Lipid droplets as substrates for protein phase separation.

Membrane-associated protein phase separation plays critical roles in cell biology, driving essential cellular phenomena from immune signaling to membrane traffic. Importantly, by reducing dimensionality from three to two dimensions, lipid bilayers can nucleate phase separation at far lower concentrations compared with those required for phase separation in solution. How might other intracellular lipid substrates, such as lipid droplets, contribute to nucleation of phase separation? Distinct from bilayer membranes, lipid droplets consist of a phospholipid monolayer surrounding a core of neutral lipids, and they are energy storage organelles that protect cells from lipotoxicity and oxidative stress. Here, we show that intrinsically disordered proteins can undergo phase separation on the surface of synthetic and cell-derived lipid droplets. Specifically, we find that the model disordered domains FUS LC and LAF-1 RGG separate into protein-rich and protein-depleted phases on the surfaces of lipid droplets. Owing to the hydrophobic nature of interactions between FUS LC proteins, increasing ionic strength drives an increase in its phase separation on droplet surfaces. The opposite is true for LAF-1 RGG, owing to the electrostatic nature of its interprotein interactions. In both cases, protein-rich phases on the surfaces of synthetic and cell-derived lipid droplets demonstrate molecular mobility indicative of a liquid-like state. Our results show that lipid droplets can nucleate protein condensates, suggesting that protein phase separation could be key in organizing biological processes involving lipid droplets.

Effectiveness of hybrid digital breast tomosynthesis/digital mammography compared to digital mammography in women presenting for routine screening at Maroondah BreastScreen: Study protocol for a co-designed, non-randomised prospective trial.

BACKGROUND: Digital breast tomosynthesis (DBT) for breast cancer screening has been shown in international trials to increase cancer detection compared with mammography; however, results have varied across screening settings, and currently there is limited and conflicting evidence on interval cancer rates (a surrogate for screening effectiveness). Australian pilot data also indicated substantially longer screen-reading time for DBT posing a barrier for adoption. There is a critical need for evidence on DBT to inform its role in Australia, including evaluation of potentially more feasible models of implementation, and quantification of screening outcomes by breast density which has global relevance. METHODS: This study is a prospective trial embedded in population-based Australian screening services (Maroondah BreastScreen, Eastern Health, Victoria) comparing hybrid screening comprising DBT (mediolateral oblique view) and digital mammography (cranio-caudal view) with standard mammography screening in a concurrent group attending another screening site. All eligible women aged ≥40 years attending the Maroondah service for routine screening will be enrolled (unless they do not provide verbal consent and opt-out of hybrid screening; are unable to provide consent; or where a 'pushback' image on hybrid DBT cannot be obtained). Each arm will enrol 20,000 women. The primary outcomes are cancer detection rate (per 1000 screens) and recall rate (percentage). Secondary outcomes include 'opt-out' rate; cohort characteristics; cancer characteristics; assessment outcomes; screen-reading time; and interval cancer rate at 24-month follow-up. Automated volumetric breast density will be measured to allow stratification of outcomes by mammographic density. Stratification by age and screening round will also be undertaken. An interim analysis will be undertaken after the first 5000 screens in the intervention group. DISCUSSION: This is the first Australian prospective trial comparing hybrid DBT/mammography with standard mammography screening that is powered to show differences in cancer detection. Findings will inform future implementation of DBT in screening programs world-wide and provide evidence on whether DBT should be adopted in the broader BreastScreen program in Australia or in subgroups of screening participants. TRIAL REGISTRATION: The trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR, ACTRN12623001144606, https://www.anzctr.org.au/). Registration will be updated to reflect trial progress and protocol amendments.

Type III-B CRISPR-Cas cascade of proteolytic cleavages.

The generation of cyclic oligoadenylates and subsequent allosteric activation of proteins that carry sensory domains is a distinctive feature of type III CRISPR-Cas systems. In this work, we characterize a set of associated genes of a type III-B system from Haliangium ochraceum that contains two caspase-like proteases, SAVED-CHAT and PCaspase (prokaryotic caspase), co-opted from a cyclic oligonucleotide-based antiphage signaling system (CBASS). Cyclic tri-adenosine monophosphate (AMP)-induced oligomerization of SAVED-CHAT activates proteolytic activity of the CHAT domains, which specifically cleave and activate PCaspase. Subsequently, activated PCaspase cleaves a multitude of proteins, which results in a strong interference phenotype in vivo in Escherichia coli. Taken together, our findings reveal how a CRISPR-Cas-based detection of a target RNA triggers a cascade of caspase-associated proteolytic activities.

