Explainable machine learning for the prediction and assessment of complex drought impacts.

Drought is a common and costly natural disaster with broad social, economic, and environmental impacts. Machine learning (ML) has been widely applied in scientific research because of its outstanding performance on predictive tasks. However, for practical applications like disaster monitoring and assessment, the cost of the models failure, especially false negative predictions, might significantly affect society. Stakeholders are not satisfied with or do not "trust" the predictions from a so-called black box. The explainability of ML models becomes progressively crucial in studying drought and its impacts. In this work, we propose an explainable ML pipeline using the XGBoost model and SHAP model based on a comprehensive database of drought impacts in the U.S. The XGBoost models significantly outperformed the baseline models in predicting the occurrence of multi-dimensional drought impacts derived from the text-based Drought Impact Reporter, attaining an average F2 score of 0.883 at the national level and 0.942 at the state level. The interpretation of the models at the state scale indicates that the Standardized Precipitation Index (SPI) and Standardized Temperature Index (STI) contribute significantly to predicting multi-dimensional drought impacts. The time scalar, importance, and relationships of the SPI and STI vary depending on the types of drought impacts and locations. The patterns between the SPI variables and drought impacts indicated by the SHAP values reveal an expected relationship in which negative SPI values positively contribute to complex drought impacts. The explainability based on the SPI variables improves the trustworthiness of the XGBoost models. Overall, this study reveals promising results in accurately predicting complex drought impacts and rendering the relationships between the impacts and indicators more interpretable. This study also reveals the potential of utilizing explainable ML for the general social good to help stakeholders better understand the multi-dimensional drought impacts at the regional level and motivate appropriate responses.

Using Climate to Explain and Predict West Nile Virus Risk in Nebraska.

We used monthly precipitation and temperature data to give early warning of years with higher West Nile Virus (WNV) risk in Nebraska. We used generalized additive models with a negative binomial distribution and smoothing curves to identify combinations of extremes and timing that had the most influence, experimenting with all combinations of temperature and drought data, lagged by 12, 18, 24, 30, and 36 months. We fit models on data from 2002 through 2011, used Akaike's Information Criterion (AIC) to select the best-fitting model, and used 2012 as out-of-sample data for prediction, and repeated this process for each successive year, ending with fitting models on 2002-2017 data and using 2018 for out-of-sample prediction. We found that warm temperatures and a dry year preceded by a wet year were the strongest predictors of cases of WNV. Our models did significantly better than random chance and better than an annual persistence naïve model at predicting which counties would have cases. Exploring different scenarios, the model predicted that without drought, there would have been 26% fewer cases of WNV in Nebraska through 2018; without warm temperatures, 29% fewer; and with neither drought nor warmth, 45% fewer. This method for assessing the influence of different combinations of extremes at different time intervals is likely applicable to diseases other than West Nile, and to other annual outcome variables such as crop yield.

Financial Conflicts of Interest at FDA Drug Advisory Committee Meetings.

The U.S. Food and Drug Administration's drug advisory committees provide expert assessments of the safety and efficacy of new therapies considered for approval. A committee hears from a variety of speakers, from six groups, including voting members of the committee, FDA staff members, employees of the pharmaceutical company seeking approval of a therapy, patient and consumer representatives, expert speakers invited by the company, and public participants. The committees convene at the request of the FDA when the risks and harms of novel products are not immediately clear, and their final decisions carry significant weight, as most therapies that receive advisory committee approval are subsequently approved by the FDA. In recent years, across a series of diverse publications, the financial conflicts of interest of each category of participants in the meetings have been investigated. Here, we summarize these findings and their ethical implications, focusing on the FDA Oncologic Drugs Advisory Committee, and we suggest ways to move toward more transparent and impartial advisory committee meetings.

Most medical practices are not parachutes: a citation analysis of practices felt by biomedical authors to be analogous to parachutes.

