Background
This study highlights the multiple sources of delay along a hip fracture clinical pathway. The national recommendation is that ‘patients with a hip fracture should be admitted within 4 ...hours of arrival at the Emergency Department to which they first presented’.
Methods
Granular analysis and process mapping of all available hospital and ‘Irish Hip Fracture Database’ data for a 2-month period were used to highlight and compare causes of delay.
Discussion
We identified numerous sources of delay, occurring at every point along the pathway, emphasising the complexity of providing acute integrated care. There was no single stage that persistently contributed to the delay in the patient pathway. The focus is now to achieve marginal gains in each area. Increased staff and resources to the front line are a clear solution but this is complex to achieve.
Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. ...Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases.
Gambling among adolescents is associated with gambling disorder in adulthood. This study investigated factors associated with gambling and excessive gambling in adolescents.
This secondary analysis ...of the cross-sectional European School Survey Project on Alcohol and Other Drugs (ESPAD) used nationally representative data from the Irish cohort of the 2019 ESPAD wave. Data were collected between March and May 2019. We included 1949 students aged 15–16 years (946 48·5% male, 1003 51·5% female), with a response rate of 85%. We calculated past year gambling prevalence as the rate of those who had gambled for money on at least one of four games of chance (slot machines, cards or dice, the lottery, betting on sports or animals) in the past 12 months. An adapted version of the three-item Consumption Screen for Problem Gambling was used to identify excessive gambling (score ≥4). We carried out descriptive and logistic regression analyses using binary covariates with Stata v16.1. We included 19 variables in the multivariable analysis. Ethics approval was granted by Dublin Institute of Technology's Ethics Committee. Non-consent forms were issued to all parents to opt out.
Overall, 447 (23%) of 1949 students gambled in the past year, of whom 45 (10%) engaged in excessive gambling. Using a mutually adjusted multivariable logistic regression analysis, past year gambling was associated with alcohol use (adjusted odds ratio aOR 1·6, 95% CI 1·1–2·2), experiencing serious arguments (aOR 1·4, 1·1–1·9), and trouble with the police (aOR 1·9, 1·2–2·8). Female gender was a protective factor (aOR 0·6, 0·4–0·9). In the univariable analysis, excessive gambling was associated with gaming (OR 2·3, 1·0–5·1), tobacco use (2·1, 1·1–4·2), e-cigarette use (2·1, 1·1–4·1), heavy episodic drinking (2·7, 1·4–5·1), trouble with the police (2·8, 1·5–5·4, p<0·01), and deliberately hurting themselves (2·8, 1·4–5·6). Female gender (OR 0·3, 0·1–0·6) and social media use (0·4, 0·2–0·8) were protective factors. Excessive gambling was also associated with betting on sports and animals (OR 3·6, 1·6–8·4), slot machines (2·9, 1·5–5·8), card or dice (2·4, 1·2–4·6), and online gambling (4·2, 2·0–8·0).
A large proportion of 15–16 year olds in Ireland have gambled for money in the past year, with one in ten of those having engaged in excessive gambling. This number is likely to be underestimated due to recall and social desirability bias. Reducing the availability, access, and appeal of gambling products in Ireland should be addressed through ongoing gambling reform.
Institute of Public Health.
Background:
The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic ...side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown.
Method:
We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales.
Results:
Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv.
Conclusion:
Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions.
Bovine respiratory disease (BRD) in dairy calves is a multifactorial condition, involving environmental, host, and pathogen factors. Thoracic ultrasound scoring (TUS) has recently been validated as ...an accurate method of detecting BRD-related lung pathology in dairy calves. Previous studies investigating the use of TUS in preweaned dairy calves have largely been based on cross-sectional data from all-year production systems. The objectives of this longitudinal observational study were to characterize the temporal transitions in TUS scores in dairy calves from pasture-based, seasonal-calving herds using sequential examinations during the preweaning period, and to investigate the relationship between the presence and temporal pattern of BRD, diagnosed by TUS or clinical respiratory scoring (CRS), and average daily gain (ADG). In spring of 2019, 317 preweaned calves from 7 commercial dairy farms were recruited at less than 4 wk old (ranging from 1–27 d of age). Each farm was examined on at least 3 occasions at 20- to 28-d intervals and housed indoors in group or individual pens. At each visit TUS scores, CRS scores based on the University of Wisconsin Calf Respiratory Score Chart (https://www.vetmed.wisc.edu/fapm/wp-content/uploads/2020/01/calf_respiratory_scoring_chart.pdf), and live weight using a dairy breed–specific weigh band were recorded. All data were recorded by the same 2 veterinarians over the course of the study. The final data set consisted of 966 TUS and CRS scores collected from 317 calves over a period of approximately 6 wk from 7 farms. The data were analyzed in multivariable, mixed effects, linear regression models, with separate models constructed for TUS and CRS scores. Random effects (intercepts) were included for calf, farm, and visit week. Additionally, a random slope was included for age at sampling by farm. Median farm TUS score ranged from 0 to 2.5 over the 3 visits (possible range: 0–5). The percentage of calves with a TUS score ≥3 (consolidation of the full thickness of 1 lung lobe), on each farm ranged from 0 to 50%. The median CRS in calves on individual farms ranged from 1 to 3 over the 3 visits (possible range: 0–12). The percentage of calves on each farm with a CRS score ≥5 (possible range: 0–12) ranged from 0 to 26%. The TUS and CRS scores were weakly correlated. The TUS was associated with reduced ADG. Calves with TUS scores ≥3 grew at 126 g/d less than unaffected calves over the 3-wk period before examination. The predicted effect on ADG was dependent on the age and duration over which the animal was affected. Calves affected later (i.e., between visits 2 and 3) had lower predicted weights at 63 d compared with calves with increased TUS scores earlier in the study period. Calves with a TUS score ≥3 at each of the 3 sampling points had the lowest weight at 63 d of age. There was no association of CRS with ADG. This study showed that in contrast to CRS, higher TUS scores are associated with lower ADG, with weight loss being more pronounced in chronic cases.
Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including ...tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.
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•Mal has a TLR-independent role in IFNGR signaling•IFNGR signaling via Mal leads to p38 phosphorylation, autophagy, and killing of TB•The S180L mutation attenuates responses to IFN-γ stimulation•S180L mutations impair in vitro and in vivo responses to TB
Mal (encoded by TIRAP) is a signaling adaptor in the TLR pathway. Ní Cheallaigh and colleagues demonstrate an additional role for Mal in IFN-γ signaling and find that it is required to kill intracellular M. tuberculosis. The common human Mal S180L polymorphism attenuates IFN-γ signaling and impairs responses to tuberculosis infection.
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