Lipidomics studies reveal dynamic changes in polar lipids of developing endosperm of oat and wheat varieties with differing oil contents.

Polar lipids have biosynthetic pathways which intersect and overlap with triacylglycerol biosynthesis; however, polar lipids have not been well characterized in the developing endosperms of oat with high oil accumulation. The polar lipids in endosperms of oat and wheat varieties having different oil contents were analyzed and compared at different developmental stages. Our study shows that the relative contents of polar lipid by mass were decreased more slowly in wheat than in oat. Phosphatidylcholine and phosphatidylethanolamine were the major phospholipids, which showed similar abundance and gradual decreases during endosperm development in oat and wheat, while lysophospholipids were noticeably higher in oat. Monogalactosyldiacylglycerol showed a gradual increase in wheat and a decrease in oat during endosperm development. The relative contents of some polar lipid species and their unsaturation index were significantly different in their endosperms. These characteristics of polar lipids might indicate an adaption of oat to accommodate oil accumulation.

The impact of mitotane therapy on serum-free proteins in patients with adrenocortical carcinoma.

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression. Aim: The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort. Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI. Results: Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1-133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups. Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.

Acceptability of aspirin for cancer preventive therapy: a survey and qualitative study exploring the views of the UK general population.

OBJECTIVES: Aspirin could be offered for colorectal cancer prevention for the UK general population. To ensure the views of the general population are considered in future guidance, we explored public perceptions of aspirin for preventive therapy. DESIGN: We conducted an online survey to investigate aspirin use, and awareness of aspirin for cancer prevention among the UK general population. We conducted semistructured interviews with a subsample of survey respondents to explore participants' acceptability towards aspirin for cancer preventive therapy. We analysed the interview data using reflexive thematic analysis and mapped the themes onto the Theoretical Domains Framework, and the Necessity and Concerns Framework. SETTING: Online survey and remote interviews. PARTICIPANTS: We recruited 400 UK respondents aged 50-70 years through a market research company to the survey. We purposefully sampled, recruited and interviewed 20 survey respondents. RESULTS: In the survey, 19.0% (76/400) of respondents were aware that aspirin can be used to prevent cancer. Among those who had previously taken aspirin, 1.9% (4/216) had taken it for cancer prevention. The interviews generated three themes: (1) perceived necessity of aspirin; (2) concerns about side effects; and (3) preferred information sources. Participants with a personal or family history of cancer were more likely to perceive aspirin as necessary for cancer prevention. Concerns about taking aspirin at higher doses and its side effects, such as gastrointestinal bleeding, were common. Many described wanting guidance and advice on aspirin to be communicated from sources perceived as trustworthy, such as healthcare professionals. CONCLUSIONS: Among the general population, those with a personal or family history of cancer may be more receptive towards taking aspirin for preventive therapy. Future policies and campaigns recommending aspirin may be of particular interest to these groups. Multiple considerations about the benefits and risks of aspirin highlight the need to support informed decisions on the medication.

The Ribosome Assembly Factor Reh1 is Released from the Polypeptide Exit Tunnel in the Pioneer Round of Translation.

Assembly of functional ribosomal subunits and successfully delivering them to the translating pool is a prerequisite for protein synthesis and cell growth. In S. cerevisiae, the ribosome assembly factor Reh1 binds to pre-60S subunits at a late stage during their cytoplasmic maturation. Previous work shows that the C-terminus of Reh1 inserts into the polypeptide exit tunnel (PET) of the pre-60S subunit. Unlike canonical assembly factors, which associate exclusively with pre-60S subunits, we observed that Reh1 sediments with polysomes in addition to free 60S subunits. We therefore investigated the intriguing possibility that Reh1 remains associated with 60S subunits after the release of the anti-association factor Tif6 and after subunit joining. Here, we show that Reh1-bound nascent 60S subunits associate with 40S subunits to form actively translating ribosomes. Using selective ribosome profiling, we found that Reh1-bound ribosomes populate open reading frames near start codons. Reh1-bound ribosomes are also strongly enriched for initiator tRNA, indicating they are associated with early elongation events. Using single particle cryo-electron microscopy to image cycloheximide-arrested Reh1-bound 80S ribosomes, we found that Reh1-bound 80S contain A site peptidyl tRNA, P site tRNA and eIF5A indicating that Reh1 does not dissociate from 60S until early stages of translation elongation. We propose that Reh1 is displaced by the elongating peptide chain. These results identify Reh1 as the last assembly factor released from the nascent 60S subunit during its pioneer round of translation.

