Cognitive impairment following consumption of alcohol with and without energy drinks.

BACKGROUND: The aim of this study was to assess the relative effects of alcohol mixed with energy drink (AmED) versus alcohol alone on cognitive performance across the ascending and descending breath alcohol concentration (BrAC) limb using doses similar to real-world intake. METHODS: Using a single-blind, placebo-controlled, crossover design, 19 participants completed 4 sessions where they received: (i) placebo, (ii) alcohol, (iii) AmED 500 ml energy drink (ED), and (iii) AmED 750 ml ED. Performance on measures of psychomotor function (Compensatory Tracking Task [CTT]), information processing (Digit Symbol Substitution Task [DSST]; Inspection Time Task [ITT]), and response inhibition (Brief Stop-Signal Task [Brief SST]) was assessed at ~0.05% ascending BrAC, ~0.08% peak BrAC, and ~0.05% descending BrAC. RESULTS: The ITT and Brief SST showed no differential effect of AmED versus alcohol (gs < 0.30 and gs < 0.36, respectively). Moderate magnitude improvements in alcohol-induced impairment of CTT and DSST performance were observed after AmED versus alcohol on the descending BrAC limb (gs > 0.45 and gs > 0.37, respectively). A moderate magnitude decrease in DSST errors was also observed after AmED relative to alcohol at 0.050% ascending target BrAC (gs > 0.43). CONCLUSIONS: Changes in cognitive function after AmED administration were dependent on the degree of intoxication, BrAC curve limb, and ED volume. Co-administration of ED doses which matched (500 ml) and exceeded (500 ml) maximum daily intake guidelines with alcohol decreased impairment of psychomotor function and global information processing after alcohol consumption. These results cannot be necessarily interpreted to suggest that people are less impaired after AmED, as behavior is the result of coordination of multiple cognitive functions, and reduced impairment on one aspect of cognition may not translate into global improvements.

Knockout of the inhibitory receptor TIGIT enhances the antitumor response of ex vivo expanded NK cells and prevents fratricide with therapeutic Fc-active TIGIT antibodies.

BACKGROUND: Inhibitory receptor T-cell Immunoreceptor with Ig and ITIM domains (TIGIT) expressed by Natural Killer (NK) and T cells regulates cancer immunity and has been touted as the next frontier in the development of cancer immunotherapeutics. Although early results of anti-TIGIT and its combinations with antiprogrammed death-ligand 1 were highly exciting, results from an interim analysis of phase III trials are disappointing. With mixed results, there is a need to understand the effects of therapeutic anti-TIGIT on the TIGIT+ immune cells to support its clinical use. Most of the TIGIT antibodies in development have an Fc-active domain, which binds to Fc receptors on effector cells. In mouse models, Fc-active anti-TIGIT induced superior immunity, while Fc receptor engagement was required for its efficacy. NK-cell depletion compromised the antitumor immunity of anti-TIGIT indicating the essential role of NK cells in the efficacy of anti-TIGIT. Since NK cells express TIGIT and Fc-receptor CD16, Fc-active anti-TIGIT may deplete NK cells via fratricide, which has not been studied. METHODS: CRISPR-Cas9-based TIGIT knockout (KO) was performed in expanded NK cells. Phenotypic and transcriptomic properties of TIGIT KO and wild-type (WT) NK cells were compared with flow cytometry, CyTOF, and RNA sequencing. The effect of TIGIT KO on NK-cell cytotoxicity was determined by calcein-AM release and live cell imaging-based cytotoxicity assays. The metabolic properties of TIGIT KO and WT NK cells were compared with a Seahorse analyzer. The effect of the Fc-component of anti-TIGIT on NK-cell fratricide was determined by co-culturing WT and TIGIT KO NK cells with Fc-active and Fc-inactive anti-TIGIT. RESULTS: TIGIT KO increased the cytotoxicity of NK cells against multiple cancer cell lines including spheroids. TIGIT KO NK cells upregulated mTOR complex 1 (mTORC1) signaling and had better metabolic fitness with an increased basal glycolytic rate when co-cultured with cancer cells compared with WT NK cells. Importantly, TIGIT KO prevented NK-cell fratricide when combined with Fc-active anti-TIGIT. CONCLUSIONS: TIGIT KO in ex vivo expanded NK cells increased their cytotoxicity and metabolic fitness and prevented NK-cell fratricide when combined with Fc-active anti-TIGIT antibodies. These fratricide-resistant TIGIT KO NK cells have therapeutic potential alone or in combination with Fc-active anti-TIGIT antibodies to enhance their efficacy.

Changes in cystic fibrosis mortality in Australia, 1979-2005.

