Overview of Current Hepatocellular Carcinoma Staging Systems: Is There an Optimal System?

Multiple hepatocellular carcinoma (HCC) staging systems have been proposed and used clinically over time. These may consider clinical, pathological, radiological, or treatment response factors, depending on the model. Given the heterogeneity of HCC treatment in its different stages and the validation of the systems in different populations, they are not universal. Likewise, the improvement in diagnostic tools, as well as novel therapeutic alternatives, have made these models more complex. Despite this, some have been modified over time in line with advances in the field, and although there is no universally accepted one, each has its usefulness, strengths, and weaknesses.

Quantum mechanical approaches and molecular docking studies of metal based anticancer drugs cis-Diammine glycolato platinum and Diaminocyclohexane oxalatoplatinum structures.

The optimized structures and theoretical studies of metal based anticancer drugs Nedaplatin (cis-Diammine glycolato platinum) (CDGP) and Oxaliplatin (Diaminocyclohexane oxalatoplatinum) (DCOP) structures by Density Functional Theory (DFT) method at the B3LYP level with LANL2DZ was applied to investigate the spectroscopic, structural optical properties, conducting properties for the chosen materials, Band Gap was predicted with the help of HOMO-LUMO values. From the calculated parameters of the title compounds CDGP and DCOP shows DCOP found to be highly reactive metal complexed anticancer drug over CDGP. On calculating the site of the lowest binding energy a receptor active site with ligand is done by Ligand-protein docking process. In this study, the difference in the coordinates of ligands and the binding (intermolecular) energy called as Root Mean Square Deviation (RMSD) estimated to estimate the drug-DNA interactions. Molecular docking is the broadly used screening studies in the visualizing of Drug-DNA interaction at an level of atom and drug designing based on structure. Chosen anticancer drugs with their binding affinities to the selected DNA and Drugs potential anticancer behavior were examined, Out of 2 drug compounds screened, CDGP and DCOP, DCOP have shown least binding energies as -6.88 kcal/mol than CDGP as -5.64 kcal/mol and the interactive studies of drug compounds conformations with RMSD values in accordance to crystal structures is less than or equal to 2.00 Å in focusing on the complete DNA structure (large grid box) done using the Autodock software.The compound with most least binding energy value with low inhibition constant found to have good binding affinity towards the DNA structure and the structural properties studied using DFT also shows good chemical reactivity in accordance with the Docking studies.From the results obtained DCOP found to have good chemical descriptors with Good binding affinity than CDGP.Thus DCOP is the best suited for biological molecular target.

Neighborhood-level COVID vaccination and booster disparities: A population-level analysis across California.

Objectives: To describe vaccine and booster uptake by neighborhood-level factors in California. Methods: We examined trends in COVID-19 vaccination up to September 21, 2021, and boosters up to March 29, 2022 using data from the California Department of Public Health. Quasi-Poisson regression was used to model the association between neighborhood-level factors and fully vaccinated and boosted among ZIP codes. Sub-analyses on booster rates were compared among the 10 census regions. Results: In a minimally adjusted model, a higher proportion of Black residents was associated with lower vaccination (HR = 0.97; 95%CI: 0.96-0.98). However, in a fully adjusted model, proportion of Black, Hispanic/Latinx, and Asian residents were associated with higher vaccination rates (HR = 1.02; 95%CI: 1.01-1.03 for all). The strongest predictor of low vaccine coverage was disability (HR = 0.89; 95%CI: 0.86-0.91). Similar trends persisted for booster doses. Factors associated with booster coverage varied by region. Conclusions: Examining neighborhood-level factors associated with COVID-19 vaccination and booster rates uncovered significant variation within the large and geographically and demographically diverse state of California. Equity-based approaches to vaccination must ensure a robust consideration of multiple social determinants of health.

Developing and Validating Models to Predict Progression to Proliferative Diabetic Retinopathy.

