Multi-site placebo-controlled randomised clinical trial to assess protection following oral immunisation with inactivated non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease.

BACKGROUND: Previous studies identified factors that modify response to an oral non-typeable Haemophilus influenzae (NTHi) vaccine in chronic obstructive pulmonary disease (COPD): severe COPD, moderate-severe exacerbations as end-point and a threshold prevalence of NTHi in the study population. More data are needed to confirm parameters that influence clinical outcomes. AIMS: The primary aim was to determine the efficacy of an oral NTHi vaccine (HI-164OV) in reducing the rate of exacerbations requiring systemic corticosteroids or hospitalisation in COPD. Secondary aims included effect on the proportion of patients experiencing such exacerbations, severity of infections and quality of life (St George Respiratory Questionnaire for COPD patients (SGRQ-C)). METHODS: This multi-centre, double-blind, placebo-controlled study was conducted at 21 Australian sites for 9 months in 2011. RESULTS: Three-hundred and twenty subjects with COPD, FEV1 <60% predicted and ≥1 moderate-severe exacerbations in the previous 12 months were recruited. The primary and secondary end-points for the intention-to-treat population aged 40-88 years were not achieved, and only 5% of subjects had an H. influenzae-positive sputum sample. Subsequent exploratory analysis of patients <65 years (91 subjects) indicated protection with respect to the primary and most of the secondary end-points, with SGRQ-C symptom scores lower at 3 and 6 months. CONCLUSION: Patients aged 40-88 years with moderate to severe COPD and low rates of H. influenzae-positive sputum were not protected against exacerbations by HI-1640V. Further studies are needed to confirm protection in subjects aged <65 years. Older age and low colonisation rates appear to affect adversely response to this vaccine.

A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea.

AIMS: To evaluate the efficacy and safety of saxagliptin as add-on therapy in adults with type 2 diabetes with inadequate glycaemic control on metformin plus a sulphonylurea. METHODS: In this 24-week, multicentre, randomized, parallel-group, double-blind study, outpatients aged ≥18 years with type 2 diabetes, body mass index ≤40 kg/m(2) and inadequate glycaemic control, received saxagliptin 5 mg or placebo once-daily added to background medication consisting of a stable maximum tolerated dose of metformin plus a sulphonylurea. The primary end point was change in glycated haemoglobin (HbA1c) from baseline to week 24. Safety and tolerability assessments included adverse events (AEs), hypoglycaemia and body weight. RESULTS: A total of 257 patients were randomized, treated and included in the safety analysis (saxagliptin, n = 129; placebo, n = 128); 255 were included in the efficacy analysis (saxagliptin, n = 127; placebo, n = 128). HbA1c reduction was greater with saxagliptin versus placebo [between-group difference in adjusted mean change from baseline, -0.66%; 95% confidence interval (CI), -0.86 to -0.47 (7 mmol/mol, -9.4 to -5.1); p < 0.0001]. The proportion of patients with ≥1 AE was 62.8% with saxagliptin and 71.7% with placebo. In the saxagliptin and placebo groups, rates of reported hypoglycaemia were 10.1 and 6.3%, respectively, and rates of confirmed hypoglycaemia (symptoms + glucose < 2.8 mmol/l) were 1.6 and 0%. Mean change in body weight was 0.2 kg for saxagliptin and -0.6 kg for placebo (p = 0.0272). CONCLUSION: Addition of saxagliptin 5 mg/day in patients inadequately controlled on metformin and sulphonylurea effectively improved glycaemic control and was well tolerated.

Thermoregulatory, metabolic and sympathoadrenal responses to repeated brief exposure to cold.

