A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.

Enzymatic basis of the Fc-selective intra-chain disulfide reduction and free thiol content variability in an antibody produced in Escherichia coli.

BACKGROUND: Escherichia coli (E. coli) is a promising host for production of recombinant proteins (including antibodies and antibody fragments) that don't require complex post-translational modifications such as glycosylation. During manufacturing-scale production of a one-armed antibody in E. coli (periplasmic production), variability in the degree of reduction of the antibody's disulfide bonds was observed. This resulted in variability in the free thiol content, a potential critical product quality attribute. This work was initiated to understand and prevent the variability in the total free thiol content during manufacturing. RESULTS: In this study, we found that the reduction in antibody's disulfide bonds was observed to occur during homogenization and the ensuing homogenate hold step where in the antibody is exposed to redox enzymes and small molecule reductants present in homogenate. Variability in the downstream processing time between the start of homogenization and end of the homogenate hold step resulted in variability in the degree of antibody disulfide bond reduction and free thiol content. The disulfide bond reduction in the homogenate is catalyzed by the enzyme disulfide bond isomerase C (DsbC) and is highly site-specific and occurred predominantly in the intra-chain disulfide bonds present in the Fc CH2 region. Our results also imply that lack of glycans in E. coli produced antibodies may facilitate DsbC accessibility to the disulfide bond in the Fc CH2 region, resulting in its reduction. CONCLUSIONS: During E. coli antibody manufacturing processes, downstream processing steps such as homogenization and subsequent processing of the homogenate can impact degree of disulfide bond reduction in the antibody and consequently product quality attributes such as total free thiol content. Duration of the homogenate hold step should be minimized as much as possible to prevent disulfide bond reduction and free thiol formation. Other approaches such as reducing homogenate temperature, adding flocculants prior to homogenization, using enzyme inhibitors, or modulating redox environments in the homogenate should be considered to prevent antibody disulfide bond reduction during homogenization and homogenate processing steps in E. coli antibody manufacturing processes.

A National Survey of Motor Vehicle Crashes Among General Surgery Residents.

OBJECTIVES: Evaluate the frequency of self-reported, post-call hazardous driving events in a national cohort of general surgery residents and determine the associations between duty hour policy violations, psychiatric well-being, and hazardous driving events. SUMMARY OF BACKGROUND DATA: MVCs are a leading cause of resident mortality. Extended work shifts and poor psychiatric well-being are risk factors for MVCs, placing general surgery residents at risk. METHODS: General surgery residents from US programs were surveyed after the 2017 American Board of Surgery In-Training Examination. Outcomes included self-reported nodding off while driving, near-miss MVCs, and MVCs. Group-adjusted cluster Chi-square and hierarchical regression models with program-level intercepts measured associations between resident- and program-level factors and outcomes. RESULTS: Among 7391 general surgery residents from 260 programs (response rate 99.3%), 34.7% reported nodding off while driving, 26.6% a near-miss MVC, and 5.0% an MVC over the preceding 6 months. More frequent 80-hour rule violations were associated with all hazardous driving events: nodding off while driving {59.8% with ≥5 months with violations vs 27.2% with 0, adjusted odds ratio (AOR) 2.86 [95% confidence interval (CI) 2.21-3.69]}, near-miss MVCs, [53.6% vs 19.2%, AOR 3.28 (95% CI 2.53-4.24)], and MVCs [14.0% vs 3.5%, AOR 2.46 (95% CI 1.65-3.67)]. Similarly, poor psychiatric well-being was associated with all 3 outcomes [eg, 8.0% with poor psychiatric well-being reported MVCs vs 2.6% without, odds ratio 2.55 (95% CI 2.00-3.24)]. CONCLUSIONS: Hazardous driving events are prevalent among general surgery residents and associated with frequent duty hour violations and poor psychiatric well-being. Greater adherence to duty hour standards and efforts to improve well-being may improve driving safety.

Association of Surgical Resident Wellness With Medical Errors and Patient Outcomes.

OBJECTIVES: The aims of this study were to: (1) measure the prevalence of self-reported medical error among general surgery trainees, (2) assess the association between general surgery resident wellness (ie, burnout and poor psychiatric well-being) and self-reported medical error, and (3) examine the association between program-level wellness and objectively measured patient outcomes. SUMMARY OF BACKGROUND DATA: Poor wellness is prevalent among surgical trainees but the impact on medical error and objective patient outcomes (eg, morbidity or mortality) is unclear as existing studies are limited to physician and patient self-report of events and errors, small cohorts, or examine few outcomes. METHODS: A cross-sectional survey was administered immediately following the January 2017 American Board of Surgery In-training Examination to clinically active general surgery residents to assess resident wellness and self-reported error. Postoperative patient outcomes were ascertained using a validated national clinical data registry. Associations were examined using multivariable logistic regression models. RESULTS: Over a 6-month period, 22.5% of residents reported committing a near miss medical error, and 6.9% reported committing a harmful medical error. Residents were more likely to report a harmful medical error if they reported frequent burnout symptoms [odds ratio 2.71 (95% confidence interval 2.16-3.41)] or poor psychiatric well-being [odds ratio 2.36 (95% confidence interval 1.92-2.90)]. However, there were no significant associations between program-level resident wellness and any of the independently, objectively measured postoperative American College of Surgeons National Surgical Quality improvement Program outcomes examined. CONCLUSIONS: Although surgical residents with poor wellness were more likely to self-report a harmful medical error, there was not a higher rate of objectively reported outcomes for surgical patients treated at hospitals with higher rates of burnout or poor psychiatric well-being.

Diet-tissue discrimination and turnover of δ13 C and δ15 N in muscle tissue of a penaeid prawn.

RATIONALE: Stable isotopes are used to study trophic and movement ecology in aquatic systems, as they provide spatially distinct, time-integrated signatures of diet. Stable isotope ecology has been used to quantify species-habitat relationships in many important fisheries species (e.g., penaeid prawns), with approaches that typically assume constant values for diet-tissue discrimination and diet-tissue steady state, but these can be highly variable. Here we provide the first report of these processes in Metapenaeus macleayi (eastern school prawn). METHODS: Here we explicitly measure and model carbon (δ13 C) and nitrogen (δ15 N) diet-tissue discrimination and turnover in eastern school prawn muscle tissue as a function of experimental time following a change in diet to an isotopically distinct food source. RESULTS: Diet-tissue discrimination factors were 5 and 0.6‰ for δ13 C and δ15 N, respectively. Prawn muscle tissue reached an approximate steady state after approximately 50 and 30 days for δ13 C and δ15 N. Half-lives indicated faster turnover of δ15 N (~8 days) than δ13 C (~14 days). CONCLUSIONS: Our diet-tissue discrimination factors deviate from 'typical' values with larger values for carbon than nitrogen isotopes, but are generally similar to those measured in other crustaceans. Similarly, our estimates of isotopic turnover align with those in other penaeid species. These findings confirm muscle tissue as a reliable indicator of long-term diet and movement patterns in eastern school prawn.

Multi-institution Evaluation of Adherence to Comprehensive Postoperative VTE Chemoprophylaxis.

OBJECTIVES: The aims of this study were to: (1) measure the rate of failure to provide defect-free postoperative venous thromboembolism (VTE) chemoprophylaxis, (2) identify reasons for failure to provide defect-free VTE chemoprophylaxis, and (3) examine patient- and hospital-level factors associated with failure. SUMMARY BACKGROUND DATA: Current VTE quality measures are inadequate. VTE outcome measures are invalidated for interhospital comparison by surveillance bias. VTE process measures (e.g., SCIP-VTE-2) do not comprehensively capture failures throughout patients' entire hospitalization. METHODS: We examined adherence to a novel VTE chemoprophylaxis process measure in patients who underwent colectomies over 18 months at 36 hospitals in a statewide surgical collaborative. This measure assessed comprehensive VTE chemoprophylaxis during each patient's entire hospitalization, including reasons why chemoprophylaxis was not given. Associations of patient and hospital characteristics with measure failure were examined. RESULTS: The SCIP-VTE-2 hospital-level quality measure identified failures of VTE chemoprophylaxis in 0% to 3% of patients. Conversely, the novel measure unmasked failure to provide defect-free chemoprophylaxis in 18% (736/4086) of colectomies. Reasons for failure included medication not ordered (30.4%), patient refusal (30.3%), incorrect dosage/frequency (8.2%), and patient off-unit (3.4%). Patients were less likely to fail the chemoprophylaxis process measure if treated at nonsafety net hospitals (OR 0.62, 95% CI 0.39-0.99, P = 0.045) or Magnet designated hospitals (OR 0.45, 95% CI 0.29-0.71, P = 0.001). CONCLUSIONS: In contrast to SCIP-VTE-2, our novel quality measure unmasked VTE chemoprophylaxis failures in 18% of colectomies. Most failures were due to patient refusals or ordering errors. Hospitals should focus improvement efforts on ensuring patients receive VTE prophylaxis throughout their entire hospitalization.