Redo Pelvic Surgery and Combined Metastectomy for Locally Recurrent Rectal Cancer with Known Oligometastatic Disease: A Multicentre Review.

INTRODUCTION: Historically, surgical resection for patients with locally recurrent rectal cancer (LRRC) had been reserved for those without metastatic disease. 'Selective' patients with limited oligometastatic disease (OMD) (involving the liver and/or lung) are now increasingly being considered for resection, with favourable five-year survival rates. METHODS: A retrospective analysis of consecutive patients undergoing multi-visceral pelvic resection of LRRC with their oligometastatic disease between 1 January 2015 and 31 August 2021 across four centres worldwide was performed. The data collected included disease characteristics, neoadjuvant therapy details, perioperative and oncological outcomes. RESULTS: Fourteen participants with a mean age of 59 years were included. There was a female preponderance (n = 9). Nine patients had liver metastases, four had lung metastases and one had both lung and liver disease. The mean number of metastatic tumours was 1.5 +/- 0.85. R0 margins were obtained in 71.4% (n = 10) and 100% (n = 14) of pelvic exenteration and oligometastatic disease surgeries, respectively. Mean lymph node yield was 11.6 +/- 6.9 nodes, with positive nodes being found in 28.6% (n = 4) of cases. A single major morbidity was reported, with no perioperative deaths. At follow-up, the median disease-free survival and overall survival were 12.3 months (IQR 4.5-17.5 months) and 25.9 months (IQR 6.2-39.7 months), respectively. CONCLUSIONS: Performing radical multi-visceral surgery for LRRC and distant oligometastatic disease appears to be feasible in appropriately selected patients that underwent good perioperative counselling.

Hospital length of stay prediction for general surgery and total knee arthroplasty admissions: Systematic review and meta-analysis of published prediction models.

Objective: Systematic review of length of stay (LOS) prediction models to assess the study methods (including prediction variables), study quality, and performance of predictive models (using area under receiver operating curve (AUROC)) for general surgery populations and total knee arthroplasty (TKA). Method: LOS prediction models published since 2010 were identified in five major research databases. The main outcomes were model performance metrics including AUROC, prediction variables, and level of validation. Risk of bias was assessed using the PROBAST checklist. Results: Five general surgery studies (15 models) and 10 TKA studies (24 models) were identified. All general surgery and 20 TKA models used statistical approaches; 4 TKA models used machine learning approaches. Risk scores, diagnosis, and procedure types were predominant predictors used. Risk of bias was ranked as moderate in 3/15 and high in 12/15 studies. Discrimination measures were reported in 14/15 and calibration measures in 3/15 studies, with only 4/39 externally validated models (3 general surgery and 1 TKA). Meta-analysis of externally validated models (3 general surgery) suggested the AUROC 95% prediction interval is excellent and ranges between 0.803 and 0.970. Conclusion: This is the first systematic review assessing quality of risk prediction models for prolonged LOS in general surgery and TKA groups. We showed that these risk prediction models were infrequently externally validated with poor study quality, typically related to poor reporting. Both machine learning and statistical modelling methods, plus the meta-analysis, showed acceptable to good predictive performance, which are encouraging. Moving forward, a focus on quality methods and external validation is needed before clinical application.

Invasive pulmonary aspergillosis presenting with tracheopleural fistula in a pediatric patient with a history of rhabdomyosarcoma.

Invasive aspergillosis is a known complication in patients with hematologic malignancies. Tracheopleural fistulas are very rare and reported in immunocompromised adults. We present a case of invasive pulmonary aspergillosis with tracheopleural fistula in a pediatric patient with a history of rhabdomyosarcoma and macrophage activation syndrome. This case highlights the importance of recognizing life-threatening fungal infections and coordinating surgical subspecialities for patient care.

