Modified PRIEST score for identification of very low-risk COVID patients.

BACKGROUND: COVID-19 transmission remains high around the world, and severe local outbreaks continue to occur. Prognostic tools may be useful in crisis conditions as risk stratification can help determine resource allocation. One published tool, the Pandemic Respiratory Infection Emergency System Triage Severity Score, seems particularly promising because of its predictive ability and ease of application at the bedside. We sought to understand the performance of a modified version of this score (mPRIEST) in our institution for identifying patients with a greater than minimal risk for adverse outcome (death or organ support) at 30 days after index visit. METHODS: Consecutive visits at two northern Manhattan EDs with a new diagnosis of symptomatic COVID-19 were identified between November and December of 2020. Demographic variables and clinical characteristics were obtained from chart review. Outcomes were obtained from chart review and follow-up phone call. RESULTS: Outcomes were available on 306 patients. The incidence of death or mechanical ventilation at 30 days for patients in patients with mPRIEST above the threshold value was 43/181 (23.8%), and for patients below 1/125 (0.8%). The sensitivity of the score for adverse outcome was 97.7% (95% CI: 93.3% to 100%). CONCLUSIONS: This data suggests the mPRIEST score, which can be calculated from clinical variables alone, has potential for use in EDs to identify patients at very low risk for adverse outcomes within 30 days of COVID diagnosis. This should be confirmed in larger formal validation studies in diverse settings.

Crisis clinical pathway for COVID-19.

The pandemic of COVID-19 has been particularly severe in the New York City area, which has had one of the highest concentrations of cases in the USA. In March 2020, the EDs of New York-Presbyterian Hospital, a 10-hospital health system in the region, began to experience a rapid surge in patients with COVID-19 symptoms. Emergency physicians were faced with a disease that they knew little about that quickly overwhelmed resources. A significant amount of attention has been placed on the problem of limited supply of ventilators and intensive care beds for critically ill patients in the setting of the ongoing global pandemic. Relatively less has been given to the issue that precedes it: the demand on resources posed by patients who are not yet critically ill but are unwell enough to seek care in the ED. We describe here how at one institution, a cross-campus ED physician working group produced a care pathway to guide clinicians and ensure the fair and effective allocation of resources in the setting of the developing public health crisis. This 'crisis clinical pathway' focused on using clinical evaluation for medical decision making and maximising benefit to patients throughout the system.

Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib.

BACKGROUND: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). METHODS: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels. RESULTS: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement. CONCLUSIONS: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.

Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.

Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors.

Advanced prostate cancer can progress to systemic metastatic tumors, which are generally androgen insensitive and ultimately lethal. Here, we report a comprehensive genomic survey for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancer-related genes using next generation sequencing. Focal homozygous deletions were detected at 8p22, 10q23.31, 13q13.1, 13q14.11, and 13q14.12. Key genes mapping within these deleted regions include PTEN, BRCA2, C13ORF15, and SIAH3. Focal high-level amplifications were detected at 5p13.2-p12, 14q21.1, 7q22.1, and Xq12. Key amplified genes mapping within these regions include SKP2, FOXA1, and AR. Furthermore, targeted mutational analysis of normal-tumor pairs has identified somatic mutations in genes known to be associated with prostate cancer including AR and TP53, but has also revealed novel somatic point mutations in genes including MTOR, BRCA2, ARHGEF12, and CHD5. Finally, in one patient where multiple independent metastatic tumors were available, we show common and divergent somatic alterations that occur at both the copy number and point mutation level, supporting a model for a common clonal progenitor with metastatic tumor-specific divergence. Our study represents a deep genomic analysis of advanced metastatic prostate tumors and has revealed candidate somatic alterations, possibly contributing to lethal prostate cancer.

Revelation of mindlines in the setting of crisis.

During the devastating early months of the unfolding COVID-19 pandemic in New York, healthcare systems and clinicians dynamically adapted to drastically changing everyday practice despite having little guidance from formal research evidence in the face of a novel virus. Through new, silo-breaking networks of communication, clinical teams transformed and synthesized provisional recommendations, rudimentary published research findings and numerous other sources of knowledge to address the immediate patient care needs they faced during the pandemic surge. These experiences illustrated underlying social processes that are always at play as clinicians integrate information from various sources, including research and published guidelines, with their own tacit knowledge to develop shared yet personal approaches to practice. In this article, we provide a narrative account of personal experience during the COVID-19 surge. We draw on the concept of mindlines as developed by Gabbay and Le May as a conceptual framework for interpreting that experience from the standpoint of how early information from research and guidelines was drawn on and transformed in the course of day-to-day struggle with the crisis in New York City emergency rooms. Finally, briefly referencing the challenges to conventional models of healthcare knowledge creation and translation through research and guideline production posed by COVID-19 crisis, we offer a provisional perspective on current and future developments.

