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Several studies have correlate improved patient outcomes with increased physician–patient contacts, particularly in chronic diseases. Extending this approach to inflammatory bowel disease (IBD) care presents a promising means of improving outcomes. At LSU Health Shreveport (LSUHS), a new approach called “STABILITY” (Symptomatic Review during Biologic Therapy) was implemented during infusion therapy visits for IBD patients. These brief 15 min physician–patient interviews aimed to discuss the patients’ current IBD-related symptoms and evaluate the need for any changes in their treatment plan. Our goal was to remove a care gap and prevent intensifying symptoms created by missed appointments and loss of contact. To analyze the effectiveness of the STABILITY approach, a retrospective chart review was conducted on 111 IBD patients (18 with ulcerative colitis, 93 with Crohn’s disease) seen at LSUHS between 2011 and 2022. Since March 2019, STABILITY has been mandatory for all infusion therapy visits. The data collected included patients’ demographics, lab levels for biomarkers (fecal calprotectin, C-reactive protein, and erythrocyte sedimentation rates), hospitalizations, medication changes, and diagnosis dates before and after the implementation of STABILITY. Additionally, voluntary, anonymous infusion patient satisfaction surveys post-STABILITY were used to gather patient responses. In males with IBD, disease severity and hospitalizations were reduced significantly (p = 0.004 and 0.0234, respectively). In females with IBD, disease severity and hospitalizations were also reduced significantly (p = 0.0001 and 0.0072, respectively). In patients with UC and CD, there were significant improvements in disease severity (p = 0.043 and p = 0.0001, respectively), and CD hospitalizations were also improved (p = 0.0013). In males and females with UC, disease severity was marginally and significantly reduced (p = 0.0781 and p = 0.0379, respectively). In males and females with CD, disease severity was significantly reduced (p = 0.0161 and 0.0003, respectively), and CD male and female hospitalizations were also reduced significantly (p = 0.0436 and 0.013). Analyzing of survey responses, we found that the most patients reported improved IBD symptoms (56%), gained understanding of their condition (84%) and were in favor of continuing STABILITY consultations during infusion therapy (93%). To further investigate the impact of STABILITY, we conducted a comparative analysis between IBD patients undergoing STABILITY infusion therapy and LSUHS patients solely on self-injectable biologics. Our paired data analysis showed significant improvements in disease severity in female IBD patients (1.69 ± 0.13 vs. 1.41 ± 0.12, p = 0.0001) and male IBD patients (1.58 ± 0.16 vs. 1.2 ± 0.135, p = 0.004), in UC patients (1.833 ± 0.4.2 vs. 1.444, p = 0.043), in all CD patients (1.59 ± 0.11 vs. 1.29 ± 0.01, p = 0.0001), in male CD patients (1.52 ± 0.167 vs. 1.15 ± 0.15, p = 0.016), in female CD patients (1.66 ± 0.15 vs. 1.4 ± 0.13, p = 0.0003), in female UC patients (1.82 ± 0.32 vs. 1.45 ± 0.31, p = 0.0379), and marginally in male UC patients (p = 0.0781). Similarly, hospitalizations were significantly reduced in CD patients considered in aggregate (0.21 ± 0.04 vs. 0.11 ± 0.03, p = 0.0013), in male IBD patients (0.175 ± 0.06 vs. 0.05 ± 0.035, p = 0.024), in female IBD patients (0.21 ± 0.05 vs. 0.11 ± 0.04, p = 0.0072), in male CD patients (0.18 ± 0.07 vs. 0.06 ± 0.042, p = 0.0436), and in females with CD (0.23 ± 0.06 vs. 0.13 ± 0.04, p = 0.013). Although average values for fecal calprotectin, CRP, and sedimentation rate were frequently reduced after STABILITY interviews, these data did not reach statistical significance. These preliminary findings suggest that STABILITY may be effective in maintaining low disease activity or remission in IBD patients.

Community tutelary shrines in Taiwan have been identified as excellent resources for grassroots-level heritage. As community ritual assemblages, they are able to encode data about a settlement’s social, political and economic history in their material composition, aesthetic choices, artefacts, displays and orientations. This data paper previews a first edition dataset related to 752 such shrines found throughout the greater Taipei area in northern Taiwan. It explores the basis for such a dataset, how it can be used and what has been produced. This dataset is available on the depositar research data repository, operated out of the Institute of Information Sciences at Academia Sinica in Taipei and is publicly available for download.

Abstract High grade serous ovarian carcinoma (HGSOC) is a highly heterogeneous disease that typically presents at an advanced, metastatic state. The multi-scale complexity of HGSOC is a major obstacle to predicting response to neoadjuvant chemotherapy (NACT) and understanding critical determinants of response. Here we present a framework to predict the response of HGSOC patients to NACT integrating baseline clinical, blood-based, and radiomic biomarkers extracted from all primary and metastatic lesions. We use an ensemble machine learning model trained to predict the change in total disease volume using data obtained at diagnosis (n = 72). The model is validated in an internal hold-out cohort (n = 20) and an independent external patient cohort (n = 42). In the external cohort the integrated radiomics model reduces the prediction error by 8% with respect to the clinical model, achieving an AUC of 0.78 for RECIST 1.1 classification compared to 0.47 for the clinical model. Our results emphasize the value of including radiomics data in integrative models of treatment response and provide methods for developing new biomarker-based clinical trials of NACT in HGSOC.

Abstract Background Racial inequities exist in treatment and outcomes in patients with acute stroke. Objectives Our objective was to determine if racial inequities exist in the time-lapse between patient presentation and provider assessment in patients with stroke-like symptoms in Emergency Departments (ED) across the U.S. Methods This study is a retrospective, observational study of the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2014–2018. We identified visits with stroke-like symptoms and stratified the proportion of door-to-provider (DTP) times by racial groups. We used broad and narrow definitions of stroke-like symptoms. We performed bivariate and multivariate analyses using race and clinical and demographic characteristics as covariates. Results Between 2014–2018, there were an average of 138.58 million annual ED visits. Of the total ED visits, 0.36% to 7.39% of the ED visits presented with stroke-like symptoms, and the average DTP time ranged from 39 to 49 min. The proportion of the visits with a triage level of 1 (immediate) or 2 (emergent) ranged from 16.03% to 23.27% for stroke-like symptoms. We did not find statistically significant racial inequities in DTP or ED triage level. We found significantly longer DTP times in non-Hispanic blacks (15.88 min, 95% CI: 4.29–27.48) and Hispanics (by 14.77 min, 95% CI: 3.37–26.16) than non-Hispanic whites that presented with atypical stroke-like symptoms. We observed that non-Hispanic whites were significantly more diagnosed with a stroke/TIA than other racial minority groups (p = 0.045) for atypical stroke-like symptoms. Conclusion In our population-based analysis, we did not identify systemic racial inequities in the DTP times or ED triage level at ED triage for stroke-like symptoms.

Mutations in GUCY2D are associated with severe early-onset retinal dystrophy, Leber congenital amaurosis type 1 (LCA1), a leading cause of blindness in children. Despite a high degree of visual disturbance stemming from photoreceptor dysfunction, patients with LCA1 largely retain normal photoreceptor structure, suggesting that they are good candidates for gene replacement therapy. The purpose of this study was to conduct the preclinical and IND-enabling experiments required to support clinical application of AAV5-hGRK1-GUCY2D in patients harboring biallelic recessive mutations in GUCY2D. Preclinical studies were conducted in mice to evaluate the effect of vector manufacturing platforms and transgene species on the therapeutic response. Dose-ranging studies were conducted in cynomolgus monkeys to establish the minimum dose required for efficient photoreceptor transduction. Good laboratory practice (GLP) studies evaluated systemic biodistribution in rats and toxicology in non-human primates (NHPs). These results expanded our knowledge of dose response for an AAV5-vectored transgene under control of the human rhodopsin kinase (hGRK1) promoter in NHPs with respect to photoreceptor transduction and safety and, in combination with the rat biodistribution and mouse efficacy studies, informed the design of a first-in-human clinical study in patients with LCA1.

Acute cholangitis is a critical medical condition requiring prompt intervention. This case report explores the complexities and uncertainties encountered in clinical decision-making when faced with a patient presenting with symptoms suggestive of acute cholangitis. We emphasise the importance of considering individual circumstances and factors in the diagnostic process. A 38-year-old woman with a history of Crohn’s colitis presented with abdominal pain, jaundice and leukocytosis. Initial evaluation raised suspicions of acute cholangitis, but unexpected findings of blast cells in the peripheral smear led to a diagnosis of B-lymphoblastic leukaemia with BCR-ABL1 fusion. Treatment with steroids and chemotherapy resulted in the resolution of liver abnormalities. This case underscores the necessity of comprehensive assessments for obstructive jaundice and highlights the potential diagnostic challenges posed by underlying haematologic malignancies. It also raises awareness about drug-induced liver injury, and emphasises the importance of complete blood counts and differentials in the initial workup. Healthcare providers should be vigilant in considering alternative diagnoses when faced with obstructive jaundice, as misdiagnosis can lead to invasive procedures with potential adverse events.

Aim: NICE’s highly specialized technology (HST) evaluations are highly restrictive in terms of entry criteria and as a consequence, the vast majority of rare disease medicines are assessed through NICE’s standard, single technology appraisal (STA) route. We explored whether NICE shows flexibility and pragmatism when evaluating treatments for rare diseases through its STA process. Materials & methods: We matched a sample of recent, randomly selected STAs for rare diseases to STAs for non-rare diseases and conducted a thematic analysis to identify patterns in NICE’s decision-making, with a specific focus on the application of NICE’s published methods and the handling of uncertainty. Results: Three themes emerged where some flexibility was shown: ‘handling of uncertainty and discretion’, ‘application of NICE methods’ and ‘commercial arrangements’. Rare disease technologies were generally subject to longer appraisal times than those for non-rare diseases. Conclusion: Although NICE shows a degree of flexibility and pragmatism toward uncertainties in the evidence base for rare disease medicines, this is often off-set by a lengthy appraisal process, which can lead to delays in patients receiving vital treatment.

Gastric peroral endoscopic pyloromyotomy (G-POEM or POP) is an endoscopic therapeutic modality for treatment of refractory gastroparesis. Since the first case reported in 2013, there are more than 200 papers published on G-POEM. In this narrative review, we summarize the short-term and long-term outcomes and review other important studies. The technical success rate is 100% and the short-term (within 1 year) success rate is about 50–80%. The procedure time is between 50 and 70 min while the average length of hospital stay was 2–3 days. The adverse event rate was around 10%. Few patients need further intervention. Three studies showed that at the 4-year follow-up, the response to G-POEM was durable, but there was a yearly recurrence rate of 13% or more. Redo G-POEM is feasible and can be of benefit for some patients. Most of the studies showed that long duration of illness is associated with poor outcomes. However, reliable predictors for successful outcomes are still unknown. Current literature indicates G-POEM is superior to gastric electric stimulator and surgical pyloroplasty. Endoflip has been used at G-POEM to predict the outcome, but the result is very preliminary. A recent sham study confirms the short-term efficacy of G-POEM. G-POEM is safe and about 50% of patients can be discharged to home on the same day. G-POEM allows for direct biopsy of the gastric muscle, which is the location of the pacemaker cells, the interstitial cells of Cajal; therefore, G-POEM may provide a new path for further research on the pathogenesis of gastroparesis.

Legalization/decriminalization of cannabis will increase the numbers of patients who have had recent exposure to recreational or medical cannabis. Currently, little has been reported about potential interactions between cannabis use and Propofol anesthesia e.g., for oropharyngeal procedures. We describe three cases of ‘cannabis-induced hypersalivation after propofol’ (CHAP) and present our institutions’ experience with this unique pharmacological combination. Increased hypersalivation may complicate procedures and represent a procedural risk of suffocation. We evaluate possible pharmacological interactions that might underlie this phenomenon and consider management options going forward.

Abstract Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection, recent studies have been focused on understanding the non-random fragmentation pattern of cfDNA. These studies have investigated fragment sizes, genomic position of fragment end points, and fragment end motifs. Although these features have been described and shown to be aberrant in cancer patients, there is a lack of understanding of how the individual and integrated analysis of these features enrich ctDNA fraction and enhance ctDNA detection. Using whole genome sequencing and copy number analysis of plasma samples from 5 high grade serious ovarian cancer patients, we observed that (1) ctDNA is enriched not only in fragments shorter than mono-nucleosomes (~ 167 bp), but also in those shorter than di-nucleosomes (~ 240–330 bp) (28–159% enrichment). (2) fragments that start and end at the border or within the nucleosome core are enriched in ctDNA (5–46% enrichment). (3) certain DNA motifs conserved in regions 10 bp up- and down- stream of fragment ends (i.e. cleavage sites) could be used to detect tumor-derived fragments (10–44% enrichment). We further show that the integrated analysis of these three features resulted in a higher enrichment of ctDNA when compared to using fragment size alone (additional 7–25% enrichment after fragment size selection). We believe these genome wide features, which are independent of genetic mutational changes, could allow new ways to analyze and interpret cfDNA data, as significant aberrations of these features from a healthy state could improve its utility as a diagnostic biomarker.

Community-engaged research must reflect the uniqueness of the specific community involved. To help researchers produce quality community-engaged research with the veteran community, the authors of this paper (a coalition of both veterans and academic researchers) have highlighted essential considerations when engaging the veteran community in the research enterprise. Research with veterans requires unique sensitivity based on the impacts of their military service, history, and experiences. Understanding the impacts of veteran culture and community on recruitment is an essential prerequisite for anyone engaging with this population. At a minimum, community-engaged researchers should have an understanding of veteran history in relation to research, how veterans have experienced “volunteering” while under the chain of command, the impacts of a veteran’s military experience, and veterans’ views of the research process. The element most crucial to a successful research project conducted with the veteran community is incorporating veterans as full research team members. Building a veteran-centered research team requires academic researchers to establish trust with veteran team members and the veteran community, to conduct the research project with respect, and to actively encourage veterans’ participation in project activities. All of these are facilitated by having veterans as full members of a research team. It is our hope that sharing the lessons we have learned through working with veteran communities, as well as our lived experiences as veteran research team members, will help pave a smoother path forward for others wishing to conduct impactful veteran-centered research.

Researchers studying cellular life cycles need to be able to monitor the phases of a cell cycle rapidly and accurately. Many of the techniques currently used to monitor the cell cycle require the use of labels and would be difficult to automate. Microwave cytometry is a promising new approach to label free monitoring of cell life cycles. This paper presents results of multiple frequency microwave measurements of two lifecycle stages of Trypanosoma brucei, a unicellular eukaryotic parasite found in sub-Saharan Africa. A microwave flow cytometer was used to show bloodstream form (BSF) and procyclic form (PCF) T. brucei have frequency dependent permittivity and impedance from 800 MHz to 7.65 GHz. The two cell forms had a strong dependence on the imaginary part of permittivity at 2.38 GHz and below and a strong dependence on the real part of permittivity at 5.55 GHz and above. Three PCF cell lines were tested to verify that the differences between the two cell forms were independent of cell strain. Additionally, impedance measurements were used to improve cell classification in cases where the permittivity of a cell cannot be detected. Quadratic discriminate analysis was employed to validate the ability to classify cells forms, with maximum cross-validation errors of 15.4% and 10% when using one and three PCF strains, respectively.

Hepatocellular carcinoma (HCC) remains an important form of cancer-related morbidity and mortality in the U.S. and worldwide. Previous U.S.-based studies on survival suggest ethnic disparities in HCC patients, but the complex interplay of multiple factors that contribute are still incompletely understood. Here we considered the influences of risk factors contributing towards HCC survival, including ethnic background, over ten years at a premier academic medical center with a majority (57.20%) African American (AA) population. Retrospective HCC data were collected from 2008–2018 at LSUHSC-Shreveport, an urban tertiary medical center. Data included demographics, comorbidities, liver disease characteristics, and tumor parameters. Statistical analysis was performed using Chi Square and one-way ANOVA. Results: 229 HCC patients were identified (male 78.6%). The mean HCC age at diagnosis was 61 years (SD = 7.3). Compared to non-Hispanic Caucasians (42.7%), AA patients (57.2% of total) were older at presentation, had more frequent diabetes/dyslipidemia/NAFLD (45 (34.3%) compared with 19 (19.3%) in non-Hispanic Caucasians, p = 0.02), and had a larger HCC burden at diagnosis. We conclude that compared to white patients, despite having similar BMI and MELD scores and rates of portal vein thrombosis, AA patients with HCC in our cohort were older at presentation, had a significantly increased incidence of modifiable metabolic risk factors including diabetes, higher AFP values, increased incidence of gallstones, and larger sized HCCs, and were more likely to be outside Milan criteria. These findings have important prognostic and diagnostic implications for developing a more targeted HCC surveillance program.

Abstract Glioma‐derived cell‐free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. We determined the glioma‐derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient’s tumor, we detected tumor‐derived DNA in the majority of CSF (7/8), plasma (10/12), and urine samples (10/16), with a median tumor fraction of 6.4 × 10−3, 3.1 × 10−5, and 4.7 × 10−5, respectively. We identified a shift in the size distribution of tumor‐derived cfDNA fragments in these body fluids. We further analyzed cfDNA fragment sizes using whole‐genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non‐malignant brain disorders, and 26 healthy individuals. cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non‐malignant brain disorders (P = 1.7 × 10−2) and healthy individuals (P = 5.2 × 10−9). Machine learning models integrating fragment length could differentiate urine samples from glioma patients (AUC = 0.80–0.91) suggesting possibilities for truly non‐invasive cancer detection.

The response to the COVID-19 pandemic has raised the profile and level of interest in the use, acceptability, safety, and effectiveness of virtual outpatient consultations and telemedicine. These models of care are not new but a number of challenges have so far hindered widespread take-up and endorsement of these ways of working. With the response to the COVID-19 pandemic, remote and virtual working and consultation have become the default. This paper explores our experience of and learning from virtual and remote consultation and questions how this experience can be retained and developed for the future.

Background. Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains common, and severe complications are associated with ERCP. There is no previous study detailing the effect of race and gender in a US-based population on risk of PEP. Methods. Data were collected on 269 “first-performed” consecutive ERCPs followed by division by race (White vs. African-American) and sex (Female vs. Male). A total of 53 probable risk factors were evaluated by uni- and multivariate analysis followed by outcomes expressed as an odds ratio (OR) (with a 95% confidence interval, 95% CI). Finally, a principal component analysis was performed to construct a risk prediction model for PEP, which can be used by clinicians at bedside. Results. After analyzing the risk factors based on race and gender-based groups, Caucasian males with PEP are more likely to have prior history of pancreatitis (p = 0.009), lower hemoglobin (p = 0.02)/blood urea nitrogen (BUN) (p = 0.01)/creatinine before ERCP (p = 0.07) and lower BUN (p = 0.01)/creatinine after ERCP (p = 0.07), while Caucasian females with PEP are more likely to have higher white blood cell (WBC) count before ERCP (p = 0.08) and lower amylase (p = 0.10)/bilirubin (p = 0.09)/aspartate aminotransferase (AST) after ERCP (p = 0.08). African-American males with PEP are more likely to have lower weight (p = 0.001)/smaller height (p = 0.0005)/lower alkaline phosphatase (p = 0.002)/AST (p = 0.04)/alanine transaminase (ALT) (p = 0.03) before ERCP and lower alkaline phosphatase (p = 0.002)/AST (p = 0.01)/ALT (p = 0.004) after ERCP, while African-American females with PEP are more likely to have prior history of pancreatitis (p = 0.004)/higher lipase before (p = 0.0001) and after (p = 0.05) ERCP along with increased risk with pancreatic duct cannulation (p = 0.0001) and injection (p = 0.0001)/biliary sphincterotomy (p = 0.0001). Importantly, prior history of ERCP, elevated AST after ERCP, and BUN prior to ERCP were found to be important clinical features predicting post-ERCP pancreatitis. To our knowledge, this is a first known attempt at developing a risk scoring system for PEP in a US population with decision tree learning. Conclusions. It is very evident that both patient and procedure-related risk factors vary by race and gender in the US population, leading to the development of a new risk assessment tool for PEP that can be used in clinical practice. We need to follow up with a larger prospective study to validate this novel race and gender-based risk scoring system for PEP.

Abstract Background Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

This study mapped the areal extent, identified the species composition, and analyzed the changes of salt marshes in the intertidal zone of China during the period 1985–2019. With the aid of the cloud platform of the Google Earth Engine, we selected Landsat 5/8 and Sentinel-2 images and used the support vector machine classification method to extract salt marsh information for the years of 1985, 1990, 1995, 2000, 2005, 2010, 2015, and 2019. Seven major species of salt marshes: Phragmites australis, Suaeda spp., Spartina alterniflora, Scirpus mariqueter, Tamarix chinensis, Cyperus malaccensis, and Sesuvium portulacastrum were identified. Our results showed that salt marshes are mainly distributed in Liaoning, Shandong, Jiangsu, Shanghai, and Zhejiang, with varying patterns of shrinking, expansion, or wavering in different places. The distribution of salt marshes has declined considerably from 151,324 ha in 1985 to 115,397 ha in 2019, a drop of 23.7%. During the same period, the area of native species has dropped 95.4% from 77,741 ha to 3,563 ha for Suaeda spp. and 45.1% from 60,511 ha to 33,193 ha for P. australis; on the contrary, the area of exotic species, S. alterniflora, has exhibited a sharp rise from just 99 ha to 67,527 ha. For the past 35 years, the driving factors causing salt marsh changes are mainly land reclamation, variations in water and sand fluxes, and interspecific competition and succession of salt marsh vegetation. These results provide fundamental reference information and could form the scientific basis for formulating policies for the conservation and utilization of salt marsh resources in China.

Abstract Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss‐of‐fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss‐of‐function screens can elucidate mechanism‐of‐action to advance drug development.

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, after BRCA1, JAK3 was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-based in vitro functional assay and identified a novel gain-of-function mutation in the kinase domain of JAK3 (p.T1022I). Importantly, p.T1022I JAK3 mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entire JAK3 coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening of CDK12 in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency of JAK3 and CDK12 mutations in a large well characterized cohort. Although p.T1022I JAK3 mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation of CDK12 mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency.

Abstract Glioma is difficult to detect or characterize using current liquid biopsy approaches. Detection of cell‐free tumor DNA (cftDNA) in cerebrospinal fluid (CSF) has been proposed as an alternative to detection in plasma. We used shallow whole‐genome sequencing (sWGS, at a coverage of

Abstract Background Network meta-analysis (NMA) allows for the estimation of comparative effectiveness of treatments that have not been studied in head-to-head trials; however, relative treatment effects for all interventions can only be derived where available evidence forms a connected network. Head-to-head evidence is limited in many disease areas, regularly resulting in disconnected evidence structures where a large number of treatments are available. This is also the case in the evidence of treatments for relapsed or refractory multiple myeloma. Methods Randomised controlled trials (RCTs) identified in a systematic literature review form two disconnected evidence networks. Standard Bayesian NMA models are fitted to obtain estimates of relative effects within each network. Observational evidence was identified to fill the evidence gap. Single armed trials are matched to act as each other’s control group based on a distance metric derived from covariate information. Uncertainty resulting from including this evidence is incorporated by analysing the space of possible matches. Results Twenty five randomised controlled trials form two disconnected evidence networks; 12 single armed observational studies are considered for bridging between the networks. Five matches are selected to bridge between the networks. While significant variation in the ranking is observed, daratumumab in combination with dexamethasone and either lenalidomide or bortezomib, as well as triple therapy of carfilzomib, ixazomib and elozumatab, in combination with lenalidomide and dexamethasone, show the highest effects on progression free survival, on average. Conclusions The analysis shows how observational data can be used to fill gaps in the existing networks of RCT evidence; allowing for the indirect comparison of a large number of treatments, which could not be compared otherwise. Additional uncertainty is accounted for by scenario analyses reducing the risk of over confidence in interpretation of results.

Abstract Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR‐mutant non‐small‐cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole‐genome sequencing on samples from three patients who underwent histological transformation to small‐cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR. Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small‐cell lung cancer‐associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non‐druggable genetic information that may guide clinical management.

p53 gain of function mutants (mutp53) are involved in the pathogenesis of most human cancers. Here, the authors show that mutp53 regulates the tumor microenvironment by inducing the release of specific exosomes containing miR-1246 that once received by macrophages turns them into tumor supportive macrophages.

Introduction: We report our experience with a modified audit tool, the modified Cappuccini test used to assess the availability and readiness of senior and expert help and supervision for trainee anaesthetists in the operating environment. Materials and Methods: We sought to provide assurance as to the level of supervision for surgical and anaesthetic trainees within our organisation, a large tertiary centre in an urban environment. We would expect this to have a direct impact on patient safety in the operative environment and also on the training experience. We modified the Cappuccini test so that it could be used for surgical and anaesthetic trainees .Over 11 days we visited operating theatres across our institution and interviewed 195 trainees (anaesthetists and surgeons) undertaking operating lists. Results: 96 (49.2%) anaesthetic trainees and 99 (50.8%) surgical trainees were interviewed. 166 (85.1%) trainees were being directly supervised by a consultant. 29 (14.9%) trainees were being remotely supervised without a physical consultant presence16 (55.2%) of these were anaesthetic trainees and the remainder were surgical trainees2 (6.9%) trainees stated that they were unsure who was directly supervising them. For the 29 remotely supervised trainees, we contacted 19(65.5%) supervising consultants/senior doctors all of whom were aware that they were supervising the operating list and confirmed that they were available to attend if required. Conclusion: The modified Cappuccini test is a simple and helpful tool, providing assurance as to the level of and access to senior and skilled supervision in the operating theatre and with the potential to be modified and deployed in a number environments. We suggest that it is a useful proxy indicator of supervision and potentially also, patient safety in the operating theatre environment. We recommend that for operating lists which are remotely supervised, the name and method of contact for the senior supervising anaesthetist or surgeon should be explicitly stated at the beginning of each case.

Abstract Background The genetic diversity of malaria parasites reflects the complexity and size of the parasite populations. This study was designed to explore the genetic diversity of Plasmodium falciparum populations collected from two southeastern areas (Shwekyin and Myawaddy bordering Thailand) and one western area (Kyauktaw bordering Bangladesh) of Myanmar. Methods A total of 267 blood samples collected from patients with acute P. falciparum infections during 2009 and 2010 were used for genotyping at the merozoite surface protein 1 (Msp1), Msp2 and glutamate-rich protein (Glurp) loci. Results One hundred and eighty four samples were successfully genotyped at three genes. The allelic distributions of the three genes were all significantly different among three areas. MAD20 and 3D7 were the most prevalent alleles in three areas for Msp1 and Msp2, respectively. The Glurp allele with a bin size of 700–750 bp was the most prevalent both in Shwekyin and Myawaddy, whereas two alleles with bin sizes of 800–850 bp and 900–1000 bp were the most prevalent in the western site Kyauktaw. Overall, 73.91% of samples contained multiclonal infections, resulting in a mean multiplicity of infection (MOI) of 1.94. Interestingly, the MOI level presented a rising trend with the order of Myawaddy, Kyauktaw and Shwekyin, which also paralleled with the increasing frequencies of Msp1 RO33 and Msp2 FC27 200–250 bp alleles. Msp1 and Msp2 genes displayed higher levels of diversity and higher MOI rates than Glurp. PCR revealed four samples (two from Shwekyin and two from Myawaddy) with mixed infections of P. falciparum and P. vivax. Conclusions This study genotyped parasite clinical samples from two southeast regions and one western state of Myanmar at the Msp1, Msp2 and Glurp loci, which revealed high levels of genetic diversity and mixed-strain infections of P. falciparum populations at these sites. The results indicated that malaria transmission intensity in these regions remained high and more strengthened control efforts are needed. The genotypic data provided baseline information for monitoring the impacts of malaria elimination efforts in the region.

Purpose: To evaluate the feasibility and to report the early outcomes of focal treatment of prostate cancer using low- dose-rate brachytherapy (LDR-PB). Material and methods: Seventeen patients were screened with multi-parametric magnetic resonance imaging (mpMRI), 14 of whom proceeded to receive trans-perineal template mapping biopsy (TTMB). Focal LDR-PB was performed on five eligible patients using dual air kerma strength treatment plans based on planning target volumes derived from cancer locations and determined by TTMB. Patient follow-up includes prostate specific antigen (PSA) measurements, urinary and sexual function questionnaires, repeated imaging and TTMB at specific intervals post-treatment. Results: Feasibility of focal LDR-PB was shown and short-term outcomes are promising. While the detection rate of tumors, a majority of which were low grade GS 3 + 3, was found to be low on mpMRI (sensitivity of 37.5%), our results suggest the potential of mpMRI in detecting the presence of higher grade (GS ≥ 3 + 4), and bilateral disease indicating its usefulness as a screening tool for focal LDR-PB. Conclusions : Low-dose-rate brachytherapy is a favorable ablation option for focal treatment of prostate cancer, requiring minimal modification to the standard (whole gland) LDR-PB treatment, and appears to have a more favorable side effect profile. Further investigation, in the form of a larger study, is needed to assess the methods used and the long-term outcomes of focal LDR-PB.

Abstract Background An increasing number of precision oncology programmes are being launched world-wide. To support this development, we present the Cancer Variant Explorer (CVE), an R package with an interactive Shiny web browser interface. Results Leveraging Oncotator and the Drug Gene Interaction Database, CVE offers exploration of variants within single or multiple tumour exomes to identify drivers, resistance mechanisms and to assess druggability. We present example applications including the analysis of an individual patient and a cohort-wide study, and provide a first extension of CVE by adding a tumour-specific co-expression network. Conclusions The CVE package allows interactive variant prioritisation to expedite the analysis of cancer sequencing studies. Our framework also includes the prioritisation of druggable targets, allows exploratory analysis of tissue specific networks and is extendable for specific applications by virtue of its modular design. We encourage the use of CVE within translational research studies and molecular tumour boards. The CVE package is available via Bioconductor ( http://bioconductor.org/packages/CVE/ ).

Epibacterium mobile BBCC367 is a marine bacterium that is common in coastal areas. It belongs to the Roseobacter clade, a widespread group in pelagic marine ecosystems. Species of the Roseobacter clade are regularly used as models to understand the evolution and physiological adaptability of generalist bacteria. E. mobile BBCC367 comprises two chromosomes and two plasmids. We used gel-free shotgun proteomics to assess its protein expression under 16 different conditions, including stress factors such as elevated temperature, nutrient limitation, high metal concentration, and UVB exposure. Comparison of the different conditions allowed us not only to retrieve almost 70% of the predicted proteins, but also to define three main protein assemblages: 584 essential core proteins, 2,144 facultative accessory proteins and 355 specific unique proteins. While the core proteome mainly exhibited proteins involved in essential functions to sustain life such as DNA, amino acids, carbohydrates, cofactors, vitamins and lipids metabolisms, the accessory and unique proteomes revealed a more specific adaptation with the expression of stress-related proteins, such as DNA repair proteins (accessory proteome), transcription regulators and a significant predominance of transporters (unique proteome). Our study provides insights into how E. mobile BBCC367 adapts to environmental changes and copes with diverse stresses.

Purpose: Apremilast, an oral phosphodiesterase-4 inhibitor, is effective and well tolerated in the treatment of moderate-to-severe psoriasis. The cost-effectiveness of introducing apremilast before biologics was assessed from a UK payer perspective. Materials and methods: A 10-year Markov cohort model was developed to compare alternative treatment sequences: (1) apremilast followed by adalimumab and etanercept and (2) adalimumab followed by etanercept. Non-responders moved to the next treatment line, and patients for whom etanercept therapy failed continued on best supportive care (BSC) in both sequences. Response was defined as a ≥ 75% reduction in Psoriasis Area and Severity Index score (PASI-75) at the end of the trial periods (12‒16 weeks). A network meta-analysis provided efficacy inputs. Results: As a treatment-extension strategy, apremilast had an incremental cost-effectiveness ratio of £20,593 per quality-adjusted life-year gained versus the comparator sequence. PASI-75 was sustained for 0.73 additional years, and the total time on biologics and BSC was reduced by 0.44 and 1.01 years, respectively. These results were consistent with findings from sensitivity and scenario analyses. Conclusions: Apremilast, an oral treatment option for the treatment of moderate-to-severe plaque psoriasis, is cost-effective from a UK payer perspective when administered before biologics based on assumptions detailed within this analysis.