Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

Most men with artificial urinary sphincter cuff erosion have low serum testosterone levels.

AIMS: To evaluate the relationship between serum testosterone (T) levels and artificial urinary sphincter (AUS) cuff erosion in a population of incontinent men who underwent AUS placement. METHODS: A retrospective analysis of our single-surgeon AUS database was performed to identify men with T levels within 24 months of AUS placement. Men were stratified into two groups based on serum testosterone: low serum testosterone (LT) (<280 ng/dl) and normal serum testosterone (NT) (>280 ng/dl). Multivariable analysis was performed to control for risk factors. The outcome of interest was the incidence of and time to spontaneous urethral cuff erosion; other risk factors for cuff erosion were also evaluated. RESULTS: Among 161 AUS patients with serum testosterone levels, 84 (52.2%) had LT (mean: 136.8 ng/dl, SD: 150.4 ng/dl) and 77 (47.8%) had NT (mean: 455.8 ng/dl, SD: 197.3 ng/dl). Cuff erosion was identified in 42 men (26.1%) at a median of 7.1 months postoperatively (interquartile range: 3.6-13.4 months), most of whom (30/42, 71.4%) were testosterone deficient. LT levels were less common (54/119, 45.4%) in the non-erosion cohort (p = 0.004). Men with low T were nearly three times as likely to suffer AUS erosion than men with normal T (odds ratio = 2.519, p = 0.021). LT level was the only factor associated with AUS erosion on multivariable analysis. CONCLUSIONS: LT is an independent risk factor for AUS cuff erosion. Men with LT are more likely to present with cuff erosion, but there is no difference in time to erosion.

The Prevalence and Mental and Physical Health Correlates of Posttraumatic Stress Disorder Symptoms in Vulnerable and Underresourced Primary Care Patients Referred to a Behavioral Health Provider.

CONTEXT: The prevalence of trauma exposure among vulnerable, impoverished patients seeking primary care services is considerable. However, assessment of trauma-related symptoms is rare, even among behavioral health patients receiving primary care services within integrated health care centers. OBJECTIVE: To determine the prevalence of clinically noteworthy trauma-related symptoms and their associations with other co-occurring mental and physical symptoms as well as self-reported resiliency. PARTICIPANTS: Primary care patients (n = 120) referred to behavioral health services (76.7% black/African American; 70.8% female). SETTING: Federally qualified health center. MAIN OUTCOME MEASURES: Abbreviated Posttraumatic Stress Disorder Checklist-Civilian, 2-item version; Patient Health Questionnaire (PHQ)-15: physical health symptoms; PHQ-9: depression symptoms; Generalized Anxiety Disorder Scale, 7-item; Connor-Davidson Resilience Scale, 2-items. RESULTS: Seventy-three percent (n = 88) of provider-referred behavioral health patients screened positive for potential posttraumatic stress disorder. Patients most likely to meet criteria for posttraumatic stress disorder reported significantly higher levels of stress, depression, anxiety, and suicide ideation as well as more severe headaches, chest pains, dizziness, and poorer health care. CONCLUSIONS: Results support the need for a trauma-informed integrated approach to health care within primary care settings, particularly those serving vulnerable populations. Integrated health care services foster an environment in which patient access to and satisfaction with services is maximized while overall well-being is enhanced. Adding resiliency-enhancing strategies to patients' integrated health care treatment plans might also be health-promoting. PTSD symptoms can be assessed as part of routine integrated practice via a 2-item screener. Information obtained from trauma screening provides the health care team with useful contextual information about patients' physical and behavioral health symptoms.

Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.

A medium-throughput analysis of signaling pathways involved in early stages of stem cell reprogramming.

The induction of pluripotency from adult cells has enormous potential in regenerative medicine. While initial efforts to study mechanisms and improve efficiency of induced pluripotent stem cell (iPSC) reprogramming focused on the direct roles of transcriptional regulators, increasing evidence indicates that cellular signal transduction pathways can modulate this process. Here, we present a medium-throughput system to study the effect of signaling pathways on the early stages of reprogramming. We generated a set of lentiviral vectors encoding 38 genes that upregulate or downregulate major signal transduction pathways and quantified each signaling factor's effect on reprogramming. This approach confirmed the role of several factors previously implicated in reprogramming, as well as identified several GTPases-factors that to date have not been largely studied in reprogramming-that improve or hinder iPSC reprogramming. In addition, this methodology is useful in determining new targets for enhancing pluripotency reprogramming, lineage reprogramming, and/or cell differentiation.

Bone Cement Fumes Generated in Laminar Airflow Versus Conventionally Ventilated Operating Rooms: Does the Mixing System Matter?

BACKGROUND: Bone cement is commonly utilized in a variety of orthopaedic procedures and contains methylmethacrylate (MMA) monomer. MMA is a colorless, clear, flammable liquid of intense odor. Its vapor concentration in the immediate breathing zone can vary considerably in the operative setting and, in higher concentrations, can become an occupational health hazard. Therefore, reducing MMA vapor is desirable. The aim of this study was to compare the MMA vapor levels emitted during mixing among 5 commercially available cement-mixing systems across 2 operative settings: an operating room (OR) with conventional ventilation (CV) and an OR with laminar airflow (LAF). METHODS: A prospective, in vitro study was conducted at a single hospital in an OR with LAF and in an OR with CV. MMA vapor release during the cement preparation of a SAWBONES femoral canal was measured with use of a calibrated MiniRAE 3000. A total of 5 different vacuum cement-mixing systems were utilized to mix the same cement type according to the manufacturer instructions of each system. MMA vapor concentrations were measured during 5 phases of mixing, and each mixing system was randomly utilized 10 times in each OR. RESULTS: When comparing the MMA concentration levels of each system between the 2 settings, emissions remained generally higher in the CV setting for every system and in nearly every phase. Among the 5 systems analyzed, System #5, the only entirely closed system, had the lowest overall emissions for each of the 5 phases in the CV setting. CONCLUSIONS: This study demonstrated that an operative environment with LAF is conducive to clearing the fumes of MMA during mixing as well as limiting the amount of time that residual fumes linger after mixing. Additionally, the entirely closed cement-mixing system was the most effective in minimizing fume levels within the CV setting. Utilizing this closed system, especially in an OR with CV, may reduce exposure to MMA fumes from bone cement, potentially creating a more favorable working environment. CLINICAL RELEVANCE: This study provides evidence that a closed cement-mixing system utilized under vacuum in both an OR with CV and an OR with LAF is effective in keeping MMA fume levels below those considered harmful by the U.S. Occupational Safety and Health Administration.

An update on oxidized regenerated cellulose (fibrillar™) in reducing postoperative corporal bleeding following inflatable penile prosthesis surgery.

BACKGROUND: Scrotal hematoma formation is a dreaded complication of penile prosthesis surgery that increases patient pain and healthcare costs, as well the risk for eventual device infection and failure. The efficacy of hemostatic agents in reducing the incidence of scrotal hematoma development has not been extensively studied in urologic prosthetic surgery. In this paper we further evaluate our experience with oxidized regenerated cellulose (ORC; Surgicel Fibrillar™) as an adjunct to standard hemostatic practices in inflatable penile prosthesis (IPP) implantation. METHODS: From April 2016 onward, intracorporal ORC pledgets were placed during corporotomy closure in all patients undergoing IPP implantation or revision by a single surgeon using an identical surgical technique. Perioperative parameters and outcomes-primarily postoperative cumulative drain output, secondarily patient phone calls in the postoperative period-were compared among successive cases with ORC (April 2016 to February 2019) and without ORC (April 2013 to March 2016). RESULTS: A total of 274 men underwent IPP implantation during the study period; 175 (64%) had ORC included in their corporotomy closures. Median drain output was significantly reduced in the ORC patients relative to the non-ORC group (50 vs. 65 mL; P=0.0001). A significant reduction in patient-initiated phone calls regarding scrotal pain, swelling, or discomfort in the first 4 weeks following surgery was also observed in the ORC group (average 0.69 vs. 1.1 calls per patient; P=0.03). A total of 9 patients underwent IPP explantation during the study period, all due to device infection; 5 of these were in the ORC group, while 4 were in the non-ORC group (P=0.73). ORC use did not constitute any additional infection risk. CONCLUSIONS: Bilateral incorporation of ORC pledgets during corporotomy closure in IPP surgery significantly decreases postoperative scrotal drain output, a well-documented risk factor for scrotal hematoma formation.

Definition and Coordination of Roles and Responsibilities Among Cancer Center Clinic and Research Personnel.

PURPOSE: Effective enrollment and treatment of patients in cancer clinical trials require definition and coordination of roles and responsibilities among clinic and research personnel. MATERIALS AND METHODS: We developed a survey that incorporated modified components of the Survey of Physician Attitudes Regarding the Care of Cancer Survivors. Surveys were administered to clinic nursing staff and research personnel at a National Cancer Institute-designated comprehensive cancer center. Results were analyzed using χ2-tests, t tests, and analyses of variance. RESULTS: Surveys were completed by 105 staff members (n = 50 research staff, n = 55 clinic staff; 61% response rate). Research staff were more likely to feel that they had the skills to answer questions, convey information, and provide education for patients on trials (all P < .05). Both clinic and research staff reported receipt of communication about responsibilities in fewer than 30% of cases, although research staff reported provision of such information in more than 60% of cases. Among 20 tasks related to care of patients in trials, no single preferred model of responsibility assignment was selected by the majority of clinic staff for nine tasks (45%) or by research staff for three tasks (15%). Uncertainty about which team coordinates care was reported by three times as many clinic staff as research staff (P = .01). There was also substantial variation in the preferred model for delivery of care to patients in trials (P < .05). CONCLUSION: Knowledge, attitudes, and perception of care and responsibilities for patients on clinical trials differ between and among clinic and research personnel. Additional research about how these findings affect efficiency and quality of care on clinical trials is needed.

Outpatient buccal mucosal graft urethroplasty outcomes are comparable to inpatient procedures.

BACKGROUND: We sought to compare outcomes between inpatient and outpatient buccal mucosal graft (BMG) urethroplasty among a large tertiary referral center series. METHODS: A retrospective review of consecutive patients who underwent BMG urethroplasty between 2007 and 2018 was performed, including only first stage and one stage graft procedures. Patients were divided into inpatient and outpatient groups. Demographic and outcome data were collected and analyzed, with success defined as no need for further endoscopic or open reoperative management. RESULTS: Of 143 patients undergoing BMG urethroplasty during the study period, 87 cases (60.8%) were performed on an inpatient basis, and 56 (39.2%) on an outpatient basis. Patient characteristics such as age, BMI, prior endoscopic procedures and co-morbid factors were similar between inpatient and outpatient groups. Perioperative characteristics such as estimated blood loss were also similar between groups, but the inpatient cohort had a longer operative time (157.6 vs. 123.1 min, P<0.0001). Operative success was comparable in the two groups (74.7% inpatient vs. 76.8% outpatient, P=0.7) as were rates of complications (29.9% inpatient vs. 26.8% outpatient, P=0.07). CONCLUSIONS: BMG urethroplasty can be safely performed in an ambulatory setting without increased complications or compromised outcomes.

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4).

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile ( in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 µM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Oxidized Regenerated Cellulose (Fibrillar) Reduces Risk of Postoperative Corporal Bleeding Following Inflatable Penile Prosthesis Surgery.

OBJECTIVE: To report our initial experience with oxidized regenerated cellulose (ORC; Surgicel Fibrillar) as a hemostatic adjunct during inflatable penile prosthesis (IPP) surgery. MATERIALS AND METHODS: Beginning in April 2016, ORC pledgets were placed within the corporotomy closures of all men undergoing IPP insertion. Perioperative characteristics and outcomes including cumulative postoperative drain output were evaluated among consecutive cases with (April 2016 to October 2016) and without ORC (December 2015 to March 2016) using an identical surgical technique by a single surgeon. RESULTS: During the study period, 64 men underwent IPP implantation, of whom 32 (50%) received ORC. There was a significant reduction in median drain output relative to controls (33 mL vs 65 mL; P = .01). Postoperatively, ORC use was associated with a reduction in the number of patient phone calls for scrotal-related concerns in the immediate postoperative period (average 0.5 vs 1.1; P = .03). There were 3 IPP explantations in the non-ORC group (2/3 for infection)-one of which was directly related to an infected hematoma. After controlling for other clinical features, the use of ORC (ß -32, 95% confidence interval: -61 to -5; P = .02) was independently associated with a reduction in drain output. CONCLUSION: ORC use during IPP corporotomy closure reduces postoperative drain output, a known risk factor for hematoma-related complications.

Efficacy and Safety of Nonopioid Analgesics in Perioperative Pain Control.

Opioids have been the mainstay for management of acute postoperative pain for several decades. Extensive use, however, has been associated with multiple side effects. Multimodal approaches that incorporate nonopioid medications and techniques have been observed to achieve optimum pain control whilst decreasing side effects. Such strategies are particularly important to consider for opioid-dependent and tolerant patients with various comorbidities undergoing different types of surgery. This review assesses recent data on nonopioid analgesics for postoperative pain control, highlighting evidence of their safety profiles in contemporary pain management.

Differential Collective- and Single-Cell Behaviors on Silicon Micropillar Arrays.

Three-dimensional vertically aligned nano- and micropillars have emerged as promising tools for a variety of biological applications. Despite their increasing usage, the interaction mechanisms of cells with these rigid structures and their effect on single- and collective-cell behaviors are not well understood for different cell types. In the present study, we examine the response of glioma cells to micropillar arrays using a new microfabricated platform consisting of rigid silicon micropillar arrays of various shapes, sizes, and configurations fabricated on a single platform. We compare collective- and single-cell behaviors at micropillar array interfaces and show that glial cells under identical chemical conditions form distinct arrangements on arrays of different shapes and sizes. Tumor-like aggregation and branching of glial cells only occur on arrays with feature diameters greater than 2 µm, and distinct transitions are observed at interfaces between various arrays on the platform. Additionally, despite the same side-to-side spacing and gaps between micropillars, single glial cells interact with the flat silicon surface in the gap between small pillars but sit on top of larger micropillars. Furthermore, micropillars induced local changes in stress fibers and actin-rich filopodia protrusions as the cells conformed to the shape of spatial cues formed by these micropillars.

Measuring drug action in the cellular context using protein-fragment complementation assays.

Cellular signal transduction occurs in the context of dynamic multiprotein complexes in highly ramified pathways. These complexes in turn interact with the cytoskeleton, protein scaffolds, membranes, lipid rafts, and specific subcellular organelles, contributing to the exquisitely tight regulation of their localization and activity. However, these realities of drug target biology are not addressed by currently available drug discovery platforms. In this article, we describe the use of protein-fragment complementation assays (PCAs) to assess drugs and drug targets in the context of their native environment. The PCA process allows for the detection of protein-protein complexes following the expression of full-length mammalian genes linked in-frame to polypeptide fragments of rationally dissected reporter genes. If cellular activity causes the association of two proteins linked to complementary reporter fragments, the interaction of the proteins of interest enables refolding of the fragments, which can then generate a quantifiable signal. Using a PCA based on a yellow fluorescent protein, we demonstrate that functional (p50/p65) complexes of the heterodimeric nuclear factor-kappaB transcription factor, as well as the transcription factor subunit p65 and its modulator IkappaBalpha, can be visualized and monitored in live cells. We observed similar responses of the PCA assays to the activities of the cognate endogenous proteins, including modulation by known agonists and antagonists. A proof-of-concept high throughput screen was carried out using the p50/p65 cell line, and potent inhibitors of this pathway were identified. These assays record the dynamic activity of signaling pathways in living cells and in real time, and validate the utility of PCA as a novel approach to drug discovery.

Location-specific sympatric morphological divergence as a possible response to species interactions in West Virginia Plethodon salamander communities.

1. The competitive interactions of closely related species have long been considered important determinants of community composition and a major cause of phenotypic diversification. However, while patterns such as character displacement are well documented, less is known about how local adaptation influences diversifying selection from interspecific competition. 2. We examined body size and head shape variation among allopatric and sympatric populations of two salamander species, the widespread Plethodon cinereus and the geographically restricted P. nettingi. We quantified morphology from 724 individuals from 20 geographical localities throughout the range of P. nettingi. 3. Plethodon nettingi was more robust in cranial morphology relative to P. cinereus, and sympatric localities were more robust relative to allopatric localities. Additionally, there was significantly greater sympatric head shape divergence between species relative to allopatric communities, and sympatric localities of P. cinereus exhibited greater morphological variation than sympatric P. nettingi. 4. The sympatric morphological divergence and increase in cranial robustness of one species (P. nettingi) were similar to observations in other Plethodon communities, and were consistent with the hypothesis of interspecific competition. These findings suggest that interspecific competition in Plethodon may play an important role in phenotypic diversification in this group. 5. The increase in among-population variance in sympatric P. cinereus suggests a species-specific response to divergent natural selection that is influenced in part by other factors. We hypothesize that enhanced morphological flexibility and ecological tolerance allow P. cinereus to more rapidly adapt to local environmental conditions, and initial differences among populations have allowed the evolutionary response of P. cinereus to vary across replicate sympatric locations, resulting in distinct evolutionary trajectories of morphological change.