Period-Prevalence and Risk Factors for Delirium in a Tertiary Referral ICU: A prospective cohort study.

BACKGROUND: Delirium is common in intensive care and leads to increases in morbidity, mortality, Intensive Care Unit (ICU) length of stay, and hospital length of stay. Certain risk factors predict the appearance of delirium. STUDY OBJECTIVES: To determine the rates of delirium, the rate of risk factors, and their relationship to the occurrence of delirium in an adult ICU. METHODS: Single-centre, prospective, observational study. Demographic and treatment data were collected. The Confusion Assessment Method for ICU (CAM-ICU) was performed twice daily to assess for delirium continuously during a 3-week period. Statistical analysis was used to determine the relationship between risk factors and the occurrence of delirium. RESULTS: 86 patients were screened, 44 patients were included, and 260 patient-days were analyzed. The incidence of delirium was 42.9%, the prevalence of delirium in ICU was 50%. Urinary catheters and use of opioids were the most common factors with a positive association for occurrence of delirium. Exposure to daylight and sleeping for more than 4 hours at night were the factors most commonly associated with a lack of delirium. CONCLUSION: The rates of delirium in ICU were high and risk factors occurred frequently. Addressing modifiable risk factors, including the promotion of adequate sleep, could improve outcomes.

Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

Using a model based fourth-corner analysis to explain vegetation change following an extraordinary fire disturbance.

In ecosystems where large-scale disturbances are infrequent, the mode of succession may be difficult to discern and floristic surveys alone cannot be used determine the underlying processes causing vegetation change. To determine the causes of vegetation change in response to a large-scale fire event, we combined traditional floristic survey data, plant functional traits and environmental variables in a model-based solution to the fourth-corner problem. This approach allowed us to describe the trait-environment relationship and provides an intuitive matrix of environment by trait interaction coefficients. We could then quantify the strength and direction of associations between plant traits, species life-forms and environmental factors in two alpine plant communities over nine years post-fire. Initially, the fire drastically reduced vegetation cover and species density to very low levels. The fourth-corner analysis interaction coefficients indicated that over the course of the nine-year study a high abundance of graminoids, a low abundance of shrubs, tall species and those with high leaf dry matter content had the strongest associations with the two plant communities. We also found evidence for functional homogenisation between these two communities using this novel technique. Analysing plant traits and species responses post-fire in this manner can be used to infer the ecological processes driving shifts in vegetation.

A genetic-based algorithm for personalized resistance training.

Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete's genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete's potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual's genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.

Hypersensitivity pneumonitis in workers exposed to metalworking fluids.

BACKGROUND: This study used data from a large UK outbreak investigation, to develop and validate a new case definition for hypersensitivity pneumonitis due to metalworking fluid exposure (MWF-HP). METHODS: The clinical data from all workers with suspected MWF-HP were reviewed by an experienced panel of clinicians. A new MWF-HP Score was then developed to match the "gold standard" clinical opinion as closely as possible, using standard diagnostic criteria that were relatively weighted by their positive predictive value. RESULTS: The new case definition was reproducible, and agreed with expert panel opinion in 30/37 cases. This level of agreement was greater than with any of the three previously utilized case definitions (agreement in 16-24 cases). Where it was possible to calculate, the MWF-HP Score also performed well when applied to 50 unrelated MWF-HP cases. CONCLUSIONS: The MWF-HP Score offers a new case definition for use in future outbreaks.

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.

Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

The learning curve for endoscopic tympanoplasties: a single-institution experience, in Birmingham, UK.

OBJECTIVE: This study aimed to assess whether increasing operative experience results in better surgical outcomes in endoscopic middle-ear surgery. METHODS: A retrospective single-institution cohort study was performed. Patients underwent endoscopic tympanoplasty between May 2013 and April 2019 performed by the senior surgeon or a trainee surgeon under direct supervision from the senior surgeon. Following data collection, statistical analysis compared success rates between early (learning curve) surgical procedures and later (experienced) tympanoplasties. RESULTS: In total, 157 patients (86 male, 71 female), with a mean age of 41.6 years, were included. The patients were followed up for an average of 43.2 weeks. The overall primary closure rate was 90.0 per cent. CONCLUSION: This study demonstrates an early learning curve for endoscopic ear surgery that improves with surgical experience. Adoption of the endoscopic technique did not impair the success rates of tympanoplasty.

