Influence of compliance to respiratory weaning consensus conference criteria on respiratory outcome within 48h after planned extubation

INTRODUCTION. A two-step assessment (readiness to wean (RW) followed by spontaneousbreathing trial (SBT)) of predefined criteria is recommended before planned extubation(PE)1.OBJECTIVES. We aimed to evaluate if compliance to all guideline criteria was associatedwith better respiratory outcome within 48 h after PE.METHODS. The data (extracted from our clinical information system) of 458 consecutivepatients who underwent PE after C48 h of invasive ventilation in our medico-surgical ICUwere analyzed. We evaluated compliance with guidelines [1] regarding respiratory rate, tidalvolume, PaO2, FiO2, PEEP, PaCO2, pH, heart rate, systolic arterial pressure and arrhythmiaduringRWand SBT assessment (RW and SBT within 2 h). A patient was classified as RW+ ifallRWcriteria were fulfilled andRW-if at least 1 criterion was violated. The same approachwas used to define SBT+ and SBT- patients. During the 48 h following PE, we assessed theoccurrence of post-PE respiratory failure (PRF) (defined as the presence of at least 1 consensuscriterion of respiratory failure [1]), reintubation (after NIV failure or because of immediateintubation criteria) and cumulative duration of post-PE ventilation (PPEV = Post-PE invasive+ non-invasive ventilation). ICU mortality was recorded. Comparisons for variousoutcomes were performed by Chi-square and t tests.RESULTS. All consensus criteria were fulfilled in 77.3% of the patients during RW and in68.1% of the patients during SBT.[Compliance to weaning criteria and outcome]N = 458 PRF (%) Reintubation (%) PPEV (min) ICU mortality (%)All patients 53.5 10.0 542 ± 664 6.1RW+ 50.0 9.3 490 ± 626 5.4RW- 65.4* 12.5 718 ± 757** 8.7SBT+ 52.6 8.0 498 ± 594 6.7SBT- 55.5 14.4*** 637 ± 788**** 4.8Occurrence of PRF only was not associated with increased ICU mortality: 4.2 versus 7.8%,p = 0.11. By contrast, ICU mortality was significantly increased in patients requiring reintubation:21.7 versus 4.4%. p\0.001; * p = 0.006 RW+ versus RW-; ** p = 0.003RW+ versus RW-; *** p = 0.035 SBT+ versus SBT-; **** p = 0.030 SBT+ versusSBTCONCLUSIONS.In our ICU, compliance to all criteria of the two-step published approach ofrespiratory weaning was not optimal but reintubation rate was comparable to published data.Compliance with consensus conference guidelines was associated with lower reintubation rateand shorter PPEV but not with ICU mortality. As mortality was increased by reintubation,more sensitive and specific criteria to predict the risk of reintubation are probably needed.REFERENCE. Boles JM, et al. Eur Respir J 2007;29:1033-56.

Antihypertensive drug treatment changes in the general population: the CoLaus study.

BACKGROUND: Changes in antihypertensive drug treatment are paramount in the adequate management of patients with hypertension, still, there is little information regarding changes in antihypertensive drug treatment in Switzerland. Our aim was to assess those changes and associated factors in a population-based, prospective study. METHODS: Data from the population-based, CoLaus study, conducted among subjects initially aged 35-75 years and living in Lausanne, Switzerland. 772 hypertensive subjects (371 women) were followed for a median of 5.4 years. Data Subjects were defined as continuers (no change), switchers (one antihypertensive class replaced by another), combiners (one antihypertensive class added) and discontinuers (stopped treatment). The distribution and the factors associated with changes in antihypertensive drug treatment were assessed. RESULTS: During the study period, the prescription of diuretics decreased and of ARBs increased: at baseline, diuretics were taken by 46.9% of patients; angiotensin receptor blockers (ARB) by 44.7%, angiotensin converting enzyme inhibitors (ACEI) by 28.8%, beta-blockers (BB) by 28.0%, calcium channel blockers (CCB) by 18.9% and other antihypertensive drugs by 0.3%. At follow-up (approximately 5 years later), their corresponding percentages were 42.8%, 51.7%, 25.5%, 33.0% 20.7% and 1.0%. Among all participants, 54.4% (95% confidence interval: 50.8-58.0) were continuers, 26.9% (23.8-30.2) combiners, 12.7% (10.4-15.3) switchers and 6.0% (4.4-7.9) discontinuers. Combiners had higher systolic blood pressure values at baseline than the other groups (p < 0.05). Almost one third (30.6%) of switchers and 29.3% of combiners improved their blood pressure status at follow-up, versus 18.8% of continuers and 8.7% of discontinuers (p < 0.001). Conversely, almost one third (28.3%) of discontinuers became hypertensive (systolic ≥140 mm Hg or diastolic ≥90 mm Hg), vs. 22.1% of continuers, 16.3% of switchers and 11.5% of combiners (p < 0.001). Multivariate analysis showed baseline uncontrolled hypertension, ARBs, drug regimen (monotherapy/polytherapy) and overweight/obesity to be associated with changes in antihypertensive therapy. CONCLUSION: In Switzerland, ARBs have replaced diuretics as the most commonly prescribed antihypertensive drug. Uncontrolled hypertension, ARBs, drug regimen (monotherapy or polytherapy) and overweight/obesity are associated with changes in antihypertensive treatment.