BACKGROUND: In a 2003 paper in BMJ, the authors made the tongue-in-cheek observation that there are no randomized controlled trials (RCTs) of parachutes. This paper has been widely read, cited and used to argue that RCTs are impractical or unnecessary for some medical practices. We performed a study to identify and evaluate claims that a medical practice is akin to a parachute. METHODS: Using Google Scholar, we identified all citations to the 2003 paper. We searched for claims that a specific practice was akin to a parachute. For each practice, we identified the desired outcome of the practice, and searched Google Scholar and ClinicalTrials.gov for RCTs that were conducted, ongoing, halted, planned or unpublished. RESULTS: Of 822 articles citing the original paper, 35 (4.1%) argued that a medical practice was akin to a parachute. Eighteen of the 35 (51%) concerned mortality or live birth, and 17 (49%) concerned a lesser outcome. For 22 practices (63%), we identified 1 or more RCTs: in 6 cases (27%), the trials showed a statistically significant benefit of the practice; in 5 (23%), the trials rejected the practice; in 5 (23%), the trials had mixed results; in 2 (9%), the trials were halted; and in 4 (18%), the trials were ongoing. Effect size was calculated for 5 of the 6 practices for which RCTs gave positive results, and the absolute risk reduction ranged from 11% to 30.8%, corresponding to a number needed to treat of 3-9. INTERPRETATION: Although there is widespread interest regarding the BMJ paper arguing that randomized trials are not necessary for practices of clear benefit, there are few analogies in medicine. Most parachute analogies in medicine are inappropriate, incorrect or misused.

Comparison of efficacy, pharmacokinetics, and immunogenicity between infliximab mono- versus combination therapy in ulcerative colitis.

BACKGROUND: The association of concomitant immunosuppressant use with infliximab (IFX) and therapeutic outcomes in correlation with pharmacokinetic properties in ulcerative colitis (UC) remains unclear. AIMS: To assess the effect of concomitant immunosuppressant use on the duration of IFX therapy, and the pharmacokinetic properties of IFX in patients with UC. METHODS: A retrospective analysis of UC patients treated with IFX. Duration of efficacious IFX therapy, and serum IFX and antibody-to-IFX (ATI) levels were compared between those receiving IFX as monotherapy and in combination with an immunosuppressant. RESULTS: Among the 85 UC patients who received IFX, 46 (54.1%) received concomitant immunosuppressants, and 38 (45.9%) received IFX monotherapy. Concomitant immunosuppressant use was associated with increased duration of IFX therapy as 90% of patients receiving immunosuppressants remained on therapy at 1 year versus 61% of patients on monotherapy (Log-rank, P = 0.016). Concomitant immunosuppressant use, as compared with monotherapy, was associated with greater IFX levels (20.4 mg/L vs 10.5 mg/L, P = 0.025) and less frequent ATI formation (4.5% vs 33.3%, P = 0.031). Patients receiving greater than 2.0 mg/kg of azathioprine had greater IFX lev l than those receiving less than 2.0 mg/kg (26.0 vs 10.6 mcg/mL, P = 0.03) and those receiving IFX monotherapy (26.0 vs 11.2 mcg/mL, P = 0.03). The duration of IFX therapy among patients receiving less than 2.0 mg/kg azathioprine was indistinguishable from patients on IFX monotherapy (Log-rank, P = 0.95). CONCLUSION: Concomitant immunosuppressant therapy with IFX improves outcomes in UC as shown by increased duration of therapy, decreased immunogenicity against IFX, and increased blood levels of IFX. Our data suggest that this benefit may be dependent on the dose of concomitant immunosuppression.

Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.

Capillary electrophoretic development of aptamers for a glycosylated VEGF peptide fragment.

The emergence of functional genomics and proteomics has added to the growing need for improved analysis methods that can detect and distinguish between protein variants resulting from allelic variation, mutation, or post-translational modification. Aptamers, single-stranded DNA or RNA molecules that fold into three-dimensional structures conducive to binding targets, have become an attractive alternative to antibodies for this type of analysis. Although aptamers have been developed for a wide range of target species, very few sequences have been identified that bind selectively to proteins with specific post-translational modifications. Using capillary electrophoresis-based selection, we have developed DNA aptamer sequences that selectively bind an N-glycosylated peptide fragment of vascular endothelial growth factor (VEGF). The selection method incorporates alternating positive- and counter-selection steps in free solution in order to obtain aptamers with both high affinity toward the glycosylated target and high selectivity versus a non-glycosylated variant. Affinity capillary electrophoresis and surface plasmon resonance binding assays indicate these sequences have low-µM dissociation constants and preferentially bind the glycosylated peptide with as much as 50-fold specificity. Such aptamers could serve as tools for rapid and simple monitoring of disease-linked functional changes in proteins, with potential applications in drug screening and disease diagnosis.

Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast.