Purpose: To develop models for progression of nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and determine if incorporating updated information improves model performance. Design: Retrospective cohort study. Participants: Electronic health record (EHR) data from a tertiary academic center, University of California San Francisco (UCSF), and a safety-net hospital, Zuckerberg San Francisco General (ZSFG) Hospital were used to identify patients with a diagnosis of NPDR, age ≥ 18 years, a diagnosis of type 1 or 2 diabetes mellitus, ≥ 6 months of ophthalmology follow-up, and no prior diagnosis of PDR before the index date (date of first NPDR diagnosis in the EHR). Methods: Four survival models were developed: Cox proportional hazards, Cox with backward selection, Cox with LASSO regression and Random Survival Forest. For each model, three variable sets were compared to determine the impact of including updated clinical information: Static0 (data up to the index date), Static6m (data updated 6 months after the index date), and Dynamic (data in Static0 plus data change during the 6-month period). The UCSF data were split into 80% training and 20% testing (internal validation). The ZSFG data were used for external validation. Model performance was evaluated by the Harrell's concordance index (C-Index). Main Outcome Measures: Time to PDR. Results: The UCSF cohort included 1130 patients and 92 (8.1%) patients progressed to PDR. The ZSFG cohort included 687 patients and 30 (4.4%) patients progressed to PDR. All models performed similarly (C-indices ∼ 0.70) in internal validation. The random survival forest with Static6m set performed best in external validation (C-index 0.76). Insurance and age were selected or ranked as highly important by all models. Other key predictors were NPDR severity, diabetic neuropathy, number of strokes, mean Hemoglobin A1c, and number of hospital admissions. Conclusions: Our models for progression of NPDR to PDR achieved acceptable predictive performance and validated well in an external setting. Updating the baseline variables with new clinical information did not consistently improve the predictive performance. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

A case series evaluation of comprehensive drug testing in the pediatric acute care setting.

Introduction: Drug testing typically follows a one-size-fits-all approach that is inadequate in some clinical scenarios, such as child maltreatment, neglect, and unintentional drug exposure. Results from immunoassay-based testing, which are non-specific, insensitive, and far from comprehensive, can lead to unintended consequences for children and their families. Objectives: The objective of this retrospective case series study is to evaluate the utility of real-time (0-1 day) comprehensive drug testing as an alternative to immunoassay-based testing in the pediatric acute care setting. Methods: Comprehensive drug testing results obtained by mass spectrometry testing and associated medical data for all pediatric cases (0-12 years) at one institution from 2019 to 2022 were included in the analysis. The final case series (n = 7) included all cases from patients <3 years with comprehensive drug testing results that were inconsistent with medication history and/or toxicology results by immunoassay. Results: Comprehensive drug testing by mass spectrometry was ordered for 174 urine and blood samples representing 97 patients (0-12 years) from 2019 to 2022. Of these, 76 cases were from patients <3 years old; results were consistent with medication history and confirmatory for immunoassay results (n = 34), consistent with medication history (n = 14), confirmatory for immunoassay results (n = 10), negative (n = 9), or medical history was incomplete (n = 2). The remaining 7 cases were included in the final case series. Conclusions: The cases highlight the value of real-time comprehensive drug testing in acute pediatric cases. Testing results can rule out toxic exposure from the diagnostic differential when negative, and lead to appropriate medical and social interventions when positive.

Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein.

The use of computer-aided methods have continued to propel accelerated drug discovery across various disease models, interestingly allowing the specific inhibition of pathogenic targets. Chloride Intracellular Channel Protein 4 (CLIC4) is a novel class of intracellular ion channel highly implicated in tumor and vascular biology. It regulates cell proliferation, apoptosis and angiogenesis; and is involved in multiple pathologic signaling pathways. Absence of specific inhibitors however impedes its advancement to translational research. Here, we integrate structural bioinformatics and experimental research approaches for the discovery and validation of small-molecule inhibitors of CLIC4. High-affinity allosteric binders were identified from a library of 1615 Food and Drug Administration (FDA)-approved drugs via a high-performance computing-powered blind-docking approach, resulting in the selection of amphotericin B and rapamycin. NMR assays confirmed the binding and conformational disruptive effects of both drugs while they also reversed stress-induced membrane translocation of CLIC4 and inhibited endothelial cell migration. Structural and dynamics simulation studies further revealed that the inhibitory mechanisms of these compounds were hinged on the allosteric modulation of the catalytic glutathione (GSH)-like site loop and the extended catalytic ß loop which may elicit interference with the catalytic activities of CLIC4. Structure-based insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated pathologies.

Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions.

Cirrhosis predisposes to abnormalities in energy, hormonal, and immunological homeostasis. Disturbances in these metabolic processes create susceptibility to sarcopenia or pathological muscle wasting. Sarcopenia is prevalent in cirrhosis and its presence portends significant adverse outcomes including the length of hospital stay, infectious complications, and mortality. This highlights the importance of identification of at-risk individuals with early nutritional, therapeutic and physical therapy intervention. This manuscript summarizes literature relevant to sarcopenia in cirrhosis, describes current knowledge, and elucidates possible future directions.

ArtiaX: An electron tomography toolbox for the interactive handling of sub-tomograms in UCSF ChimeraX.

Cryo-electron tomography analysis involves the selection of macromolecular complexes to be used for subsequent sub-tomogram averaging and structure determination. Here, we describe a plugin developed for UCSF ChimeraX that allows for the display, selection, and editing of particles within tomograms. Positions and orientations of selected particles can be manually set, modified and inspected in real time, both on screen and in virtual reality, and exported to various file formats. The plugin allows for the parallel visualization of particles stored in several meta data lists, in the context of any three-dimensional image that can be opened with UCSF ChimeraX. The particles are rendered in user-defined colors or using colormaps, such that individual classes or groups of particles, cross-correlation coefficients, or other types of information can be highlighted to the user. The implemented functions are fast, reliable, and intuitive, exploring the broad range of features in UCSF ChimeraX. They allow for a fluent human-machine interaction, which enables an effective understanding of the sub-tomogram processing pipeline, even for non-specialist users.

Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

First Report of a Paediatric Collision Tumour in the Liver Recognised After Liver Transplantation: Blissful Ignorance Has Benefits!

Liver tumours are uncommon in the paediatric population, constituting 1-2 % of all paediatric tumours and 4% of all paediatric liver tumours. Hepatoblastoma followed by hepatocellular carcinoma is the most common tumours in this age group. Simultaneous development of two discrete liver tumours of distinct histologies (collision tumour) has been occasionally reported in adults but never in children. We hereby present the first reported case of hepatic collision tumours (hepatocellular carcinoma and cholangiocarcinoma) in the explant liver of a child who underwent living donor liver transplantation for end-stage liver disease and severe hepatopulmonary syndrome. The manuscript describes the clinical, radiological and histopathological findings of this case and also highlights the dilemma associated with management of this case had the diagnosis been made in the preoperative setting and also about the proposed management plan for this case in the postoperative period.

Patients Benefit from Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria without Harming the Health Care System.

Liver transplantation (LT) is the only definitive treatment to cure hepatocellular carcinoma (HCC) in cirrhosis. Waiting-list candidates are selected by the model for end-stage liver disease (MELD). However, many indications are not sufficiently represented by labMELD. For HCC, patients are selected by Milan-criteria: Milan-in qualifies for standard exception (SE) and better organ access on the waiting list; while Milan-out patients are restricted to labMELD and might benefit from extended criteria donor (ECD)-grafts. We analyzed a cohort of 102 patients (2011−2020). Patients with labMELD (no SE, Milan-out, n = 56) and matchMELD (SE-HCC, Milan-in, n = 46) were compared. The median overall survival was not significantly different (p = 0.759). No difference was found in time on the waiting list (p = 0.881), donor risk index (p = 0.697) or median costs (p = 0.204, EUR 43,500 (EUR 17,800−185,000) for labMELD and EUR 30,300 (EUR 17,200−395,900) for matchMELD). Costs were triggered by a cut-off labMELD of 12 points. Overall, the deficit increased by EUR 580 per labMELD point. Cost drivers were re-operation (p < 0.001), infection with multiresistant germs (p = 0.020), dialysis (p = 0.017), operation time (p = 0.012) and transfusions (p < 0.001). In conclusion, this study demonstrates that LT for HCC is successful and cost-effective in low labMELD patients independent of Milan-criteria. Therefore, ECD-grafts are favorized in Milan-out HCC patients with low labMELD.

International study on the outcome of locoregional therapy for liver transplant in hepatocellular carcinoma beyond Milan criteria.

BACKGROUND & AIMS: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'. METHODS: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. RESULTS: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers. CONCLUSIONS: Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT. CLINICAL TRIAL NUMBER: This study was registered as part of an open public registry (NCT03775863). LAY SUMMARY: Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT.

Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists.

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.

Living donor liver transplantation or hepatic resection combined with intraoperative radiofrequency ablation for Child-Pugh A hepatocellular carcinoma patient with Multifocal Tumours Meeting the University of California San Francisco (UCSF) criteria.

BACKGROUND: How much difference there is between hepatic resection (HR) combined with intraoperative radiofrequency ablation (RFA) and living donor liver transplantation (LDLT) in treatment of multifocal hepatocellular carcinomas (HCCs) remains unclear. This study compared outcomes for patients with multifocal HCCs meeting the University of California San Francisco (UCSF) criteria treated by LDLT or HR + RFA. METHODS: A total of 126 consecutive Child-Pugh A patients with multifocal HCCs meeting the UCSF criteria, who underwent LDLT (n = 51) or HR + RFA (n = 75), were included. Propensity score (PS) matching was performed to adjust for baseline differences. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and subgroup, multivariate and nomogram analyses were performed. RESULTS: LDLT provided significantly better OS and RFS than did HR + RFA before and after PS matching and reduced the dropout rate on waiting list, but HR + RFA was more convenient, less invasive and less cost. Patients with all lesions located in the same lobe had better OS and RFS than those located in the different lobes after HR + RFA. Multivariate and nomogram analyses revealed that HR + RFA, alpha-fetoprotein ≥ 400 ng/mL, the major tumour size > 3 cm and microvascular invasion were independent predictors of poor prognosis. CONCLUSION: For Child-Pugh A patients with multiple HCCs meeting the UCSF criteria, LDLT may offer significantly better long-term results than did HR + RFA, and HR + RFA may still be considered as an acceptable curative therapy for those without considering transplantation or as a bridge treatment for a patient, with a plan for transplantation in the future.

Are Antimotility Agents Safe for Use in Clostridioides difficile Infections? Results From an Observational Study in Malignant Hematology Patients.

OBJECTIVES: To evaluate the safety of antimotility agents (AAs) in a population of patients with hematologic malignancies and concurrent Clostridioides difficile infection (CDI) and to describe the outcomes of AA use in a hospital setting. PATIENTS AND METHODS: We used the electronic health record to identify patients who were hospitalized in the adult malignant hematology service who had 1 or more toxin-positive C difficile stool assay between April 1, 2012, and September 21, 2017. We reviewed medical charts to obtain information on the use of AAs and any subsequent gastrointestinal complications. RESULTS: There were 339 patients who were stool toxin positive for CDI during the study period. Of those, 94 patients (27%) were prescribed AAs within 14 days of CDI diagnosis. All patients received CDI antimicrobial therapy within the first 24 hours. There were 2 adverse gastrointestinal events in the group that received AAs and 6 in the group that did not receive AAs. The risk of adverse events did not differ between patients who received AAs and those who did not (adjusted odds ratio, 0.36; 95% CI, 0.06 to 2.10). The mean age of the full cohort was 52.7±15.5 years, and the mean length of stay was 26.7±22.6 days. Early AA use (<48 hours of diagnosis) was not associated with increased adverse effects. CONCLUSION: There was no increase in the incidence of gastrointestinal events in the arm that used AAs compared with the control arm. The evidence suggests that for patients with hematologic malignancies and CDI, the addition of AAs to appropriate antimicrobial therapy poses no additional risk.

Long-term pain outcomes in elderly patients with trigeminal neuralgia: comparison of first-time microvascular decompression and stereotactic radiosurgery.