In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate

Background: Leishmaniasis is a common parasitic disease in Southern Europe, caused by Leishmania infantum. The failures of current treatment with pentavalent antimonials are partially attributable to the emergence of antimony-resistant Leishmania strains. This study analyses the in vitro susceptibility to pentavalent antimony of intracellular amastigotes from a range of L. infantum strains, derived from the same infected animal, during in vitro and in vivo passages and after host treatment with meglumine antimoniate. Results: SbV-IC50 values for strains from two distinct isolates from the same host and one stock after two years of culture in NNN medium and posterior passage to hamster were similar (5.0 ± 0.2; 4.9 ± 0.2 and 4.4 ± 0.1 mgSbV/L, respectively). In contrast, a significant difference (P < 0.01, t test) was observed between the mean SbV-IC50 values in the stocks obtained before and after treatment of hosts with meglumine antimoniate (4.7 ± 0.4 mgSbV/L vs. 7.7 ± 1.5 mgSbV/L). Drug-resistance after drug pressure in experimentally infected dogs increased over repeated drug administration (6.4 ± 0.5 mgSbV/L after first treatment vs. 8.6 ± 1.4 mgSbV/L after the second) (P < 0.01, t test). Conclusions: These results confirm previous observations on strains from Leishmania/HIV co-infected patients and indicate the effect of the increasing use of antimony derivatives for treatment of canine leishmaniasis in endemic areas on the emergence of Leishmania antimony-resistant strains.

Corticosterone inhibits the lipid-mobilizing effects of oleoyl-estrone in adrenalectomized rats

Oleoyl-estrone (OE) is an adipose-derived signal that decreases energy intake and body lipid, maintaining energy expenditure and glycemic homeostasis. Glucocorticoids protect body lipid and the metabolic status quo. We studied the combined effects of OE and corticosterone in adrenalectomized female rats: daily OE gavages (0 or 10 nmol/g) and slow-release corticosterone pellets at four doses (0, 0.5, 1.7, and 4.8 mg/d). Intact and sham-operated controls were also included. After 8 d, body composition and plasma metabolites and hormones were measured. OE induced a massive lipid mobilization (in parallel with decreased food intake and maintained energy expenditure). Corticosterone increased fat deposition and inhibited the OE-elicited mobilization of body energy, even at the lowest dose. OE enhanced the corticosterone-induced rise in plasma triacylglycerols, and corticosterone blocked the OE-induced decrease in leptin. High corticosterone and OE increased insulin resistance beyond the effects of corticosterone alone. The presence of corticosterone dramatically affected OE effects, reversing its decrease of body energy (lipid) content, with little or no change on food intake or energy expenditure. The maintenance of glycemia and increasing insulin in parallel to the dose of corticosterone indicate a decrease in insulin sensitivity, which is enhanced by OE. The reversal of OE effects on lipid handling, insulin resistance, can be the consequence of a corticosterone-induced OE resistance. Nevertheless, OE effects on cholesterol were largely unaffected. In conclusion, corticosterone administration effectively blocked OE effects on body lipid and energy balance as well as insulin sensitivity and glycemia.

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Development of an aggregation assay to screen FimH antagonists.