PURPOSE: Metaplastic carcinomas are distinct invasive breast carcinomas with aberrant nonglandular differentiation, which may be spindle, squamous, or chondroid. The limited effective treatments result from the lack of knowledge of its molecular etiology. Given the role of the Wnt pathway in cell fate and in the development of breast cancer, we hypothesized that defects in this pathway may contribute to the development of metaplastic carcinomas. DESIGN: In 36 primary metaplastic carcinomas, we comprehensively determined the prevalence of and mechanism underlying beta-catenin and Wnt pathway deregulation using immunohistochemistry for beta-catenin expression and localization and mutational analysis for CTNNB1 (encoding beta-catenin), APC, WISP3, AXIN1, and AXIN2 genes. By immunohistochemistry, normal beta-catenin was seen as membrane staining, and it was aberrant when >5% of tumor cells had nuclear or cytoplasmic accumulation or reduced membrane staining. RESULTS: By immunohistochemistry, aberrant beta-catenin was present in 33 of 36 (92%) cases, revealing deregulation of the Wnt pathway. CTNNB1 missense mutations were detected in 7 of 27 (25.9%) tumors available for mutation analyses. All mutations affected the NH(2)-terminal domain of beta-catenin, presumably rendering the mutant protein resistant to degradation. Two of 27 (7.4%) tumors had mutations of APC, and 5 (18.5%) carried a frame shift mutation of WISP3. No AXIN1 or AXIN2 mutations were found. CONCLUSIONS: Activation of the Wnt signaling pathway is common in this specific subtype of breast carcinoma. The discovery of CTNNB1, APC, and WISP3 mutations may result in new treatments for patients with metaplastic carcinomas of the breast.

Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.

PURPOSE: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). PATIENTS AND METHODS: Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. RESULTS: In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (+/- SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. CONCLUSION: Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

First-receiver hospital decontamination: an 8-step approach to a progressive and practical program.

The effectiveness of hospital decontamination programs begins with planning, preparation, and practice. A well-thought-out hospital decontamination program encompasses complexities that are not always apparent. In disaster situations, the victim, hospital, patients, and staff are placed at serious risk if untrained, unprepared employees perform emergency decontamination procedures at the hospital-receiving site. The authors describe 8 steps to developing an emergency preparedness program and team with decontamination capabilities to facilitate emergency response in the first-receiver hospital.

Low IgE monoclonal gammopathy level in serum highlights 20-yr survival in a case of IgE multiple myeloma.

This report describes the diagnosis, follow-up, and problems measuring serum immunoglobulin E (IgE) levels in a case of IgE myeloma with 20-yr survival. Serum and urine protein electrophoresis, immunofixation, and the N Latex IgE test were used to characterize the monoclonal proteins. The diagnosis of multiple myeloma in a 56-yr-old man was based on 5.4 g/24 h of monoclonal free lambda chain in urine and bone marrow findings of 23.5% plasma cells (19% mature and 4.5% atypical). IgE lambda monoclonal protein in serum measured 506,000 microg/L (210 833 IU/mL). The lack of other clinical findings of multiple myeloma places this case in the category of 'smoldering or indolent myeloma'. Measurement of serum IgE levels was complicated by the need to predilute serum to avoid antigen excess. Following chemotherapy, the patient went into clinical remission, eventually dying of complications of emphysema. This case expands the recognized clinical spectrum of IgE multiple myeloma.

Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion.

The purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400-mg oral dose of imatinib in capsule form or as a solution or a 100-mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by C(max), partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400-mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).

Regioselective oxidations of benzocarbaporphyrins with ferric chloride: a facile synthesis of bridged [18]annulene ketals with strong absorptions in the far red and an unexpected halogenation reaction at the interior carbon atom.