External Validation of the Recalibrated HEART Score for Evaluation of Possible Acute Coronary Syndrome.

A single high-sensitivity troponin-T (hs-TnT) measurement may be sufficient to risk-stratify emergency department (ED) patients with possible acute coronary syndrome (ACS) using the recalibrated History, Electrocardiogram, Age, Risk Factors, Troponin (rHEART) score. We sought to validate this approach in a multiethnic population of United States patients and investigate gender-specific differences in performance. We conducted a secondary analysis of a prospective cohort study of adult ED patients with possible ACS at a single, urban, academic hospital. We investigated the diagnostic performance of rHEART for the incidence of type-1 acute myocardial infarction (AMI) and other major adverse cardiac events (MACE) at 30 days, using both single (19 ng/L) and gender-specific (14 ng/L for women, 22 ng/L for men) 99th percentile hs-TnT thresholds. The 821 patients included were 54% women, 57% Hispanic, and 26% Black. Overall, 4.6% of patients had MACE, including 2.4% with AMI. Single-threshold rHEART ≤3 had a sensitivity of 94.4% (95% confidence interval 81% to 99%) and negative predictive values of 99.3% (98% to 100%) for MACE; gender-specific thresholds performed nearly identically. Sensitivity and negative predictive values for AMI were 90.0% (67% to 98%) and 99.3% (97% to 100%). Excluding patients presenting <3 hours from symptom onset improved sensitivity for MACE and AMI to 97.0% (84% to 100%) and 94.1% (71% to 100%). Logistic regression demonstrated odds of MACE increased with higher rHEART scores at a similar rate for men and women. In conclusion, a single initial hs-TnT and rHEART score can be used to risk-stratify male and female ED patients with possible ACS, especially when drawn >3 hours after symptom onset.

Bioconjugation by native chemical tagging of C-H bonds.

A general C-H functionalization method for the tagging of natural products and pharmaceuticals is described. An azide-containing sulfinate reagent allows the appendage of azidoalkyl chains onto heteroaromatics, the product of which can then be attached to a monoclonal antibody by a "click" reaction. This strategy expands the breadth of bioactive small molecules that can be linked to macromolecules in a manner that is beyond the scope of existing methods in bioconjugation to permit tagging of the "seemingly untaggable".

Flexible-Interval High-Sensitivity Troponin Velocity for the Detection of Acute Coronary Syndromes.

Many algorithms for emergency department (ED) evaluation of acute coronary syndrome (ACS) using high-sensitivity troponin assays rely on the detection of a "delta," the difference in concentration over a predetermined interval, but collecting specimens at specific times can be difficult in the ED. We evaluate the use of troponin "velocity," the rate of change of troponin concentration over a flexible short interval for the prediction of major adverse cardiac events (MACEs) at 30 days. We conducted a prospective, observational study on a convenience sample of 821 patients who underwent ACS evaluation at a high-volume, urban ED. We determined the diagnostic performance of a novel velocity-based algorithm and compared the performance of 1- and 2-hour algorithms adapted from the European Society of Cardiology (ESC) using delta versus velocity. A total of 7 of 332 patients (2.1%) classified as low risk by the velocity-based algorithm experienced a MACE by 30 days compared with 35 of 221 (13.8%) of patients classified as greater than low risk, yielding a sensitivity of 83.3% (95% confidence interval [CI] 68.6% to 93.0%) and negative predictive value (NPV) of 97.9% (95% CI 95.9% to 98.9%). The ESC-derived algorithms using delta or velocity had NPVs ranging from 98.4% (95% CI 96.4% to 99.3%) to 99.6% (95% CI 97.0% to 99.9%) for 30-day MACEs. The NPV of the novel velocity-based algorithm for MACE at 30 days was borderline, but the substitution of troponin velocity for delta in the framework of the ESC algorithms performed well. In conclusion, specimen collection within strict time intervals may not be necessary for rapid evaluation of ACS with high-sensitivity troponin.

Updating a Healthcare System-wide Clinical Pathway for Managing Chest Pain and Acute Coronary Syndromes.

