Canine Atopic Dermatitis: Prevalence, Impact, and Management Strategies.

Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.

Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation.

BACKGROUND: Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. METHODS: NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. RESULTS: The study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76-0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74-0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99-0.99). CONCLUSION: Clinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.

Paul Clairmont and his connections to American surgery.

PURPOSE: To examine the life and influences of Paul Clairmont (1875-1942). METHOD: Review and analysis of published and archival information. RESULTS: The Clairmont family was associated with famous individuals in English literary history. Paul Clairmont himself was born, educated, and trained as a surgeon under Anton von Eiselsberg in Vienna. As a junior faculty member in 1908, he was the first general surgeon to publish a report for German readers on the remarkable progress of American surgery. Later, as Professor of Surgery in Zürich, he was a mentor to Alton Ochsner, who became a leader in the further development of surgery in the USA. CONCLUSION: Paul Clairmont's interesting life was an important link between the classical science and practice of surgery in Europe and its continuation in America.

Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.

The International Abstract of Surgery and the migration of scientific leadership from Europe to America.

PURPOSE: The International Abstract(s) of Surgery (IAS) was a monthly supplement to Surgery, Gynecology & Obstetrics (SG&O, later Journal of the American College of Surgeons) from 1913-1994, approximately equal in size to the journal itself. It followed the example of the Zentralblatt für Chirurgie (ZblCh), which had been compiling abstracts of the current world surgical literature since 1874 (but in the German language). This article seeks to review the relationships of these surgical abstract journals in historical context. METHODS: Citations in the IAS were systematically sampled for 1913-1990, and in the ZblCh and other American and German surgical publications for 1905-1940. Changes in the proportions of citations by language category were tabulated over time and related to concurrent international events and the publication histories of the sampled journals. RESULTS: German-language citations were most frequent until the First World War, even in America. They subsequently became less frequent in America, but remained dominant in Germany. Articles in French or other languages were occasionally cited by Americans, but in German publications, they were cited as frequently as those in English. Contemporary observations from this time confirm that the American literature was being disregarded by most German surgeons. Since the Second World War, surgical publications have become predominantly English-language, even in Germany, and printed abstract compilations have become irrelevant. CONCLUSIONS: The history of the IAS and ZblCh reflects world events of the early twentieth century, the isolation and decline of German scientific leadership, the rise of American surgery, and the transition from a multilingual print-based era to one where scientific communication is primarily electronic and in English.

Upfront resection versus neoadjuvant therapy for T1/T2 pancreatic cancer.

BACKGROUND: The role of neoadjuvant therapy remains controversial for resectable pancreatic neoplasms. We evaluated treatment outcomes for T1/T2 tumors. METHODS: Retrospective study of patients with T1/T2 (Stage I-II) pancreatic cancer within the NCDB. Treatment-sequence variables were used for classification: "surgery + chemotherapy" (S+C), "chemotherapy + surgery" (C+S), "surgery only" (SO), and "chemotherapy only" (CO). RESULTS: 13 412 patients were included; the majority had T2 tumors. 8 490 received upfront surgery; 4 922 preoperative chemotherapy. In the surgery branch, 5 684 received surgery and chemotherapy (S+C); 2 806 did not receive chemotherapy (SO). Of those intended to receive preoperative chemotherapy, 3 804 received only chemotherapy (CO); 1 118 proceeded to surgery (C+S). Median survival for S+C and C+S groups was similar (25.9 vs 26.2) [HR 0.92, p= 0.41]. Compared to the CO group, the SO group had improved median survival (13.5 vs. 10.8) [HR 0.63, p<0.001]. Branched analyses demonstrated improved median and 5-year (20.8% vs 12.7%) survival for patients receiving upfront resection [HR 0.77, p<0.001]. CONCLUSION: Patients with T1/T2 pancreatic cancer have similar survival irrespective of the timing of chemotherapy and surgery, if they receive both. Upfront resection ensures surgery is delivered, increasing the possibility of long-term survival.

Virtual Screening: Is Bigger Always Better? Or Can Small Be Beautiful?

