Association between apolipoprotein E4 and cognitive decline in elderly adults

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective study. SETTING: Scotland, Ireland, and the Netherlands. PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). MEASUREMENTS: Subjects were assessed at baseline and over a mean 3.2‐year (range 0.7–4.2) follow‐up for memory (Picture‐Word Recall), speed of information processing (Stroop and Letter‐Digit Coding), global cognitive function (Mini‐Mental State Examination), and activities of daily living. RESULTS: At baseline, subjects with apolipoprotein E₄ versus those without E₄ had poorer memory performance (mean score difference ?0.20 (95% confidence interval (CI)=?0.31 to ?0.09) for immediate recall and ?0.32 (95% CI=?0.48 to ?0.16) for delayed recall and slower information processing (difference in Stroop, 2.79 seconds, (95% CI=1.20–4.28); Letter‐Digit score, ?0.36, (95% CI=?0.77–0.05). Subjects with apolipoprotein E₄ showed a greater decline in immediate (?0.22, 95% CI=?0.33 to ?0.11) and delayed (?0.30, 95% CI=?0.46 to ?0.15) memory scores but no significant change in speed of information processing (Stroop, P=.17; Letter‐Digit, P=.06). Memory scores decreased 2.5% from baseline in those without E₄, 4.3% in E₄ heterozygotes (P=.01 for immediate and P=.03 for delayed, vs no E₄) and 8.9% to 13.8% in E₄ homozygotes (P=.04 for immediate and P=.004 for delayed, vs heterozygotes). Apolipoprotein E₄ was associated with greater decline in instrumental activities of daily living (P<.001). Cognitive decline was not associated with lipoprotein levels. CONCLUSION: Findings in PROSPER indicate that E₄ is associated with more‐rapid cognitive decline and may, therefore, predispose to dementia.     

Monounsaturated, trans, and saturated Fatty acids and cognitive decline in women

OBJECTIVES: To prospectively assess effects of select dietary fats on cognitive decline. DESIGN: Prospective observational; 3‐year follow‐up. SETTING: Northwestern University. PARTICIPANTS: Four hundred eighty‐two women aged 60 and older who participated in the Women's Health Initiative (WHI) Observational Study or in the control group of the WHI Diet Modification arm. MEASUREMENTS: Dietary intake from a validated food frequency questionnaire (FFQ) administered twice (mean 2.7 years apart) before baseline cognitive assessment (mean 2.9 years after second FFQ) was averaged. Testing of memory, vision, executive function, language, and attention was performed twice, 3 years apart. A global Z‐score was created for both time points by averaging all Z‐scores for each participant, and global cognitive change was defined as the difference between follow‐up and baseline Z‐scores. RESULTS: Median intake of saturated fat (SFA), trans‐fat, (TFA), dietary cholesterol (DC), and monounsaturated fat (MUFA) was 18.53, 3.45, 0.201, and 19.39 g/d, respectively. There were no associations between degree of cognitive decline and intake of SFA (P=.69), TFA (P=.54), or DC (P=.64) after adjusting for baseline cognition, total energy intake, age, education, reading ability, apolipoprotein E ?4 allele, body mass index, estrogen and beta‐blocker use, and intake of caffeine and other fatty acids. In contrast, MUFA intake was associated with lower cognitive decline in fully adjusted linear regression models, with mean decline (standard error) of 0.21 (0.05) in the lowest and 0.05 (0.05) in the highest quartiles (P=.02). This effect of MUFA intake was primarily in the visual and memory domains (P=.03 for both). CONCLUSION: Greater intake of SFA, TFA, and DC was not associated with cognitive decline, whereas greater MUFA intake was associated with less cognitive decline.     

Accelerated weight loss and incident dementia in an elderly African-American cohort

OBJECTIVES: To examine the association between changes in body mass index (BMI), dementia, and mild cognitive impairment (MCI). DESIGN: Prospective observational study. SETTING: Urban community in Indianapolis, Indiana. PARTICIPANTS: Participants were African Americans aged 65 and older enrolled in the Indianapolis Dementia Project and followed through 2007. This analysis included 1,331 participants who did not have dementia at their first BMI measurement. MEASUREMENTS: Cognitive assessment and clinical evaluations were conducted every other year to identify participants with dementia or MCI during 12 years of follow‐up (mean follow‐up 6.4 years). BMI measures; alcohol and smoking history; and medical conditions including history of cancer, hypertension, diabetes mellitus, heart attack, stroke; and depression were collected at each follow‐up evaluation. Mixed‐effect models were used to examine the differences in BMI between participants who developed dementia or MCI and those who did not, adjusting for covariates. RESULTS: Mean BMI at baseline was 29.8 ± 5.7 for women and 28.3 ± 4.8 for men. Participants with incident dementia or MCI had greater decline in BMI than those without (P=.02 for dementia, P=.04 for MCI). BMI in participants with incident dementia, MCI, and normal cognition did not differ 12 or 9 years before diagnosis, but 6 years before diagnosis, participants with incident dementia had significantly lower BMI than participants with normal cognition (P=.03), as did participants with MCI (P=.006). CONCLUSION: Decline in BMI appears to be an early marker for dementia. There is a need for the close monitoring of weight loss in older adults.     

Age is a predictor of a small decrease in lung function in children with sickle cell anemia

The longitudinal pattern of lung function in children with sickle cell anemia (SCA) has shown a decrease in FEV₁% predicted, a risk factor for death in adults with SCA, but predictors for this decline are poorly characterized. In a prospective longitudinal multi‐center cohort of children with SCA, we tested the hypotheses that: (1) FEV₁% predicted declines over time; and (2) SCA‐specific characteristics and therapy predict this decline. At three clinical centers, children with SCA (HbSS or HbSβ⁰ thalassemia), unselected for respiratory disease, were enrolled in the Sleep and Asthma Cohort (SAC) study. Study‐certified pulmonary function technicians performed spirometry and lung volumes. Each assessment was reviewed centrally. Predicted values were determined for TLC, FEV₁, FVC, and FEV₁/FVC ratio. A total of 197 participants, mean age 11.0 years at first testing (range 4‐19.3 years), had a minimum of three spirometry measurements, over an average of 4.4 years (range 1.1‐6.5 years) from baseline to endpoint. In a multivariable model, FEV₁% predicted declines by 0.3% for every additional year of age (95% CI ?0.56 to ?0.05, P = .020). Sex, asthma history, hemoglobin, reticulocyte count, white blood cell count, incidence rate of severe acute pain and acute chest syndrome episodes, and hydroxyurea therapy were not associated with a decline in FEV₁% predicted. In a large, rigorously evaluated, prospective cohort of an unselected group of children with SCA, FEV₁% predicted declines minimally over an average of 4 years, and none of the examined disease features predict the decline.     

Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study

OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative. DESIGN: A 2‐year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993. SETTING: Community‐dwelling and institutionalized participants. PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini‐Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33‐point greater decline in MMSE score (95% confidence interval (CI)=0.03–0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=?0.14–0.11, P=.79). Two‐year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30–2.16; P<.001) and possible (OR=1.56; 95% CI=1.36–1.79; P<.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality.     

Association between sex steroids and cognition in elderly men

Objective To examine the association of cognitive function with sex steroid and sex hormone binding globulin (SHBG) levels among elderly men. Design Prospective cohort study, The Osteoporotic Fractures in Men Study (MrOS), consisting of 5995 US community dwelling men of 65 years or older. Patients One thousand six hundred and two men were chosen randomly from MrOS cohort for sex steroid level measurements by Mass Spectrometry (MS) at baseline. Two thousand six hundred and twenty‐three MrOS participants with sex steroids measured using RIA were also examined. Measurements Baseline and follow‐up (4·5 years later) performance on two cognitive tests: Trails B (executive function and motor speed) and 3MS (global cognitive function). Baseline total testosterone and oestradiol were measured by MS. Free testosterone (free‐T) and free oestradiol (free‐E) were calculated. SHBG was measured by radioimmunoassay. Data were analysed using linear regression. Results Baseline free‐T and free‐E levels were not associated with cognitive performance or change in cognition, following adjustment for age, education, race, health status and alcohol use. Baseline SHBG levels were inversely associated with follow‐up trails B (P = 0·03) and 3MS performance (P = 0·02). Higher SHBG was associated with an increased risk of cognitive decline. Total sex steroid levels were not associated with cognitive performance. Conclusions Despite large numbers of participants and rigorous sex steroid measurements, we did not observe an association between cognition and either testosterone or oestradiol levels. We conclude that endogenous sex steroids in the normal range are not related to executive function or global cognitive function in elderly men. High SHBG deserves further examination as a risk factor for cognitive decline.     

Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4‐year COPD trial. Methods: Subgroup analysis from a randomized, double‐blinded, placebo‐controlled trial of tiotropium 18 µg daily in COPD. Primary end‐point was rate of decline in FEV₁. Secondary end‐points included spirometry at individual time points, health‐related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m²; post‐bronchodilator FEV₁: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV₁ although annual decline was less in Asian patients. Morning pre‐bronchodilator FEV₁ and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57–0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62–1.05) and 0.85 (0.61–1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5–6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. Conclusions: In COPD patients from Asia, tiotropium improves lung function, improves health‐related quality of life and reduces exacerbations over 4 years of treatment.     

Improvement in memory with plasticity-based adaptive cognitive training: results of the 3-month follow-up

OBJECTIVES: To investigate maintenance of training effects of a novel brain plasticity–based computerized cognitive training program in older adults after a 3‐month no‐contact period. DESIGN: Multisite, randomized, controlled, double‐blind trial with two treatment groups. SETTING: Communities in northern and southern California and Minnesota. PARTICIPANTS: Four hundred eighty‐seven community‐dwelling adults aged 65 and older without diagnosis of clinically significant cognitive impairment. INTERVENTION: Random assignment into a broadly available brain plasticity–based computerized cognitive training program experimental group or a novelty‐ and intensity‐matched cognitive stimulation active control. Assessments at baseline, after training, and at 3 months. MEASUREMENTS: The primary outcome was a composite of auditory subtests of the Repeatable Battery for the Assessment of Neuropsychological Status. Secondary measures included trained task performance, standardized neuropsychological assessments of overall memory and attention, and participant‐reported outcomes (PROs). RESULTS: A significant difference in improvement from baseline to 3‐month follow‐up was seen between the experimental training and control groups on the secondary composite of overall memory and attention, (P=.01, d=0.25), the trained processing‐speed measure (P<.001, d=0.80), word list total recall (P=.004, d=0.28), letter–number sequencing (P=.003, d=0.29), and the cognitive subscale of PRO (P=.006, d=0.27). Previously significant improvements became nonsignificant at the 3‐month follow‐up for the primary outcome, two secondary measures of attention and memory, and several PROs. Narrative memory continued to show no advantage for the experimental group. Effect sizes from baseline to follow‐up were generally smaller than effect sizes from baseline to posttraining. CONCLUSION: Training effects were maintained but waned over the 3‐month no‐contact period.     

Serum levels of matrix metalloproteinase‐9, tissue inhibitors of metalloproteinase‐1 and their ratio are associated with impaired lung function in the elderly: A population‐based study

Background and objective: Matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metalloproteinases (TIMP), regulate homeostasis and turnover of the extra cellular matrix. The aim of this study was to investigate the associations of serum MMP‐9 and TIMP‐1 with lung function. Methods: Spirometry was performed in a population‐based sample of 888 subjects aged 70 years. Serum MMP‐9 and TIMP‐1 concentrations were measured by ELISA. Results: Lower FEV₁ values were associated with higher serum levels of MMP‐9 (P = 0.001) and TIMP‐1 (P < 0.001), and a higher ratio of MMP‐9 to TIMP‐1 (P = 0.02). These associations were significant after adjustment for gender, weight, height, BMI, current smoking, pack years of smoking and the time for which samples were frozen. After stratification for gender, the associations between FEV₁ and MMP‐9, TIMP‐1, and their ratio, were significant in men but not in women. Conclusions: Lower FEV₁ was significantly but weakly associated with higher serum levels of MMP‐9, TIMP‐1 and a higher MMP‐9/TIMP‐1 ratio. This association was stronger in men than in women, suggesting a possible role for extracellular matrix remodelling in the development of impaired lung function. These associations may also partly explain the association between low FEV₁ and cardiovascular disease.     

Use of specific airway resistance to assess bronchodilator response in children

Background and objective: Changes in specific airway resistance (ΔsRaw) after bronchodilation, as measured by plethysmography and FEV₁, are frequently considered to be interchangeable indices of airway obstruction. However, the baseline relationship between these two indices is weak, and the value of ΔsRaw that best predicts FEV₁ reversibility in children has yet to be determined. The aim of this study was (i) to establish the sRaw cut‐off value that best distinguishes between positive and negative bronchodilator responses, as measured by FEV₁ reversibility; (ii) to determine whether the discrepancy between ΔsRaw and ΔFEV₁ might be explained by independent correlations between ΔFEV₁ and both ΔsRaw (mainly airway obstruction) and ΔFVC (airway closure); and (iii) to assess the effect of height and age on the relationship between ΔsRaw and ΔFEV₁. Methods: A retrospective study was performed in 481 children (median age 10.5 years, range 6.1–17.6) with actual or suspected asthma, for whom sRaw and spirometry data were obtained at baseline and after administration of a bronchodilator. Results: The sRaw cut‐off value that best predicted FEV₁ reversibility was a 42% decrease from baseline (P = 0.0001, area under the curve 0.70, sensitivity 55%, specificity 77%) and was independent of height and age. Changes in FEV₁ were significantly but independently related to ΔsRaw and ΔFVC (index of air trapping) (r = 0.40, P < 0.0001 and r = 0.39, P < 0.0001, respectively). Conclusions: A 42% decrease in sRaw predicted FEV₁ reversibility reasonably well, whereas a smaller decrease in sRaw failed to detect approximately one out of two positive responses detected by FEV₁, with no influence of height or age.     

A prospective study of the effect of hypertension and baseline blood pressure on cognitive decline and dementia in postmenopausal women: the Women's Health Initiative Memory Study

OBJECTIVES: To examine the relationship between baseline hypertension, blood pressure, and the development of cognitive decline in participants in the Women's Health Initiative Memory Study (WHIMS). DESIGN: Prospective analyses. SETTING: Thirty‐nine centers. PARTICIPANTS: Seven thousand one hundred forty‐nine women aged 65 and older. MEASUREMENTS: The Modified Mini‐Mental State Examination (3MS) was used to assess global cognitive functioning. Participants who scored below pre‐established cutpoints were scheduled for more‐extensive neurocognitive assessments. Results from these assessments were centrally adjudicated. RESULTS: The mean age of this group of 7,149 participants at baseline was 71.0 ± 3.8, and the mean 3MS score was 95.2 ± 4.3. During a mean follow‐up period of 4.5 years, women without hypertension tended to have slightly higher 3MS scores than women with hypertension (P=.001), but the difference was not seen after adjustment for covariates (P=.17). Women with hypertension also appeared to be at greater risk for probable dementia or mild cognitive impairment (MCI) (hazard ratio=1.35, 95% confidence interval=1.07–1.70, P=.01), although when potential cofounders were accounted for, this association was no longer significant (P=.06). CONCLUSION: Hypertension and high blood pressure at baseline were not independently associated with MCI or probable dementia over time in older, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension.     

Sodium cromoglycate and eformoterol attenuate sensitivity and reactivity to inhaled mannitol in subjects with bronchiectasis

Background and objective: Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV₁ has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre‐medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV₁. Methods: A double‐blind, placebo‐controlled, randomized cross‐over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re‐assessed after pre‐medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV₁ (PD₁₅), and reactivity to mannitol, expressed as the % fall in FEV₁ per mg of mannitol (response–dose ratio, RDR), are reported. Results: Subjects had an FEV₁ of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV₁/FVC of 71 ± 8%. They were mildly hypoxemic and the SpO₂ was 95 ± 2%.They had a PD₁₅ to mannitol of 235 mg (95% CI: 150–368 mg) and a RDR of 0.057% fall in FEV₁ per mg (95% CI: 0.038–0.085). After pre‐medication with SCG, PD₁₅ increased (773 mg, P < 0.05) and RDR was reduced (0.013, P < 0.05). Pre‐medication with eformoterol also resulted in an increased PD₁₅ (1141 mg, P < 0.01) and a reduced RDR (0.009, P < 0.01). A small but significant decrease in SpO₂ from baseline was noted after mannitol in the presence of SCG (P < 0.05). Conclusions: Pre‐medication with either SCG or eformoterol protects patients with bronchiectasis from developing a significant reduction in FEV₁ after inhaling mannitol.     

Simultaneously measuring gait and cognitive performance in cognitively healthy and cognitively impaired older adults: the Basel motor-cognition dual-task paradigm