Ecological characteristics impact PFAS concentrations in a U.S. North Atlantic food web.

This is the first comprehensive study of per- and polyfluoroalkyl substances (PFAS) in a coastal food web of the U.S. North Atlantic, in which we characterize the presence and concentrations of 24 targeted PFAS across 18 marine species from Narragansett Bay, Rhode Island, and surrounding waters. These species reflect the diversity of a typical North Atlantic Ocean food web with organisms from a variety of taxa, habitat types, and feeding guilds. Many of these organisms have no previously reported information on PFAS tissue concentrations. We found significant relationships of PFAS concentrations with respect to various ecological characteristics including species, body size, habitat, feeding guild, and location of collection. Based upon the 19 PFAS detected in the study (5 were not detected in samples), benthic omnivores (American lobsters = 10.5 ng/g ww, winter skates = 5.77 ng/g ww, Cancer crabs = 4.59 ng/g ww) and pelagic piscivores (striped bass = 8.50 ng/g ww, bluefish = 4.30 ng/g ww) demonstrated the greatest average ∑PFAS concentrations across all species sampled. Further, American lobsters had the highest concentrations detected in individuals (∑PFAS up to 21.1 ng/g ww, which consisted primarily of long-chain PFCAs). The calculation of field-based trophic magnification factors (TMFs) for the top 8 detected PFAS determined that perfluorodecanoic acid (PFDA), perfluorooctane sulfonic acid (PFOS), and perfluorooctane sulfonamide (FOSA) associated with the pelagic habitat biomagnified, whereas perfluorotetradecanoic acid (PFTeDA) associated with the benthic habitat demonstrated trophic dilution in this food web (calculated trophic levels ranged from 1.65 to 4.97). While PFAS exposure to these organisms may have adverse implications for ecological impacts via toxicological effects, many of these species are also key recreational and commercial fisheries resulting in potential for human exposure via dietary consumption.

GPs' willingness to prescribe aspirin for cancer preventive therapy in Lynch syndrome: a factorial randomised trial investigating factors influencing decisions.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) 2020 guidelines recommends aspirin for colorectal cancer prevention for people with Lynch syndrome. Strategies to change practice should be informed by understanding the factors influencing prescribing. AIM: To investigate the optimal type and level of information to communicate with GPs to increase willingness to prescribe aspirin. DESIGN AND SETTING: GPs in England and Wales (n = 672) were recruited to participate in an online survey with a 23 factorial design. GPs were randomised to one of eight vignettes describing a hypothetical patient with Lynch syndrome recommended to take aspirin by a clinical geneticist. METHOD: Across the vignettes, the presence or absence of three types of information was manipulated: 1) existence of NICE guidance; 2) results from the CAPP2 trial; 3) information comparing risks/benefits of aspirin. The main effects and all interactions on the primary (willingness to prescribe) and secondary outcomes (comfort discussing aspirin) were estimated. RESULTS: There were no statistically significant main effects or interactions of the three information components on willingness to prescribe aspirin or comfort discussing harms and benefits. In total, 80.4% (540/672) of GPs were willing to prescribe, with 19.7% (132/672) unwilling. GPs with prior awareness of aspirin for preventive therapy were more comfortable discussing the medication than those unaware (P = 0.031). CONCLUSION: It is unlikely that providing information on clinical guidance, trial results, and information comparing benefits and harms will increase aspirin prescribing for Lynch syndrome in primary care. Alternative multilevel strategies to support informed prescribing may be warranted.

A push-pull strategy to suppress stable fly (Diptera: Muscidae) attacks on pasture cattle via a coconut oil fatty acid repellent formulation and traps with m-cresol lures.

