Athlete Multiple Perpetrator Rape (MPR) as Interactional and Organizational Deviance: Heuristic Insights from a Multilevel Framework.

Although athlete multiple perpetrator rape (MPR) has frequently been covered in the media, it has received more limited scholarly attention. Accordingly, I synthesize findings from multiple disciplines and integrate insights from the MPR, institutional betrayal, and organizational deviance literatures to establish a heuristic framework for understanding athlete MPR. I ultimately argue that athlete MPR is both an act of interactional deviance and an act of organizational deviance. This undertaking represents one of the only works to focus explicitly on athlete MPR. It is additionally the first to examine any form of sexual assault through an organizational deviance lens.

Impact of Social Determinants of Health, Health Literacy, Self-perceived Risk, and Trust in the Emergency Physician on Compliance with Follow-up.

INTRODUCTION: Patients presenting to the emergency department (ED) with "low-risk" acute coronary syndrome (ACS) symptoms can be discharged with outpatient follow-up. However, follow-up compliance is low for unknown nonclinical reasons. We hypothesized that a patient's social factors, health literacy, self-perceived risk, and trust in the emergency physician may impact follow-up compliance. METHODS: This was a prospective study of a convenience sample of discharged ED patients presenting with chest pain and given a follow-up appointment prior to departing the ED. Patients were asked about social and demographic factors and to estimate their own risk for heart disease; they also completed the Short Assessment of Health Literacy-English (SAHL-E) and the Trust in Physician Scale (TiPS). RESULTS: We enrolled146 patients with a follow-up rate of 36.3%. Patients who had a low self-perceived heart disease risk (10% or less) were significantly less likely to attend follow-up than those with a higher perceived risk (23% vs 44%, P = 0.01). Other factors did not significantly predict follow-up rates. CONCLUSION: In an urban county ED, in patients who were deemed low risk for ACS and discharged, only self-perception of risk was associated with compliance with a follow-up appointment.

Growth and Antifungal Resistance of the Pathogenic Yeast, Candida Albicans, in the Microgravity Environment of the International Space Station: An Aggregate of Multiple Flight Experiences.

This report was designed to compare spaceflight-induced cellular and physiological adaptations of Candida albicans cultured in microgravity on the International Space Station across several payloads. C. albicans is a common opportunistic fungal pathogen responsible for a variety of superficial infections as well as systemic and more severe infections in humans. Cumulatively, the propensity of this organism to be widespread through the population, the ability to produce disease in immunocompromised individuals, and the tendency to respond to environmental stress with characteristics associated with increased virulence, require a better understanding of the yeast response to microgravity for spaceflight crew safety. As such, the responses of this yeast cultivated during several missions using two in-flight culture bioreactors were analyzed and compared herein. In general, C. albicans had a slightly shorter generation time and higher growth propensity in microgravity as compared to terrestrial controls. Rates of cell filamentation differed between bioreactors, but were low and not significantly different between flight and terrestrial controls. Viable cells were retrieved and cultured, resulting in a colony morphology that was similar between cells cultivated in flight and in terrestrial control conditions, and in contrast to that previously observed in a ground-based microgravity analog system. Of importance, yeast demonstrated an increased resistance when challenged during spaceflight with the antifungal agent, amphotericin B. Similar levels of resistance were not observed when challenged with the functionally disparate antifungal drug caspofungin. In aggregate, yeast cells cultivated in microgravity demonstrated a subset of characteristics associated with virulence. In addition, and beyond the value of the specific responses of C. albicans to microgravity, this report includes an analysis of biological reproducibility across flight opportunities, compares two spaceflight hardware systems, and includes a summary of general flight and payload timelines.

The Effectiveness of Anti-Nerve Growth Factor Monoclonal Antibodies in the Management of Pain in Osteoarthritis of the Hip and Knee: A PRISMA Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the efficacy of anti-nerve growth factor (NGF) monoclonal antibodies in osteoarthritis pain (hip and knee). DESIGN: Grade the evidence for anti-NGF use. METHODS: An interdisciplinary work group conducted a literature search for anti-NGF use in osteoarthritis. The systematic review was performed in accordance with methods described by the Cochrane collaboration. General inclusion criteria included all osteoarthritis trials studying any monoclonal anti-NGF antibody at any dose/phase. Excluded studies were those where participants received NSAIDs or analgesics other than anti-NGF antibodies. The Jadad Scale score was used to assess the quality of the included studies. RESULTS: Thirteen studies were included in the analysis, involving 8145 participants with a diagnosis of hip and/or knee osteoarthritis. Anti-NGF antibody treatment was associated with a significant improvement in all Western Ontario and McMaster Universities Arthritis Index (WOMAC) indices when compared to placebo. These agents were not associated with a significantly increased incidence of serious adverse events but were associated with significant increases in therapy discontinuation due to adverse events or side effects (e.g., peripheral neuropathy). CONCLUSIONS: Future randomized clinical trials are needed to characterize the overall risk-to-benefit ratio of anti-NGF antibodies in managing pain associated with OA, particularly with long-term use, in order to verify their efficacy and safety in clinical practice.

