The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor's activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli ...pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them is the reduction of autophagic flux through direct interaction with the Unc-51, like the autophagy activating kinase (ULK) complex subunit autophagy-related protein-101 (ATG101). With the aim of investigating whether this function of PTCH1 is important in cancer cell fitness, we first identified frameshift mutations in the CTD of PTCH1 in cancer databases. We demonstrated that those mutations disrupt PTCH1 interaction with ATG101 and increase autophagic flux. Using deletion mutants of the PTCH1 CTD in co-immunoprecipitation studies, we established that the 1309-1447 region is necessary and sufficient for interaction with ATG101. We next showed that the three most common PTCH1 CTD mutations in endometrial, stomach and colon adenocarcinomas that cause frameshifts at S1203, R1308 and Y1316 lack the ability to interact with ATG101 and limit autophagic flux, determined by bafilomycin A1-sensitive accumulation of the autophagy markers LC3BII and p62. We next engineered PTCH1 indel mutations at S1223 by CRISPR/Cas9 in SW620 colon cancer cells. Comparison of two independent clones harbouring PTCH1 S1223fs mutations to their isogenic parental cell lines expressing wild-type PTCH1 showed a significant increase in basal and rapamycin-stimulated autophagic flux, as predicted by loss of ATG101 interaction. Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions.
ObjectivesPatient and public involvement (PPI) in health research is required by some funders and publications but we know little about how common it is. In this study we estimated the frequency of ...PPI inclusion in health research papers and analysed how it varied in relation to research topics, methods, funding sources and geographical regions.DesignCross-sectional.MethodsOur sample consisted of 3000 research papers published in 2020 in a general health-research journal (BMJ Open) that requires a statement on whether studies included PPI. We classified each paper as ‘included PPI’ or ‘did not include PPI’ and analysed the association of this classification with location (country or region of the world), methods used, research topic (journal section) and funding source. We used adjusted regression models to estimate incident rate ratios of PPI inclusion in relation to these differences.Results618 (20.6%) of the papers in our sample included PPI. The proportion of papers including PPI varied in relation to location (from 44.5% (95% CI 40.8% to 48.5%) in papers from the UK to 3.4% (95% CI 1.5% to 5.3%) in papers from China), method (from 38.6% (95% CI 27.1% to 50.1%) of mixed-methods papers to 5.3% (95% CI –1.9% to 12.5%) of simulation papers), topic (from 36.9% (95% CI 29.1% to 44.7%) of papers on mental health to 3.4% (95% CI –1.3% to 8.2%) of papers on medical education and training, and funding source (from 57.2% (95% CI 51.8% to 62.6%) in papers that received funding from the UK’s National Institute for Health Research to 3.4% (95% CI 0.7% to 6.0%) in papers that received funding from a Chinese state funder).ConclusionsMost research papers in our sample did not include PPI and PPI inclusion varied widely in relation to location, methods, topic and funding source.
This article explores whether an extended doctrine of implied consent can better balance copyright interests in the digital environment, particularly users’ access to digital content. Implied ...licences are analysed from a variety of jurisdictions including the United Kingdom, the European Union, Germany, the United States and Australia to submit that the role of implied consent emerges as a fundamental legal principle in both common and civil law jurisdictions. Given the significance of consent within the doctrine of exhaustion, the article also evaluates its application in the digital environment and the extent to which this could impact the proposal for an extended doctrine of implied consent. The boundaries of the extended doctrine along with its practical impact will be assessed through an example illustrating users’ access and interaction with digital content. It then becomes clear from the discussion that follows, that an extended doctrine of implied consent has the potential to balance copyright interests in the digital environment due to its status as a fundamental legal principle and inherent flexibility to consider a range of factors regarding users’ subsequent use of digital content.
Abstract
Thaler v Commissioner of Patents 2021 FCA 879, Federal Court of Australia, 30 July 2021
The Federal Court of Australia finds a patent application was correctly lodged despite naming an ...artificial intelligence system as its inventor.
Objective
To report the incidence of medial epicondylar fissure fracture (MEFF) after medial‐to‐lateral transcondylar screw placement in dogs with humeral intracondylar fissure (HIF) and to identify ...risk factors for MEFF.
Study design
Retrospective study.
Sample population
Seventy‐four client‐owned dogs (88 elbows).
Methods
Medical records of dogs surgically treated for HIF, and postoperative imaging studies were reviewed for demographics, fracture characteristics, and repair techniques. The width of the transcondylar screw was expressed relative to the height of the condyle. Screw angle and degree of countersinking were recorded. Information from case records and follow‐up radiographs were used to identify complications.
Results
Medial epicondylar fissure fracture was identified in 10 elbows (11.4%) following medial‐to‐lateral transcondylar screw placement: 4 cases were detected intraoperatively, 2 on immediate postoperative radiographs, 1 during routine radiographic follow up, and 3 when radiographs were reviewed for this study. A larger relative screw size was found to increase the risk of MEFF (P = .004, OR = 1.5). Fifteen additional complications were identified in 13/80 elbows at a median of 6 weeks postoperatively (range 1–56 weeks). Screw loosening was the most frequent complication (n = 9) and was the only complication in dogs with MEFF (n = 3); MEFF tended to increase the risk of perioperative screw loosening (P = .06).