National Evaluation of Patient Preferences in Selecting Hospitals and Health Care Providers.

BACKGROUND: Patient utilization of public reporting has been suboptimal despite attempts to encourage use. Lack of utilization may be due to discordance between reported metrics and what patients want to know when making health care choices. OBJECTIVE: The objective of this study was to identify measures of quality that individuals want to be presented in public reporting and explore factors associated with researching health care. RESEARCH DESIGN: Patient interviews and focus groups were conducted to develop a survey exploring the relative importance of various health care measures. SUBJECTS: Interviews and focus groups conducted at local outpatient clinics. A survey administered nationally on an anonymous digital platform. MEASURES: Likert scale responses were compared using tests of central tendency. Rank-order responses were compared using analysis of variance testing. Associations with binary outcomes were analyzed using multivariable logistic regression. RESULTS: Overall, 4672 responses were received (42.0% response rate). Census balancing yielded 2004 surveys for analysis. Measures identified as most important were hospital reputation (considered important by 61.9%), physician experience (51.5%), and primary care recommendations (43.2%). Unimportant factors included guideline adherence (17.6%) and hospital academic affiliation (13.3%, P<0.001 for all compared with most important factors). Morbidity and mortality outcome measures were not among the most important factors. Patients were unlikely to rank outcome measures as the most important factors in choosing health care providers, irrespective of age, sex, educational status, or income. CONCLUSIONS: Patients valued hospital reputation, physician experience, and primary care recommendations while publicly reported metrics like patient outcomes were less important. Public quality reports contain information that patients perceive to be of relatively low value, which may contribute to low utilization.

Gender Differences in Utilization of Duty-hour Regulations, Aspects of Burnout, and Psychological Well-being Among General Surgery Residents in the United States.

OBJECTIVE: The aim of the study was to (1) assess differences in how male and female general surgery residents utilize duty-hour regulations and experience aspects of burnout and psychological well-being, and (2) to explore reasons why these differing experiences exist. BACKGROUND: There may be differences in how women and men enter, experience, and leave residency programs. METHODS: A total of 7395 residents completed a survey (response rate = 99%). Logistic regression models were developed to examine the association between gender and resident outcomes. Semistructured interviews were conducted with 42 faculty and 56 residents. Transcripts were analyzed thematically using a constant comparative approach. RESULTS: Female residents reported more frequently staying in the hospital >28 hours or working >80 hours in a week (≥3 times in a month, P < 0.001) and more frequently feeling fatigued and burned out from their work (P < 0.001), but less frequently "treating patients as impersonal objects" or "not caring what happens" to them (P < 0.001). Women reported more often having experienced many aspects of poor psychological well-being such as feeling unhappy and depressed or thinking of themselves as worthless (P < 0.01). In adjusted analyses, associations remained significant. Themes identified in the qualitative analysis as possible contributory factors to gender differences include a lack of female mentorship/leadership, dual-role responsibilities, gender blindness, and differing pressures and approaches to patient care. CONCLUSIONS: Female residents report working more, experiencing certain aspects of burnout more frequently, and having poorer psychological well-being. Qualitative themes provide insights into possible cultural and programmatic shifts to address the concerns for female residents.

Scar outcomes in dermatological surgery.

BACKGROUND/OBJECTIVES: Significant functional impairment and psychological burden may result from poor scar quality and its impact on patient's quality of life has been well-established. It is important to identify measures to reduce the risk of surgical complications. METHOD: 212 patients undergoing dermatological surgery were recruited from March 2011 to February 2014. Their age, sex, surgical site, closure type, defect size (length and width), scar length, number of deep sutures, suture type and size were recorded. The patients were followed up at 6 weeks and 6 months for complications including abscess formation, granuloma formation, scar spreading, suture spitting and hypertrophic scar formation. RESULTS: At 6 weeks complications included suture spitting (14%), granuloma (11%), scar spreading (7%), hypertrophic scarring (3%) and abscess formation (1%), and at 6 months; scar spreading (17%), hypertrophic scarring (2%) and suture spitting (1%). In our multivariate analysis there were no predictors for spreading or spitting at 6 weeks, and only the defect size width was a predictor for granulomas in the stepwise analysis. For scar spreading at 6 months, younger age, site (trunk or limbs), higher number of deep sutures and surgeon were independent predictors (P < 0.0001 for the model). CONCLUSION: Complications following dermatological surgery are low and tend to resolve with time, except for scar spreading. The surgeon who experienced more complications was placing sutures more superficially to the skin surface and was throwing more knots per closure; factors that we did not record in our study and merit further study.

Consensus recommendations on the use of daylight photodynamic therapy with methyl aminolevulinate cream for actinic keratoses in Australia.

Australia has the highest prevalence of actinic keratoses (AK) worldwide. Because of the risk of transformation of AK to invasive squamous cell carcinomas, consensus guidelines recommend that AK are removed using appropriate therapies to prevent progression to invasive disease. Daylight photodynamic therapy (PDT) is emerging as an efficacious treatment for AK, particularly for patients who require treatment of large areas of chronic actinic damage that can be exposed easily to daylight. Daylight PDT with methyl aminolevulinate (MAL) cream is a simple treatment for AK, almost painless, well tolerated and convenient, requiring minimal time in the clinic. Randomised controlled studies from northern Europe and Australia support the use of daylight PDT as an effective therapy for grade I and II AK on the face and scalp. There is sufficient daylight to conduct daylight PDT in Australia at any time of the year and during most weather conditions. Hence, daylight PDT with MAL can be included as an effective and well-tolerated new treatment option for the treatment of AK in Australia. These consensus recommendations provide guidelines for Australian clinicians on the use of daylight PDT in the treatment of diagnosed AK.

Treatment of face and scalp solar (actinic) keratosis with daylight-mediated photodynamic therapy is possible throughout the year in Australia: Evidence from a clinical and meteorological study.

BACKGROUND/OBJECTIVES: Solar (actinic) keratosis (AK) is an emergent concern worldwide and is associated with an increased risk of development of non-melanoma skin cancer, especially squamous cell carcinoma. Daylight-mediated photodynamic therapy (DL-PDT) using methyl aminolaevulinate cream has proved to be an effective, nearly painless, and more convenient alternative to conventional PDT for the treatment of AK. In a phase III, randomised, controlled trial performed in Australia, the mean irradiance (light intensity) received by patients during DL-PDT treatment, assessed via a spectroradiometer, was 305 W/m(2) (min. 40 to max. 585 W/m(2) ) with similar efficacy irrespective of intensity or dose. The objective of the present meteorological study was to assess the suitability of natural daylight to perform DL-PDT for the treatment of face and scalp AK during different periods of the year and different geographical locations and latitudes across Australia. METHODS: To determine daylight irradiance during a complete year in eight different geographical locations throughout Australia, we used meteorological software (Meteonorm, Meteotest, Bern, Switzerland), and available solar radiation and weather data from 1986-2005. RESULTS: The average daily irradiance remained within the levels (40-585 W/m(2) ) measured during the clinical DL-PDT study in Australia, throughout the year and in all geographical locations investigated (yearly average from Darwin 548 W/m(2) to Hobart 366 W/m(2) ). CONCLUSIONS: DL-PDT for the treatment of face and scalp AK in Australia can be performed effectively throughout the entire year as long as weather conditions permit daylight exposure and allow participants to remain under direct light for 2 h.

Characterization and stability study of polysorbate 20 in therapeutic monoclonal antibody formulation by multidimensional ultrahigh-performance liquid chromatography-charged aerosol detection-mass spectrometry.

Polysorbate 20 is a nonionic surfactant commonly used in the formulation of therapeutic monoclonal antibodies (mAb) to prevent protein denaturation and aggregation. It is critical to understand the molecular heterogeneity and stability of polysorbate 20 in mAb formulations as polysorbate can gradually degrade in aqueous solution over time by multiple pathways losing surfactant functions and leading to protein aggregation. The molecular heterogeneity of polysorbate and the interference from proteins and the excipient in the formulation matrix make it a challenge to study polysorbate in protein formulations. In this work, the characterization and stability study of polysorbate 20 in the presence of mAb formulation sample matrix is first reported using two-dimensional liquid chromatography (2DLC) coupled with charged aerosol detection (CAD) and mass spectrometry (MS) detection. A mixed-mode column that has both anion-exchange and reversed-phase properties was used in the first dimension to separate protein and polysorbate in the formulation sample, while polysorbate 20 esters were trapped online and then analyzed using an reversed-phase ultrahigh-performance liquid chromatography (RP-UHPLC) column in the second dimension to further separate the ester species. The MS served as the third dimension to further resolve as well as to identify the polysorbate ester subspecies. Another 2DLC method using a cation-exchange column in the first dimension and the same RP-UHPLC method in the second dimension was developed to analyze the degradation products of polysorbate 20. Stability samples of a protein drug product were studied using these two 2DLC-CAD-MS methods to separate, identify, and quantify the multiple ester species in polysorbate 20 and also to monitor the change of their corresponding degradants. We found different polysorbate esters degrade at different rates, and importantly, the degradation rates for some esters are different in the protein formulation compared to a placebo that has no protein. The multidimensional UHPLC-CAD-MS approach provides insights into the heterogeneous stability behaviors of polysorbate 20 subspecies in real-time stability samples of a mAb formulation.

Crabs ride the tide: incoming tides promote foraging of Giant Mud Crab (Scylla serrata).

BACKGROUND: Effective fisheries management of mobile species relies on robust knowledge of animal behaviour and habitat-use. Indices of behaviour can be useful for interpreting catch-per-unit-effort data which acts as a proxy for relative abundance. Information about habitat-use can inform stocking release strategies or the design of marine protected areas. The Giant Mud Crab (Scylla serrata; Family: Portunidae) is a swimming estuarine crab that supports significant fisheries harvest throughout the Indo-West Pacific, but little is known about the fine-scale movement and behaviour of this species. METHODS: We tagged 18 adult Giant Mud Crab with accelerometer-equipped acoustic tags to track their fine-scale movement using a hyperbolic positioning system, alongside high temporal resolution environmental data (e.g., water temperature), in a temperate south-east Australian estuary. A hidden Markov model was used to classify movement (i.e., step length, turning angle) and acceleration data into discrete behaviours, while also considering the possibility of individual variation in behavioural dynamics. We then investigated the influence of environmental covariates on these behaviours based on previously published observations. RESULTS: We fitted a model with two well-distinguished behavioural states describing periods of inactivity and foraging, and found no evidence of individual variation in behavioural dynamics. Inactive periods were most common (79% of time), and foraging was most likely during low, incoming tides; while inactivity was more likely as the high tide receded. Model selection removed time (hour) of day and water temperature (°C) as covariates, suggesting that they do not influence Giant Mud Crab behavioural dynamics at the temporal scale investigated. CONCLUSIONS: Our study is the first to quantitatively link fine-scale movement and behaviour of Giant Mud Crab to environmental variation. Our results suggest Giant Mud Crab are a predominantly sessile species, and support their status as an opportunistic scavenger. We demonstrate a relationship between the tidal cycle and foraging that is likely to minimize predation risk while maximizing energetic efficiency. These results may explain why tidal covariates influence catch rates in swimming crabs, and provide a foundation for standardisation and interpretation of catch-per-unit-effort data-a commonly used metric in fisheries science.

Rapid identification of low level glycation sites in recombinant antibodies by isotopic labeling with 13C6-reducing sugars.

Recombinant antibodies exhibit low levels of glycation from exposure to reducing sugars during production. As the glycation sites are typically distributed across the entire antibody, the levels at any one site are low and it becomes difficult to detect them in the conventional peptide maps. A model antibody was subjected to forced glycation by incubating with a high concentration of a 1:1 mixture of (12)C(6)/(13)C(6) reducing sugars with the assumption that the same sites in the native antibody will be glycated but to a lower extent. This approach simplified the detection of glycated tryptic peptide elution in the LC/MS analysis by giving a unique signature of two molecular ions with equal intensity and differing by 6.018 Da. An in-house developed script automatically processed large data files to generate a list of such peptide mass pairs. The high mass accuracy of the Orbitrap allowed us to assign the sequences unambiguously by comparison with all possible glycated peptide masses. This sequence list was subsequently used to verify their presence/absence in the digest of the native antibody. This work flow enabled rapid and confident identification of site-specific glycation even when levels are below 0.5%. We found the glycation sites to be distributed across the entire antibody studied.

Identification and characterization of buried unpaired cysteines in a recombinant monoclonal IgG1 antibody.

The heterogeneity in therapeutic antibodies arising from buried unpaired cysteines has not been well studied. This paper describes the characterization of two unpaired cysteines in a recombinant humanized IgG1 monoclonal antibody (referred to as mAb A). The reversed-phase high-performance liquid chromatography (RP-HPLC) analysis of mAb A samples showed three distinct peaks, indicating the presence of three species. The heterogeneities observed in the RP-HPLC have been determined to arise from unpaired cysteines (Cys-22 and Cys-96) that are buried in the V(H) domain. The Fab containing free thiols (referred to as "free-thiol Fab") and the Fab containing the disulfide (referred to as "intact Fab") of mAb A were generated through limited Lys-C digestion and purified with an ion exchange chromatography method. The binding of free-thiol Fab and intact Fab to its antigen was measured in a cell-based binding assay and an enzyme linked immunosorbent assay. The unpaired cysteines in the Fab of mAb A were found to have no significant impact on the binding to its target. Consistent with these Fab binding data, the enriched intact mAb A containing free thiols was determined to be fully active in a potency assay. The data reported here demonstrate that the redox status of cysteines is potentially a major source of heterogeneity for an antibody.

The Role of Biomarkers in the Management of Colorectal Liver Metastases.

Surgical management combined with improved systemic therapies have extended 5-year overall survival beyond 50% among patients with colorectal liver metastases (CRLM). Furthermore, a multitude of liver-directed therapies has improved local disease control for patients with unresectable CRLM. Unfortunately, a significant portion of patients treated with curative-intent hepatectomy develops disease recurrence. Traditional markers fail to risk-stratify and prognosticate patients with CRLM appropriately. Over the last few decades, advances in molecular sequencing technology have greatly expanded our knowledge of the pathophysiology and tumor microenvironment characteristics of CRLM. These investigations have revealed biomarkers with the potential to better inform management decisions in patients with CRLM. Actionable biomarkers such as RAS and BRAF mutations, microsatellite instability/mismatch repair status, and tumor mutational burden have been incorporated into national and societal guidelines. Other biomarkers, including circulating tumor DNA and radiomic features, are under active investigation to evaluate their clinical utility. Given the plethora of therapeutic modalities and lack of evidence on timing and sequence, reliable biomarkers are needed to assist clinicians with the development of patient-tailored management plans. In this review, we discuss the current evidence regarding biomarkers for patients with CRLM.

Machine learning accelerated high-throughput screening of zeolites for the selective adsorption of xylene isomers.

The production of widely used polymers such as polyester currently relies upon the chemical separation of and transformation of xylene isomers. The least valuable but most prevalent isomer is meta-xylene which can be selectively transformed into the more useful and expensive para-xylene isomer using a zeolite catalyst but at a high energy cost. In this work, high-throughput screening of existing and hypothetical zeolite databases containing more than two million structures was performed, using a combination of classical simulation and deep neural network methods to identify promising materials for selective adsorption of meta-xylene. Novel anomaly detection techniques were applied to the heavily biased classification task of identifying structures with a selectivity greater than that of the best performing existing zeolite, ZSM-5 (MFI topology). Eight hypothetical zeolite topologies are found to be several orders of magnitude more selective towards meta-xylene than ZSM-5 which may provide an impetus for synthetic efforts to realise these promising materials. Moreover, the leading hypothetical frameworks identified from the screening procedure require a markedly lower operating temperature to achieve the diffusion seen in existing materials, suggesting significant energetic savings if the frameworks can be realised.