Varlitinib plus capecitabine in second-line advanced biliary tract cancer: a randomized, phase II study (TreeTopp).

BACKGROUND: Patients with advanced biliary tract cancer who progress on first-line therapy have limited treatment options. The TreeTopp study assessed varlitinib, a reversible small molecule pan-human epidermal growth factor receptor inhibitor, plus capecitabine in previously treated advanced biliary tract cancer. PATIENTS AND METHODS: This global, double-blind, randomized, placebo-controlled phase II study enrolled patients with confirmed unresectable or metastatic biliary tract cancer and disease progression after one prior line of gemcitabine-containing chemotherapy. Patients received oral varlitinib 300 mg or placebo twice daily (b.i.d.) for 21 days, plus oral capecitabine 1000 mg/m2 b.i.d. on days 1-14, in 21-day treatment cycles. Co-primary endpoints were objective response rate and progression-free survival (PFS) according to RECIST v1.1 by Independent Central Review. RESULTS: In total, 127 patients received varlitinib plus capecitabine (n = 64) or placebo plus capecitabine (n = 63). The objective response rate was 9.4% with varlitinib plus capecitabine versus 4.8% with capecitabine alone (odds ratio 2.28; P = 0.42). Median PFS was 2.83 versus 2.79 months [hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.60-1.37; P = 0.63] and overall survival was 7.8 versus 7.5 months (HR, 1.11; 95% CI, 0.69-1.79; P = 0.66), respectively. In a subgroup analysis, the addition of varlitinib appeared to provide a PFS benefit in female patients (median, 4.1 versus 2.8 months; HR, 0.59; 95% CI, 0.28-1.23) and those with gallbladder cancer (median, 2.9 versus 1.6 months; HR, 0.55; 95% CI, 0.26-1.19). Grade ≥3 treatment-emergent adverse events were reported in 65.6% of patients receiving varlitinib plus capecitabine versus 58.7% of those receiving capecitabine alone. CONCLUSIONS: In patients with advanced biliary tract cancer, second-line treatment with varlitinib plus capecitabine was well tolerated but did not improve efficacy versus capecitabine alone. A PFS benefit was suggested in female patients and those with gallbladder cancer.

NOD-like receptor activation by outer membrane vesicles from Vibrio cholerae non-O1 non-O139 strains is modulated by the quorum-sensing regulator HapR.

Vibrio cholerae is an inhabitant of aquatic systems and one of the causative agents of severe dehydrating diarrhea in humans. It has also emerged as an important cause of different kinds of inflammatory responses, and in particular, V. cholerae strains of the non-O1 non-O139 serogroups (NOVC) have been associated with such infections in human. We analyzed the potential of outer membrane vesicles (OMVs) derived from the NOVC strain V:5/04 to induce inflammatory responses in human host cells. V:5/04 OMVs were taken up by human epithelial cells and induced inflammatory responses. Small interfering RNA (siRNA)-mediated gene knockdown revealed that the inflammatory potential of NOVC OMVs was partially mediated by the nucleotide-binding domain-, leucine-rich repeat-containing family member NOD1. Physiochemical analysis of the content of these OMVs, in conjunction with NOD1 and NOD2 reporter assays in HEK293T cells, confirmed the presence of both NOD1 and NOD2 active peptidoglycan in the OMVs. Furthermore, we show that deletion of the quorum-sensing regulator HapR, which mimics an infective life style, specifically reduced the inflammatory potential of the V:5/04 OMVs and their ability to activate NOD1 and NOD2. In conclusion, our study shows that NOVC OMVs elicit immune responses mediated by NOD1 and NOD2 in mammalian host cells. Moreover, we provide evidence that the quorum-sensing machinery plays an important regulatory role in this process by attenuating the inflammatory potential of OMVs under infective conditions. This work thus identifies a new facet of how Vibrio affects host immune responses and defines a role for the quorum-sensing machinery in this process.

Impact of dystonia on quality of life and health in a Swedish population.

OBJECTIVES: Dystonia is often disabling and disfiguring. The aim of the study was to identify factors influencing the impact of dystonia on self-reported quality of life and health. MATERIAL AND METHODS: Members of the Swedish Dystonia Patient Association participated in a survey covering demographic variables, satisfaction with treatment, physiotherapy and physical activity. Quality of life and health were assessed by the Craniocervical Dystonia Questionnaire and the Cervical Dystonia Impact Profile, respectively. Of 378 questionnaires, 76% were analysed. Multiple linear regression analyses were performed to evaluate associations of the above variables with quality of life and health. RESULTS: Level of physical activity and satisfaction with treatment showed the highest association with quality of life and health. No significant relationship was found between form of dystonia and quality of life. CONCLUSIONS: The study indicates a need for health care professionals to encourage physical activity and to question dystonia patients about satisfaction with treatment. Further investigations with prospective controlled trials are necessary to evaluate the value of physiotherapy and physical activity in patients with dystonia.

