Search

Healthcare personnel with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection were interviewed to describe activities and practices in and outside the workplace. Among 2,625 healthcare personnel, workplace-related factors that may increase infection risk were more common among nursing-home personnel than hospital personnel, whereas selected factors outside the workplace were more common among hospital personnel.

Campus recreational sport programs strive to create an environment that is accessible to diverse participants, including LGBTQ population groups. While improvement has been made in promoting resources and workgroups related to diversity management practices, little empirical evidence exists as it relates to the efficacy of diversity trainings for recreational sport employees. This study analyzed the impact of a diversity training program geared toward the development of affirming recreational sport practices for LGBTQ populations and exploring the professional competencies related to LGBTQ inclusion that are practiced within in a collegiate recreational sport setting. Results indicated that the targeted training initiative was effective in statistically improving employee confidence as it relates to LGBTQ professional competencies ( p < .000), while nonattendance at the training showed no statistically significant differences in such competencies. This study serves as a starting point for investigating the impact of LGBTQ-specific diversity training programs on recreational sport staff members.

Cancer survivors are at higher risk of developing HPV-associated cancers later in life, yet their HPV vaccination rates remain lower than the general population. Improving HPV vaccination uptake among survivors is essential to preventing second malignancies. We interviewed HPV vaccine eligible adolescent and young adult (AYA) cancer survivors (18-26 years) and caregivers of HPV vaccine eligible childhood cancer survivors approaching the AYA age range (9-17 years) about their HPV vaccine experiences and preferences as informed by the HPV Vaccination Roundtable Best Practices. Interviews (N = 20) were recorded, transcribed, and analyzed using interpretive description. Of AYA survivors (n = 10), 50% had received at least one HPV vaccine dose. Of caregivers (n = 10), 30% reported their child had received at least one HPV vaccine dose. Three distinct categories emerged including (1) HPV vaccine knowledge, (2) HPV vaccination recommendation preferences, and (3) HPV vaccination reminder preferences. The first two categories were oncology focused. Participants lacked knowledge regarding HPV vaccine safety and applicability due to their complex cancer history. Most participants strongly preferred that their oncologist provide an HPV vaccine recommendation. The third category was mixed, with some participants preferring oncology-based HPV vaccine reminders while others preferred primary care-based reminders. Almost all participants preferred digital reminders (e.g., text messages). Our results suggest that oncologists play an essential role in recommending the HPV vaccine and providing information to assist survivors and caregivers with vaccine decision-making. Additionally, HPV vaccination uptake among pediatric and childhood and AYA survivors could be improved through the use of tailored, electronically delivered vaccine reminders.

OBJECTIVES Colloid carcinoma (CC) of the pancreas is associated with an improved prognosis compared with pancreatic ductal adenocarcinoma (PDAC), yet studies on the optimal management of these rare lesions are lacking. METHODS Patients with CC or PDAC treated from 2004 to 2014 were identified in the National Cancer Database. Clinicopathologic characteristics were compared between groups and stratified by disease stage. Survival analysis evaluating the role of perioperative chemotherapy was performed. RESULTS A total of 1295 CC patients (11%) and 10,855 PDAC patients (89%) were identified. Pancreatic ductal adenocarcinoma was associated with a higher likelihood of mortality compared with CC (hazard ratio, 1.35; 95% confidence interval, 1.25-1.45; P < 0.001). When stratifying by stage, perioperative chemoradiation improved overall survival in early stage (I/IIA) PDAC but had no effect in CC patients. However, for node-positive disease (stage IIB), median overall survival was improved with adjuvant chemoradiation for both CC patients (22 vs 13 months; P < 0.001) and PDAC patients (20 vs 11 months; P < 0.001) compared with surgery alone. CONCLUSIONS Surgery alone may be sufficient for the management of node-negative (I/IIA) CC lesions in contrast to conventional PDAC, whereas CC patients with stage IIB disease have a survival benefit from perioperative chemoradiation.

Purpose Probe-based dynamic (4-D) imaging modalities capture breast intratumor heterogeneity both spatially and kinetically. Characterizing heterogeneity through tumor sub-populations with distinct functional behavior may elucidate tumor biology to improve targeted therapy specificity and enable precision clinical decision making. Methods We propose an unsupervised clustering algorithm for 4-D imaging that integrates Markov-Random Field (MRF) image segmentation with time-series analysis to characterize kinetic intratumor heterogeneity. We applied this to dynamic FDG PET scans by identifying distinct time-activity curve (TAC) profiles with spatial proximity constraints. We first evaluated algorithm performance using simulated dynamic data. We then applied our algorithm to a dataset of 50 women with locally advanced breast cancer imaged by dynamic FDG PET prior to treatment and followed to monitor for disease recurrence. A functional tumor heterogeneity (FTH) signature was then extracted from functionally distinct sub-regions within each tumor. Cross-validated time-to-event analysis was performed to assess the prognostic value of FTH signatures compared to established histopathological and kinetic prognostic markers. Results Adding FTH signatures to a baseline model of known predictors of disease recurrence and established FDG PET uptake and kinetic markers improved the concordance statistic (C-statistic) from 0.59 to 0.74 (p = 0.005). Unsupervised hierarchical clustering of the FTH signatures identified two significant (p p = 0.04) across the two phenotypes. Conclusions Our findings suggest that imaging markers of FTH add independent value beyond standard PET imaging metrics in predicting recurrence-free survival in breast cancer and thus merit further study.

Background and purpose Prelicensure nursing students lack the situational awareness to promote timely intervention with a patient in septic shock. This study evaluated a multifaceted educational project that determined the impact on nursing students' knowledge retention and time to task (TTT). Methods A quasi-experimental, repeated-measures design was used to evaluate students' knowledge retention and TTT. Eighty-four prelicensure nursing students participated in groups of 4 students to participate in a high-fidelity simulation. Results Results show knowledge retention was significant between the pretest scores and 2 repeated assessment scores. The repeated-measures analysis of variance time effect P value was .02. The overall TTT group response suggested most (64/84, 76%) students responded within 5 minutes of patient deterioration. Conclusions A multifaceted approach was effective to influence knowledge of septic shock over time and demonstrate students' ability to intervene with a septic shock patient in a timely manner.