The magnitude of Yo-Yo test improvements following an aerobic training intervention are associated with total genotype score.

Recent research has demonstrated that there is considerable inter-individual variation in the response to aerobic training, and that this variation is partially mediated by genetic factors. As such, we aimed to investigate if a genetic based algorithm successfully predicted the magnitude of improvements following eight-weeks of aerobic training in youth soccer players. A genetic test was utilised to examine five single nucleotide polymorphisms (VEGF rs2010963, ADRB2 rs1042713 and rs1042714, CRP rs1205 & PPARGC1A rs8192678), whose occurrence is believed to impact aerobic training adaptations. 42 male soccer players (17.0 ± 1y, 176 ± 6 cm, 69 ± 9 kg) were tested and stratified into three different Total Genotype Score groups; "low", "medium"and "high", based on the possession of favourable polymorphisms. Subjects underwent two Yo-Yo tests separated by eight-weeks of sports-specific aerobic training. Overall, there were no significant differences between the genotype groups in pre-training Yo-Yo performance, but evident between-group response differentials emerged in post-training Yo-Yo test performance. Subjects in the "high" group saw much larger improvements (58%) than those in the 'medium" (35%) and "low" (7%) groups. There were significant (p<0.05) differences between the groups in the magnitude of improvement, with athletes in the "high" and medium group having larger improvements than the "low" group (d = 2.59 "high" vs "low"; d = 1.32 "medium" vs "low"). In conclusion, the magnitude of improvements in aerobic fitness following a training intervention were associated with a genetic algorithm comprised of five single nucleotide polymorphisms. This information could lead to the development of more individualised aerobic training designs, targeting optimal fitness adaptations.

Diabetic Goto-Kakizaki rats display pronounced hyperglycemia and longer-lasting cognitive impairments following ischemia induced by cortical compression.

Hyperglycemia has been shown to worsen the outcome of brain ischemia in several animal models but few experimental studies have investigated impairments in cognition induced by ischemic brain lesions in hyperglycemic animals. The Goto-Kakizaki (GK) rat naturally develops type 2 diabetes characterized by mild hyperglycemia and insulin resistance. We hypothesized that GK rats would display more severe cerebral damage due to hyperglycemia-aggravated brain injury and, accordingly, more severe cognitive impairments. In this study, recovery of motor and cognitive functions of GK and healthy Wistar rats was examined following extradural compression (EC) of the sensorimotor cortex. For this purpose, tests of vestibulomotor function (beam-walking) and combined tests of motor function and learning (locomotor activity from day (D) 1 to D5, operant lever-pressing from D14 to D25) were used. EC consistently reduced cerebral blood flow in both strains. Anesthesia-challenge and EC resulted in pronounced hyperglycemia in GK but not in Wistar rats. Lower beam-walking scores, increased locomotor activity, impairments in long-term habituation and learning of operant lever-pressing were more pronounced and observed at later time-points in GK rats. Fluoro-Jade, a marker of irreversible neuronal degeneration, revealed consistent degeneration in the ipsilateral cortex, hippocampus and thalamus at 2, 7 and 14 days post-compression. The amount of degeneration in these structures was considerably higher in GK rats. Thus, GK rats exhibited marked hyperglycemia during EC, as well as longer-lasting behavioral deficits and increased neurodegeneration during recovery. The GK rat is thus an attractive model for neuropathologic and cognitive studies after ischemic brain injury in hyperglycemic rats.

Predictors of early leaving from the cotton spinning mill environment in newly hired workers.