Conclusion
Medial epicondylar fissure fracture occurred in 10/88 elbows treated for HIF and was more common in elbows treated with a larger screw size relative to the height of the condyle.
Clinical significance
Placing transcondylar screws with a diameter inferior to 41% of the height of the condyle is recommended to avoid MEFF. Medial epicondylar fissure fracture appears to have a low clinical significance in the perioperative period, although its effect on long‐term outcome remains unknown.
Children and young people have much to contribute to the design and delivery of health research and care. Nevertheless, there are multiple barriers to meaningful and impactful involvement of children ...and young people. This narrative review synthesised existing literature on the involvement of children and young people as partners in health research. Authors screened electronic databases and reference lists to identify relevant studies. Data were extracted on how involvement was described, what young people contributed to, and the impact of their involvement. The review identified 15 reports; these reported researcher observations and findings from focus group discussions and questionnaires about the involvement. Impacts recorded in these studies included influence on research; outputs from involvement activities; shifts in researchers’ attitudes; a sense of achievement in young people; and fulfilling relationships. These impacts were associated with principles being followed: building relationships over time to allow for unexpected involvement in the research, flexibility so young people could contribute in ways that work for them, and training. Methods adapted to be youth-appropriate such as visual aids and icebreaker games also enabled impact. Impactful involvement relies on processes that respond to young people’s preferences for engagement and activities that support them to share their views.
Nonsurgical reduction of prolapsed colocolic intussusception in 2 puppies Moores, Alison L.; Urraca, Carolina I.; Sousa, Ricardo J. R. ...
Journal of veterinary emergency and critical care (San Antonio, Tex. : 2000),
September/October 2021, 2021-09-00, 20210901, Letnik:
31, Številka:
5
Journal Article
Recenzirano
Objective
To describe the nonsurgical management of prolapsed colocolic intussusception in 2 puppies.
Case Summary
Two 3‐month‐old male intact puppies (Pug and Labrador Retriever) developed ...intussusceptions that had prolapsed from the anus after they had suffered from tenesmus with soft feces or diarrhea. Reduction of the prolapsed tissue was performed and colocolic intussusception was diagnosed ultrasonographically in 1 dog. Rectal manipulation and saline enema were performed in both dogs, and reduction of the intussusception was confirmed endoscopically or ultrasonographically. Bupivacaine and prednisolone foam enemas were administered to reduce tenesmus. Abdominal ultrasonography the following day in 1 dog confirmed a normal appearing colon. No further tenesmus was noted in 1 dog; the other had a brief rectal prolapse after an episode of tenesmus that was manually reduced. Intussusception had not recurred 4 months and 1 year following manual reduction procedures.
New or Unique Information Provided
This is the first report of successful nonsurgical management of colocolic intussusception in a companion animal. Nonsurgical management is a first‐line treatment of intussusception in children and could be considered in dogs with colocolic intussusception. Further investigation is required to define specific aspects, including rectal manipulation, saline enema, or anesthesia, that aid in resolution of this type of intussusception.
Background Thirty million small and sick newborns worldwide require inpatient care each year. Many receive antibiotics for clinically diagnosed infections without blood cultures, the current 'gold ...standard' for neonatal infection detection. Low neonatal blood culture use hampers appropriate antibiotic use, fuelling antimicrobial resistance (AMR) which threatens newborn survival. This study analysed the gap between blood culture use and antibiotic prescribing in hospitals implementing with Newborn Essential Solutions and Technologies (NEST360) in Kenya, Malawi, Nigeria, and Tanzania. Methods Inpatient data from every newborn admission record (July 2019-August 2022) were included to describe hospital-level blood culture use and antibiotic prescription. Health Facility Assessment data informed performance categorisation of hospitals into four tiers: (Tier 1) no laboratory, (Tier 2) laboratory but no microbiology, (Tier 3) neonatal blood culture use < 50% of newborns receiving antibiotics, and (Tier 4) neonatal blood culture use > 50%. Results A total of 144,146 newborn records from 61 hospitals were analysed. Mean hospital antibiotic prescription was 70% (range = 25-100%), with 6% mean blood culture use (range = 0-56%). Of the 10,575 blood cultures performed, only 24% (95%CI 23-25) had results, with 10% (10-11) positivity. Overall, 40% (24/61) of hospitals performed no blood cultures for newborns. No hospitals were categorised as Tier 1 because all had laboratories. Of Tier 2 hospitals, 87% (20/23) were District hospitals. Most hospitals could do blood cultures (38/61), yet the majority were categorised as Tier 3 (36/61). Only two hospitals performed > 50% blood cultures for newborns on antibiotics (Tier 4). Conclusions The two Tier 4 hospitals, with higher use of blood cultures for newborns, underline potential for higher blood culture coverage in other similar hospitals. Understanding why these hospitals are positive outliers requires more research into local barriers and enablers to performing blood cultures. Tier 3 facilities are missing opportunities for infection detection, and quality improvement strategies in neonatal units could increase coverage rapidly. Tier 2 facilities could close coverage gaps, but further laboratory strengthening is required. Closing this culture gap is doable and a priority for advancing locally-driven antibiotic stewardship programmes, preventing AMR, and reducing infection-related newborn deaths. Keywords: Newborn, Neonatal, Blood culture, Antibiotics, Low- and middle-income countries, Inpatient care, Antimicrobial resistance, Small and sick newborn care, Quality of care, Infection, Sepsis
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