OBJECTIVES: To investigate dual‐task performance of gait and cognition in cognitively healthy and cognitively impaired older adults using a motor–cognition dual‐task paradigm. DESIGN: Cross‐sectional retrospective study. SETTING: The Basel Memory Clinic and the Basel Study on the Elderly (Project BASEL). PARTICIPANTS: Seven hundred eleven older adults (mean age 77.2 ± 6.2, 350 (49.2%) female and 361 (50.8%) male). MEASUREMENTS: Gait velocity and cognitive task performance using a working memory (counting backward from 50 by 2s) and a semantic memory (enumerating animal names) task were measured during single‐ and dual‐task conditions. Gait was assessed using the GAITRite electronic walkway system. Cognitive impairment was defined as a score less than 25 on the Mini‐Mental State Examination. RESULTS: During dual tasks, participants reduced gait velocity (P<.001) and calculated fewer numbers (P=.03) but did not enumerate fewer animals and did not make more errors or repetitions (P>.10). Cognitively impaired individuals had lower baseline gait velocity and a greater reduction in gait velocity but not cognitive performance during dual tasks than cognitively healthy participants (P<.01). CONCLUSION: Gait velocity was lower during both dual tasks, whereas decrease in cognitive performance depended on the cognitive ability needed in the dual‐task condition. Cognitively impaired individuals generally have poorer baseline performance and greater dual task–related gait velocity reduction than those who are cognitively healthy. Future research should include different conditions for gait to determine adaptive potentials of older adults.     

White matter lesions on brain magnetic resonance imaging scan and 5-year cognitive decline: the Honolulu-Asia aging study

OBJECTIVES: To study white matter lesions (WMLs) and 5‐year cognitive decline in elderly Japanese‐American men. DESIGN: Longitudinal cohort study. SETTING: Population‐based study in Honolulu, Hawaii. PARTICIPANTS: Japanese‐American men aged 74 to 95 from the Honolulu‐Asia Aging Study (HAAS) who were free of prevalent dementia, underwent a protocol brain MRI scan at the fifth HAAS examination (1994–1996), and returned for cognitive testing 5 years later (N=267). MEASUREMENTS: WMLs were dichotomized as present (grade 3–9, 38.2%) or absent (grade 1–2, 61.8%). Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI), and 5‐year cognitive decline was defined as a drop in CASI score of 12 points or more (1 standard deviation). RESULTS: Men with WMLs on MRI at baseline were significantly more likely to experience cognitive decline at 5 years than those without (22.4% vs 34.4%, P=.03). Using multiple logistic regression, adjusting for age, education, apolipoprotein (Apo)E4 allele, large or small infarcts on MRI, baseline CASI score, and hypertension, those with WMLs were significantly more likely to develop 5‐year cognitive decline (odds ratio=2.00, 95% confidence interval=1.10–3.65, P=.02). This association was stronger in men who were cognitively intact and free of the ApoE4 genotype and clinical stroke at baseline. CONCLUSION: Presence of WMLs on MRI was significantly associated with higher odds of 5‐year cognitive decline in older Japanese‐American men. Presence of WMLs may help identify people at risk for developing dementia, who may benefit from early intervention.     

The prevalence and predictors of airway hyperresponsiveness in sarcoidosis

Background and objective: Obstructive airflow limitation is the most common physiological impairment in sarcoidosis. This study determined the prevalence of airway hyperresponsiveness (AHR) in sarcoidosis, the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge, and the clinical, physiological and radiological predictors of AHR. Methods: Subjects with sarcoidosis and a baseline forced expiratory volume in 1 s (FEV₁) >35% predicted underwent hypertonic and histamine challenge, lung function testing and high resolution computed tomography (HRCT) of the chest. AHR was defined as a 15% fall in FEV₁ to hypertonic saline and a 20% fall in FEV₁ to histamine. Results: The 52 subjects had well‐preserved lung function (FEV₁ = 2.8 ± 0.7 L, 87% predicted). AHR was detected in 5/47 (11%) to hypertonic saline and 19/43 (44%) to histamine challenge. On univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (P = 0.02) and reticular pattern (P = 0.03) on HRCT. The baseline % predicted forced expiratory volume in 1 s was significantly inversely associated with AHR on univariate (P = 0.004) and multivariate analysis (P = 0.01) when adjusted by HRCT patterns. Conclusions: The higher prevalence of AHR using histamine challenge than hypertonic saline challenge and the association with baseline % predicted FEV₁ suggest that the AHR in sarcoidosis may reflect the consequences of airway remodelling following inflammation.     

Baseline Lower Extremity Strength and Subsequent Decline in Functional Performance at 6‐Year Follow‐Up in Persons with Lower Extremity Peripheral Arterial Disease