OBJECTIVE: This longitudinal study aimed to identify the predictors of leaving during the first year of employment from the cotton spinning mill environment in newly hired workers. METHODS: One hundred and ninety eight consecutively appointed new employees were investigated by questionnaire, lung function test, and skin test. They were examined before employment and at the end of the 1st week, and the 1st, 3rd, 6th, and 12th month after starting work and when possible before leaving their job. 572 personal dust sampling and 191 endotoxin measurements were performed to assess the environmental exposure. For the univariate analysis chi2, Student t tests, ANOVA, and Kruskall Wallis tests were used. Cox proportional hazards analysis was used to identify factors associated with leaving the job. RESULTS: Fifty three per cent of workers left the mill environment during their first working year. Work related lower respiratory tract symptoms reported at the third month were associated with an increase rate of leaving the industry compared to those remaining in the industry (25% v 4.8%; p<0.005). Having respiratory symptoms at the first month of work predicted those leaving the industry at some point in the next 11 months. According to the Cox model, increasing age and having work related lower respiratory tract symptoms were found to be predictors for leaving job at the first working year. Atopic status, dust and endotoxin levels, and lung function changes were not consistently predictive of workers who left the industry in the follow up period. CONCLUSION: This study demonstrated that work related respiratory symptoms can predict workers likely to leave the cotton mill environment during the first year of employment, but atopy or acute lung function changes do not.

Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation.

We describe two patients with histologically proven pulmonary Langerhans' cell histiocytosis in whom radiologic improvement occurred following smoking cessation. The patients had 23- and 25-pack-year smoking histories, respectively. High-resolution CT revealed multiple small nodules, located predominantly in the upper and middle lung fields. There was a close temporal relationship between smoking cessation and radiologic improvement.

The platelet defect in acute myeloid leukaemia.

In a study of platelets from 13 patients with acute myeloid leukaemia abnormal aggregation and release reactions were found. A previously unrecognised quantitative defect of thromboxane B2 production may, at least in part, explain these findings. In contrast to a previous report, we were unable to show a convincing storage pool defect in these platelets. The platelet membrane glycoproteins were largely normal.

Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method.

To assess tolerance to cocaine in a self-administration paradigm, rats were trained to self-administer cocaine (0.25 mg/injection) on a fixed-ratio 2 (FR2) schedule of reinforcement. The development of tolerance was studied during chronic administration of cocaine (20 mg/kg per 8 h for 10 days), given either contingently (self-administered by the rats) or non-contingently (infused by the experimenter). Both contingent and non-contingent administration of cocaine produced comparable tolerance, as indicated by a faster rate of cocaine self-administration (the average inter-reinforcer time, ISRT, decreased significantly). Tolerance developed by day 2 of the chronic regimen and reached a floor value (60% of baseline) from day 4 through day 10. Termination of chronic cocaine then resulted in recovery from tolerance, with ISRTs returning to baseline within 6 days of termination. A second set of experiments determined whether tolerance could be studied using a multi-dose method to obtain dose-response data in a single session. A system of multiple pumps allowed testing of three doses of cocaine during a single experimental session. Cocaine dose-response curves obtained from the multi-dose method: (i) did not differ from that obtained from a single-dose method; (ii) were reproducible; and (iii) were shifted to the right by Schering 23390. Rats were then subjected to a 7-day chronic regimen of infused cocaine (20 mg/kg per 8 h) or infused saline. At the end of this chronic cocaine period, they were tested with the multi-dose method. Chronic cocaine, as compared to chronic saline, shifted the cocaine dose-response curve to the right, indicating that the multi-dose method can be successfully applied to demonstrate tolerance to the effects of cocaine in a self-administration paradigm.

Failure of ondansetron to block the discriminative or reinforcing stimulus effects of cocaine in the rat.

Ondansetron (GR38032F), a serotonin 5HT3 antagonist, is active in numerous behavioral paradigms and neurochemical systems. Since 5HT3 antagonists have been suggested as therapeutic agents for the treatment of drug abuse, the action of ondansetron on cocaine drug discrimination and self-administration paradigms in rats was investigated. Doses of ondansetron (0.001 - 1.0 mg/kg) had no effect on the discriminative stimulus properties of 10 mg/kg cocaine. In contrast SCH23390, a dopamine D1 antagonist known to block cocaine discrimination, acted as previously reported. Ondansetron did not augment the effects of SCH23390, but at higher doses, combinations of ondansetron and SCH23390 produced disruption of lever pressing in the presence of cocaine. Ondansetron (0.001-1.0 mg/kg) had no effect on the self-administration of various doses of cocaine, nor did it have any effect on reacquisition of cocaine self-administration in animals with a history of active administration followed by a period of abstinence. As before, SCH23390, known to block cocaine self-administration, acted as previously reported. Although other 5HT antagonists may prove to be efficacious in cocaine abuse, ondansetron appears unlikely to alter the subjective or rewarding stimulus properties of cocaine.