Clinical pathways are useful tools for conveying and reinforcing best practices to standardize care and optimize patient outcomes across myriad conditions. The NewYork-Presbyterian Healthcare System has utilized a clinical chest pain pathway for more than 20 years to facilitate the timely recognition and management of patients presenting with chest pain syndromes and acute coronary syndromes. This chest pain pathway is regularly updated by an expanding group of key stakeholders, which has extended from the Columbia University Irving Medical Center to encompass the entire regional healthcare system, which includes 8 hospitals. In this 2023 update of the NewYork-Presbyterian clinical chest pain pathway, we present the key changes to the healthcare system-wide clinical chest pain pathway.

Association of prostate cancer risk with SNPs in regions containing androgen receptor binding sites captured by ChIP-On-chip analyses.

BACKGROUND: Genome-wide association studies (GWAS) have identified approximately three dozen single nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. Despite the reproducibility of these associations, the molecular mechanism for most of these SNPs has not been well elaborated as most lie within non-coding regions of the genome. Androgens play a key role in prostate carcinogenesis. Recently, using ChIP-on-chip technology, 22,447 androgen receptor (AR) binding sites have been mapped throughout the genome, greatly expanding the genomic regions potentially involved in androgen-mediated activity. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that sequence variants in AR binding sites are associated with PCa risk, we performed a systematic evaluation among two existing PCa GWAS cohorts; the Johns Hopkins Hospital and the Cancer Genetic Markers of Susceptibility (CGEMS) study population. We demonstrate that regions containing AR binding sites are significantly enriched for PCa risk-associated SNPs, that is, more than expected by chance alone. In addition, compared with the entire genome, these newly observed risk-associated SNPs in these regions are significantly more likely to overlap with established PCa risk-associated SNPs from previous GWAS. These results are consistent with our previous finding from a bioinformatics analysis that one-third of the 33 known PCa risk-associated SNPs discovered by GWAS are located in regions of the genome containing AR binding sites. CONCLUSIONS/SIGNIFICANCE: The results to date provide novel statistical evidence suggesting an androgen-mediated mechanism by which some PCa associated SNPs act to influence PCa risk. However, these results are hypothesis generating and ultimately warrant testing through in-depth molecular analyses.

Antiproliferative acetogenins from a Uvaria sp. from the Madagascar dry forest.

Investigation of the endemic Madagascan plant Uvaria sp. for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new acetogenins. The structures of these two compounds were elucidated on the basis of analysis of their 1D and 2D NMR spectra, circular dichroism, and mass spectrometric data, together with chemical modification. The two acetogenins display weak antiproliferative activity against the A2780 ovarian cancer, the A2058 melanoma, and the H522 lung cancer cell lines.

Impact of a rapid high-sensitivity troponin pathway on patient flow in an urban emergency department.

Study Objective: To evaluate whether the introduction of a 1-hour high-sensitivity cardiac troponin-T (hs-TnT) pathway for patients who present to the emergency department (ED) with suspected acute coronary syndrome (ACS) improves ED patient flow without changing the rate of "missed" major adverse cardiac events (MACE), compared to use of conventional cardiac troponin with an associated 3-hour pathway. Methods: This was a prospective, uncontrolled observational study conducted before and after implementation of a 1-hour hs-TnT pathway at a high-volume urban ED. Patients undergoing evaluation for ACS in the ED were enrolled during their initial visit and clinical outcomes were assessed at 30 and 90 days. Throughput markers were extracted from the electronic medical record and compared. The primary outcome was provider-to-disposition decision time. Results: A total of 1892 patients were enrolled, 1071 patients while using conventional troponin and 821 after introduction of hs-TnT. With the new assay and pathway, median interval between troponin tests decreased from 4.7 hours (interquartile range [IQR] 3.9-5.7 hours) to 2.3 hours (IQR 1.5-3.4 hours) (P < 0.001). However, there was no difference in median provider-to-disposition decision time, which measured 4.7 hours (IQR 2.9-7.2) and 4.8 hours (IQR 3.1-7.1) (P = 0.428) respectively. Total 30-day MACE rate in discharged patients was low in both groups, occurring in only 4/472 (0.85%) encounters in the first cohort and 4/381 (1.0%) encounters in the second. Conclusion: Introduction of a 1-hour hs-TnT ACS evaluation pathway reduced the troponin collection interval but did not reduce provider to disposition time. There was no difference in rate of 30-day MACE in patients discharged from the ED.

G-SQZ: compact encoding of genomic sequence and quality data.