Potential Impact of COVID-19 on Recently Resettled Refugee Populations in the United States and Canada: Perspectives of Refugee Healthcare Providers.

Recently resettled refugee populations may be at greater risk for exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that causes coronavirus 2019 (COVID-19), and face unique challenges in following recommendations to protect their health. Several factors place resettled refugees at elevated risk for exposure to persons with COVID-19 or increased severity of COVID-19: being more likely to experience poverty and live in crowded housing, being employed in less protected, service-sector jobs, experiencing language and health care access barriers, and having higher rates of co-morbidities. In preparing for and managing COVID-19, resettled refugees encounter similar barriers to those of other racial or ethnic minority populations, which may then be exacerbated by unique barriers experienced from being a refugee. Key recommendations for resettlement and healthcare providers include analyzing sociodemographic data about refugee patients, documenting and resolving barriers faced by refugees, developing refugee-specific outreach plans, using culturally and linguistically appropriate resources, ensuring medical interpretation availability, and leveraging virtual platforms along with nontraditional community partners to disseminate COVID-19 messaging.

BIOANALYSIS AND BIOTRANSFORMATION OF OLIGONUCLEOTIDE THERAPEUTICS BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY.

Since 2016, eight new oligonucleotide therapies have been approved which has led to increased interest in oligonucleotide analysis. There is a particular need for powerful bioanalytical tools to study the metabolism and biotransformation of these molecules. This review provides the background on the biological basis of these molecules as currently used in therapies. The article also reviews the current state of analytical methodology including state of the art sample preparation techniques, liquid chromatography-mass spectrometry methods, and the current limits of detection/quantitation. Finally, the article summarizes the challenges in oligonucleotide bioanalysis and provides future perspectives for this emerging field. © 2020 John Wiley & Sons Ltd.

A Daily Hospital Progress Note that Increases Physician Usability of the Electronic Health Record by Facilitating a Problem-Oriented Approach to the Patient and Reducing Physician Clerical Burden.

We suggest changes in the electronic health record (EHR) in hospitalized patients to increase EHR usability by optimizing the physician's ability to approach the patient in a problem-oriented fashion and by reducing physician data entry and chart navigation. The framework for these changes is a Physician's Daily Hospital Progress Note organized into 3 sections: Subjective, Objective, and a combined Assessment and Plan section, subdivided by problem titles. The EHR would consolidate information for each problem by: 1) juxtaposing to each problem title relevant medications, key durable results, and limitations; 2) entering in the running lists under Assessment and Plan the most relevant information for that day, including abbreviated versions of relevant reports; and 3) generating a flow sheet in a problem's progress note for any key results tracked daily. To reduce physician EHR navigation, the EHR would place in the Objective section abbreviated versions of notes of other physicians, nurses, and allied health professionals as well as recent orders. The physician would enter only the analysis and plan and new information not included in the EHR. The consolidation of information for each problem would facilitate physician communication at points of transition of care including generation of a problem-oriented discharge summary.

Late Development of a Large Arteriovenous Fistula with Aneurysm in an In Situ Vein Bypass Graft.

We report a case of saphenous vein bypass aneurysm and arteriovenous fistula in a 65-year-old man, 20 years after an in situ vein bypass for occlusive disease. He was found to have patent venous branches which kept the bypass open despite distal anastomotic occlusion. The saphenous vein was successfully excised without distal revascularization due to sufficient native arterial flow. This is the first reported case of aneurysmal degeneration of an in situ vein conduit with occluded distal anastomosis and patent venous side branches. Ultrasound surveillance is warranted for all bypass procedures, and early endovascular or open revisions can prevent late complications.

Prisoners' Personal Networks in the Months Preceding Prison: A Descriptive Portrayal.

This study examined personal networks of adult male prisoners ( N = 250) during a high-risk period prior to their incarceration. We present a descriptive portrait of network size, density, and relational type, and we then document the nature of ties within that network, focusing specifically on alters' criminal involvement, criminal opportunity, and reinforcement of criminal behavior. We found that prisoners' networks were large and dense, and that they were composed primarily of family and romantic partners. Most prisoners are not embedded in a personal network saturated with criminal influence before coming to prison. Yet, a small proportion are exposed to exceptionally negative influence, which, it is argued, may increase the risk of negative outcomes upon release if not addressed by evidence-based programs.

Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis.

In sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis.

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors.

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.

CSF1R-dependent myeloid cells are required for NK­mediated control of metastasis.

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis.

Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.

PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.

The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.

Vancomycin-induced eosinophilic peritonitis.

PURPOSE: A case of eosinophilic peritonitis (EP) with severe cardiovascular compromise in a patient receiving intraperitoneal vancomycin therapy is described. SUMMARY: A woman with a medical history including hypertension, end-stage renal disease, and anemia of chronic disease was hospitalized for complaints of severe abdominal pain and loss of appetite over the preceding four days; she had been undergoing peritoneal dialysis for about one year. Bacterial infection was diagnosed on the basis of peripheral blood and peritoneal fluid analyses showing highly elevated neutrophil and total nucleated cell (TNC) counts. Vancomycin was added to the peritoneal dialysis bags, with subsequent dramatic TNC and neutrophil reductions over two days, but the woman's condition continued to worsen; she developed severe hypotension and on hospital day 13 was transferred to the intensive care unit for central line placement and vasopressor support. The clinician team determined that conversion from bacterial peritonitis to EP had occurred. After the exclusion of other potential causes of EP (e.g., a reaction to dialysis equipment, antihypertensive medication use), intraperitoneal administration of vancomycin was deemed to be the probable cause. Within days of discontinuation of vancomycin use, the patient's hypotension abated, her abdominal symptoms resolved, and she was discharged home. In this case, the diagnosis of EP was complicated by the initial presentation of bacterial peritonitis (confirmed by laboratory and culture data). A literature search identified one other published report of vancomycin-induced EP. CONCLUSION: A 37-year-old woman developed EP after receiving vancomycin intraperitoneally. The infection resolved after discontinuation of vancomycin.

CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.

Our previous studies showed that MYB is required for proliferation of, and confers protection against apoptosis on, estrogen receptor-positive (ER(+ve)) breast cancer cells, which are almost invariably also MYB(+ve). We have also shown that MYB expression in ER(+ve) breast cancer cells is regulated at the level of transcriptional elongation and as such, is suppressed by CDK9i. Here we examined the effects of CDK9i on breast cancer cells and the involvement of MYB in these effects. ER(+ve) breast cancer cell lines including MCF-7 were much more sensitive (> 10 times) to killing by CDK9i than ER(-ve)/MYB(-ve) cells. Moreover, surviving cells showed a block at the G2/M phase of the cell cycle. Importantly, ectopic MYB expression conferred resistance to apoptosis induction, cell killing and G2/M accumulation. Expression of relevant MYB target genes including BCL2 and CCNB1 was suppressed by CDK9 inhibition, and this too was reversed by ectopic MYB expression. Nevertheless, inhibition of BCL2 alone either by MYB knockdown or by ABT-199 treatment was insufficient for significant induction of apoptosis. Further studies implied that suppression of MCL-1, a well-documented target of CDK9 inhibition, was additionally required for apoptosis induction, while maximal levels of apoptosis induced by CDK9i are likely to also involve inhibition of BCL2L1 expression. Taken together these data suggest that MYB regulation of BCL2 underlies the heightened sensitivity of ER(+ve) compared to ER(-ve) breast cancer cells to CDK9 inhibition, and that these compounds represent a potential therapeutic for ER(+ve) breast cancers and possibly other MYB-dependent cancers.

Molecular Basis of mRNA Cap Recognition by Influenza B Polymerase PB2 Subunit.

Influenza virus polymerase catalyzes the transcription of viral mRNAs by a process known as "cap-snatching," where the 5'-cap of cellular pre-mRNA is recognized by the PB2 subunit and cleaved 10-13 nucleotides downstream of the cap by the endonuclease PA subunit. Although this mechanism is common to both influenza A (FluA) and influenza B (FluB) viruses, FluB PB2 recognizes a wider range of cap structures including m(7)GpppGm-, m(7)GpppG-, and GpppG-RNA, whereas FluA PB2 utilizes methylated G-capped RNA specifically. Biophysical studies with isolated PB2 cap-binding domain (PB2(cap)) confirm that FluB PB2 has expanded mRNA cap recognition capability, although the affinities toward m(7)GTP are significantly reduced when compared with FluA PB2. The x-ray co-structures of the FluB PB2(cap) with bound cap analogs m(7)GTP and GTP reveal an inverted GTP binding mode that is distinct from the cognate m(7)GTP binding mode shared between FluA and FluB PB2. These results delineate the commonalities and differences in the cap-binding site between FluA and FluB PB2 and will aid structure-guided drug design efforts to identify dual inhibitors of both FluA and FluB PB2.

Ion pair liquid chromatography method for the determination of thiamine (vitamin B1) homeostasis.

A new method for reversed phase HPLC determination of thiamine and its major in vivo phosphorylation products, thiamine monophosphate (TMP) and thiamine pyrophosphate (TPP), was developed using tetrabutylammonium hydroxide as the ion-pairing agent. The separation was performed on a Phenomenex Kinetex EVO C18 column with a gradient of a phosphate-buffered aqueous solution of the ion-pair reagent and methanol. The duty cycle for the assay was 13 min and pyrithiamine was successfully used as the internal standard for the first time in a thiamine HPLC measurement protocol. Detection of the fluorescence derivatives of the analytes as well as the IS allowed for lower detection limits in order to support biological applications in cell culture models. The linearity, sensitivity, specificity, accuracy and precision of the method were evaluated and met the requirements specified by the US Food and Drug Administration. The calibration curves proved to be linear and the method was validated over the range from 1.0-4000 nM for both cells and the media where complete recovery of the analytes was also achieved.