This viewpoint is intended to counterbalance some recent publications describing large-scale virtual screening by illustrating how success in launching drug discovery projects has been achieved with much more modest resources. Two examples of small-scale virtual screening that led to the discovery of clinical candidates are cited in favor of this argument.

Moose-Motor Vehicle Collision: A Continuing Hazard in Northern New England.

BACKGROUND: Moose-motor vehicle collisions (MMVC) are especially dangerous to vehicle occupants because of the height and mass of the animal, which often collapses the roof and has a direct impact into the passenger compartment. STUDY DESIGN: Public data on MMVC were obtained from the states of New England (NE), and trauma registry data from centers in NH and ME. RESULTS: For all of NE, the annual incidence of reported MMVC has declined from a peak of >1,200 in 1998, but has still averaged >500 over the last 5 years, predominantly in ME, NH, and VT. Public education may have contributed to the decline, but the moose population has also apparently decreased due to environmental changes. In NE, MMVCs are most frequent in the summer months and evening hours. Maine data on crashes involving wild ungulates from 2003 to 2017 document 50,281 collisions with deer and 7,061 collisions with moose; 26 of the latter (0.37%) resulted in a human fatality. Logistic regression models demonstrate that vehicle occupant mortality, after controlling for multiple factors related to vehicle speed, is greatly increased when striking a moose rather than a deer (odds ratio [OR] 13.4, 95% CI 6.3, 28.7). In these data, there were no fatalities among occupants of Swedish cars, which are specifically engineered to tolerate MMVC. Three NH/ME trauma centers registered 124 cases of MMVC: median Injury Severity Score was 9; 5 patients died (4%); and 76 patients (61%) had injuries of the head, face, and/or cervical spine. CONCLUSIONS: Moose-motor vehicle collisions remain a frequent and serious hazard to motor vehicle occupants in northern NE. Trauma services should recognize characteristic injury patterns. Continuing public education, cautious driving, and moose herd management are warranted.

Automated De Novo Drug Design: Are We Nearly There Yet?

Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

Racial disparities exist among burn patients despite insurance coverage.

BACKGROUND: Age, total burn surface area (TBSA), and inhalation injury are proven predictors of mortality and morbidity following burn injury. Most previous studies have also found that African Americans and females with burns also fare worse. We sought to determine whether these disparities were reduced when burn victims were analyzed separately by categories of insurance coverage. METHODS: We evaluated records in the National Burn Registry (NBR) from 2002 to 2011. Multivariate logistic regression was performed to determine factors associated with inpatient mortality, including age, TBSA, inhalation injury, race, and sex, and allowing for clustering by hospital. Separate models were constructed for each category of insurance. 95% confidence intervals (CI) not including 1 for any odds ratio were considered evidence of statistical significance (designated by * in the table below). RESULTS: NBR included records from 172,640 patients (55.8% Caucasian, 18.1% African American, 14.2% Hispanic, 6.4% other minority groups, 5.4% unknown). Age, TBSA, and inhalation were strong predictors of mortality as expected. Non-African American males were the largest group for all insurance categories, and had the lowest mortality. Controlling for these factors, and compared with non-African American males, African American males had consistently increased odds of mortality regardless of insurance coverage. African American females had increased odds of mortality if they had Private, Medicare, or Medicaid insurance, and Non-African American females had increased odds of mortality if they had Private or Medicaid insurance. The association of Hispanic ethnicity with mortality was inconsistent or insignificant, and other minority groups had too few members to evaluate. Most patients were missing comorbidity data, and no other socioeconomic or hospital data were available in NBR. CONCLUSIONS: African American males with burn injury are at increased risk of mortality regardless of insurance coverage, and most females are at increased risk regardless of race. Analyzing the reasons for these disparities will require databases containing more complete comorbidity, socioeconomic, and/or hospital data.

Open-access programs for injury categorization using ICD-9 or ICD-10.