SUMMARY: Large volumes of data generated by high-throughput sequencing instruments present non-trivial challenges in data storage, content access and transfer. We present G-SQZ, a Huffman coding-based sequencing-reads-specific representation scheme that compresses data without altering the relative order. G-SQZ has achieved from 65% to 81% compression on benchmark datasets, and it allows selective access without scanning and decoding from start. This article focuses on describing the underlying encoding scheme and its software implementation, and a more theoretical problem of optimal compression is out of scope. The immediate practical benefits include reduced infrastructure and informatics costs in managing and analyzing large sequencing data. AVAILABILITY: http://public.tgen.org/sqz. Academic/non-profit: SOURCE: available at no cost under a non-open-source license by requesting from the web-site; Binary: available for direct download at no cost. For-Profit: Submit request for for-profit license from the web-site.

Cardenolides of Leptadenia madagascariensis from the Madagascar dry forest.

Investigation of the endemic Madagascar plant Leptadenia madagascariensis Decne. (Apocynaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new cardenolides 1-4. The structure elucidations of these compounds were based on analyzes of their 1D and 2D NMR spectra and mass spectrometric data. The cardenolides were strongly antiproliferative to the A2780 ovarian cancer cell line, with IC(50) values of 0.18, 0.21, 0.17, and 0.29µM line, and to the H460 human lung cancer cell line, with IC(50) values of 0.16, 0.68, 0.37, and 0.48µM, respectively.

Isolation and synthesis of antiproliferative eupolauridine alkaloids of Ambavia gerrardii from the Madagascar Dry Forest.

Investigation of the Madagascan endemic plant Ambavia gerrardii for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the three new alkaloids 8-hydroxyeupolauridine (1), 9-methoxyeupolauridine 1-oxide (2), and 11-methoxysampangine (3) and the three known alkaloids 4-6. The structures of 1 and 2 were confirmed by synthesis. Compounds 3, 4, and 6 showed moderate to good antiproliferative activities, with IC50 values of 10.3, 3.5, and 0.60 µM, respectively, against the A2780 human ovarian cancer cell line and with IC50 values of 0.57, 1.77, and 0.58 µM, respectively, against the H460 human lung cancer cell line.

A motif-based analysis of glycan array data to determine the specificities of glycan-binding proteins.

Glycan arrays have enabled detailed studies of the specificities of glycan-binding proteins. A challenge in the interpretation of glycan array data is to determine the specific features of glycan structures that are critical for binding. To address this challenge, we have developed a systematic method to interpret glycan array data using a motif-based analysis. Each glycan on a glycan array is classified according to its component sub-structures, or motifs. We analyze the binding of a given lectin to each glycan in terms of the motifs in order to identify the motifs that are selectively present in the glycans that are bound by the lectin. We compared two different methods to calculate the identification, termed intensity segregation and motif segregation, for the analysis of three well-characterized lectins with highly divergent behaviors. Both methods accurately identified the primary specificities as well as the weaker, secondary specificities of all three lectins. The complex binding behavior of wheat germ agglutinin was reduced to its simplified, independent specificities. We compiled the motif specificities of a wide variety of plant lectins, human lectins, and glycan-binding antibodies to uncover the relationships among the glycan-binding proteins and to provide a means to search for lectins with particular binding specificities. This approach should be valuable for rapidly analyzing and using glycan array data, for better describing and understanding glycan-binding specificities, and as a means to systematize and compare data from glycan arrays.

Antiproliferative compounds from Pongamiopsis pervilleana from the Madagascar Dry Forest.

Bioassay-guided fractionation of an ethanol extract of the roots of the endemic Malagasy plant Pongamiopsis pervilleana led to the isolation of the three new compounds (2'R)-4'-hydroxyemoroidocarpan (1), pongavilleanine (3), and epipervilline (4) together with two known compounds, identified as emoroidocarpan (2) and rotenolone (5). The structures of all compounds were determined by physical, chemical, and spectroscopic evidence. The stereochemistry at C-2' of the previously reported compound emoroidocarpan was determined to be R by the observation of a negative Cotton effect at 474 nm in the CD spectrum of its osmate ester derivative. Compounds 2-5 displayed moderate antiproliferative activity against the A2780 human ovarian cancer cell line, and rotenolone also showed micromolar antiproliferative activity toward the breast cancer BT-549, prostate cancer DU 145, NSCLC NCI-H460, and colon cancer HCC-2998 cell lines.