confounders were controlled for using propensity weighted regression analyses. RESULTS: Relative to low level involvement of practice nurses in the provision of clinical-based activities to obese patients, high level involvement was associated with lower costs and better outcomes (more patients losing weight, and larger mean reductions in BMI). Excluding hospital costs, high level practice nurse involvement was associated with slightly higher costs. Incrementally, the high level model gets one additional obese patient to lose weight at an additional cost of $6,741, and reduces mean BMI by an additional one point at an additional cost of $563 (upper 95% confidence interval $1,547). CONCLUSION: Converted to quality adjusted life year (QALY) gains, the results provide a strong indication that increased involvement of practice nurses in clinical activities is associated with additional health benefits that are achieved at reasonable additional cost. Dissemination activities and incentives are required to encourage general practices to better integrate practice nurses in the active provision of clinical services.

Prediction of incident osteoporotic fractures in elderly women using the free estradiol index.

A decline in postmenopausal estrogen concentration accelerates postmenopausal bone loss. We have examined the predictive power of endogenous estrogen production, DXA hip bone density (BMD), and heel quantitative ultrasound (QUS) on incident clinical fracture in a prospective 3-year population based, randomised controlled trial of calcium supplementation. Baseline blood testing on 1499 women mean (SD) age 75 (3) years for estradiol and sex hormone binding globulin measurements and ankle QUS measurements (Lunar Achilles) was undertaken. Bone density was measured using DXA (Hologic 4500A) at 1 year. Incident clinical fractures were confirmed by X-ray. At 3 years, 10% had sustained more than one incident fracture. The fracture group had significantly lower levels of free estradiol index (FEI) (0.40+/-0.44 versus 0.49+/-0.54 pmol/nmol), hip BMD (0.776+/-0.129 versus 0.815+/-0.124 g/cm(2)) and measures of QUS (BUA 98+/-8 versus 101+/-8 db/Hz, SOS 1504+/-22 versus 1514 +/-26 m/s; stiffness 67+/-11 versus 71+/-11 % mean young adult), respectively, than the non-fracture group. After adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture, incident fracture was predicted by free estradiol index (HR per SD: 1.43:95%CI: 1.08-1.91, P=0.013). After adjustment for BMD, SOS or stiffness, the free estradiol index no longer predicted fracture. When examined separately, the presence of a vertebral or an appendicular fracture was associated with an 18% lower free estradiol index compared with no fracture. The risk of vertebral fracture increased with decreased free estradiol index (HR per SD reduction: 1.63:95% CI: 0.91-2.92); the risk of appendicular fracture also increased with decreased free estradiol index (HR per SD reduction: 1.45:95% CI: 1.05-2.01) after adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture. After further adjustment for hip BMD or QUS measures, the effect of free estradiol index was no longer significant for vertebral or appendicular fractures. Therefore, a low free estradiol index increases the probability of having an incident fracture as a result of decreased BMD. These data confirm the importance of postmenopausal estrogen concentration in the pathogenesis of osteoporosis in elderly women.

Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women.

High postmenopausal endogenous estrogen concentrations are an important determinant of preservation of bone mass and reduced fracture in elderly women. Calcium supplementation can also reduce bone loss in these patients, suggesting an interaction between estrogen deficiency and calcium balance. Potential mechanisms of estrogen on calcium transport include direct effects on the bone, the kidney, and the bowel. Previous studies have demonstrated effects of estrogen on renal phosphate handling. We have used a cross-sectional, population-based analysis of biochemical data obtained from ambulant elderly women to determine the association of endogenous estradiol with urine calcium and phosphorus excretion. The subjects were 293 postmenopausal women >70 yr old. Factors associated with renal calcium and phosphate excretion were measured, including the filtered calcium and phosphate load, parathyroid hormone (PTH), estradiol, and sex hormone-binding globulin (SHBG). The free estradiol concentration (FE) was calculated from a previously described formula. A high plasma estradiol concentration (r(2) = 0.023, P = 0.01) and a high FE (r(2) = 0.045, P = 0.001) were associated with reduced renal calcium excretion. The estradiol and FE effect on renal calcium excretion remained significant after adjusting for calcium filtered at the glomerulus and serum PTH. A high FE was associated with a reduced renal phosphate threshold in univariate analysis (r(2) = 0.023, P = 0.010). The effect remained significant after adjustment for serum PTH. The size of the effect of the FE was of the same order of magnitude as the effect of PTH on reducing renal calcium excretion and increasing renal phosphate excretion. These data support in vitro and animal data demonstrating an effect of estradiol on renal calcium and phosphate handling and indicate that, in elderly postmenopausal women, the effect is of a similar magnitude to the well-recognized effects of PTH on these physiologically regulated parameters.