This study examined the metabolic, thermoregulatory and sympathoadrenal response pattern of eight male subjects to repeated bouts of brief cold stress. Water immersion (WI) was used to induce cold stress over a 60 min period on three separate occasions on three successive days. Rectal temperature (T(re)), mean skin temperature (T(sk)) and metabolic rate (VO2) were measured at 10 min intervals throughout WI and for 20 min post-immersion (PI). Blood was drawn and assayed for plasma adrenaline (ADR), noradrenaline (NDR) and cortisol at rest, at the end of immersion and PI. Acute cold stress was induced for each of the three exposures with a reduction in T(re) of approximately 0.63 degrees C (p<0.01) and approximately 1.2 degrees C (p<0.01) at the end of immersion and PI, respectively. T(sk) was reduced for all trials by approximately 6.0 degrees C (p<0.01) at the end of immersion and approximately 3.0 degrees C (p<0.01) at PI. VO2 peaked at 40-50 min of WI to 83%, 58% and 47% above rest for each consecutive trial. Plasma ADR did not show any change (p=0.34) as a consequence of cold stress between trials. Plasma NDR increased at the end of immersion (p<0.01) and remained elevated at PI (p<0.01). Plasma cortisol showed no change for any of the exposure periods. DeltaT(re) was more pronounced for the last exposure and was negatively correlated (r= -0.78, p<0.02) with plasma NDR. The results of this investigation complement previous findings of cold adaptation and suggest a possible adaptive response to repeated brief bouts of cold exposure evidenced by the changing trends in body temperature, metabolic rate and plasma NDR.

Metabolic consequences of reduced frequency breathing during submaximal exercise at moderate altitude.

The intention of this study was to determine the metabolic consequences of reduced frequency breathing (RFB) at total lung capacity (TLC) in competitive cyclists during submaximal exercise at moderate altitude (1520 m; barometric pressure, PB = 84.6 kPa; 635 mm Hg). Nine trained males performed an RFB exercise test (10 breaths.min-1) and a normal breathing exercise test at 75-85% of the ventilatory threshold intensity for 6 min on separate days. RFB exercise induced significant (P less than 0.05) decreases in ventilation (VE), carbon dioxide production (VCO2), respiratory exchange ratio (RER), ventilatory equivalent for O2 consumption (VE/VO2), arterial O2 saturation and increases in heart rate and venous lactate concentration, while maintaining a similar O2 consumption (VO2). During recovery from RFB exercise (spontaneous breathing) a significant (P less than 0.05) decreases in blood pH was detected along with increases in VE, VO2, VCO2, RER, and venous partial pressure of carbon dioxide. The results indicate that voluntary hypoventilation at TLC, during submaximal cycling exercise at moderate altitude, elicits systemic hypercapnia, arterial hypoxemia, tissue hypoxia and acidosis. These data suggest that RFB exercise at moderate altitude causes an increase in energy production from glycolytic pathways above that which occurs with normal breathing.

Metabolic and heart rate responses to submaximal arm lever and arm crank ergometry.

Previous studies have shown that arm cranks and arm levers, working as propulsion mechanisms for nonambulatory individuals, may have mechanical and physiologic advantages over standard handrim wheelchairs. This study evaluated physiologic responses to arm lever and arm crank ergometry using identical workloads. An arm lever ergometer (ALE) was constructed and adapted to an arm crank ergometer (ACE) so that equal workloads could be applied with both ergometers. Fifteen able-bodied men and 15 able-bodied women exercised at a low (15 watts) and a high (45 watts) workload, with a three-minute rest interval. While exercising at each level, oxygen consumption (VO2), minute ventilation (VE), and heart rate (HR) were monitored. When low workloads with ALE and ACE were compared, no significant differences (p greater than 0.05) were demonstrated in any of the variables for men or women. For the men, at the high workload, the ALE elicited significantly lower (p less than 0.05) VO2 (by 9.8%), HR (by 6.3%), and VE (by 7.5%), than did the ACE. For the women, at the high workload, VO2 was significantly lower (p less than 0.05) (by 7.6%) with the ALE, as was VE (by 7.5%), but HR, although 3.3% lower with the ALE, was not significantly different (p greater than 0.05) from the ACE. These data suggest that the ALE is physiologically less stressful than the ACE at high workloads. Arm levers may, therefore, provide an advantage for handicapped persons when they propel themselves in wheelchairs.