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

BACKGROUND: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. METHODS: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. RESULTS: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). CONCLUSIONS: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

Objective assessment of cervical dystonia: a pilot study.

OBJECTIVES: The aims were to characterize the movements in cervical dystonia (CD) by using an estimate of the mechanical power and work involved in the movements and to describe this through a movement energy index (MEI). MATERIALS AND METHODS: The subjects (patients n = 6, controls n = 6) were seated in front of a screen with a laser pointer attached to a headband while they performed standardized movements. A three-dimensional motion capture system was used and a test-retest was performed. RESULTS: The mean value of MEI was significantly higher for the patients than for the controls. There was no significant difference between MEI from test to retest for the patients but there was a significant difference between MEI from test to retest for the controls. CONCLUSION: This study suggests that MEI could be a useful measure for the quantification of movement dysfunction in CD and thus an objective outcome measure in comparison of different therapies.

Pulmonary function 4 months after coronary artery bypass graft surgery.

The objective of this study was to describe the pulmonary function and pain 4 months after coronary artery bypass graft surgery. Twenty-five male patients performed pulmonary function tests before surgery, on the 4th postoperative day and 4 months after surgery. A severe reduction in pulmonary function was present after surgery. Four months postoperatively, the patients still showed a significant decrease (6-13% of preoperative values) in vital capacity (P<0.001), inspiratory capacity (P<0.001), forced expiratory volume in 1 s (P<0.001) peak expiratory flow rate (P<0.001), functional residual capacity (P=0.05) total lung capacity (P<0.001) and single-breath carbon monoxide diffusing capacity (P<0.01). Residual volume and single-breath carbon monoxide diffusing capacity per litre of alveolar volume had returned to the preoperative level. Four months postoperatively, the median values for sternotomy pain while taking a deep breath was 0.2 and while coughing 0.3 on a 10 cm visual analogue pain scale. In conclusion, a significant restrictive pulmonary impairment persisting up to 4 months into the postoperative period was found after CABG. Measured levels of pain were low and could not explain the impairment.

The Falls-Efficacy Scale, Swedish version: does it reflect clinically meaningful changes after stroke?

PURPOSE: The overall aim of this prospective investigation was to evaluate the ability of the Falls Efficacy Scale (Swedish version) (FES(S)) to reflect clinically meaningful changes over time. METHOD: Changes on the FES(S) scale were compared with changes in two different standardized measures of observer-assessed balance, the Berg Balance Scale (BBS), the Fugl-Meyer balance subscale (FMB), and of motor function and ambulation in 62 stroke patients. Assessments took place on admission for rehabilitation, at discharge and 10 months after the stroke. Indices of effect size were used to evaluate responsiveness of the instruments. Three time periods were studied: admission to discharge (early response), discharge to 10 month follow-up (late response) and admission to follow-up (overall response). RESULTS: The main findings are that the FES(S) is as responsive as BBS and FMB in detecting changes during the early and overall response periods. Changes in FES(S) scores between admission and discharge correlated significantly with changes in observer-assessed balance, motor function and ambulation scores. CONCLUSIONS: The present results suggest that measurement of perceived confidence in task performance using the FES(S) scale is responsive to improvement in patients with hemiparesis at an early stage after stroke.

Adult height in women with childhood asthma--a population-based study.

PURPOSE: To study adult height in children that grew up with asthma before inhaled steroids became first-line therapy. METHODS: Data from the Swedish Medical Birth Register (self-reported asthma) and the Hospital Discharge Register (first hospitalization for asthma) were used, to compare adult height for asthmatic and non-asthmatic pregnant women. The analysis was restricted to women in their first full-term pregnancy, born in Sweden between 1960-1974 and of Swedish citizenship. RESULTS: The mean height of all the women in the study population was 166.7 cm (SD = 8.8, n = 287,750) and of the women who reported asthma 166.5 cm (SD = 6.1, n = 13,059, p < 0.01). The mean height of women first hospitalized because of asthma at age 0-8 years was 165.5 cm (SD = 5.9 cm, n = 555, p < 0.01). Among the asthmatic women, there was no skew distribution of heights. CONCLUSIONS: Girls with moderate to severe childhood asthma who grew up before inhaled glucocorticosteroids became first-line therapy attained 0.7-1.2 cm lower adult height. The differences in height. while of statistical relevance, are not clinically relevant.

Chest physiotherapy after coronary artery bypass graft surgery--a comparison of three different deep breathing techniques.

The effectiveness of three deep breathing techniques was evaluated in 98 male patients after coronary artery bypass graft surgery in a randomized trial. The techniques examined were deep breathing with a blow bottle-device, an inspiratory resistance-positive expiratory pressure mask (IR-PEP) and performed with no mechanical device. Pulmonary function and roentgenological changes were evaluated. Four days post-operatively there were significantly decreased vital capacity, inspiratory capacity, forced expiratory volume in 1 second, functional residual capacity, total lung capacity and single-breath carbon monoxide diffusing capacity in all three groups (p < 0.0001). No major differences between the treatment groups were found, but the impairment in pulmonary function tended to be less marked using the blow bottle technique. The Blow bottle group had significantly less reduction in total lung capacity (p = 0.01) compared to the Deep breathing group, while the IR-PEP group did not significantly differ from the other two groups.

Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients.

The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.

Association between intraocular pressure and budesonide inhalation therapy in asthmatic patients.

BACKGROUND: The extent to which inhaled glucocorticoids increase the risk of intraocular pressure elevation has been controversial. OBJECTIVE: The authors attempt to assess such risk attributable to budesonide, an inhaled glucocorticoid for asthma therapy. METHODS: Data were pooled from four prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trials of 12 to 20 weeks in duration. One thousand two hundred and fifty-five patients, 6 to 70 years of age whose intraocular pressures (IOPs) were less than 23 mmHg at screening were randomized to receive placebo or inhaled budesonide at doses ranging from 100 to 800 microg, administered twice daily. Intraocular pressure was measured at screening and at the end of double-blind treatment. Intraocular change was compared between budesonide and placebo, accounting for the confounding effects of gender, race, age, history of diabetes, history of hypertension, clinical trial, systemic glucocorticoid use during the trials, ophthalmic glucocorticoid use during the trials, and prior oral glucocorticoid use. RESULTS: No budesonide treatment effect on the IOP was evident either in the crude analysis or after adjustment for possible confounding factors. For patients exposed to budesonide at a total daily dose of 1600 microg for 20 weeks, there was no difference in IOP change compared with the placebo controls. CONCLUSIONS: No association with an increased IOP was observed in asthmatic patients treated with budesonide at daily doses ranging from 200 to 1600 microg for durations of 12 to 20 weeks. The subgroup analysis, which focused on the highest dose and longer term therapy was reassuring, as was the overall result.

Reduced height in swedish men with asthma at the age of conscription for military service.

OBJECTIVE: To investigate the influence of asthma on growth in Swedish children during a period when inhaled corticosteroids (ICS) have been first-line therapy for persistent asthma. STUDY DESIGN: We analyzed the height of conscripts with and without asthma in the year they turned 18 years old, using Swedish military conscription records from 1983, 1986, 1993, and 1996, and assessed exposure to ICS using prescription records over the same period. RESULT: The mean height for conscripts without asthma was 179.3 cm (SD = 6.6 cm, n = 164,503) and for conscripts with asthma 178.6 cm (SD = 6.6 cm, n = 8,531, P <.001). The severity of asthma had a negative correlation with height in all study populations (P <.001 in each year tested). Since 1985, increasing numbers of children with asthma have been treated with ICS in Sweden. Sales of ICS for males from birth to age 19 years increased from 68,000 daily doses in 1983 to more than 3, 000,000 in 1995-1996. During this period, there was no statistically significant change in the height difference between conscripts with and without asthma. CONCLUSION: The introduction of inhaled steroids in Sweden, where budesonide is the predominant medication, has not changed the mean difference in heights between Swedish conscripts with and without asthma.

Community health care nursing in Rajasthan. A registered nurse's perspective.

This study focused on the great shortage of registered nurses (RNs) in primary health care in Rajasthan, India. It dealt especially with the nurses' own opinions about working in primary health care and their reasons for not working in it. Nurses at different levels in the health care organization were interviewed. The study was based on interviews with six RNs individually, three groups of six to eight nursing students each, and three policy-making chief nurses individually. The Minister of Health in Rajasthan also participated in the study. The study showed that the reasons for the lack of RNs in community health care were as follows: a government policy decision to place less educated nurses in the communities; the great shortage of nurses in general; the system whereby a nurse is not able to choose her/his place of work; unwillingness on the part of the nurses to work in community health care because of the great security problems; lack of support from authorities and lack of equipment. In general, community health care nursing as a work area was despised by society at large in Rajasthan.

Fear of falling in patients with stroke: a reliability study.

OBJECTIVE: To examine the scaling properties and test-retest reliability of an expanded version of the Falls Efficacy Scale (FES) and to compare group differences in the scores. The expanded version focuses on more basic, primary activities of daily living (ADL), which makes the scale more suitable for subjects with moderate to low functional ability, e.g. patients with stroke. DESIGN: A test-retest reliability study with one group convenience sample. SETTING: Two day-care units: a rehabilitation unit and a geriatric rehabilitation unit. SUBJECTS: A volunteer sample of 30 patients (mean age 65 years, SD 11 years) who had sustained stroke between 5 and 84 months prior to the investigation. MAIN OUTCOME MEASURE: A 13-activity questionnaire (the Swedish modification of the Falls Efficacy Scale (FES(S)) comprising the 10 activities of the original FES and three additional activities was used. Falls efficacy was rated on a 10-point visual analogue scale for each activity on two occasions, 5-22 (mean 10, Md 7) days apart. RESULTS: The overall test-retest reliability of the FES(S) was high (intraclass correlation coefficient (ICC) = 0.97). The ICC for the personal ADL (items 1-6) scores was 0.93 and for the instrumental ADL (items 8-13) 0.97. ICC for the individual items ranged from 0.76 to 0.97. CONCLUSIONS: On the basis of these preliminary findings, the FES(S) appears to have acceptable test-retest reliability. The test may be a reasonable addition for assessing stroke patients with balance disturbances and risk for falls.

Performance in functional balance tests during menopausal hormone replacement: a double-blind placebo-controlled study.

BACKGROUND AND PURPOSE: Recent studies have indicated that oestrogens might have an effect on postural control. The purpose of this study was to investigate the short-term effect of hormone replacement therapy (HRT) on postural control in menopausal women and to analyse the correlation between sway velocity measures and results of functional balance tests. SUBJECTS: 100 menopausal women who were randomized to receive either HRT or placebo for three months were included in the study. METHOD: The balance function was measured with nine different static and dynamic functional balance tests. The sway velocities were measured on a computerized force platform. RESULTS: No significant differences were found between the two groups in the results of the functional balance tests after the three-month placebo-controlled period or in the changes over time. However, some significant improvements occurred within both groups over this three-month period. The correlations between different sway velocities and the results of the functional balance tests were all very low (r < 0.35). CONCLUSION: It can not be concluded that HRT had a positive effect on the performance in the functional balance tests, as some improvement occurred in both groups. The low correlations indicate that the sway velocity and functional balance tests measure different aspects of balance function.

Better postural balance in elderly women receiving estrogens.

OBJECTIVE: The amount of bone mass and the tendency to fall are main risk factors for hip fractures and both deteriorate with advancing age. The dynamics between estrogen exposure and fracture protection seem too rapid to be explained by an effect on bone mass only. Postural balance function may be another potential mechanism for the fracture-protecting effect of estrogens. STUDY DESIGN: We examined 16 long-term users of 17 beta-estradiol implants (20 mg) (mean age 67.9 years and mean duration of treatment 17.3 years [3.3 to 34 years]) and 16 age-matched (+/-2 years) nonusers (mean age 68.3 years). Postural balance (sway velocity) was measured by static posturography before and after blindfolding and application of vibration stimulus (20 to 100 Hz) to the calf muscles to disturb the proprioception and to induce imbalance. RESULTS: Sway velocities were significantly lower in estrogen users than in nonusers (p = 0.0067) and similar to those in young premenopausal women. The differences were accentuated after provocation by blindfolding and by increasing frequencies of vibration stimulus to the calf muscle. Serum levels of estradiol and estradiol/sex hormone-binding globulin were negatively and follicle-stimulating hormone levels positively associated with sway velocity (p = 0.0194, p = 0.0036, and p = 0.0052, respectively) and independent of age (p = 0.02 to 0.005), supporting causality between estrogen exposure and postural balance. CONCLUSIONS: These data indicate that postural balance function is better preserved in long-term estrogen users than in nonusers. Effects on postural balance function may be one mechanism explaining the rapid increase in distal forearm fractures early after menopause and the rapid dynamics between estrogen exposure and hip fracture protection and may potentially reduce the fracture risk in elderly women starting estrogen replacement therapy in spite of marginal increases in bone mass.