The high sensitivity and total-body coverage of total-body PET scanners will be valuable for a number of clinical and research applications outlined in this article.

New protocols for imaging cancer have been developed to take advantage of the improved imaging capabilities of long axial field-of-view PET scanners. Both research and clinical applications have been pursued with encouraging early results. Clinical studies have demonstrated improved image quality and the ability to image with less injected activity or for shorter duration. With the increased sensitivity inherent in total-body PET scanners and new imaging paradigms, new challenges in image interpretation have emerged. New research applications have also emerged, including dosimetry, cell tracking, and dual-tracer applications.

Background: Assessment of kidney function is fundamental to optimize drug dosing. The Cockcroft–Gault (CG) equation is widely used but has questionable validity for females, changing renal function, and the critical ill. Eight-hour urine collections (U8h) offer direct measurement of creatinine clearance (CrCl) but lack the data for drug dosing. The primary objective of this study was to determine if there was a difference in renal drug dosing based on the estimation of CG CrCl (CrClCG) versus 8-h CrCl (CrCl8h). Methods: This was an observational, retrospective cohort study of adult patients admitted between March 2018 and September 2018 with a collection U8h during hospitalization. The primary outcome was discordance of renal drug dosing defined as the percentage of U8h for which at least one different active medication CrCl dosing cutoff would result using the CrClCG versus CrCl8h. The secondary outcomes were correlation between CrClCG and CrCl8h and percentage of CrClCG values outside ± 20% of the CrCl8h. Results: One hundred collections drawn from 85 unique patients (50.6% male, median age 55 [41–70] years, intensive care unit 88%) were included in the analysis. Median serum creatinine was 0.76 (0.52–1.06) mg/dL and blood urea nitrogen was 20 (14–28) mg/dL at time of collection8h. Median CrCl8h was 86.2 (43.5–140.3) mL/min versus 99.7 (56.5–166.9) mL/min CrClCG(P < 0.001) and discordance was 25%. The correlation between CrCl8h and CrClCG was 0.76 (P < 0.001). Only 31% of CrClCG values were within ± 20% of the CrCl8h value. Conclusion: We found 25% discordance for drug dosing between CrCl8h and CrClCG. Further studies are needed to determine the impact on clinical outcomes.

Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients., Abdominal adhesions are a common cause of bowel obstruction, but knowledge regarding adhesion biology and anti-adhesion therapies remains limited. Here the authors report a systematic analysis of mouse and human adhesion tissues demonstrating that visceral fibroblast JUN and associated PDGFRA expression promote adhesions, and JUN suppression can prevent adhesion formation.

Objective To describe how young adult cancer caregivers (YACC) use social media for social support during a cancer experience. Methods Eligible YACC were 18 to 39 years, used Facebook and/or Instagram at least once per week, and cared for an adult cancer patient diagnosed 6 months to 5 years prior (N = 34). Recruitment of a cross-sectional sample occurred through oncology clinics in Utah and online advertising by caregiving and cancer organizations from September 2017 to June 2018. Semi-structured telephone interviews were recorded, transcribed, iteratively coded, and qualitatively analyzed, yielding four categories concerning how YACC use social media. Results Caregivers were most commonly spouses aged 29 years on average (range 21-38); cancer patients were 37 years (range 19-76). Analysis yielded four distinct yet related categories: Category 1: Posting about cancer on social media often begins as a strategy for YACC to efficiently provide updates about the cancer patient. Category 2: Caregivers who actively post on social media experience a variety of different functional social supports to which they otherwise would not have access. Category 3: Posting about cancer online presents an opportunity for negative consequences. Category 4: Potential for negative consequences influences how some caregivers use social media. Conclusions Supportive services, including social media-based supports, are needed for YACC in formats that are convenient for them as they balance their caretaking duties with their daily lives.

BackgroundGiven the growing number of people worldwide living with human immunodeficiency virus (HIV), a larger subset of these patients are now susceptible to sustaining a traumatic injury. However, the impact of HIV on outcomes in trauma with modern antiretroviral treatment remains unclear.We hypothesized mortality and rates of infectious and inflammatorycomplicationswould be higher in HIV positive (HIV+) trauma patients.MethodsThe Trauma Quality Improvement Programwas queriedtoidentify trauma patients ≥ 18years of age with HIV.Due to the imbalance between HIV+ and HIV negative(HIV-)trauma patients, a 1:2 propensity-matched model was utilized. Matched variables included age, injury severity score, mechanism of injury, systolic blood pressure, pulse rate, Glasgow Coma Scale score, and patient comorbidities.Results84 HIV+ patients were matched to 168 HIV- patients.Compared toHIV-patients, HIV+ patientshad no significant differences in mortality rate (9.5% vs.4.8%, p = 0.144) or infectious complications, including pneumonia (6.0% vs.4.2%, p = 0.530), urinary tract infection (1.2% vs. 1.2%, p = 1.000), or severe sepsis (1.2% vs.0.0%, p = 0.156). However, higher rates of acute respiratory distress syndrome (ARDS) (9.5% vs.0.6%, p

Objectives Our institution has developed an educational program in which first-year radiology residents teach first-year medical students during gross anatomy laboratory sessions. The purpose of this study is to assess the impact of this program on medical student knowledge and perceptions of radiology, and on resident attitudes toward teaching. Materials and Methods First-year resident pairs taught small groups of medical students during weekly 15-minute interactive sessions, and were evaluated on teaching skills by senior residents. A survey about attitudes toward radiology and a knowledge quiz were sent to the medical students, and a survey about attitudes toward teaching was sent to the first-year radiology residents, both pre-course and post-course. Results Students’ radiology knowledge significantly increased between the pre-course and post-course survey across all categories tested (P Conclusions Resident-led small-group teaching sessions during anatomy laboratory are mutually beneficial for medical students and radiology residents. The program also allows radiology residents to be exposed early on in residency to teaching and academic medicine.

Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis in vivo. Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. Implications: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited., How epigenetic regulation affects pancreatic development is unclear. Here, the authors show that the histone demethylase LSD1 regulates the epigenetic state of developmental enhancers during pancreatic specification and controls how these enhancers respond to extracellular signals, namely retinoic acid.