Characterization of the effect of retinol on Plasmodium falciparum in vitro.

A preliminary study from our laboratory found retinol (vitamin A alcohol) to have in vitro activity against Plasmodium falciparum at concentrations close to those in normal human serum (1-3 microM). To characterize the antimalarial potential of retinol in more detail, the 3D7 and K1 laboratory strains of P. falciparum were maintained in continuous culture and [3H]hypoxanthine incorporation and microscopy were used to assess the effect of retinol against asexual stages of the parasite life-cycle. Losses of retinol and retinol-associated hemolysis were also quantified in the in vitro culture system. There were retinol losses of >50% but no hemolysis was observed with added retinol concentrations up to 100 microM. All stages of parasite development showed comparable sensitivity to retinol including merozoite invasion (range of mean IC50 values 10.1-21.4 microM after adjustment for losses). Retinol pre-treatment of uninfected RBC did not inhibit merozoite invasion. Retinol treatment was associated with increased vacuolization within the parasite food vacuole and evidence of parasite membrane rupture. These appearances were similar to those seen with quinoline and artemisinin compounds. Although these data do not support a role for acute retinol supplementation in the treatment of falciparum malaria, they add to knowledge regarding potential antimalarial therapies and justify assessment of more potent synthetic retinoids and their metabolites.

Pregnancy outcome following women's participation in a randomised controlled trial of acupuncture to treat nausea and vomiting in early pregnancy.

OBJECTIVES: Recent studies have concluded that acupuncture is safe in the hands of a qualified practitioner. This study assessed the risk of adverse effects of acupuncture administered during pregnancy. METHODS: 593 women with nausea and vomiting in early pregnancy volunteered to participate in a randomised controlled trial, conducted at the Women's and Children's Hospital, in South Australia. Patients were given either traditional acupuncture, formula acupuncture, sham acupuncture or no acupuncture. OUTCOME MEASURES: Data were collected on perinatal outcome, congenital abnormalities, pregnancy complications and the newborn. RESULTS: No differences were found between study groups in the incidence of perinatal outcome, congenital abnormalities, pregnancy complications and other infant outcomes. CONCLUSION: Our findings suggest that no serious adverse effects arise from acupuncture administered in early pregnancy.

Pre-exercise oral creatine ingestion does not improve prolonged intermittent sprint exercise in humans.

BACKGROUND: This investigation determined whether pre-exercise oral Cr ingestion could enhance prolonged intermittent sprint exercise performance. EXPERIMENTAL DESIGN: a randomised, double-blind crossover design was employed. SETTING: testing was performed at the Western Australian Institute of Sport and participants were monitored and treated by both scientific and medical personnel. PARTICIPANTS: eight active, but not well-trained males with a background in multiple-sprint based sports acted as subjects for this investigation. INTERVENTIONS: subjects ingested either 15 g Cr.H2O or placebo 120 min and 60 min prior to the start of an 80-min maximal sprint cycling task (10 sets of multiple 6-sec sprints with varying active recoveries). Subjects were retested 14 days later, being required to ingest the alternate supplement and repeat the exercise test. MEASURES: performance variables (work done and peak power) were obtained throughout the exercise challenge. Muscle biopsies (vastus lateralis) were raised to a peak of 2348+/-223 micromol x l(-1) prior to the commencement of exercise after Cr ingestion. There were no significant changes in any cycling performance parameters following Cr ingestion, although blood La- was significantly lower (p<0.05) than placebo at all time points during were taken preexercise as well as immediately and 3 min post-exercise in order to determine concentrations of ATP, PCr, Cr, La- and glycogen. Venous blood was drawn prior to and on four occasions during the exercise test, and analysed for Cr, NH3+, La- and pH. RESULTS: Serum Cr concentrations exercise, and plasma NH3+ accumulation was also significantly reduced (p<0.05) in the Cr condition, but only in the second half of the 80-min exercise test. Muscle ATP and TCr levels as well as postexercise PCr replenishment were unaffected following Cr administration. CONCLUSIONS: The data suggest that although the pre-exercise ingestion of a large Cr dose was shown to have some impact on blood borne metabolites, it does not improve maximal prolonged intermittent sprint exercise performance, possibly due to an insufficient time allowed for uptake of serum Cr by skeletal muscle to occur. Therefore, this form of loading does not provide an alternative method of Cr supplementation to the traditional five-day supplementation regimes established by previous research.

Effect of Vitamin C and E supplementation on biochemical and ultrastructural indices of muscle damage after a 21 km run.

This study investigated whether 4 weeks of daily supplementation with 500 or 1000 mg of Vitamin C and 500 or 1000 IU of Vitamin E could modify biochemical and ultrastructural indices of muscle damage following a 21 km run. Fifteen experienced male distance runners were divided into two groups (vitamin or placebo) and received supplementation for four weeks before completing the first 21 km run in as fast a time as possible. A four-week "washout" period followed before the subjects crossed over and received the alternate supplement for the next four weeks. They then completed a second 21 km run. Before, immediately after and 24 h after each run venous blood samples were taken and analysed for serum creatine kinase, myoglobin, malondialdehyde and vitamin C and E (before-samples only) concentrations. A subgroup of six subjects also had muscle biopsy (gastrocnemius) samples taken 24 h before and 24 h after each 21 km run, which were later analysed by electron microscopy. The two dosages of supplementation produced similar results, so a single vitamin group was formed for further analysis of results. Significant increases (p < 0.05) in creatine kinase and myoglobin, but not in malondialdehyde, were found post-run in both groups. However, no significant differences were found between the vitamin and placebo groups for creatine kinase, myoglobin and malondialdehyde concentrations recorded after the 21 km runs. A qualitative ultrastructural examination of pre-run muscle samples revealed changes consistent with endurance training, but little further change was seen after the 21 km run in either the vitamin or placebo groups. It was concluded that vitamin C and E supplementation (500 or 1000 mg or IU per day) for four weeks does not reduce either biochemical or ultrastructural indices of muscle damage in experienced runners after a half marathon.

Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS).

OBJECTIVES: This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population. BACKGROUND: Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease. METHODS: We studied 1,111 subjects (558 men and 553 women; age 52 +/- 13 years [mean +/- SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging. RESULTS; After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque. CONCLUSIONS: This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.

Effect of creatine loading on long-term sprint exercise performance and metabolism.

PURPOSE: This study examined whether creatine (Cr) supplementation could enhance long-term repeated-sprint exercise performance of approximately 80 min in duration. METHODS: Fourteen active, but not well-trained, male subjects initially performed 10 sets of either 5 or 6 x 6 s maximal bike sprints, with varying recoveries (24, 54, or 84 s between sprints) over a period of 80 min. Work done (kJ) and peak power (W) were recorded for each sprint, and venous blood was collected preexercise and on four occasions during the exercise challenge. Muscle biopsies (vastus lateralis) were obtained preexercise as well as 0 min and 3 min postexercise. Subjects were then administered either 20 g.d-1 Cr.H2O (N = 7) or placebo (N = 7) for 5 d. Urine samples were collected for each 24 h of the supplementation period. Subjects were then retested using the same procedures as in test 1. RESULTS: Total work done increased significantly (P < 0.05) from 251.7 +/- 18.4 kJ presupplementation to 266.9 +/- 19.3 kJ (6% increase) after Cr ingestion. No change was observed for the placebo group (254.0 +/- 10.4 kJ to 252.3 +/- 9.3 kJ). Work done also improved significantly (P < 0.05) during 6 x 6 s sets with 54-s and 84-s recoveries and approached significance (P = 0.052) in 5 x 6 s sets with 24-s recovery in the Cr condition. Peak power was significantly increased (P < 0.05) in all types of exercise sets after Cr loading. No differences were observed for any performance variables in the placebo group. Resting muscle Cr and PCr concentrations were significantly elevated (P < 0.05) after 5 d of Cr supplementation (Cr: 48.9%; PCr: 12.5%). Phosphocreatine levels were also significantly higher (P < 0.05) immediately and 3 min after the completion of exercise in the Cr condition. CONCLUSION: The results of this study indicate that Cr ingestion (20 g.day-1 x 5 d) improved exercise performance during 80 min of repeated-sprint exercise, possibly due to an increased TCr store and improved PCr replenishment rate.

Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria.

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (<1.0 micromol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7-15.1 h), a bioavailability of 55% (19-100%) and an elimination half-life of 13.5 h (4.2-23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P<0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7-15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.

Acupuncture in Australian general practice: patient characteristics.

OBJECTIVE: To ascertain the incidence of acupuncture claims and the characteristics of patients claiming for acupuncture. DESIGN: Secondary analysis of Health Insurance Commission data on claims for acupuncture performed by a medical practitioner. PARTICIPANTS: A summary of all Medicare acupuncture claims for financial years 1984-85 to 1996-97 and a random sample of patients claiming a Medicare rebate in calendar year 1996. MAIN OUTCOME MEASURES: Claims for acupuncture by patients' State, sex, age, and the socioeconomic disadvantage index of patients' residences. RESULTS: Between 1984-85 and 1996-97 the number of acupuncture claims increased, but declined as a proportion of total Medicare claims. In 1996, 1.16% of patients claimed for acupuncture, which constituted 0.5% of all Medicare claims. Adjusting for age and socioeconomic disadvantage, women were more likely than men to claim for acupuncture (odds ratio, 1.40; 95% confidence interval, 1.36-1.45). This sex difference is proportionately greater than that for all medical services. Propensity to claim for acupuncture increased with age, peaking at 65-69 years, then declining. Acupuncture claims were more likely in areas just above those assessed as having the greatest social disadvantage. CONCLUSION: The number of acupuncture claims has increased since 1984. As a proportion of all Medicare claims, acupuncture has remained stable since declining in 1991-92. This suggests that acupuncture is now an established complementary medical practice.

Acupuncture in Australian general practice: practitioner characteristics.

OBJECTIVES: To ascertain the extent of the use of acupuncture and the characteristics of general practitioners using acupuncture. DESIGN: Secondary analysis of 1996 Health Insurance Commission data on claims by all non-specialist medical practitioners for Medicare Benefits Schedule items for an attendance where acupuncture was performed by a medical practitioner. MAIN OUTCOME MEASURES: Use of acupuncture by general practitioners and the practitioners' sex, age, place of primary medical qualification, and the socioeconomic disadvantage index of the practitioners' practice. RESULTS: 15.1% of general practitioners claimed for acupuncture. Acupuncture was more likely to be provided by male practitioners, by those aged 35-54 years, and by practitioners who have an overseas primary medical qualification. The socioeconomic index of the practice did not significantly affect the number of claims for acupuncture. CONCLUSION: Acupuncture is used by about one in seven general practitioners. Its use is associated with middle-aged practitioners, who presumably have more clinical experience. This level of use by experienced doctors suggests that a critical review of the appropriate role of acupuncture in general practice should be considered.

Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene.

Former blue asbestos workers known to be at high risk of asbestos-related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo-prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to beta-carotene or retinol. Subjects were assigned randomly to take 30 mg/day beta-carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention-to-treat analyses and efficacy analyses based on treatment actually taken. Median follow-up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to beta-carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on beta-carotene was 0.24 (95% CI 0.07-0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic beta-carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation.

Effect of indomethacin on blood pressure control during treatment with nitrendipine.

This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist. Fifteen essential hypertensives (ages 58-80 years) had a supine diastolic blood pressure (DBP) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5-20 mg twice daily. They entered a double-blind randomised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration. Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared. Supine blood pressure (mean +/- SE) was higher in the indomethacin phase (158 +/- 4/80 +/- 2) than in the placebo phase (154 +/- 4/76 +/- 3) (p < 0.01 for DBP). In 6/15 (40%) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg. Plasma urea was also increased in the indomethacin phase: 7.6 +/- 0.6 mmol/l compared with placebo: 6.3 +/- 0.5 mmol/l (p < 0.001). The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine. This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine. This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects.