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A lack of fine, spatially-resolute case data for the U.S. has prevented the examination of how COVID-19 burden has been distributed across neighborhoods, a known geographic unit of both risk and resilience, and is hampering efforts to identify and mitigate the long-term fallout from COVID-19 in vulnerable communities. Using spatially-referenced data from 21 states at the ZIP code or census tract level, we documented how the distribution of COVID-19 at the neighborhood-level varies significantly within and between states. The median case count per neighborhood (IQR) in Oregon was 3,608 (2,487) per 100,000 population, indicating a more homogenous distribution of COVID-19 burden, whereas in Vermont the median case count per neighborhood (IQR) was 8,142 (11,031) per 100,000. We also found that the association between features of the neighborhood social environment and burden varied in magnitude and direction by state. Our findings underscore the importance of local contexts when addressing the long-term social and economic fallout communities will face from COVID-19.

To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large datasets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise. Matcher enables unprecedented control over the search and clustering of MMP transformations based on both variable fragment and constant environment structure, which is critical for disentangling relevant and irrelevant data to a given problem. Users can exert such control through a built-in chemical sketcher, and with a few mouse clicks can navigate between resulting MMP transformations, statistics, property distribution graphs and structures with raw experimental data, for confident and accelerated decision making. Matcher can be used with any collection of structure/property data; here we demonstrate usage with a public ChEMBL dataset of about 20,000 small molecules with CYP3A4 and/or hERG inhibition data. Users can reproduce all examples demonstrated herein via unique links within Matcher’s interface – a functionality that anyone can use to preserve and share their own analyses. Matcher and all its dependencies are open-source with permissive licenses and trivial containerized deployment, and is freely available at https://github.com/Merck/Matcher. Matcher makes large structure/property datasets more transparent than ever before and accelerates the data-driven solution of common problems in drug discovery.

Purpose Minimally invasive surgery is becoming widely adopted to decrease surgical morbidity and mortality, however data is still evolving and the optimal approach remains an area of controversy. We compared our unique single-institution experience with transhiatal, transthoracic, and minimally invasive approaches to examine survival and toxicity outcomes among patients treated for esophageal cancer. Methods Consecutive patients undergoing esophagectomy for esophageal or gastroesophageal junction (GEJ) cancer at a single institution between 2008 and 2017 were retrospectively reviewed. The patients were stratified by surgical approach. The Kaplan-Meier method was performed using the log-rank test to calculate two-year overall survival (OS) and two-year progression-free survival (PFS). Results A total of 198 consecutive patients were identified: 118 transhiatal esophagectomy (THE), 34 Ivor Lewis esophagectomy (ILE), and 46 minimally invasive esophagectomy (MIE) with a median follow-up of 30.0 months (range, 0.5-136.9 months). Most tumors were adenocarcinoma (89.9%) located in the distal esophagus and GEJ (94%). Neoadjuvant chemoradiotherapy was received by 75.8% of patients. Length of hospitalization, readmission rate, perioperative adverse events, reoperation rates, tracheoesophageal fistula, anastomotic leak, anastomotic stenosis, and 30-day mortality were comparable. Two-year overall survival rates for MIE, THE, and ILE were 71.7%, 67.8%, and 58.8%, respectively (p = 0.003). Progression-free survival at 2 years for MIE, THE, and ILE were 69.6%, 58.5%, and 35.3%, respectively (p = 0.002). Conclusion Minimally invasive esophagectomy is an effective approach which results in comparable perioperative complications and long-term survival outcomes to a transhiatal approach. Minimally invasive esophagectomy can safely be performed and should continue to be studied prospectively.

Demonstrating a viable development for the Ekofisk reservoir directly above the producing Tor reservoir in the Halfdan Field (Danish North Sea) has historically been challenging. A recent well shows the value of cross-disciplinary collaboration and new technology to maximize recovery and mitigate reservoir and drilling risks. Specifically, 4D seismic was utilized when planning the well, while placement was optimized by using advanced geosteering tools. Well optimization was further enhanced by adopting novel completion and stimulation technologies. Pressure data and 4D seismic show that Tor and Ekofisk are in dynamic communication, but the degree of communication varies locally. The integration of 4D seismic with other disciplines’ input succeeded in optimizing the well placement and narrowed the significant pore pressure uncertainty along the 12,000-ft reservoir section. To maximize well length within the target zone and reduce the risk of being faulted out of the target reservoir deep resistivity was used to steer the well in the optimal layers. This contributed to 99% of the reservoir section being placed in the target zone. Lessons learnt from an earlier appraisal well and modest production experience in this part of the Ekofisk reservoir helped to justify the choice of selective completion zones (Sliding Side Door) in the inner part of the horizontal drain in order to minimize the impact of potential water or premature water breakthrough from high-rate injection wells located in the underlying Tor reservoir. This decision was validated after drilling the inner part of the well, where water-swept zones were encountered in the heel, followed by a long gas pay zone in line with 4D seismic signal in the remainder of the inner well section. To mitigate the risk of an unwanted fracture connection and increase contact with the tight oil-saturated reservoir, a novel stimulation and completion technology was successfully deployed in the outer 6-inch open-hole section of the well. The acid needles completion, deployed across a 3,000-ft reservoir interval and comprising 224 needles deployed by pumping acid, was the first installation of its kind in the Danish North Sea. For the acid needles completion, this installation holds two distinctions: the largest number of acid needles installed in a well, and the combination of the acid needles completion with a different completion system in a single lateral for the first time.

e16254 Background: Neo-adjuvant therapy (NAT) and associated pathologic complete response (pCR) rates have correlated with improved survival in resected pancreatic ductal adenocarcinoma (PDAC). In this study, we explored the relationship between pathologic response, peri-operative therapy, and survival, especially the impact of change in adjuvant therapy in patients with no/poor path response to NAT. Methods: Retrospectively reviewed 66 PDAC patients who received NAT ± radiation and underwent resection at KU Cancer Center between 2011-2022. We compared DFS and OS between Path Responders vs Non-Responders based on standard Tumor Regression Scores from pathology reports. A subanalysis was performed in path non-responders based on switch in adjuvant therapy (AT) versus not. Results: Patient characteristics are summarized in the table. Among 66 PDAC patients, 50 (75.8%) achieved a path response (G0-G2), 16 (24.2%) experienced no/poor path response (G3). Of the 50 pts who achieved a path response, 4 (8.0%) had a complete path response (pCR; G0), 5 (10%) marked response (G1), 41 (82%) moderate response (G2). Median DFS (mDFS) was 17.3 months (95% CI: 12.7-22.4) in Path Responders vs 15.9m (95% CI: 9.6-35.8) in Non-Responders [p=0.59]. Median OS (mOS) was 32.9m (95% CI: 23.4-41.5) vs 27.7m (95% CI: 15.2-38.2), respectively [p=0.39). A sub-analysis in the Non-Responders (n=16) based on switch in AT (n=8) vs not (n=3), revealed mDFS 16.4m (95% CI: 9.6-41.8) when AT was switched vs mDFS 11.3m (95% CI: 5.9-16.6) when AT was not switched [p=0.24]; and mOS 30.6m (95% CI: 15.7-60.3) vs 17.2 months (95% CI: 6.7-27.7), respectively [p=0.18]. Conclusions: Our study found no statistical difference in DFS and OS between Pathologic Responders and Non-Responders to neo-adjuvant therapy. However, a sub-analysis within Pathologic Non-Responders revealed a longer DFS and OS after switching adjuvant therapy without reaching statistical significance, likely due to small sample size. Our findings warrant validation in a larger cohort as switch in adjuvant therapy could potentially change the treatment landscape for Pathologic Non-Responders.[Table: see text]

Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1E,4E)-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1H-imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1E,4E)-5-(1-alkyl-1H-imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4H-chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells.

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