The purpose of this study was to examine the initiatives that current aquatic managers in campus recreation are implementing to create environments that are inclusive to lesbian, gay, bisexual, transgender, and queer (LGBTQ) participation and to assess the barriers to such initiatives. The study utilized in-depth semistructured interviews with nine campus recreation aquatic managers to examine steps that are currently being taken when it comes to creating environments that are perceived to be open, or closed, to LGBTQ participants. A grounded theory–based process of data collection and analysis resulted in emergent themes. These themes included (a) “I am not an expert but…,” (b) reactive programming and management, (c) inclusion as a general practice, and (d) the importance of gender-inclusive practices. Management strategies and implications for campus recreation aquatic managers around these emergent themes are discussed regarding the creating of inclusive environments for LGBTQ participants.

Background: As the prevalence of obesity climbs, dosing of antimicrobials, particularly cephalosporins, is becoming a greater challenge for clinicians. Data are lacking for appropriate dosing of cefepime, an anti-pseudomonal cephalosporin that is widely used as an empiric anti-pseudomonal agent. Objective: The purpose of this study was to determine the rate of clinical treatment failure in obese patients compared with nonobese patients receiving cefepime as definitive monotherapy. Methods: Adult inpatients treated with cefepime monotherapy for ≥72 hours were included. Patients were excluded if they (1) were not able to achieve culture clearance within 72 hours and (2) had polymicrobial infections requiring more than one antibiotic for definitive therapy. Results: Fifty-eight obese patients and 56 nonobese patients were included. Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp were the most prevalent organisms isolated. Most organisms had a minimum inhibitory concentration of ≤1 µg/mL to cefepime with no differences in minimum inhibitory concentration distributions between groups. Definitively, 60% of patients received cefepime 1 g, while almost 40% received cefepime 2 g. Clinical failure occurred in 52% of patients (67% obese vs 36% nonobese; P = .001), with study group (odds ratio = 1.057, 95% confidence interval = 1.008-1.109) and respiratory source (odds ratio = 3.251, 95% confidence interval = 1.378-7.667) being independent predictors of failure. There were no differences in hospital length of stay, all-cause mortality, or 30-day readmissions. Conclusions: Obese patients treated with cefepime are more likely to experience treatment failure than nonobese patients. Larger trials examining the reasons for clinical failure in obese patients treated with cefepime are needed to confirm the findings from this preliminary work.

Bilateral shoulder adhesive capsulitis may develop in association with the administration of an influenza vaccine. Vaccine administration should utilize proper technique to avoid injection into the shoulder capsule.

This report describes an isolated superior gluteal nerve injection injury following a corticosteroid injection for greater trochanteric pain syndrome. Ultrasound‐guided injections may be beneficial to target multiple pain‐producing regions of the hip while avoiding nerves and tendons.

After dedicated CT and MRI, Ga-DOTATATE PET/CT was performed in a patient with a temporal bone mass with primary diagnostic considerations of an endolymphatic sac tumor versus a glomus jugulotympanicum paraganglioma. The Ga-DOTATATE PET showed mild radiotracer uptake in the mass (SUVmax, 10.9). After surgical resection, pathology revealed an endolymphatic sac tumor. Immunohistochemical staining demonstrated somatostatin receptor type 2A expression in the vasculature of the mass, but not in the tumor cells.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality following distal pancreatectomy (DP). However, the influence of operative technique on VTE risk after DP is unknown. The purpose of this study was to examine the association between the MIS technique versus the open technique and the development of postoperative VTE after DP. Patients who underwent DP from 2014 to 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program pancreas-specific database. Multivariable logistic regression was then used to identify independent associations with the development of postoperative VTE after DP. A total of 3558 patients underwent DP during this time period. Of these cases, 47.8% (n = 1702) were performed via the MIS approach. After adjusting for significant covariates, the MIS approach was independently associated with the development of any VTE (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.06–2.40; p = 0.025), as well as increasing the risk of developing a postdischarge VTE (OR 1.80, 95% CI 1.05–3.08; p = 0.033) when compared with the open approach. There was an association between VTE and the development of numerous postoperative complications, including pneumonia, unplanned intubation, need for prolonged mechanical ventilation, and cardiac arrest. Compared with the open approach, the MIS approach is associated with higher rates of postoperative VTE in patients undergoing DP. The majority of these events are diagnosed after hospital discharge.

Familial adenomatous polyposis (FAP) patients are at risk for numerous malignancies. Multiple surgeries exist to mitigate the risk of colorectal cancer. Surgeons must weigh future quality of life versus the risk of dysplasia. As FAP patient longevity increases, there remains a risk of other malignancies. This study examines surgical interventions, development of cancers, and causes of mortality in a FAP registry. Patients with FAP or attenuated FAP (aFAP) were identified by linking the Hereditary Gastrointestinal Cancer Registry with University of Utah’s medical records. Patients without sufficient information were excluded. Patient demographics, surgical histories, cancer diagnoses, and causes of death were extracted. Logrank and Fisher’s exact tests were employed to detect significant differences between groups. After exclusion criteria, 140 patients were analyzed. Sixty patients (42.9%) underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA) followed by 50 (35.7%) having total colectomy with ileorectal anastomosis (IRA). IPAA patients were more likely female (p = 0.01) and have FAP (p

Background Hip osteoarthritis (OA) limits lower extremity physical function. Exercise therapy may improve physical function and reduce pain in patients with hip OA. Objective To evaluate the feasibility of a randomized controlled trial (RCT) to measure the effect of a structured hip-specific resistance and aerobic exercise program on physical function and self-reported pain in adults with hip OA. Design Pilot RCT. Setting Academic medical center. Participants Thirty one adults with radiographic hip OA. Interventions Participants were randomly allocated in a 2:1 ratio to a 3-month structured exercise intervention (n = 21) or a 3-month waitlist control (n = 10). Main outcome measures The 6-minute walk test was the primary outcome measure. Self-reported physical function was assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale and pain visual analog scale (VAS). Measures of feasibility were assessed as secondary outcomes. Results From baseline to 3 months, the median change from baseline in distance covered during the 6-minute walk test in the intervention group (49 m) was double that of the control group (22 m), but the difference was not statistically significant (P = .13). Likewise, the WOMAC physical function subscale score median changes in the intervention group (5 points) were double that of the controls (2 points), although the difference was not statistically significant (P = .06). Median change in pain scores was slightly reduced in each group but not significantly different between groups (P = .53). Conclusion Although no statistically significant between-group differences were found in this pilot RCT, improvements were seen in measures of physical function compared to controls. A larger RCT of this structured exercise program may be warranted.

Perioperative blood transfusion is common after pancreaticoduodenectomy (PD) and may predispose patients to infectious complications. The purpose of this study is to examine the association between perioperative blood transfusion and the development of post-surgical infection after PD.Patients who underwent PD from 2014 to 2015 were identified in the NSQIP pancreas-specific database. Logistic regression analysis was used to compute adjusted odds ratios (aOR) to identify an independent association between perioperative red blood cell transfusion (within 72 h of surgery) and the development of post-operative infection after 72 h.A total of 6869 patients underwent PD during this time period. Of these, 1372 (20.0%) patients received a perioperative blood transfusion. Patients receiving transfusion had a higher rate of post-operative infection (34.7% vs 26.5%, p 0.001). After adjusting for significant covariates, perioperative transfusion was independently associated the subsequent development of any post-operative infection (aOR 1.41 [1.23-1.62], p 0.001), including pneumonia (aOR 2.01 [1.48-2.74], p 0.001), sepsis (aOR 1.62 [1.29-2.04], p 0.001), and septic shock (aOR 1.92 [1.38-2.68], p 0.001).There is a strong independent association between perioperative blood transfusion and the development of subsequent post-operative infection following PD.

Background:We describe a thick fascial band arising from the medial aspect of the lateral plantar aponeurosis diving deep into the forefoot crossing over a branch of the lateral plantar nerve. Because a review of current literature resulted in limited and outdated sources, we sought to first determine the frequency of this fascial band and the location where it crosses the lateral plantar nerve and, second, discuss the clinical applications these anatomical findings could have.Methods:50 pairs of cadaveric feet (n = 100) were dissected to investigate for presence of the fascial band and its interaction with the lateral plantar nerve. Images were taken of each foot with the fascial band. ImageJ was used to take 2 measurements assessing the relationship of the tuberosity of the base of the fifth metatarsal to where the nerve crossed deep to the fascial band.Results:Overall, 38% of the feet possessed the fascial band. It was found unilaterally in 10 pairs and bilaterally in 14 pairs. On average, the point at which the lateral plantar nerve passed deep to the fascial band was 2.0 cm medial and 1.7 cm anterior to the tuberosity of the base of the fifth metatarsal.Conclusion:When present, the deep band of the lateral plantar aponeurosis (PA) was consistently found to be crossing the lateral plantar nerve. The discovery of the location where this most commonly occurs has not been previously reported and adds an interesting dimension that elevates an anatomical study to one that has clinical potential.Clinical Relevance:The established target zone gives a precise location for where the relationship between the deep band of the lateral PA and the lateral plantar nerve exists when evaluating the foot. The target zone provides a potential springboard for future investigations concerning said relationship clinically.

Mitochondrial decline is a hallmark of aging, and cells are equipped with many systems to regulate mitochondrial structure and function in response to stress and metabolic alterations. Here, using budding yeast, we identify a proteolytic pathway that contributes to alterations in mitochondrial structure in aged cells through control of the mitochondrial fusion GTPase Fzo1. We show that mitochondrial fragmentation in old cells correlates with reduced abundance of Fzo1, which is triggered by functional alterations in the vacuole, a known early event in aging. Fzo1 degradation is mediated by a proteolytic cascade consisting of the E3 ubiquitin ligases SCFMdm30and Rsp5, and the Cdc48 cofactor Doa1. Fzo1 proteolysis is activated by metabolic stress that arises from vacuole impairment, and loss of Fzo1 degradation severely impairs mitochondrial structure and function. Together, these studies identify a new mechanism for stress-responsive regulation of mitochondrial structure that is activated during cellular aging.

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure, with ~70% of DCM cases considered idiopathic. We showed recently, through genetic ablation of the MGAT1 gene, which encodes an essential glycosyltransferase (GlcNAcT1), that prevention of cardiomyocyte hybrid/complex N-glycosylation was sufficient to cause DCM that led to heart failure and early death. Our findings are consistent with increasing evidence suggesting a link between aberrant glycosylation and heart diseases of acquired and congenital etiologies. However, the mechanisms by which changes in glycosylation contribute to disease onset and progression remain largely unknown. Activity and gating of voltage-gated Na+ and K+ channels (Nav and Kv respectively) play pivotal roles in the initiation, shaping and conduction of cardiomyocyte action potentials (APs) and aberrant channel activity was shown to contribute to cardiac disease. We and others showed that glycosylation can impact Nav and Kv function; therefore, here, we investigated the effects of reduced cardiomyocyte hybrid/complex N-glycosylation on channel activity to investigate whether chronic aberrant channel function can contribute to DCM. Ventricular cardiomyocytes from MGAT1 deficient (MGAT1KO) mice display prolonged APs and pacing-induced aberrant early re-activation that can be attributed to, at least in part, a significant reduction in Kv expression and activity that worsens over time suggesting heart disease-related remodeling. MGAT1KO Nav demonstrate no change in expression or maximal conductance but show depolarizing shifts in voltage-dependent gating. Together, the changes in MGAT1KO Nav and Kv function likely contribute to observed anomalous electrocardiograms and Ca2+ handling. These findings provide insight into mechanisms by which altered glycosylation contributes to DCM through changes in Nav and Kv activity that impact conduction, Ca2+ handling and contraction. The MGAT1KO can also serve as a useful model to study the effects of aberrant electrical signaling on cardiac function and the remodeling events that can occur with heart disease progression.

Tandem-running is a recruitment behaviour in ants that has been described as a form of teaching, where spatial information possessed by a leader is conveyed to following nestmates. Within Temnothorax ants, tandem-running is used within a variety of contexts, from foraging and nest relocation to-in the case of slavemaking species-slave raiding. Here, we elucidate the transcriptomic basis of scouting, tandem-leading and tandem-following behaviours across two species with divergent lifestyles: the slavemaking Temnothorax americanus and its primary, nonparasitic host T. longispinosus. Analysis of gene expression data from brains revealed that only a small number of unique differentially expressed genes are responsible for scouting and tandem-running. Comparison of orthologous genes between T. americanus and T. longispinosus suggests that tandem-running is characterized by species-specific patterns of gene usage. However, within both species, tandem-leaders showed gene expression patterns median to those of scouts and tandem-followers, which was expected, as leaders can be recruited from either of the other two behavioural states. Most importantly, a number of differentially expressed behavioural genes were found, with functions relating to learning and memory formation in other social and nonsocial insects. This includes a number of up-regulated receptor genes such as a glutamate and dopamine receptor, as well as serine/threonine-protein phosphatases and kinases. Learning and memory genes were specifically up-regulated within scouts and tandem-followers, not only reinforcing previous behavioural studies into how Temnothorax navigate novel environments and share information, but also providing insight into the molecular underpinnings of teaching and learning within social insects.

Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation. Various physiologic conditions and disease states alter bile composition and metabolism, thus increasing the risk of developing gallstones.

Background Olecranon osteotomy is a commonly used method for obtaining adequate exposure of the articular surface in complex distal humeral fractures. We describe a new technique whereby a precontoured olecranon plate is first fixed to the olecranon, and a Gigli saw is used to perform the osteotomy while the plate is in place. Methods By use of a standard posterior approach, a precontoured olecranon plate is applied to the olecranon and affixed with screws both proximally and distally to the planned osteotomy site. A Gigli saw is passed anterior to the olecranon and is used to create an osteotomy through the bare area of the sigmoid notch. The plate is removed from the distal fragment. The proximal olecranon fragment, plate, and extensor mechanism are retracted proximally en bloc to expose the articular surface. After fracture repair, the osteotomy fragments are reapproximated, and the plate is reattached to the distal fragment. QuickDASH (short version of the Disabilities of the Arm, Shoulder and Hand questionnaire) and Veterans RAND 12-Item Health Survey (VR-12) scores for patients treated with this technique were compared with those of patients treated with the standard chevron osteotomy method. Results All patients achieved radiographic and clinical union of the osteotomy site. QuickDASH, VR-12 physical, and VR-12 mental scores were not significantly different from those of patients in the chevron osteotomy group ( P = .93, P = .79, and P = .68, respectively; t test). Conclusion The described method provides excellent visualization of the joint, is less technically challenging than the standard chevron osteotomy, and reduces operative time. Osteotomy union was attained in all 5 cases, with functional outcomes comparable with those attained with the chevron technique.

Case We describe a 71-year-old patient with inclusion body myositis (IBM), characterized by progressive atrophy and weakness in his left upper extremity. This patient underwent extensor carpi radialis longus to flexor pollicis longus and brachioradialis to flexor digitorum profundus tendon transfers in the left upper extremity to reduce IBM-related functional deficits. He had noticeable improvements in finger flexion after the transfers, which have been sustained for 2 years after the procedure. Conclusion This case reinforces that this novel tendon transfer may be an effective treatment option to improve hand function and activities of daily living in patients with IBM.

Importance Controlling antimicrobial resistance in health care is a public health priority, although data describing antimicrobial use in US nursing homes are limited. Objective To measure the prevalence of antimicrobial use and describe antimicrobial classes and common indications among nursing home residents. Design, Setting, and Participants Cross-sectional, 1-day point-prevalence surveys of antimicrobial use performed between April 2017 and October 2017, last survey date October 31, 2017, and including 15 276 residents present on the survey date in 161 randomly selected nursing homes from selected counties of 10 Emerging Infections Program (EIP) states. EIP staff reviewed nursing home records to collect data on characteristics of residents and antimicrobials administered at the time of the survey. Nursing home characteristics were obtained from nursing home staff and the Nursing Home Compare website. Exposures Residence in one of the participating nursing homes at the time of the survey. Main Outcomes and Measures Prevalence of antimicrobial use per 100 residents, defined as the number of residents receiving antimicrobial drugs at the time of the survey divided by the total number of surveyed residents. Multivariable logistic regression modeling of antimicrobial use and percentages of drugs within various classifications. Results Among 15 276 nursing home residents included in the study (mean [SD] age, 77.6 [13.7] years; 9475 [62%] women), complete prevalence data were available for 96.8%. The overall antimicrobial use prevalence was 8.2 per 100 residents (95% CI, 7.8-8.8). Antimicrobial use was more prevalent in residents admitted to the nursing home within 30 days before the survey date (18.8 per 100 residents; 95% CI, 17.4-20.3), with central venous catheters (62.8 per 100 residents; 95% CI, 56.9-68.3) or with indwelling urinary catheters (19.1 per 100 residents; 95% CI, 16.4-22.0). Antimicrobials were most often used to treat active infections (77% [95% CI, 74.8%-79.2%]) and primarily for urinary tract infections (28.1% [95% CI, 15.5%-30.7%]). While 18.2% (95% CI, 16.1%-20.1%) were for medical prophylaxis, most often use was for the urinary tract (40.8% [95% CI, 34.8%-47.1%]). Fluoroquinolones were the most common antimicrobial class (12.9% [95% CI, 11.3%-14.8%]), and 33.1% (95% CI, 30.7%-35.6%) of antimicrobials used were broad-spectrum antibiotics. Conclusions and Relevance In this cross-sectional survey of a cohort of US nursing homes in 2017, prevalence of antimicrobial use was 8.2 per 100 residents. This study provides information on the patterns of antimicrobial use among these nursing home residents.