An investigation of the relationship between microbial and particulate indoor air pollution and the sick building syndrome.

The sick building syndrome has been the subject of research for approximately 10 years. Although it is often suggested that symptoms in office workers are due to circulating micro-organisms or particles, epidemiological studies investigating the relationship between them have been lacking. This cross-sectional study has combined medical and aerobiological assessments of offices in Great Britain and has found that, although airborne particulates and micro-organisms are unlikely to be the sole cause of the sick building syndrome, positive associations between symptom prevalence rates and levels of airborne viable bacteria and fungi within groups of buildings with similar ventilation systems, suggest a possible causal link that should be explored.

Domiciliary air filtration units, symptoms and lung function in atopic asthmatics.

Air infiltration units (AFUs) incorporating a high efficiency particulate air filter are theoretically able to remove almost all potential airborne allergens. This may have implications for subjects with allergic lower respiratory disease. AFUs were placed in the living room of 12 atopic asthmatics, and the internal filters were inserted and removed in a double-blind fashion. No difference in subjective symptom scoring, spirometry or bronchial reactivity was demonstrated. Peak expiratory flow rate (PEFR) variability was significantly improved from baseline readings, and there was a trend towards higher mean PEFRs when the filters were present in the AFU. Trends towards lower levels of airborne micro-organisms were also demonstrated when the filters were present, however no effect upon total airborne dust and airborne Der pI could be demonstrated.

Mutagenicity of methyl-, ethyl-, propyl- and butylnitrosourea towards Escherichia coli WP2 strains with varying DNA repair capabilities.

Methyl- (MNUA), ethyl- (ENUA), propyl- (PNUA) and butylnitrosourea (BNUA) have been tested for toxicity and mutation in a liquid suspension assay towards Escherichia coli WP2 and some of its repair deficient derivatives. A comparison of survival rates after nitrosourea exposure between WP2 and WP2 uvrA showed no difference between the two strains but a consistent difference in potency between the various nitrosoureas studied. Toxicity increased in the order MNUA less than PNUA less than ENUA less than BNUA. ENUA and PNUA induced a greater number of trp+ revertants in both strains than did MNUA and BNUA, particularly at low survival rates. None of these differences in biological potency could be accounted for by differences in rates of hydrolysis. ENUA, PNUA and BNUA were non-mutagenic towards WP2 lexA, WP2 recA and WP2 uvrA lexA, whereas MNUA did induce mutations. Ethyl methanesulphonate (EMS) was able to mutate WP2 lexA. These results are discussed in the light of current theories regarding the mechanism of action of these compounds.

The effects of reduced dietary intake upon the body and organ weights, and some clinical chemistry and haematological variates of the young Wistar rat.

Two groups, one of each sex, of 5-week-old Wistar rats were fed ab lib for 5 weeks with a commercial diet (LAD 2). Four other groups of each sex, were given the same diet daily; each male received 21, 19, 17 or 15 g and each female 17, 16, 15 or 13 g. In a second experiment, in addition to the groups fed ad lib, each day for 5 weeks males were given 30 ('daily ad lib' group), 23, 22 or 21 g and females 25 ('daily ad lib' group), 19, 18 or 17 g. Rats, particularly males, fed ad lib showed differences, e.g. in body weight, with rats fed 'daily ad lib' even though food consumption was similar. Rats fed reduced amounts of diet had smaller livers, increased haemoglobin concentration, erythrocyte count, haematocrit, and plasma chloride. These rats excreted an increased volume of more alkaline urine of lower specific gravity with more precipitated triple phosphate than rats fed ad lib. In the comparisons of the modestly reduced food intake groups with the ad lib groups the significant decreases found in plasma protein, urea and alkaline phosphatase activity probably arose mainly from differences in post-prandial intervals. In groups where the reduction in food intake was greater, the decreases observed were not wholly dependent upon the post-prandial interval.