OBJECTIVE: To assess mortality trends among people with cystic fibrosis (CF) in Australia. DESIGN AND SETTING: We augmented Australian summary data for deaths from CF registered during 1979-2005 with information from Australian transplant centres on lung transplantation among CF patients for 1989-2005 to allow us to follow trends in all "mortality events" (death or lung transplantation). MAIN OUTCOME MEASURE: Age at death or lung transplantation. RESULTS: Between 1979 and 2005, the mean age at death increased from 12.2 years to 27.9 years for males and from 14.8 years to 25.3 years for females. Overall, female deaths in childhood (0-14 years) occurred at an age-standardised rate of 0.40 per 100,000 (95% CI, 0.34-0.45) during 1979-2005, which exceeded the corresponding rate for males of 0.24 (95% CI, 0.20-0.28) per 100,000. Among 0-14-year-old boys, event rates declined markedly after 1989, but they declined later and more gradually for girls, with the result that the age-standardised rate for girls was 2.38 times that of boys during 1989-2005 (95% CI, 1.69-3.36). CONCLUSIONS: The pattern of CF mortality in Australia has changed substantially. Mortality rates continue to be higher for girls than for boys, but death in childhood has become uncommon. Survival has increased since 1979, but females continue to have reduced length of life.

Delayed postoperative diet is associated with a greater incidence of prolonged postoperative ileus and longer stay in hospital for patients undergoing gastrointestinal surgery.

AIM: Recent evidence favours a move away from delaying postoperative nutrition towards early feeding practices for better patient outcomes after gastrointestinal surgery. The aim of the present study was to investigate postoperative diet progression and patient outcomes in a secondary hospital with a view to inform future practice. METHODS: This was a retrospective study of gastrointestinal surgery patients (n = 69) at a Western Australian general hospital. Demographic data and outcomes were collected from patient records and included presence or absence of prolonged postoperative ileus, length of stay in hospital, days on minimal nutrition and days until first flatus or stool. RESULTS: A significant positive association was observed between number of days a patient remained on minimal nutrition and length of stay in the overall group (r = 0.66, P < 0.01). Patients who developed prolonged postoperative ileus (n = 18, 26%) had a greater number of days on minimal nutrition (20.0 vs 8.0 days, P < 0.01), longer stay in hospital (15.0 vs 8.0 days, P < 0.01) and increased number of days to first flatus or stool (4.0 vs 2.4 days, P < 0.01) compared with those who did not develop prolonged postoperative ileus (n = 51, 74%). CONCLUSIONS: This retrospective study of current practice in a secondary-care general hospital highlights the gap between traditional care and the improved outcomes reported in the literature when early feeding practices are adopted after GI surgery. Further investigation of barriers and enablers is necessary to provide insight into developing the most appropriate strategy to achieve this.

Day-by-day variation in affect, arousal and alcohol consumption in young adults.

INTRODUCTION AND AIMS: Alcohol consumption has a well-established relationship with mood, with higher positive and negative affect predicting alcohol use. More recently, researchers have explored whether alcohol consumption occurs as a response to affect variability as an attempt to self-medicate and stabilise affect. Studies have revealed a positive association between alcohol use and intra- and inter-individual affect variability in clinical and university student samples; however not much is known of this relationship among the general community. DESIGN AND METHODS: Ecological Momentary Assessment (EMA) methods were used to investigate the relationship between affect and arousal variability and alcohol use in 53 community volunteers. Participants self-reported affect and arousal at three to five randomly timed moments throughout the day, as well as every time they drank. RESULTS: On a day-to-day basis, higher positive affect was associated with increased alcohol consumption. When analyses were restricted to self-reported affect prior to alcohol consumption, only increased arousal and decreased variability in arousal predicted the likelihood of alcohol consumption. Mean level of arousal was associated with the extent of alcohol consumed. DISCUSSION AND CONCLUSIONS: In this moderate drinking sample day-to-day affect and arousal, and arousal variability, were associated with alcohol consumption. Analyses restricted to pre-drinking observations provide further evidence that self-medication accounts of alcohol consumption may explain drinking initiation but that the relationship between affect factors and drinking behaviour may change around the point of first drink.

Detecting impairment: sensitive cognitive measures of dose-related acute alcohol intoxication.

The cognitive impairment that results from acute alcohol intoxication is associated with considerable safety risks. Other psychoactive substances, such as medications, pose a similar risk to road and workplace safety. However, there is currently no legal limit for operating vehicles or working while experiencing drug-related impairment. The current study sought to identify a brief cognitive task sensitive to a meaningful degree of impairment from acute alcohol intoxication to potentially stand as a reference from which to quantify impairment from other similar substances. A placebo-controlled single-blind crossover design was employed to determine the relative sensitivity of four commonly-administered cognitive tasks (Compensatory Tracking Task, Digit Symbol Substitution Test, Brief Stop Signal Task and Inspection Time Task) to alcohol-related impairment in male social drinkers at ~0.05% ascending breath alcohol concentration (BrAC), ~0.08% peak BrAC and 0.05% descending BrAC. The Inspection Time Task was identified as the most sensitive task, detecting a medium to large magnitude increase in impairment (g ≈ 0.60) at 0.05% ascending and descending BrAC, and a large magnitude effect size (g = 0.80) at 0.08% peak BrAC. The remaining tasks failed to demonstrate sensitivity to dose-dependent and limb-dependent changes in alcohol-induced impairment. The Inspection Time Task was deemed the most sensitive task for screening alcohol-related impairment based on the present results. Confirmation of equivalence with other drug-related impairment and sensitivity to alcohol-induced impairment in real-world settings should be established in future research.