BACKGROUND: The article introduces Programs for Injury Categorization, using the International Classification of Diseases (ICD) and R statistical software (ICDPIC-R). Starting with ICD-8, methods have been described to map injury diagnosis codes to severity scores, especially the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). ICDPIC was originally developed for this purpose using Stata, and ICDPIC-R is an open-access update that accepts both ICD-9 and ICD-10 codes. METHODS: Data were obtained from the National Trauma Data Bank (NTDB), Admission Year 2015. ICDPIC-R derives CDC injury mechanism categories and an approximate ISS ("RISS") from either ICD-9 or ICD-10 codes. For ICD-9-coded cases, RISS is derived similar to the Stata package (with some improvements reflecting user feedback). For ICD-10-coded cases, RISS may be calculated in several ways: The "GEM" methods convert ICD-10 to ICD-9 (using General Equivalence Mapping tables from CMS) and then calculate ISS with options similar to the Stata package; a "ROCmax" method calculates RISS directly from ICD-10 codes, based on diagnosis-specific mortality in the NTDB, maximizing the C-statistic for predicting NTDB mortality while attempting to minimize the difference between RISS and ISS submitted by NTDB registrars (ISSAIS). Findings were validated using data from the National Inpatient Survey (NIS, 2015). RESULTS: NTDB contained 917,865 cases, of which 86,878 had valid ICD-10 injury codes. For a random 100,000 ICD-9-coded cases in NTDB, RISS using the GEM methods was nearly identical to ISS calculated by the Stata version, which has been previously validated. For ICD-10-coded cases in NTDB, categorized ISS using any version of RISS was similar to ISSAIS; for both NTDB and NIS cases, increasing ISS was associated with increasing mortality. Prediction of NTDB mortality was associated with C-statistics of 0.81 for ISSAIS, 0.75 for RISS using the GEM methods, and 0.85 for RISS using the ROCmax method; prediction of NIS mortality was associated with C-statistics of 0.75-0.76 for RISS using the GEM methods, and 0.78 for RISS using the ROCmax method. Instructions are provided for accessing ICDPIC-R at no cost. CONCLUSIONS: The ideal methods of injury categorization and injury severity scoring involve trained personnel with access to injured persons or their medical records. ICDPIC-R may be a useful substitute when this ideal cannot be obtained.

Procedure-based postoperative risk prediction using NSQIP data.

BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) has proposed using procedure-based hierarchical models to predict adverse outcomes, but it is not clear whether this approach was used to develop the NSQIP "Surgical Risk Calculator". We therefore wished to demonstrate how procedure-based hierarchical models can be constructed and to describe their results. METHODS: NSQIP data from 2015 were used to construct statistical models predicting 30-day postoperative mortality and morbidity, using two-level logistic regression with preoperative patient-level variables as fixed effects and procedure-specific codes as a random intercept. Model performance was validated using NSQIP data from 2014. RESULTS: NSQIP for 2015 contained records for 885,502 patients, of whom 8986 died (1.0%) and 104,836 suffered a complication (11.8%). Complete model specifications and results are presented, including odds ratios for patient-level variable effects and random procedure effects. Most comorbidities were associated with increased morbidity and mortality, but overweight and obesity were associated with lower risk. Odds ratios for individual procedures ranged from 0.117 to 10.85 for mortality and from 0.615 to 8.09 for morbidity. Validation C-statistics were 0.940 for the mortality model and 0.833 for the morbidity model; Brier Scores were 0.0086 and 0.085, respectively. Graphs for 20 quantiles showed good conformity of observed and predicted risk. CONCLUSIONS: Procedure-based hierarchical logistic regression models of NSQIP outcomes had satisfactory overall performance statistics. Model specifications and results are provided for criticism and improvement, and several possible refinements are suggested.

Discovery of LRRK2 inhibitors by using an ensemble of virtual screening methods.

In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain. From the virtual screening, 662 compounds were purchased, of which 35 showed IC50 values below 10µM in wild-type and/or mutant LRRK2 (a hit rate of 5.3%). Of these 35 hits, four were deemed to have potential for medicinal chemistry follow-up.

R A Cowley, the "Golden Hour," the "Momentary Pause," and the "Third Space".

R Adams Cowley (1917-1991), the Baltimore thoracic and trauma surgeon, was an outstanding politician and promoter of emergency medical services. His skills included the effective use of language, for example, identifying the critical time immediately after injury as a "golden hour," and describing shock as a "momentary pause in the act of death." Conversely, Cowley avoided the tendency of some contemporaries to justify massive crystalloid infusion by invoking a "third space." Cowley is often assumed to have originated the first two phrases, but, in fact, their histories go back at least to the 19th century and illustrate the development of surgical science. The "third space" is often assumed to have originated with Cowley's contemporary, Tom Shires (1925-2007), but, in fact, neither of them used the phrase to describe Shires' controversial theories about an extracellular fluid deficit after trauma. Reviewing the actual etymology of these terms may help clarify the history of the underlying scientific ideas and enable more effective communication in the future.

Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.

NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.

Colorectal carcinoma in pediatric patients: A comparison with adult tumors, treatment and outcomes from the National Cancer Database.

BACKGROUND: Pediatric colorectal cancer (CRC) is rare. Comparison with adult CRC tumors, management, and outcomes may identify opportunities for improvement in pediatric CRC care. STUDY DESIGN: CRC patients in the National Cancer Data Base from 1998 to 2011, were grouped into Pediatric (≤21years), early onset adult (22-50) and older adult (>50) patients. Groups were compared with χ(2) and survival analysis. RESULTS: A total of 918 pediatric (Ped), 157,779 early onset adult (EA), and 1,304,085 older adults (OA) were identified (p<0.01 for all comparisons). Patients ≤50 presented more frequently with stage 3 and 4 disease (Ped: 62.0%, EA: 49.7%, OA: 37.3%) and rectal cancer (Ped: 23.6%, EA: 27.5%, OA: 19.2%). Pediatric histology was more likely signet ring, mucinous, and poorly differentiated. Initial treatment was usually surgery, but patients ≤50 were more likely to have radiation (Ped: 15.1%, EA: 18.6%, and OA: 9.2%) and chemotherapy (Ped: 42.0%, EA: 38.2%, and OA: 22.7%). Children and older adults showed poorer overall survival at 5years when compared to early onset adults. Adjusting for covariates, age ≤21 was a significant predictor of mortality for colon and rectal cancers (colon HR: 1.22, rectal HR: 1.69). CONCLUSIONS: This is the largest cohort of pediatric CRC patients, revealing more aggressive tumor histology and behavior in children, particularly in rectal cancer. Despite standard oncologic treatment, age ≤21 was a significant predictor of mortality. This is likely owing to worse tumor biology rather than treatment disparities and may signal the need for different therapeutic strategies.

A Multistate Model Predicting Mortality, Length of Stay, and Readmission for Surgical Patients.

OBJECTIVE: Simultaneously evaluate postoperative mortality, length of stay (LOS), and readmission. DATA SOURCE: National Surgical Quality Improvement Program (NSQIP). DESIGN: Retrospective cohort. METHODS: Data from elective general surgical patients were obtained from the 2012 NSQIP Participant Use File. For each postoperative day, each patient's state was classified as index hospitalization, discharged home, discharged to long-term care (LTC), readmitted, or dead. Transition rates were estimated using exponential regression, assuming constant rates for specified time periods. These estimates were combined into a multistate model, simulated results of which were compared to observed outcomes. FINDINGS: Age, comorbidities, more complex procedures, and longer index LOS were associated with lower rates of discharge home and higher rates of death, discharge to LTC, and readmission. The longer patients had been discharged, the less likely they were to die or be readmitted. The model predicted 30-day mortality 0.38 percent (95 percent CI: 0.36-0.41), index LOS 2.85 days (95 percent CI: 2.83-2.86), LTC discharge 2.76 percent (95 percent CI: 2.69-2.82), and readmissions 5.53 percent (95 percent CI: 5.43-5.62); observed values were 0.39 percent, 2.82 days, 2.87 percent, and 5.70 percent, respectively. CONCLUSIONS: Multistate models can simultaneously predict postoperative mortality, LOS, discharge destination, and readmissions, which allows multidimensional comparison of surgical outcomes.