Trauma pancreaticoduodenectomy (TP) remains a challenging operation with morbidity and mortality rates as high as 80% and 50%. Many trauma surgeons consider it surgical dogma to avoid performing a TP during the index operation for patients with severe pancreatic or duodenal injuries. However, there is no modern analysis evaluating this belief. Therefore, we hypothesized no difference in risk of mortality between patients with severe pancreatic or duodenal injury undergoing a TP for penetrating trauma to propensity-matched controls undergoing laparotomy without TP. The Trauma Quality Improvement Program (2010-2016) was queried for adults with severe penetrating pancreatic or duodenal injuries undergoing laparotomy. A 1:2 propensity-matching including demographics/comorbidities, injury severity score, vitals on admission, Glasgow Coma Scale and concomitant injuries for laparotomy with or without TP was performed. Risk of mortality was reported using a univariable logistic regression model. Of 2182 patients with severe pancreatic or duodenal injuries undergoing laparotomy, 54 (2.5%) underwent TP and 2128 (97.5%) underwent laparotomy without TP. There were no differences in propensity-matching characteristics. Patients undergoing TP had a similar mortality rate (20.0% vs. 28.7%, p = 0.302) but a longer length of stay (LOS) (27.5 vs. 16.5days, p = 0.017). The TP group had a similar associated risk of mortality (OR = 0.62, p = 0.302) but higher risk of major complications (OR 3.44, CI 1.35-17.47, p = 0.015). In appropriately selected penetrating trauma patients with severe pancreatic/duodenal injuries, TP is associated with a similar risk of mortality compared to laparotomy without TP. However, TP patients did have an increased associated risk of major complications and longer LOS.

BACKGROUND [18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment. METHODS Two single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer. RESULTS Thirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding. CONCLUSION [18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker. TRIAL REGISTRATION ClinicalTrials.gov identifiers NCT03083288 and NCT03846167. FUNDING Metavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge., Human PARP inhibitor drug-target engagement can be visualized, with future possibilities including a precision diagnostic and drug discovery tool.

Current search systems are effective in helping users complete simple search tasks (e.g., fact-finding). However, they provide less support for users completing complex search tasks. Complex search tasks involve a diverse set of cognitive and metacognitive activities, such as goal-setting, organizing information, drawing inferences, monitoring progress, and updating mental models. We report on a lab study (N=32) that investigated the uses and influences of a novel knowledge representation tool called the "OrgBox'', developed to support searchers with complex tasks. The OrgBox was integrated into a custom-built search system and allowed participants to save information by drag-and-dropping textual passages into the tool, organize passages into "boxes'', and make notes on passages and boxes. The OrgBox tool was compared to a baseline tool (the "Bookmark'') that allowed participants to save passages, but not organize them nor make notes. We investigate four research questions. In RQ1, we investigate the effects of the knowledge representation tool on participants' post-task perceptions. In RQ2-RQ4, we investigate: (RQ2) how participants used different features of each tool; (RQ3) the perceived benefits and challenges of each tool; and (RQ4) the influences of each tool on the approaches taken by participants to complete the task. To address RQ2-RQ4, we conducted a qualitative analysis of participants' responses during an exit interview. We discuss implications from our results for designing tools to support users with complex search tasks.

Learning the underlying details of a gene network with feedback is critical in designing new synthetic circuits. Yet, quantitative characterization of these circuits remains limited. This is due to the fact that experiments can only measure partial information from which the details of the circuit must be inferred. One potentially useful avenue is to harness hidden information from single-cell stochastic gene expression time trajectories measured for long periods of time—recorded at frequent intervals—over multiple cells. This raises the feasibility vs. accuracy dilemma while deciding between different models of mining these stochastic trajectories. We demonstrate that inference based on the Maximum Caliber (MaxCal) principle is the method of choice by critically evaluating its computational efficiency and accuracy against two other typical modeling approaches: (i) a detailed model (DM) with explicit consideration of multiple molecules including protein-promoter interaction, and (ii) a coarse-grain model (CGM) using Hill type functions to model feedback. MaxCal provides a reasonably accurate model while being significantly more computationally efficient than DM and CGM. Furthermore, MaxCal requires minimal assumptions since it is a top-down approach and allows systematic model improvement by including constraints of higher order, in contrast to traditional bottom-up approaches that require more parameters or ad hoc assumptions. Thus, based on efficiency, accuracy, and ability to build minimal models, we propose MaxCal as a superior alternative to traditional approaches (DM, CGM) when inferring underlying details of gene circuits with feedback from limited data.

In the analysis of large-scale network data, a fundamental operation is the comparison of observed phenomena to the predictions provided by null models: when we find an interesting structure in a family of real networks, it is important to ask whether this structure is also likely to arise in random networks with similar characteristics to the real ones. A long-standing challenge in network analysis has been the relative scarcity of reasonable null models for networks; arguably the most common such model has been the configuration model, which starts with a graph $G$ and produces a random graph with the same node degrees as $G$. This leads to a very weak form of null model, since fixing the node degrees does not preserve many of the crucial properties of the network, including the structure of its subgraphs. Guided by this challenge, we propose a new family of network null models that operate on the $k$-core decomposition. For a graph $G$, the $k$-core is its maximal subgraph of minimum degree $k$; and the core number of a node $v$ in $G$ is the largest $k$ such that $v$ belongs to the $k$-core of $G$. We provide the first efficient sampling algorithm to solve the following basic combinatorial problem: given a graph $G$, produce a random graph sampled nearly uniformly from among all graphs with the same sequence of core numbers as $G$. This opens the opportunity to compare observed networks $G$ with random graphs that exhibit the same core numbers, a comparison that preserves aspects of the structure of $G$ that are not captured by more local measures like the degree sequence. We illustrate the power of this core-based null model on some fundamental tasks in network analysis, including the enumeration of networks motifs.

The microbial communities living on and in vertebrate hosts have myriad effects on their hosts, potentially including fitness and speciation. Microbiomes are influenced by both intrinsic (from the host) and extrinsic (from the environment) factors, but the relative contributions of each are unknown for most non-model species. Abiotic environmental factors can influence the microbiome directly but it is less clear how abiotic gradients shape microbiome communities in the wild. Here, we captured eight wild Anna’s hummingbirds from three different elevations along their elevational distribution in California and moved them directly to a middle (“Within Range”) elevation. After some time at this elevation, the birds were moved in captivity to an “Above Range” elevation, and two birds were later moved back to the Within Range elevation. Fecal and food samples were collected longitudinally and the V4 region of the 16S rRNA gene analyzed. The most abundant phyla in all samples were Fusobacteria, Firmicutes, Actinobacteria, and Proteobacteria. Individual Bird ID explained the greatest amount of microbiome variation at 27.5%, signifying some amount of stability in the Anna’s hummingbird fecal microbiome. Sample elevation explained 19.6% (p = 0.001) of the variation using weighted UniFrac, but only 2.0% (p = 0.047) using unweighted UniFrac, implying a change in abundance of bacterial lineages in the microbiome but not in the presence or absence of the microbes. Additionally, Fusobacteria were 7.0x more abundant in the Above Range elevation samples while Firmicutes were 0.3x lower. A thorough understanding of how the environment can shape the microbiome may assist in conservation efforts and a general understanding of host-microbiome relationships in an era of rapid and global environmental change.

To control reaching, the nervous system must generate large changes in muscle activation to drive the limb toward the target, and must also make smaller adjustments for precise and accurate behavior. Motor cortex controls the arm through projections to diverse targets across the central nervous system, but it has been challenging to identify the roles of cortical projections to specific targets. Here, we selectively disrupt cortico-cerebellar communication in the mouse by optogenetically stimulating the pontine nuclei in a cued reaching task. This perturbation did not typically block movement initiation, but degraded the precision, accuracy, duration, or success rate of the movement. Correspondingly, cerebellar and cortical activity during movement were largely preserved, but differences in hand velocity between control and stimulation conditions predicted from neural activity were correlated with observed velocity differences. These results suggest that while the total output of motor cortex drives reaching, the cortico-cerebellar loop makes small adjustments that contribute to the successful execution of this dexterous movement.

Methods We carried out a retrospective cohort study of patients with BR after primary treatment of PC who received imaging with 18F-fluciclovine PET/CT at our institution between January 2010 and January 2019. PET/CT results were compared with biopsy, conventional imaging results, and/or response to PC therapy. 18F-Fluciclovine PET/CT performance statistics and effects on treatment planning were calculated. Results A total of 328 patients with a median age of 71 years (range, 47-90 years) and median serum prostate-specific antigen level of 1.6 ng/mL (0.02-186.7 ng/mL) were included. Three hundred thirty-six 18F-fluciclovine PET/CT scans were analyzed and classified as positive (65%), negative (25%), or equivocal (10%) based on radiology reports. Sensitivity was 93% (95% confidence interval, 86%-96%) and specificity was 63% (95% confidence interval, 45%-77%). Of patients with known management recommendations post-PET/CT, scan results changed or influenced pre-PET/CT management plans in 73%, and 58% of recommendations involved treatment modality decisions. Overall, 82% of patients' actual management was concordant with post-PET/CT recommendations. Of evaluable patients, 116 (35%) had some form of post-PET radiotherapy included in their care plans, with 95% receiving radiotherapy at a PET-avid target. Conclusions In the largest single-institutional cohort to date, 18F-fluciclovine PET/CT showed value in the workup of PC in the setting of BR, with noteworthy influence over clinical management decisions. Further studies are needed to evaluate whether PET/CT-based changes in management are associated with improved outcomes.

Background The objective of this study was to describe young adult cancer caregivers' exposure to cancer misinformation on social media. Methods Eligible participants were 18 to 39 years old, used social media weekly, and cared for an adult patient with cancer diagnosed 6 months to 5 years before (N = 21). Recruitment occurred from August 2017 to June 2018 in person at oncology clinics and online. Semistructured telephone interviews were recorded and analyzed with grounded theory methods through 2 rounds of coding (κ = 0.88). Results Caregivers were on average 29.1 years old, female (76.2%), non-Hispanic White (90.5%), college educated (57.1%), and caring for a spouse/partner (47.6%). Caregivers were exposed to a variety of cancer misinformation topics; some felt uncertain in their caregiving ability when confronted with cancer misinformation. Caregivers crosschecked online sources and consulted trusted individuals (eg, family, friends, and health care providers) to determine the quality of cancer-related information and manage cancer misinformation. Conclusions Cancer misinformation on social media may influence caregiving behaviors and decision making. Whether caregivers correctly and consistently identify cancer misinformation on social media is unknown. Supporting digital literacy to mitigate cancer misinformation on social media may improve young cancer caregivers' access to credible cancer information. Lay summary Cancer misinformation on social media affects young adult cancer caregivers' perceptions of their social support network. Caregivers differ in how they evaluate cancer information for quality and in how this information influences their health behaviors and caregiving decisions.

Link prediction is a common problem in network science that cuts across many disciplines. The goal is to forecast the appearance of new links or to find links missing in the network. Typical methods for link prediction use the topology of the network to predict the most likely future or missing connections between a pair of nodes. However, network evolution is often mediated by higher-order structures involving more than pairs of nodes; for example, cliques on three nodes (also called triangles) are key to the structure of social networks, but the standard link prediction framework does not directly predict these structures. To address this gap, in recent work, we propose a new link prediction task called “pairwise link prediction” that directly targets the prediction of new triangles, where one is tasked with finding which nodes are most likely to form a triangle with a given edge. We extend this work in this manuscript, and we evaluate a variety of natural extensions to link prediction methods including neighborhood and PageRank-based methods. A key difference from our previous work is the definition of the neighborhood of an edge, which has a surprisingly large impact on the empirical performance. Our experiments on a variety of networks show that diffusion-based methods are less sensitive to the type of graphs used and more consistent in their results. We also show how our pairwise link prediction framework can be used to get better predictions within the context of standard link prediction evaluation.

To explore how family/friend young adult cancer caregivers (YACC) used social media for social support in a cross-sectional retrospective mixed-methods study. Eligible YACC were recruited online and in-person from September 2017 to June 2018, were 18–39 years, used social media weekly, and cared for an adult cancer patient diagnosed 6 months–5 years prior (N = 34). Social media posts were randomly sampled, and content analyzed for five types of social support (emotional, informational, validation, companionship, instrumental). Generalized linear models were fit to estimate changes in the prevalence of social support in posts over the 6-month period following diagnosis. The investigators analyzed N = 2090 social media posts, 26.9% made by YACC, and 73.1% by followers; 36.8% were cancer-related. The most common type of social support for YACC on social media was emotional (63.3%), followed by informational (27.7%), validation (15.3%), companionship (5.7%), and instrumental (1.3%). When controlling for platform (e.g., Instagram), the odds of posts containing emotional support decreased significantly over the first 6 months of caregiving (adjusted odds ratio [aOR]: 0.90, 95%CI 0.85–0.94), while informational (aOR: 1.15, 95%CI 1.09–1.21) and companionship (aOR: 1.12, 95%CI 1.02–1.24) support increased. YACC and their followers share emotional and informational support on social media. Next steps should determine how social media may improve (e.g., social support) or hinder (e.g., misinformation) cancer caregiving throughout survivorship. Caregivers and patients should be aware of possible fluctuations in social media support after diagnosis and the utility of using social media for different types of social support.

Objective The aim of this study is to assess the diagnostic yield and economic cost of radiologic imaging for urgent and emergent ophthalmic conditions in an emergency room (ER) setting Design Retrospective, consecutive case series. Methods Charts of all patients who underwent radiologic imaging in a dedicated eye ER over a single year were reviewed. Data collected included age, patient reported chief complaint, visual acuity, principal examination finding, indication for imaging, imaging modalities performed, and the current procedural terminology (CPT) codes billed for the imaging performed. Imaging results were classified into three groups with binary outcomes: normal or abnormal; significant if it led to a change in patient management, and relevant if the imaging findings were related to the chief complaint or principal examination finding. Imaging costs were calculated using the billed CPT codes. Results A total of 14,961 patients were evaluated during the 1-year study and 1,371 (9.2%) patients underwent imaging. Of these, 521 patients (38.0%) had significant findings. A majority of this group had significant and relevant findings (469, 34.2% of total). Subgroup analysis was performed based upon patient chief complaint, principal examination finding, and indication for imaging. Overall, the total cost of imaging was $656,078.34 with an average cost of $478.54 per patient. Conclusion Imaging for urgent and emergent ophthalmic conditions in an eye ER resulted in significant management changes in 38.0% of patients. Radiographic imaging contributes to healthcare expenditures; however, these costs must be weighed against the substantial costs of delayed and misdiagnoses, especially when patients present with acute ophthalmological symptoms.

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58–71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098–0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042–7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p, Highlights • Patients receiving tocilizumab within 12 days of COVID-19 symptom onset had an increase in 28 day in-hospital survival. • A higher severity of illness prior to tocilizumab administration was associated with increased mortality. • Secondary infections occurred in 22.2% receiving tocilizumab, but infection was not associated with increased mortality.

Traditionally, two-dimensional (2D) monolayer cell culture models have been used to study in vitro conditions for their ease of use, simplicity and low cost. However, recently, three-dimensional (3D) cell culture models have been heavily investigated as they provide better physiological relevance for studying various disease behaviors, cellular activity and pharmaceutical interactions. Typically, small-sized tumor spheroid models (100&ndash, 500 &mu, m) are used to study various biological and physicochemical activities. Larger, millimetric spheroid models are becoming more desirable for simulating native tumor microenvironments (TMEs). Here, we assess the use of ultra-large spheroid models (~2000 &mu, m) generated from scaffolds made from a nozzle-free, ultra-high resolution printer, these models are explored for assessing chemotherapeutic responses with molecular doxorubicin (DOX) and two analogues of DoxilⓇ (Dox-NPⓇ, DoxovesTM) on MDA-MB-231 and MCF-7 breast cancer cell lines. To provide a comparative baseline, small spheroid models (~500 &mu, m) were developed using a self-aggregation method of MCF-7 breast cancer cell lines, and underwent similar drug treatments. Analysis of both large and small MCF-7 spheroids revealed that Dox-NP tends to have the highest level of inhibition, followed by molecular doxorubicin and then Doxoves. The experimental advantages and drawbacks of using these types of ultra-large spheroids for cancer research are discussed.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A–treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

The Src family of non-receptor tyrosine kinases are frequently activated in pancreatic ductal adenocarcinoma (PDAC), contributing to disease progression through downregulation of E-cadherin and induction of epithelial-to-mesenchymal transition (EMT). The purpose of this study was to examine the efficacy of Src kinase inhibition in restoring E-cadherin levels in PDAC. Immunohistochemical analysis of human PDAC samples showed Src activation is inversely correlated with E-cadherin levels. Protein and mRNA levels of E-cadherin, the gene expression of its various transcriptional repressors (Zeb1, Snail, Slug, LEF-1, TWIST), and changes in sub-cellular localization of E-cadherin/β-catenin in PDAC cells were characterized in response to treatment with the Src inhibitor, dasatinib (DST). DST repressed Slug mRNA expression, promoted E-cadherin transcription, and increased total and membranous E-cadherin/β-catenin levels in drug-sensitive PDAC cells (BxPC3 and SW1990), however no change was observed in drug-resistant PANC1 cells. BxPC3, PANC1, and MiaPaCa-2 flank tumor xenografts were treated with DST to examine changes in E-cadherin levels in vivo. Although DST inhibited Src phosphorylation in all xenograft models, E-cadherin levels were only restored in BxPC3 xenograft tumors. These results suggest that Src kinase inhibition reverses EMT in drug-sensitive PDAC cells through Slug-mediated repression of E-cadherin and identifies E-cadherin as potential biomarker for determining response to DST treatment.

Background There is no proven antiviral or immunomodulatory therapy for coronavirus disease 2019 (COVID-19). The disease progression associated with the proinflammatory host response prompted us to examine the role of early corticosteroid therapy in patients with moderate to severe COVID-19. Methods We conducted a single pretest, single posttest quasi-experiment in a multicenter health system in Michigan from 12 March to 27 March 2020. Adult patients with confirmed moderate to severe COVID were included. A protocol was implemented on 20 March 2020 using early, short-course, methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. Outcomes of standard of care (SOC) and early corticosteroid groups were evaluated, with a primary composite endpoint of escalation of care from ward to intensive care unit (ICU), new requirement for mechanical ventilation, and mortality. All patients had at least 14 days of follow-up. Results We analyzed 213 eligible subjects, 81 (38%) and 132 (62%) in SOC and early corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the early corticosteroid group (34.9% vs 54.3%, P = .005). This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (5 vs 8 days, P < .001). Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14-days controlling for other factors (adjusted odds ratio: 0.41; 95% confidence interval, .22 – .77). Conclusions An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes. Clinical Trials Registration NCT04374071.

Background and aims Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. Approach and results In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. Conclusions These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.