Alpha-D-mannopyranosides are potent FimH antagonists, which inhibit the adhesion of Escherichia coli to highly mannosylated uroplakin Ia on the urothelium and therefore offer an efficient therapeutic opportunity for the treatment and prevention of urinary tract infection. For the evaluation of the therapeutic potential of FimH antagonists, their effect on the disaggregation of E. coli from Candida albicans and guinea pig erythrocytes (GPE) was studied. The mannose-specific binding of E. coli to yeast cells and erythrocytes is mediated by type 1 pili and can be monitored by aggregometry. Maximal aggregation of C. albicans or GPE to E. coli is reached after 600 s. Then the FimH antagonist was added and disaggregation determined by light transmission over a period of 1400 s. A FimH-deleted mutant of E. coli, which does not induce any aggregation, was used in a control experiment. The activities of FimH antagonists are expressed as IC(50)s, the half maximal inhibitory concentration of the disaggregation potential. n-Heptyl alpha-D-mannopyranoside (1) was used as a reference compound and exhibits an IC(50) of 77.14 microM , whereas methyl alpha-D-mannopyranoside (2) does not lead to any disaggregation at concentrations up to 800 microM. o-Chloro-p-[N-(2-ethoxy-3,4-dioxocyclobut-1-enyl)amino]phenyl alpha-D-mannopyranoside (3) shows a 90-fold and 2-chloro-4-nitrophenyl alpha-D-mannopyranoside (4) a 6-fold increased affinity compared to 1. Finally, 4-nitrophenyl alpha-D-mannopyranoside (5) exhibits an activity similar to 1. As negative control, D-galactose (6) was used. The standardized aggregation assay generates concentration-dependent, reproducible data allowing the evaluation of FimH antagonists according to their potency to inhibit E. coli adherence and can therefore be employed to select candidates for experimental and clinical studies for treatment and prevention of urinary tract infections.

Freeway Work Zone Lane Capacity, TPF-5(081), 2009

The focus of this report is a capacity analysis of two long-term urban freeway Work Zones. Work Zone #1 tapered four mainline lanes to two, using two separate tapers; Work Zone #2 tapered two mainline lanes to one. Work Zone throughput was analyzed throughout the day over multiple days and traffic operations conditions were analyzed up to a distance of five miles upstream of the Work Zone entrance. Historical data from pavement-embedded detectors were used to analyze traffic conditions. The database consisted of five-minute volume, speed and occupancy data collected from 78 detectors for a total of 50 days. Congestion during each analyzed Work Zone existed for more than fourteen hours each day; Work Zone impacts adversely affected freeway operations over distances of 3.7 to 4.2 miles. Speed and occupancy conditions further upstream were, however, not affected, or even improved due to significant trip diversion. Work Zone capacity was defined based on the maximum traffic flows observed over a one-hour period; throughput values were also compiled over longer periods of time when traffic was within 90% of the maximum observed one-hour flows, as well as over the multi-hour mid-day period. The Highway Capacity Manual freeway capacity definition based on the maximum observed 15-min period was not used, since it would have no practical application in estimating Work Zone throughput when congested conditions prevail for the majority of the hours of the day. Certain noteworthy changes took place for the duration of the analyzed Work Zones: per-lane throughput dropped; morning peak periods started earlier, evening peak periods ended later and lasted longer; mid-day volumes dropped accompanied by the highest occupancies of the day. Trip diversion was evident in lower volumes entering the analyzed freeway corridor, higher volumes using off-ramps and lower volumes using onramps upstream of the Work Zones. The majority of diverted traffic comprised smaller vehicles (vehicles up to 21 feet in length); combination truck volumes increased and their use of the median lane increased, contrary to smaller vehicles that shifted toward a heavier use of the shoulder lane.

Training in hypoxia fails to further enhance endurance performance and lactate clearance in well-trained men and impairs glucose metabolism during prolonged exercise.

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise.

High prevalence and lineage diversity of avian malaria in wild populations of great tits (Parus major) and mosquitoes (Culex pipiens).

Avian malaria studies have taken a prominent place in different aspects of evolutionary ecology. Despite a recent interest in the role of vectors within the complex interaction system of the malaria parasite, they have largely been ignored in most epidemiological studies. Epidemiology of the disease is however strongly related to the vector's ecology and behaviour, and there is a need for basic investigations to obtain a better picture of the natural associations between Plasmodium lineages, vector species and bird hosts. The aim of the present study was to identify the mosquito species involved in the transmission of the haemosporidian parasites Plasmodium spp. in two wild populations of breeding great tits (Parus major) in western Switzerland. Additionally, we compared Plasmodium lineages, based on mitochondrial DNA cytochrome b sequences, between the vertebrate and dipteran hosts, and evaluated the prevalence of the parasite in the mosquito populations. Plasmodium spp. were detected in Culex pipiens only, with an overall 6.6% prevalence. Among the six cytochrome b lineages of Plasmodium identified in the mosquitoes, three were also present in great tits. The results provide evidence for the first time that C. pipiens can act as a natural vector of avian malaria in Europe and yield baseline data for future research on the epidemiology of avian malaria in European countries.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial.

BACKGROUND: Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo. METHODS: This multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland), parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26) or placebo (N = 24) for four weeks. The institution's pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA) levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland). Trial registration: ISRCTN 22063938. RESULTS: Baseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26) lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19) more than the change observed in the placebo group (N = 23). The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4). A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months), significant differences in MMA levels were no longer detected. CONCLUSIONS: Oral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency. However, a one-month daily treatment with 1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months, and treatment had no effect on haematological signs of B12 deficiency.