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Vaccine hesitancy is an ongoing public health concern defined as the refusal of a vaccine that is readily available. Therefore, we developed a project to explore why patients in a safety net medical center were hesitant or refused the COVID-19 vaccine. The project was conducted by healthcare learners to promote “learning by doing”. Responses were collected through a previously developed and ongoing survey among both hospitalized and ambulatory patients that had no previous history of COVID-19 infection, were currently infected, or had recovered from COVID-19. Results were analyzed using a priori power analysis and Chi-squared test. We discovered that different self-reported ethnic groups had different reasons for vaccine hesitancy; specifically, 69% of Black/African American respondents stated that their main reason for hesitancy was vaccine safety compared to 13.9% of non-Hispanic Whites (p = 0.005). Furthermore, our cohort was significantly more likely to disagree rather than agree with the statement: “getting vaccinated is important for the health of others in my community”(p = 0.016). The learners discovered that a more specific approach to vaccine education would be required to understand and overcome vaccine hesitancy in our cohort of socioeconomic and ethnically diverse groups.

The impact of interhospital transfer on outcomes of patients undergoing emergency general surgery (EGS) procedures is incompletely studied. We set out to determine if transfer before definitive surgical care leads to worse outcomes in EGS patients.Using the National Surgical Quality Improvement Project database (2013-2019), a retrospective cohort study was conducted including nine surgical procedures encompassing 80% of the burden of EGS diseases, performed on an urgent/emergent basis. The procedures were classified as low risk (open and laparoscopic appendectomy and laparoscopic cholecystectomy) and high risk (open cholecystectomy, laparoscopic and open colectomy, lysis of adhesions, perforated ulcer repair, small bowel resection, and exploratory laparotomy). Time to surgery was recorded in days. The impact of interhospital transfer on outcomes (mortality, major complications, 30-day reoperations, and 30-day readmissions) and length of stay, according to procedure risk and time to surgery, were analyzed by multivariate logistic regression and inverse probability treatment of the weighting with treatment effect in the treated.A total of 329,613 patients were included in the study (284,783 direct admission and 44,830 transfers). Adjusted mortality (3.1% vs. 10.4%; adjusted odds ratio [AOR], 1.28; p0.001), major complications (6.7% vs. 18.9%; AOR, 1.39; p0.001), 30-day reoperations (3.1% vs. 6.4%; AOR, 1.22; p0.001), and length of stay (2 vs. 5) were higher in transferred patients. Transfer had no effect on 30-day readmissions (6% vs. 8.5%; AOR, 1.04; p = 0.063). These results were also observed in high-risk surgery patients and in the late surgery group. The results were further confirmed after robust propensity score weighting was performed.We have demonstrated that delays to surgical intervention affect outcomes and that interhospital transfer of EGS patients for definitive surgical care has a negative impact on mortality, development of postoperative complications, and reoperations in patients undergoing high-risk EGS procedures. These findings may have important implications for regionalization of EGS care.Prognostic/epidemiological, level III.

Modifiable risk factors associated with procedure-related 30-day readmission after emergency general surgery (EGS) have not been comprehensively studied. We set out to determine risk factors associated with EGS procedure-related 30-d unplanned readmissions.A retrospective cohort study was conducted using the NSQIP database (2013-2019). It included 9 surgical procedures encompassing 80% of the burden of EGS diseases, performed on an urgent/emergent basis. The procedures were classified as low risk (open and laparoscopic appendectomy and laparoscopic cholecystectomy) and high risk (open cholecystectomy, laparoscopic and open colectomy, lysis of adhesions, perforated ulcer repair, small bowel resection, and exploratory laparotomy). Data on patient characteristics, admission status, procedure risk, hospital length of stay (HLOS), and discharge disposition were analyzed by multivariate logistic regression.A total of 312,862 patients were included [16,306 procedure-related 30-d readmissions (5.2%)]. 30-day readmission patients were older, had higher ASA scores, were more often underweighted or markedly obese, and more frequently presented with sepsis. Risk factors associated with EGS procedure-related 30-d unplanned readmissions included Age40 years (AOR = 1.15), ASA ≥ 3 (AOR = 1.41), sepsis present at the time of surgery (AOR = 1.84), BMI18 (AOR = 1.16), BMI ≥ 40 (AOR = 1.12), high-risk procedures (AOR = 1.51), LOS ≥ 4 d (AOR = 2.04), and discharge except to home (AOR = 1.33). 30-day readmissions following low-risk procedures occurred at a median of 5 days (IQR: 2-11), and 6 days (IQR:3-11) after high-risk procedures. Surgical site infections, postop sepsis, wound disruption, and thromboembolic events were more prevalent in the 30-d readmission group. Mortality rate was 4-fold higher in the 30-d readmission group (2.4% vs. 0.6%).We identified several unmodifiable patients and EGS disease-related factors associated with 30-day unplanned readmissions. Readmissions could be potentially reduced by the implementation of a post-discharge surveillance systems between hospitals and post-discharge destination facilities, leveraging telehealth and outpatient care.III, Prognostic and Epidemiological.

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase...

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1–5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc., link_to_OA_fulltext

A form of planetary perturbation theory based on canonical equations of motion, rather than on the use of osculating orbital elements, is developed and applied to several problems of interest. It is proved that, with appropriately selected initial conditions on the orbital elements, the two forms of perturbation theory give rise to identical predictions for the observable coordinates and velocities, while the orbital elements themselves may be strikingly different. Differences between the canonical form of perturbation theory and the classical Lagrange planetary perturbation equations are discussed. The canonical form of perturbation theory in some cases has advantages when the perturbing forces are velocity-dependent, but the two forms of perturbation theory are equivalent if the perturbing forces are dependent only on position and not on velocity. The canonical form of the planetary perturbation equations are derived and applied to the Lense Thirring precession of a test body in a Keplerian orbit around a rotating mass source.

The study presented below is about which variables influence the percentage of female candidates in Canadian political parties. The study is divided into two main parts: the first part being a comparison of the two main parties in Canada over 24 years in terms of the numbers of selected and elected female candidates. The second part deals with 8 variables and the amount of influence each has on the level of female candidates in Canadian political parties. The data used in my study is taken from the 2006 Canadian census on the Statistics Canada website, and election records from the official site of the Parliament of Canada. The analysis of the data was done in conjunction with analysis program called SPSS to produce cross tabulations of the 8 independent variables with the dependent variable. In the opening chapter the reader will find a discussion of the rationale for the topic and the history of women's political representation in Canada. Chapters two, three, and four describe how the methodology of my study works, the related research, and the theoretical framework. The fifth chapter contains a literature review of political parties from different nations and the state of women's representation in those nations. In the sixth chapter, the study of the elections from 1984 to 2008 to determine which party has selected and elected more female candidates is presented. The seventh chapter deals with the analysis of the data from the election study and the conclusions produced from the data. In chapter eight, the results from the electoral district survey are displayed for the reader. In chapter nine, the analysis of the results from the data from the electoral district survey is presented there. Finally, the last chapter deals with closing comments on the findings of my study and the generalizations that I think can be made from the findings. AORG351 MASV-PUBAD

This study examines the usefulness of common off the shelf compression software such as gzip in enhancing already existing summaries and producing summaries from scratch. Since the gzip algorithm works by removing repetitive data from a file in order to compress it, we should be able to determine which sentences in a summary contain the least repetitive data by judging the gzipped size of the summary with the sentence compared to the gzipped size of the summary without the sentence. By picking the sentence that increased the size of the summary the most, we hypothesized that the summary will gain the sentence with the most new information. This hypothesis was found to be true in many cases and to varying degrees in this study.

The production of accurate and complete multiple-document summaries is challenged by the complexity of judging the usefulness of information to the user. Our aim is to determine whether identifying sub-events in a news topic could help us capture essential information to produce better summaries. In our first experiment, we asked human judges to determine the relative utility of sentences as they related to the sub-events of a larger topic. We used this data to create summaries by three different methods, and we then compared these summaries with three automatically created summaries. In our second experiment, we show how the results of our first experiment can be applied to a cluster-based automatic summarization system. Through both experiments, we examine the use of inter-judge agreement and a relative utility metric that accounts for the complexity of determining sentence quality in relation to a topic.

BACKGROUND—Epidemiologically-based rheumatology healthcare needs assessment requires an understanding of the incidence and prevalence of musculoskeletal disorders in the community, of the reasons why people consult in primary care, and of the proportion of people who would benefit from referral to secondary care and paramedical services. This paper reports the first phase of such a needs assessment exercise. SPECIFIC OBJECTIVE—To estimate the relative frequency of musculoskeletal pain in different, and multiple, anatomical sites in the adult population. SETTING—Three general practices in the former Tameside and Glossop Health Authority, Greater Manchester, UK, a predominantly urban area. DESIGN—Population survey. METHODS—An age and sex stratified sample of 6000 adults from the three practices was mailed a questionnaire that sought data on demographic factors, musculoskeletal symptoms (pain in the past month lasting for more than a week), and physical disability (using the modified Health Assessment Questionnaire- mHAQ). The areas of pain covered were neck, back, shoulder, elbow, hand, hip, knee, and multiple joints. The Carstairs index was used as a measure of social deprivation of the postcode sector in which the person lived. RESULTS—The response rate after two reminders was 78.5%. Non-responders were more likely to live in areas of high social deprivation. People who lived in more deprived areas were also more likely to report musculoskeletal pain, especially backpain. After adjusting for social deprivation the rates of musculoskeletal pain did not differ between the practices and so their results were combined. After adjustment for social deprivation, the most common site of pain was back (23%; 95% CI 21, 25) followed by knee (19%; 95% CI 18, 21), and shoulder (16%; 95% CI 14, 17). The majority of subjects who reported pain had pain in more than one site. The prevalence of physical disability in the community rose with age. It was highest in those with multiple joint problems but was also high in those with isolated back or knee pain. CONCLUSION—Musculoskeletal pain is common in the community. People who live in socially deprived areas have more musculoskeletal symptoms. Estimates of the overall burden of musculoskeletal pain that combine the results of site specific surveys will be too high, those that do not adjust for socioeconomic factors will be too low. Keywords: prevalence; pain; social deprivation