Benzocarbaporphyrins 4 were found to undergo regioselective oxidations with ferric chloride in methanol, ethanol, isopropyl alcohol, or ethylene glycol to give bridged benzo[18]annulene ketal derivatives 5 in excellent yields. These polar derivatives were generally isolated in a monoprotonated form and the corresponding free bases appeared to be relatively unstable. Addition of TFA resulted in the formation of spectroscopically distinct dications. The ketals 5 were highly diatropic in nature, showing the internal alkoxy substituents upfield beyond -1 ppm in their proton NMR spectra. The external meso-protons resonated near 10 ppm, confirming the presence of a strong aromatic ring current. The UV-vis spectra for 5 showed a Soret band at 422 nm, and two strong absorptions in the far red at 751 and 832 nm. A carbaporphyrin with a fused acenaphthylene ring was also oxidized with ferric chloride and this produced a ketal derivative with still further bathochromically shifted absorptions particularly for the Soret band. Also, the use of different alcohols in these reactions allows the overall polarity of these ketal products to be controlled and this could have merit in biomedical applications. Reaction of carbaporphyrin 4a with aqueous ferric chloride afforded the corresponding 21-chloro derivative 20 in good yields, and at longer reaction times a nonaromatic dione was isolated. Aqueous ferric bromide gave a 21-bromocarbaporphyrin product but in this case very poor yields (<10%) were noted. Mechanisms are proposed to explain the formation of these unusual oxidation products. The structure of 21-chlorocarbaporphyrin 20 was further demonstrated by X-ray crystallography. The presence of the interior chlorine atom was found to tilt the indene moiety by 29.59(4) degrees relative to the [18]annulene macrocyclic ring. The crystal packing for 20 shows offset face-to-face pi-stacking interactions that link the porphyrinoid molecules as closely paired dimers.

Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.

Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250 x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.

Liquid chromatographic-mass spectrometric assay for quantitation of imatinib and its main metabolite (CGP 74588) in plasma.

Imatinib mesylate (Gleevec, Glivec, STI571) is a targeted, small molecule inhibitor of the oncogenes, BCR/ABL and c-KIT, and has striking antitumor activity in patients with chronic myelogenous leukemia or gastrointestinal stromal tumors. We have developed a liquid chromatographic-electrospray ionization mass spectrometric (LC-MS) method for quantifying imatinib and its main metabolite (CGP 74588) in plasma. The assay uses deuterated imatinib as the internal standard; acetonitrile deproteination; a Phenomenex Luna C(18)(2) (5 microm, 50 x 4.6 mm) reversed-phase analytical column; a gradient mobile phase of 0.1% formic acid in methanol and water; and mass spectrometric detection using electrospray positive mode electron ionization. The assay has a lower limit of quantitation (LLOQ) of 30 ng/ml and is linear between 30 and 10000 ng/ml for both imatinib and CGP 74588. We demonstrated the suitability of this assay for imatinib using it to quantify the concentrations of imatinib and CGP 74588 in plasma of a patient given a 200-mg dose of imatinib orally. We believe that this LC-MS assay should be an important tool for future pharmacokinetic studies of imatinib.

Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.

Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P(2) surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P(1) and P(3) moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC(50) against TF/VIIa with >6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.

Conjugated macrocycles related to the porphyrins. 21. Synthesis, spectroscopy, electrochemistry, and structural characterization of carbaporphyrins.

The "3 + 1" variant of the MacDonald condensation has been shown to be an excellent methodology for synthesizing carbaporphyrins. In particular, 1,3-indenedicarbaldehyde condenses with tripyrranes in the presence of TFA to give, following oxidation with DDQ, a series of benzocarbaporphyrins in excellent yields. Triformylcyclopentadienes also afford carbaporphyrin products, albeit in low yields ranging from 5 to 8%. These hybrid bridged annulene structures have porphyrin-like electronic absorption spectra with strong Soret bands near 420 nm and a series of Q-bands through the visible region. The proton NMR spectrum confirms the presence of a strong diamagnetic ring current, and the meso-protons show up at 10 ppm, while the internal CH is shielded to approximately -7 ppm. Carbaporphyrins undergo reversible protonation with TFA. Initial addition of acid affords a monocation, although mixtures of protonated species are observed in the presence of moderate concentrations of TFA. However, in the presence of 50% TFA a C-protonated dication is generated. The dications relocate the pi-delocalization pathway through the benzo moiety of benzocarbaporphyrins, and these therefore represent bridged benzo[18]annulenes, although they nevertheless retain powerful macrocyclic ring currents. Carbaporphyrins with fused acenaphthylene and phenanthrene rings have been prepared, and the former demonstrated significantly larger bathochromic shifts in UV-vis spectroscopy that parallel previous observations for acenaphthoporphyrins. A diphenyl-substituted benzocarbaporphyrin 19b was also characterized by X-ray crystallography, and these data show that the macrocycle is reasonably planar although the indene subunit is tilted out of the mean macrocyclic plane by 15.5 degrees. The structural data indicates that the preferred tautomer in the solid state has the two NH's flanking the pyrrolene unit in agreement with previous spectroscopic and theoretical studies. Cyclic voltammetry for carbaporphyrin 19a was more complex than for true porphyrins, showing five anodic waves and two quasi-reversible reductive couples.