OBJECTIVE: Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD) and stereotactic radiosurgery (SRS). The use of MVD in elderly patients has been described but has yet to be prospectively compared to SRS, which is well-tolerated and noninvasive. The authors aimed to directly compare long-term pain control and adverse event rates for first-time surgical treatments for idiopathic TN in the elderly. METHODS: A prospectively collected database was reviewed for TN patients who had undergone treatment between 1997 and 2017 at a single institution. Standardized collection of preoperative demographics, surgical procedure, and postoperative outcomes was performed. Data analysis was limited to patients over the age of 65 years who had undergone a first-time procedure for the treatment of idiopathic TN with at least 1 year of follow-up. RESULTS: One hundred ninety-three patients meeting the study inclusion criteria underwent surgical procedures for TN during the study period (54 MVD, 24 MVD+Rhiz, 115 SRS). In patients in whom an artery was not compressing the trigeminal nerve during MVD, a partial sensory rhizotomy (MVD+Rhiz) was performed. Patients in the SRS cohort were older than those in the MVD and MVD+Rhiz cohorts (mean ± SD, 79.2 ± 7.8 vs 72.9 ± 5.7 and 70.9 ± 4.8 years, respectively; p < 0.0001) and had a higher mean Charlson Comorbidity Index (3.8 ± 1.1 vs 3.0 ± 0.9 and 2.9 ± 1.0, respectively; p < 0.0001). Immediate or short-term postoperative pain-free rates (Barrow Neurological Institute [BNI] pain intensity score I) were 98.1% for MVD, 95.8% for MVD+Rhiz, and 78.3% for SRS (p = 0.0008). At the last follow-up, 72.2% of MVD patients had a favorable outcome (BNI score I-IIIa) compared to 54.2% and 49.6% of MVD+Rhiz and SRS patients, respectively (p = 0.02). In total, 0 (0%) SRS, 5 (9.3%) MVD, and 1 (4.2%) MVD+Rhiz patients developed any adverse event. Multivariate Cox proportional hazards analysis demonstrated that procedure type (p = 0.001) and postprocedure sensory change (p = 0.003) were statistically significantly associated with pain control. CONCLUSIONS: In this study cohort, patients who had undergone MVD had a statistically significantly longer duration of pain freedom than those who had undergone MVD+Rhiz or SRS as their first procedure. Fewer adverse events were seen after SRS, though the MVD-associated complication rate was comparable to published rates in younger patients. Overall, the results suggest that both MVD and SRS are effective options for the elderly, despite their advanced age. Treatment choice can be tailored to a patient's unique condition and wishes.

Surgical management of incidentally discovered low-grade gliomas.

OBJECTIVE: Although most patients with low-grade glioma (LGG) present after a seizure, a small proportion is diagnosed after neuroimaging is performed for a sign or symptom unrelated to the tumor. While these tumors invariably grow, some surgeons argue for a watchful waiting approach. Here, the authors report on their experience in the surgical treatment of patients with incidental LGG (iLGG) and describe the neurological outcomes, survival, and complications. METHODS: Relevant cases were identified from a prospective registry of patients undergoing glioma resection at the University of California, San Francisco, between 1997 and 2019. Cases were considered iLGG when the lesion was noted on imaging performed for a reason unrelated to the tumor. Demographic, clinical, pathological, and imaging data were extracted from the electronic medical record. Tumor volumes, growth, and extent of resection were calculated from pre- and postoperative volumetric FLAIR sequences. RESULTS: One hundred thirteen of 657 (17.2%) first-time resections for LGG were for incidental lesions. The most common reasons for the discovery of an iLGG were headaches (without mass effect, 34.5%) or trauma (16.8%). Incidental tumors were no different from symptomatic lesions in terms of laterality or location, but they were significantly smaller (22.5 vs 57.5 cm3, p < 0.0001). There was no difference in diagnosis between patients with iLGG and those with symptomatic LGG (sLGG), incorporating both molecular and pathological data. The median preoperative observation time for iLGG was 3.1 months (range 1 month-12 years), and there was a median growth rate of 3.9 cm3/year. Complete resection of the FLAIR abnormality was achieved in 57% of patients with incidental lesions but only 23.8% of symptomatic lesions (p < 0.001), and the residual volumes were smaller for iLGGs (2.9 vs 13.5 cm3, p < 0.0001). Overall survival was significantly longer for patients with incidental tumors (median survival not reached for patients with iLGG vs 14.6 years for those with sLGG, p < 0.0001). There was a 4.4% rate of neurological deficits at 6 months. CONCLUSIONS: The authors present the largest cohort of iLGGs. Patient age, tumor location, and molecular genetics were not different between iLGGs and sLGGs. Incidental tumors were smaller, a greater extent of resection could be achieved, and overall survival was improved compared to those for patients with sLGG. Operative morbidity and rates of neurological deficit were acceptably low; thus, the authors advocate upfront surgical intervention aimed at maximal safe resection for these incidentally discovered lesions.

Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists.

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information (supplementary material) provides an illustrated step-by-step guide for the inhibitor design, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.

The association between lower Hounsfield units on computed tomography and cage subsidence after lateral lumbar interbody fusion.

OBJECTIVE: One vexing problem after lateral lumbar interbody fusion (LLIF) surgery is cage subsidence. Low bone mineral density (BMD) may contribute to subsidence, and BMD is correlated with Hounsfield units (HUs) on CT. The authors investigated if lower HU values correlated with subsidence after LLIF. METHODS: A retrospective study of patients undergoing single-level LLIF with pedicle screw fixation for degenerative conditions at the University of California, San Francisco, by 6 spine surgeons was performed. Data on demographics, cage parameters, preoperative HUs on CT, and postoperative subsidence were collected. Thirty-six-inch standing radiographs were used to measure segmental lordosis, disc space height, and subsidence; data were collected immediately postoperatively and at 1 year. Subsidence was graded using a published grade of disc height loss: grade 0, 0%-24%; grade I, 25%-49%; grade II, 50%-74%; and grade III, 75%-100%. HU values were measured on preoperative CT from L1 to L5, and each lumbar vertebral body HU was measured 4 separate times. RESULTS: After identifying 138 patients who underwent LLIF, 68 met the study inclusion criteria. All patients had single-level LLIF with pedicle screw fixation. The mean follow-up duration was 25.3 ± 10.4 months. There were 40 patients who had grade 0 subsidence, 15 grade I, 9 grade II, and 4 grade III. There were no significant differences in age, sex, BMI, or smoking. There were no significant differences in cage sizes, cage lordosis, and preoperative disc height. The mean segmental HU (the average HU value of the two vertebrae above and below the LLIF) was 169.5 ± 45 for grade 0, 130.3 ± 56.2 for grade I, 100.7 ± 30.2 for grade II, and 119.9 ± 52.9 for grade III (p < 0.001). After using a receiver operating characteristic curve to establish separation criteria between mild and severe subsidence, the most appropriate threshold of HU value was 135.02 between mild and severe subsidence (sensitivity 60%, specificity 92.3%). After univariate and multivariate analysis, preoperative segmental HU value was an independent risk factor for severe cage subsidence (p = 0.017, OR 15.694, 95% CI 1.621-151.961). CONCLUSIONS: Lower HU values on preoperative CT are associated with cage subsidence after LLIF. Measurement of preoperative HU values on CT may be useful when planning LLIF surgery.

When to call it off: defining transplant candidacy limits in liver donor liver transplantation for hepatocellular carcinoma.

BACKGROUND: Living donor liver transplantation (LDLT) is an acceptable treatment option for hepatocellular carcinoma (HCC). Traditional transplant criteria aim at best utilization of donor organs with low risk of post transplant recurrence. In LDLT, long term recurrence free survival (RFS) of 50% is considered acceptable. The objective of the current study was to determine preoperative factors associated with high recurrence rates in LDLT. METHODS: Between April 2012 and December 2019, 898 LDLTs were performed at our center. Out of these, 242 were confirmed to have HCC on explant histopathology. We looked at preoperative factors associated with ≤ 50%RFS at 4 years. For survival analysis, Kaplan Meier curves were used and Cox regression analysis was used to identify independent predictors of recurrence. RESULTS: Median AFP was 14.4(0.7-11,326.7) ng/ml. Median tumor size was 2.8(range = 0.1-11) cm and tumor number was 2(range = 1-15). On multivariate analysis, AFP > 600 ng/ml [HR:6, CI: 1.9-18.4, P = 0.002] and microvascular invasion (MVI) [HR:5.8, CI: 2.5-13.4, P <  0.001] were independent predictors of 4 year RFS ≤ 50%. When AFP was > 600 ng/ml, MVI was seen in 88.9% tumors with poor grade and 75% of tumors outside University of California San Francisco criteria. Estimated 4 year RFS was 78% for the entire cohort. When AFP was < 600 ng/ml, 4 year RFS for well-moderate and poor grade tumors was 88 and 73%. With AFP > 600 ng/ml, RFS was 53% and 0 with well-moderate and poor grade tumors respectively (P <  0.001). CONCLUSION: Patients with AFP < 600 ng/ml have acceptable outcomes after LDLT. In patients with AFP > 600 ng/ml, a preoperative biopsy to rule out poor differentiation should be considered for patient selection.