OBJECTIVES: To evaluate associations between baseline lower extremity strength and decline in functional performance over 6 years of follow‐up in men and women with lower extremity peripheral arterial disease (PAD). DESIGN: Prospective observational study. SETTING: Three Chicago‐area hospitals. PARTICIPANTS: Three hundred seventy‐four men and women with PAD. MEASUREMENTS: Baseline isometric hip extension, hip flexion, knee flexion, and knee extension strength were measured using a musculoskeletal fitness evaluation chair. Usual and fastest‐paced 4‐m walking speed, 6‐minute walk, and Short Physical Performance Battery (SPPB) were assessed at baseline and annually thereafter. Analyses were adjusted for age, sex, race, ankle–brachial index (ABI), comorbidities, and other confounders. RESULTS: In women with PAD, weaker baseline hip and knee flexion strength were associated with faster average annual decline in usual‐pace 4‐m walking speed (P trend <.001 and .02, respectively) and SPPB (P trend=.02 and .01, respectively). In women, weaker hip extension strength was associated with faster decline in usual‐pace 4‐m walking speed and SPPB (P trend=.01 and <.01, respectively). There were no significant associations between baseline strength and decline in 6‐minute walk in women. There were no significant associations between any baseline strength measure and functional decline in men. CONCLUSION: Weaker baseline leg strength is associated with faster functional decline in nonendurance measures of functional performance in women with PAD but not in men with PAD.     

Roflumilast in Asian patients with COPD: A randomized placebo-controlled trial

Background and objective: Roflumilast, an oral, selective phosphodiesterase 4 inhibitor, has been shown to reduce exacerbations and improve pulmonary function in patients with COPD. This study examined the efficacy, safety and tolerability of roflumilast in Asian patients with COPD. Methods: Patients with COPD were randomized 1:1 to enter a 12‐week treatment period and receive either oral roflumilast, 500 µg once daily, or placebo, following a single‐blind, 4‐week baseline period in which all patients received placebo. The primary end point was mean change in FEV₁ from baseline to each postrandomization visit during the treatment period. Other spirometric lung function measurements were evaluated as secondary end points. COPD exacerbations were monitored. Safety was assessed from clinical laboratory tests, vital signs, physical examination (including electrocardiogram) and monitoring of adverse events (AEs). Results: Of 551 patients recruited, 410 were randomized and received at least one dose of study medication (roflumilast, n = 203; placebo, n = 207). Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV₁ (79 mL, P < 0.0001). Other spirometry end points, including prebronchodilator FEV₁, pre‐and postbronchodilator FEV₆, forced vital capacity and peak expiratory flow significantly favoured roflumilast over placebo. AEs were more common with roflumilast than with placebo, but were comparable with those reported in previous studies. Conclusions: Roflumilast, 500 µg once daily, improves pulmonary function in Asian patients with COPD. The safety and tolerability of roflumilast in this population was similar to that in a Caucasian population.     

Intensification with pegylated interferon during treatment with tenofovir in HIV–hepatitis B virus co‐infected patients

In hepatitis B “e” antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono‐infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long‐term effect of adding PegIFN to tenofovir (TDF)‐containing antiretroviral therapy on seroclearance in HBeAg‐positive patients co‐infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1‐year PegIFN intensification during TDF‐containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time‐dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed‐effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4–59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log₁₀IU/mL, respectively (P>.5 between groups). Median follow‐up was 33.4 months (IQR=19.0–36.3). During intensification, faster average declines of qHBeAg (?0.066 vs ?0.027 PEIU/mL/month, P=.001) and qHBsAg (?0.049 vs ?0.026 log₁₀IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person·years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person·years, P=.7). In conclusion, PegIFN intensification in HBeAg‐positive co‐infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN.     

Bronchodilator reversibility in Australian adults with chronic obstructive pulmonary disease

Abstract Background and aims: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex‐smokers who were experiencing breathlessness to attend for lung function testing. Methods: One hundred and fifty‐four volunteers responded. Forced expiratory volume (FEV₁) was measured before and after 400 µg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (≥12% plus 200 mL of baseline FEV₁ or forced vital capacity), (ii) the British ­Thoracic Society (BTS) (≥15% plus 200 mL of baseline FEV₁), (iii) the European Thoracic Society (≥10% predicted FEV₁), and (iv) the most commonly used criteria in Australia and New Zealand (≥15% of baseline FEV₁). Results: One hundred and twenty‐three subjects (33 female; 40 current smokers; median pack years 48 (range 5?144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV₁ within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV₁ 60?80% predicted), 31 (24%) patients had moderate disease (FEV₁ 40?59% predicted), and 48 (39%) patients had severe disease (FEV₁ <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV₁ (r = ?0.2; P < 0.01), and greater BDR (r = 0.3; P < 0.005). Conclusion: Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many individuals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno­pathology has been determined they cannot be assumed to have ‘asthma’ or even an ‘asthmatic element’. (Intern Med J 2003; 33: 572?577)