BACKGROUND: Stable flies [Stomoxys calcitrans (L.)] are economically important pests of cattle and other livestock. As an alternative to conventional insecticides, we tested a push-pull management strategy using a coconut oil fatty acid repellent formulation and an attractant-added stable fly trap. RESULTS: In our field trials we found that weekly applications of a push-pull strategy can reduce stable fly populations on cattle as well as a standard insecticide (permethrin). We also found that the efficacy periods of the push-pull and permethrin treatments following on-animal application were equivalent. Traps with an attractant lure used as the pull component of the push-pull strategy captured sufficient numbers of stable flies to reduce on-animal numbers by an estimated 17-21%. CONCLUSIONS: This is the first proof-of-concept field trial demonstrating the effectiveness of a push-pull strategy using a coconut oil fatty acid-based repellent formulation and traps with an attractant lure to manage stable flies on pasture cattle. Also notable is that the push-pull strategy had an efficacy period equivalent to that of a standard, conventional insecticide under field conditions. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Bioengineering of Soybean Oil and Its Impact on Agronomic Traits.

Soybean is a major oil crop and is also a dominant source of nutritional protein. The 20% seed oil content (SOC) of soybean is much lower than that in most oil crops and the fatty acid composition of its native oil cannot meet the specifications for some applications in the food and industrial sectors. Considerable effort has been expended on soybean bioengineering to tailor fatty acid profiles and improve SOC. Although significant advancements have been made, such as the creation of high-oleic acid soybean oil and high-SOC soybean, those genetic modifications have some negative impacts on soybean production, for instance, impaired germination or low protein content. In this review, we focus on recent advances in the bioengineering of soybean oil and its effects on agronomic traits.

Tracking cadmium pollution from source to receptor: A health-risk focused transfer continuum approach.

Cadmium (Cd) exposure poses a substantial risk to human health. Despite this, the multi-stage process through which Cd is released to the environment before being taken up and impacting human receptors has rarely been investigated. Here we utilized an integrated model involving Cd emissions, atmospheric transport, deposition, uptake by rice, receptor ingestion and metabolic processing in quantifying the critical emission sources and human health risks of Cd. Atmospheric Cd emissions in the study area in southeastern China were estimated at 147 kg (2016), with >53 % of emissions from non-ferrous metals (NFM) smelting activities. Atmospheric Cd depositions caused elevated Cd content in soil and rice, accounting for 3-79 % and 50-85 % of, respectively, soil and rice Cd. Cumulative frequency analysis showed that an estimated 1.3 % of predicted urine Cd through the consumption of Cd-contaminated rice and exceeded existing safety standards (1 µg g-1), thus highlighting the risks posed to health from high levels of Cd pollution. Applying stricter industrial emission standards to the NFM sector in particular and effective soil management practices could substantially reduce exposure to Cd pollution. The results contribute to understanding of the Cd transfer process and draw attention to the relative health benefits of interventions aimed at mitigating Cd levels and exposure risks at different stages along the Cd transfer continuum from source to receptor.

Early Versus Delayed Microdiscectomy for Chronic Sciatica Lasting 4-12 Months Secondary to Lumbar Disc Herniation: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVES: To compare the effect of delaying surgery on clinical outcome in patients with chronic sciatica secondary to lumbar disc herniation. METHODS: Patients with sciatica lasting 4-12 months and lumbar disc herniation at the L4-L5 or L5-S1 level were randomized to undergo microdiscectomy (early surgery) or to receive 6 months of nonoperative treatment followed by surgery if needed (delayed surgery). Outcomes were leg pain, Oswestry Disability Index score (ODI), back pain, SF-36 physical component (PCS) and mental component (MCS) summary scores, employment, and satisfaction measured preoperatively and at 6 weeks, 3 months, 6 months, and 1 year after surgery. RESULTS: Of the 64 patients in the early surgery group, 56 underwent microdiscectomy an average of 3 ± 2 weeks after enrollment. Of the 64 patients randomized to nonoperative care, 22 patients underwent delayed surgery an average of 53 ± 24 weeks after enrollment. The early surgery group experienced less leg pain than the delayed surgery group, which was the primary outcome, at 6 months after surgery (early surgery 2.8 ± .4 vs delayed surgery 4.8 ± .7; difference, 2.0; 95% confidence interval, .5-3.5). The overall estimated mean difference between groups significantly favored early surgery for leg pain, ODI, SF36-PCS, and back pain. The adverse event rate was similar between groups. CONCLUSIONS: Patients presenting with chronic sciatica treated with delayed surgery after prolonging standardized non-operative care have inferior outcomes compared to those that undergo expedited surgery.

Evaluation of factors associated with limb thrombus formation after endovascular aortic aneurysm repair.

BACKGROUND: Limb thrombus formation is a complication that can occur after endovascular aortic repair (EVAR), and its clinical significance has continued to be debated. Our objective was to report the incidence of limb thrombus after EVAR and determine the association of specific demographic, anatomic, and/or graft variables. METHODS: A retrospective analysis of EVAR patients at a single tertiary center between January 2010 and December 2018 was performed to determine the limb thrombus rate. Demographic, graft, and anatomic variables were analyzed for an association with limb thrombus. RESULTS: A total of 301 patients were included. The average follow-up was 27.6 ± 4.9 months. The mean age was 76.5 ± 0.5 years, and 85% were men. Limb thrombus occurred in 22 patients (7.3%). Of these 22 patients, 11 (50.0%) had had occlusive limb thrombus, 14 (63.6%) were symptomatic, and 17 (77.3%) had required intervention. The patients with limb thrombus were younger (69.8 ± 1.3 years vs 77.1 ± 0.5 years; P < .0001) and more likely to be smokers (10.2% vs 5.2%; P = .10). The incidence of limb thrombus with the Alpha graft (10.7%; Cook Medical Inc, Bloomington, IN) was compared with that with non-Cook grafts (4.0%; P = .07). The average common iliac artery diameter for patients with and without limb thrombus was 14.1 mm and 16.1 mm, respectively (P < .01). Right-sided limb thrombus was more likely in smaller right iliac arteries (14.7 ± 0.9 cm vs 17.0 ± 0.6 cm; P < .05), with a similar finding on the left (13.6 ± 0.9 cm vs 15.2 ± 0.4 cm; P = .13). Unilateral limb thrombus was almost twice as likely on the main body side than on the contralateral side (11 vs 6). Limb thrombus was not associated with aortoiliac disease (odds ratio [OR], 1.31; 95% confidence interval [CI], 0.37-4.62), limb extension (OR, 0.47; 95% CI, 0.06-3.62), or nonmatching limb heights (OR, 1.36; 95% CI, 0.54-3.43). Limb thrombus was also not associated with increased 30-day mortality (P > .05). CONCLUSIONS: Limb thrombus formation is a complication that can occur after EVAR (7.3%). In our study, limb thrombus was seen more frequently in younger patients and those who smoked. Cook Alpha grafts had a thrombus formation rate of 10.7%, which was not significantly higher than that with other brands. Limb thrombus was more likely in smaller iliac arteries and on the main body side.

Reasons for admission to a general medical hospital for patients taking clozapine.

Background: Clozapine is associated with a diverse range of side effects. In addition, patients prescribed clozapine commonly suffer with medical comorbidities. Objectives: This study aimed to characterise patients prescribed clozapine who required medical admission, understand reasons for admission, identify areas for interventions to prevent future admission and describe clozapine management during the inpatient stay. Design: We conducted a retrospective analysis of patients prescribed clozapine who were admitted to a general medical hospital in a 12-month period. Method: Data were collected using electronic drug charts and notes. Results: In total, 114 clozapine patients were hospitalised. Twenty-eight patients (25%) were admitted because of infection, 12 (11%) were elective admissions and 12 (11%) had gastrointestinal problems. Most patients admitted were Black (54%) and half were female. Few changes were made to clozapine dosing on admission or during the inpatient stay. Most patients had been taking clozapine for many years at the point of admission, the majority were able to continue taking it for the duration of their medical treatment and were discharged on the same dose they were taking prior to admission. Clozapine plasma concentrations were not consistently measured with only 18 (16%) patients having one or more plasma concentrations determined during their admission. The median clozapine plasma concentration on admission was 0.48 mg/L (nor-clozapine 0.21 mg/L), with a range of 0.09 to 3.9 mg/L. Three patients were admitted to the intensive care unit during their admission; all were discharged on clozapine. Four patients died; one from lung adenocarcinoma, one bowel obstruction, one cardiac arrest and one chest sepsis. In total, 27 patients (23%) had their clozapine stopped on admission, 6 (22% of this group) unintentionally. Conclusions: Our study found that the most common reason for admission for patients taking clozapine was infection. Plasma concentrations were not measured routinely despite clozapine having a narrow therapeutic index and enhanced potential for toxicity in the medically unwell patient.

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma.

Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein−protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1's structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1's intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm.