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Marissa C Salvo,1 Amie D Brooks,2 Stacey M Thacker3 1Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, 2Department of Pharmacy Practice, St Louis College of Pharmacy, St Louis, MO, 3Department of Pharmacy Practice, Southern Illinois University Edwardsville, Edwardsville, IL, USA Abstract: Type 2 diabetes affects more than 350 million people worldwide, and its prevalence is increasing. Many patients with diabetes do not achieve and/or maintain glycemic targets, despite therapy implementation and escalation. Multiple therapeutic classes of agents are available for the treatment of type 2 diabetes, and the armamentarium has expanded significantly in the past decade. Selective sodium glucose co-transporter 2 inhibitors, including dapagliflozin, represent the latest development in pharmacologic treatment options for type 2 diabetes. This class has a unique mechanism of action, working by increasing glucose excretion in the urine. The insulin-independent mechanism results in decreased serum glucose, without hypoglycemia or weight gain. Dapagliflozin is a once-daily oral therapy. Expanding therapy options for a complex patient population is critical, and dapagliflozin has a distinct niche that can be a viable option for select patients with diabetes. Keywords: SGLT2 inhibitor, selective sodium glucose co-transporter 2 inhibitors, pharmacological treatment

Given mounting evidence for working memory impairments in dyslexia, letter reversals during rapid automatic letter naming (phonological loop) or rapid automatic letter writing (orthographic loop) may reflect momentary inefficiency of working memory. Few of the children, with or without dyslexia, in a multi-generational family genetics study, produced reversals, but those with dyslexia produced more than those without dyslexia. Working-memory component predictors (word storing and processing units, phonological and orthographic loops, and executive functions) in regressions differentiated children with dyslexia (average age 11) who did and did not make reversals, predicted the number of reversals on specific letter naming or letter writing tasks, and explained unique variance in reading and writing outcomes. Although reversals are not a hallmark defining feature of dyslexia, children who produce reversals may benefit from instruction designed to develop specific working memory components and their efficient coordination in time. [ABSTRACT FROM AUTHOR]

Background: Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. METHODS; Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided.Results: Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity.Conclusion: Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors. [ABSTRACT FROM AUTHOR]

PURPOSE: An evaluation of the effectiveness of a program at achieving improved glycemic control, lipid levels, and adherence to preventive care measures in diabetes mellitus patients was conducted. SUMMARY: An interdisciplinary diabetes health management program (DHMP) was implemented, which included physicians, clinical pharmacists, registered nurses, and registered dieticians. The patients are seen by a clinical pharmacist with the option of individual or group visits with other members of the multidisciplinary team. Clinical pharmacist interventions include education and comprehensive medication management through collaborative practice agreements held with physicians. The collaborative agreements allow the clinical pharmacist to initiate, adjust, or discontinue pharmacotherapy and order pertinent laboratory tests and podiatry referrals that are within the scope of the medication management protocol. A retrospective review was conducted of the 707 patients enrolled in the program between April 2002 and April 2004. The mean +/- S.D. number of days between baseline and follow-up values was 140 +/- 62. Eighty-four percent of the enrolled patients were diagnosed with type 2 diabetes mellitus, 69% met the National Cholesterol Education Program's criteria for metabolic syndrome, and 51% were male. The mean glycosylated hemoglobin (HbA(1c)) value dropped significantly, and the percentage of patients who were at or below the American Diabetes Association's established HbA(1c) goal of

Abstract Background A large proportion of people attending residential alcohol and other substance abuse treatment have a co-occurring mental illness. Empirical evidence suggests that it is important to treat both the substance abuse problem and co-occurring mental illness concurrently and in an integrated fashion. However, the majority of residential alcohol and other substance abuse services do not address mental illness in a systematic way. It is likely that computer delivered interventions could improve the ability of substance abuse services to address co-occurring mental illness. This protocol describes a study in which we will assess the effectiveness of adding a computer delivered depression and substance abuse intervention for people who are attending residential alcohol and other substance abuse treatment. Methods/Design Participants will be recruited from residential rehabilitation programs operated by the Australian Salvation Army. All participants who satisfy the diagnostic criteria for an alcohol or other substance dependence disorder will be asked to participate in the study. After completion of a baseline assessment, participants will be randomly assigned to either a computer delivered substance abuse and depression intervention (treatment condition) or to a computer-delivered typing tutorial (active control condition). All participants will continue to complete The Salvation Army residential program, a predominantly 12-step based treatment facility. Randomisation will be stratified by gender (Male, Female), length of time the participant has been in the program at the commencement of the study (4 weeks or less, 4 weeks or more), and use of anti-depressant medication (currently prescribed medication, not prescribed medication). Participants in both conditions will complete computer sessions twice per week, over a five-week period. Research staff blind to treatment allocation will complete the assessments at baseline, and then 3, 6, 9, and 12 months post intervention. Participants will also complete weekly self-report measures during the treatment period. Discussion This study will provide comprehensive data on the effect of introducing a computer delivered, cognitive behavioral therapy based co-morbidity treatment program within a residential substance abuse setting. If shown to be effective, this intervention can be disseminated within other residential substance abuse programs. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000618954

Objective: To collaboratively develop a hybrid virtual curriculum for a medical school surgery clerkship within an emerging medical university in Vietnam., Design: A hybrid virtual surgery clerkship curriculum was collaboratively developed by Vietnamese and American surgeons as part of an international partnership between their respective universities. A set of 25 virtual lectures with associated materials were created and deployed in tandem with live, in-person review and skills sessions. Student quantitative and qualitative evaluation methods were developed and deployed to allow continuous iteration. A 6-month course was deployed to develop surgical faculty into effective teachers., Setting: The curriculum was deployed at VinUniversity College of Health Sciences, the youngest medical university in Vietnam. It was developed in collaboration with the University of Pennsylvania Perelman School of Medicine. Each cohort of 12 students in the surgical clerkship will participate in the curriculum., Conclusions: The development of this hybrid surgical clerkship in Vietnam leveraged local resources and expertise with those available remotely. Lessons learned are directly applicable to future collaborative curriculum development efforts at other emerging medical schools., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Our aim was to assess how ChatGPT compares to Google search in assisting medical students during their surgery clerkships., Design: We conducted a crossover study where participants were asked to complete 2 standardized assessments on different general surgery topics before and after they used either Google search or ChatGPT., Setting: The study was conducted at the Perelman School of Medicine at the University of Pennsylvania (PSOM) in Philadelphia, Pennsylvania., Participants: 19 third-year medical students participated in our study., Results: The baseline (preintervention) performance of participants on both quizzes did not differ between the Google search and ChatGPT groups (p = 0.728). Students overall performed better postintervention and the difference in test scores was statistically significant for both the Google group (p < 0.001) and the ChatGPT group (p = 0.01). The mean percent increase in test scores pre- and postintervention was higher in the Google group at 11% vs. 10% in the ChatGPT group, but this difference was not statistically significant (p = 0.87). Similarly, there was no statistically significant difference in postintervention scores on both assessments between the 2 groups (p = 0.508). Postassessment surveys revealed that all students (100%) have known about ChatGPT before, and 47% have previously used it for various purposes. On a scale of 1 to 10 with 1 being the lowest and 10 being the highest, the feasibility of ChatGPT and its usefulness in finding answers were rated as 8.4 and 6.6 on average, respectively. When asked to rate the likelihood of using ChatGPT in their surgery rotation, the answers ranged between 1 and 3 ("Unlikely" 47%), 4 to 6 ("intermediate" 26%), and 7 to 10 ("likely" 26%)., Conclusion: Our results show that even though ChatGPT was comparable to Google search in finding answers pertaining to surgery questions, many students were reluctant to use ChatGPT for learning purposes during their surgery clerkship., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Stereotypes of surgeons are pervasive and play a role in medical students' decisions about pursuing a surgical career. This study aimed to determine: (1) how medical students' perceptions of surgery and surgeons changed following exposure to surgery during clerkship rotations; and (2) if gender and racial/ethnic identification played a role in this process., Design, Setting, and Participants: In this mixed-method study, clerkship students at one U.S. medical school were asked to anonymously contribute words and phrases that they associated with surgery to an online "word cloud" at the beginning and end of their 12-week surgery clerkship. In addition, an end-of-year, anonymous survey of their perceptions was administered and analyzed using a Grounded Theory approach., Results: Of 154 students invited to complete the online survey, analysis of 24 completed surveys suggested that students believe surgical culture to be toxic, with unfriendly attitudes, strict hierarchy, and lack of work-life balance. Analysis of 678 Word Cloud responses, however, indicated that the frequency of complimentary responses increased following surgery clerkships (25% vs 36%; z = -3.26; p = 0.001), while the proportion of responses describing surgery/surgeons as male-dominated, egotistical, and scary decreased (5% vs 1%, z = 2.86, p = 0.004; 9% vs 4%, z = 2.78, p = 0.005; 3% vs 0.3%, z = 2.56, p = 0.011, respectively). The association between surgeons and being White disappeared entirely. Female students were more likely than male students to state that their perceptions did not change following exposure (40% vs 0%; z = 2.19; p = 0.029)., Conclusions: With exposure to surgery, students' preconceived notions may be positively influenced. However, students continue to hold negative perceptions, and this effect may be stratified by gender identification. Institutions should work to address these perceptions in pre-clerkship years to attract a more diverse pool of future surgeons., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Patients with advanced cancer staging have a greater risk of developing venous thromboembolism than noncancer patients. The impact of breast cancer stage and treatment on outcomes after autologous free-flap breast reconstruction (ABR) is not well-established. The objective of this retrospective study is to determine the impact of breast cancer characteristics, such as cancer stage, hormone receptor status, and neoadjuvant treatments, on vascular complications of ABR., Methods: A retrospective review was conducted examining patients who underwent ABR from 2009 to 2018. Breast cancer stage, cancer types, hormone receptor status, and treatments were collected in addition to demographic data. Intraoperative vascular concerns, postoperative vascular concerns, and flap loss were analyzed. Univariate analysis and fixed-effects models were used to associate breast cancer characteristics with outcomes., Results: Neoadjuvant hormone therapy was associated with increased risk for intraoperative vascular concern (odds ratio, 1.059 [ P = 0.0441]). Neoadjuvant trastuzumab was associated with decreased risk of postoperative vascular concern (odds ratio, 0.941 [ P = 0.018]). Breast cancer stage, somatic genetic mutation, receptor types, neoadjuvant chemotherapy, and neoadjuvant radiation had no effect on any vascular complications of ABR., Conclusion: Autologous free-flap breast reconstruction is a reliable reconstructive option for patients with all stages and types of breast cancer. There is potentially increased risk of intraoperative microvascular compromise in patients who have neoadjuvant hormone therapy. Trastuzumab is potentially protective against postoperative microvascular compromise. Patients should feel confident that, despite higher stage cancer, they can pursue their desired reconstructive option without fear of vascular compromise., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Significant disparities in surgical outcomes exist. It is imperative to prepare future doctors to eliminate disparities. Our team of senior medical students developed a surgical clerkship module examining equity in prostate cancer. Student attitudes before and after a facilitated teaching session were assessed., Methods: A surgical equity pilot module was integrated into the core surgical clerkship starting in July 2020. This module was composed of (1) asynchronous preparatory material and (2) a synchronous interactive case discussion regarding disparities in prostate cancer. Discussion sessions were facilitated by upper-level medical students. Participants answered optional anonymous Likert-style and open-ended survey questions before and after the session. Pre- and post-responses were compared., Results: One hundred and sixteen students completed the module between July 2020 and January 2021. Pre- and post-survey response rates were 66% and 29%, respectively. At baseline, almost all students (95%) agreed knowledge of disparities would make them a better physician. However, the majority (95%) described their general knowledge of surgical disparities as "nonexistent," "poor," or "average." Most students did not have a framework for assessing causes of surgical disparities (86%) and were not aware of interventions for reducing disparities (90%). After intervention, the majority rated their knowledge of surgical disparities as "good" or "excellent" (71%; P < .001). Most students indicated they had a framework 79%; P < .001) and were aware of effective interventions (62%; P < .001)., Conclusion: We demonstrated a successful pilot of an equity-focused clerkship module. Student attitudes after a single session reflected significant improvement in knowledge of causes and interventions related to surgical disparities. Equity-focused teaching can be incorporated into the surgical clerkship., (Copyright © 2021. Published by Elsevier Inc.)

Viral antagonism of innate immune pathways is a common mechanism by which viruses evade immune surveillance. Infection of host cells with reovirus leads to the blockade of NF-κB, a key transcriptional regulator of the hosts' innate immune response. One mechanism by which reovirus infection results in inhibition of NF-κB is through a diminishment in levels of upstream activators, IKKβ and NEMO. Here, we demonstrate a second, distinct mechanism by which reovirus blocks NF-κB. We report that expression of a single viral protein, σ3, is sufficient to inhibit expression of NF-κB target genes. Further, σ3-mediated blockade of NF-κB occurs without changes to IκB kinase (IKK) levels or activity. Among NF-κB targets, the expression of type I interferon is significantly diminished by σ3 expression. Expression of NF-κB target genes varies following infection with closely related reovirus strains. Our genetic analysis identifies that these differences are controlled by polymorphisms in the amino acid sequence of σ3. This work identifies a new role for reovirus σ3 as a viral antagonist of NF-κB-dependent antiviral pathways. IMPORTANCE Host cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected, cells. The NF-κB family of proteins is important for the cell to mediate this response. In this study, we show that a single protein, σ3, produced by mammalian reovirus, impairs the function of NF-κB. We demonstrate that by blocking NF-κB, σ3 diminishes the hosts' response to infection to promote viral replication. This work identifies a second, previously unknown, mechanism by which reovirus blocks this aspect of the host cell response.

Background: Results of an earlier retrospective study from our institution suggested that patients with triple negative breast cancer (TNBC) who had preoperative MRI may have had an improved local recurrence rate (LRR) after breast conserving surgery (BCS). We aimed to clarify the impact of preoperative MRI on surgical outcomes in an expanded TNBC cohort treated by BCS in a contemporary era., Methods: Our study cohort comprised 648 patients with TNBC who underwent BCS between 2009 and 2018. Demographic and clinical characteristics were compared between those with (n = 292, 45.1%) and without (n = 356, 54.9%) preoperative MRI. Multivariable logistic regression was performed to assess the association of preoperative MRI with surgical outcomes., Results: The crude LRR of 3.5% was lower than previously reported. Univariable analyses demonstrated that the LRR and re-excision rates in the MRI and no-MRI groups were 3.4 and 3.7%, 21.6% and 27.2%, p = 0.876 and p = 0.10, respectively. Multivariable logistic regression analyses demonstrated that preoperative MRI was not associated with a lower LRR: odds ratio (OR) = 1.42 (p = 0.5). During our study period, new margin guidelines and shave margins practice were adopted in 2014 and 2015. To account for their effects, the year of diagnosis/surgery and other clinical variables were adjusted in multivariable logistic regression and inverse probability weighting models to demonstrate that preoperative MRI remained associated with a lower re-excision risk, OR 0.56, p = 0.04l; and a lower re-excision rate, 23.15% versus 36.0%, p < 0.01, respectively., Conclusions: Our findings suggested that patients with TNBC anticipating BCS may benefit from preoperative MRI., (© 2022. Society of Surgical Oncology.)

Physachenolide C ( 1 ) is a 17β-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C ( 1 ) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4 - 23 were prepared by chemical transformations of a readily accessible compound, physachenolide D ( 2 ). Compound 1 and its analogues 2 - 23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC 50 s below 5.0 μM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17β-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.

Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand-dependent manner. Biochemical mechanism-of-action studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8-dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome. SIGNIFICANCE: These findings demonstrate that PCC selectively sensitizes cancer cells to immune-mediated cell death, potentially improving the efficacy of cancer immunotherapies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3374/F1.large.jpg., (©2021 American Association for Cancer Research.)

Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure HIV infection. In separate studies, we have previously shown that CD8 + T cells may contribute to the maintenance of viral latency and identified a novel SMAC mimetic/IAP inhibitor (AZD5582) capable of reversing HIV/SIV latency in vivo by activating the non-canonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody-mediated depletion of CD8α + cells to further evaluate the role of CD8 + T cells in viral latency maintenance. Six rhesus macaques (RM) were infected with SIVmac239 and treated with ART starting at week 8 post-infection. After 84-85 weeks of ART, all animals received a single dose of the anti-CD8α depleting antibody (Ab), MT807R1 (50mg/kg, s.c.), followed by 5 weekly doses of AZD5582 (0.1 mg/kg, i.v.). Following CD8α depletion + AZD5582 combined treatment, 100% of RMs experienced on-ART viremia above 60 copies per ml of plasma. In comparator groups of ART-suppressed SIV-infected RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals respectively. Furthermore, the frequency of increased viremic episodes during the treatment period was greater in the CD8α depletion + AZD5582 group as compared to other groups. Mathematical modeling of virus reactivation suggested that, in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α + cell depletion., (Copyright © 2021 Mavigner et al.)

Introduction: For the over 28 million Americans without health insurance, there is a great need to develop programs that help meet the health needs of the uninsured population. Materials and Methods: We applied the Plan-Do-Study-Act (PDSA) quality improvement framework to the development, implementation, and evaluation of a breast cancer screening navigation program for un- and under-insured women. Results: Six critical steps emerged: (1) obtain program funding; (2) navigator training; (3) establish a referral base network of community partners that serve the un- and under-insured women; (4) implement a process to address the barriers to accessing mammography; (5) develop a language- and culturally-tailored messaging and media campaign; and (6) develop measures and process evaluation to optimize and expand the program's reach. Discussion: A Plan-Do-Study-Act approach allowed identification of the key elements for successful development, implementation and optimization of a breast cancer screening navigation program aimed at reaching and screening un- and underinsured women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guerra, Verderame, Nicholson, Wan and Brooks.)

Purpose: Poor health literacy and awareness are thought to be some of the major contributors to existing racial/ethnic disparities in access to breast reconstruction after mastectomy. This study aimed to determine whether physician led, community-based educational symposium improves understanding of breast cancer care and breast reconstruction in underserved populations., Methods: Annual educational symposiums were held between 2017 and 2019 in underserved communities in the greater Philadelphia area. The symposium consisted of a series of short lectures on breast health, cancer screening, surgical management and reconstruction, patient testimonials, a Q&A panel, and an exhibitor fair. Attendees were given pre- and post-symposium surveys that evaluated knowledge of breast cancer care and reconstruction on a 0-100 scale based on percentage of correct answers., Results: Of 169 individuals, 92%, 91%, and 83% completed pre-symposium, post-symposium, and both surveys, respectively. Median age was 60 years, and 92% were Black. Knowledge/understanding survey scores significantly improved after the symposium (50 vs. 87, p < 0.01). Of all respondents, 92% found the symposium to be useful, 89% were introduced to resources that they were not previously aware of, 90% would recommend the symposium to others, and 91% would pass along the information they learned., Conclusion: This study presents an effective and reproducible strategy to increase community awareness and understanding of general breast cancer concepts and breast reconstruction options. Through community outreach and education, physicians can help underserved populations have a better understanding of their potential options for breast reconstruction and ultimately reduce this well documented but inadequately addressed disparity in cancer care.

Objective: The purpose of this study was to evaluate the use of a professionally trained, resilience coach for surgical interns., Design: Mixed-methods study with pre- and postcoaching quantitative surveys measuring burnout and resilience factors and semistructured interviews., Setting: General, Vascular, Cardiac, Plastic, and Urologic Surgery residencies at a tertiary academic center., Participants: Categorical and preliminary interns (N = 25) participated in a year-long, 8-session resilience coaching program for the academic year 2018 to 2019., Results: Program participants included 17 (68%) men and 8 (32%) women. The precoaching survey administered to interns before the start of the program identified 60% at risk of burnout as measured by the Abbreviated Maslach Burnout Inventory. The mean (standard deviation) Brief Resilience Scale score was 3.8 (0.8), with a trend toward a higher score (greater resilience) among men compared to women (4.1 [0.7] vs 3.4 [1.0], p = 0.10). Following the completion of the coaching program, the mean (standard deviation) Brief Resilience Scale score increased significantly from 3.8 [0.8] to 4.2 [0.7] p = 0.002). There were no changes in other parameters measuring burnout, satisfaction with life, or positive/negative affect. In semistructured interviews (N = 16/25 participants), most interns believed the coaching experience provided useful skills, but expressed concern about the durability of a 1-year intervention. Additionally, leadership-driven wellness at work, including optimizing team dynamics and purpose-driven engagement, were emphasized., Conclusions: About 60% of new interns at our institution were at risk of burnout. The coaching program was viewed positively and was effective in improving resilience. While this intervention was a useful first step, it should be incorporated into a longitudinal wellness program for the duration of surgical training., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

This Article describes the design, synthesis, and analysis of a new class of polymer that is capable of depolymerizing continuously, completely, and cleanly from head to tail when a detection unit on the head of the polymer is exposed to a specific applied signal. The backbone of this polymer consists of 1,3-disubstituted pyrroles and carboxy linkages similar to polyurethanes. Diverse side chains or reactive end-groups can be introduced readily, which provides modular design of polymer structure. The designed depolymerization mechanism proceeds through spontaneous release of carbon dioxide and azafulvene in response to a single triggering reaction with the detection unit. These poly(carboxypyrrole)s depolymerize readily in nonpolar environments, and even in the bulk as solid-state plastics.

Randomized controlled trials (RCTs) have challenged the need for routine radiation therapy (RT) in women ≥ age 70 with favorable early stage breast cancer (BC) due to modest improvement in local control and no survival benefit. We studied practice patterns in RT among elderly women in the United States. We analyzed data from the National Cancer Database (NCDB) of women ≥age 70 diagnosed with T1 or T2 and N0 invasive BC treated with breast conservation surgery (BCS) between 2004 and 2014. Patients were divided into four groups: (1) no RT, (2) partial breast irradiation (PBI); (3) hypofractionation (HF); and (4) conventional whole breast RT (CWBI). Univariable and multivariable analyses (MVA) were performed to compare characteristics among the four RT groups. A subgroup analysis of women with favorable disease (T1N0 ER + HER2-) was also performed with similar statistical comparisons. Of the 66,126 meeting eligibility, 9,570 (14.5%) had PBI, 16,340 (24.7%) had HF, and 40,117 (60.7%) had CWBI. Only 99 patients (0.15%) had RT omitted. Omission of RT increased marginally from 0.04% in 2004 to 0.24% in 2014. MVA identified older age (OR 1.18, CI 1.08-1.28), more comorbidities (Charlson-Deyo Score of 1) (OR 3.36, CI 1.29-8.72), and no hormone therapy (OR 22.07, CI 5.79-84.07) as more likely to have RT omitted. The use of HF increased from 3.9% to 47.0%, P < .001 with a concomitant decrease in CWBI from 88% to 41%, P < .001. MVA identified older age, treatment location, and omission of chemotherapy as associated with HF. No significant differences from the larger cohort were found among the T1N0 subgroup analysis. Despite RCT evidence, omission of RT was rare in the United States, suggesting that more effective outreach methods to disseminate clinical guideline information may be needed., (© 2019 Wiley Periodicals, Inc.)

Purpose: Globally, breast cancer represents the most common cause of cancer death among women. Early cancer diagnosis is difficult in low- and middle-income countries, most of which are unable to support population-based mammographic screening. Triage on the basis of clinical breast examination (CBE) alone can be difficult to implement. In contrast, piezo-electric palpation (intelligent Breast Exam [iBE]) may improve triage because it is portable, low cost, has a short learning curve, and provides electronic documentation for additional diagnostic workup. We compared iBE and CBE performance in a screening patient cohort from a Western mammography center., Methods: Women presenting for screening or diagnostic workup were enrolled and underwent iBE then CBE, followed by mammography. Mammography was classified as negative (BI-RADS 1 or 2) or positive (BI-RADS 3, 4, or 5). Measures of accuracy and κ score were calculated., Results: Between April 2015 and May 2017, 516 women were enrolled. Of these patients, 486 completed iBE, CBE, and mammography. There were 101 positive iBE results, 66 positive CBE results, and 35 positive mammograms. iBE and CBE demonstrated moderate agreement on categorization (κ = 0.53), but minimal agreement with mammography (κ = 0.08). iBE had a specificity of 80.3% and a negative predictive value of 94%. In this cohort, only five of 486 patients had a malignancy; iBE and CBE identified three of these five. The two cancers missed by both modalities were small-a 3-mm retro-areolar and a 1-cm axillary tail., Conclusion: iBE performs comparably to CBE as a triage tool. Only minimal cancers detected through mammographic screening were missed on iBE. Ultimately, our data suggest that iBE and CBE can synergize as triage tools to significantly reduce the numbers of patients who need additional diagnostic imaging in resource-limited areas.

Long-lasting, latently infected resting CD4 + T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir 1 . Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect 2-9 . Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4 + T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.

Aim: To understand the underlying cellular mechanisms during inactivation of Escherichia coli in response to antimicrobial solution of nonthermal plasma-activated N-acetylcysteine (NAC)., Methods and Results: The recommended techniques were used to demonstrate E. coli cellular and transcriptomic changes caused associated with peroxynitrite and compared with plasma-treated NAC solution. The findings demonstrate that E. coli cells respond to plasma-treated NAC and undergo severe oxidative and nitrosative stress, and leading to stress-induced damages to different components of bacterial cells, which includes loss of membrane potential, formation of oxidized glutathione (GSSG), formation of nitrotyrosine (a known marker of nitrosative stress), DNA damage, and generated a prominent pool of peroxynitrite. Reverse-transcriptase (RT)-polymerase chain reaction analysis of reactive nitrogen species (RNS) responsive genes indicated their differential expressions., Conclusion: For the first time, we report that the plasma-treated NAC solution activates predominantly nitrosative stress-responsive genes in E. coli and is responsible for cell death., Significance and Impact of the Study: The reactive species generated in solutions by nonthermal plasma treatment depends on the type of solution or solvent used. The plasma-treated NAC solution rapidly inactivates E. coli, mostly involving highly RNS generated in NAC solution, and has high potential as disinfectant., (© 2018 The Society for Applied Microbiology.)

Eleven withanolides including six previously undescribed compounds, 16β-hydroxyixocarpanolide, 24,25-dihydroexodeconolide C, 16,17-dehydro-24-epi-dioscorolide A, 17-epi-philadelphicalactone A, 16-deoxyphiladelphicalactone C, and 4-deoxyixocarpalactone A were isolated from aeroponically grown Physalis philadelphica. Structures of these withanolides were elucidated by the analysis of their spectroscopic (HRMS, 1D and 2D NMR, ECD) data and comparison with published data for related withanolides. Cytotoxic activity of all isolated compounds was evaluated against a panel of five human tumor cell lines (LNCaP, ACHN, UO-31, M14 and SK-MEL-28), and normal (HFF) cells. Of these, 17-epi-philadelphicalactone A, withaphysacarpin, philadelphicalactone C, and ixocarpalactone A exhibited cytotoxicity against ACHN, UO-31, M14 and SK-MEL-28, but showed no toxicity to HFF cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Nipple sparing mastectomy (NSM) is considered safe for select patients. Our objective was to examine quality of life (QOL) and satisfaction for NSM compared with skin sparing mastectomy (SSM). We aimed to evaluate these using the BREAST-Q., Methods: After IRB approval, we analyzed patients who underwent NSM and reconstruction between July 2010-June 2015. NSM patients were matched with those after SSM based on age, race, and body mass index. Telephone interviews were prospectively conducted using the BREAST-Q Mastectomy Postoperative Module. Bivariate analysis and a paired samples t-test were performed., Results: We identified 43 patients meeting our inclusion criteria with a response rate 60% (N = 26). NSM and SSM patients were matched well in age (P = 1.00), race (P = 1.00), and Body Mass Index (P = 0.99). There were no significant differences in stage, estrogen and progesterone status, HER2 expression, reconstruction type and radiation. Mean BREAST-Q scores did not vary between NSM and SSM in regards to satisfaction with breasts (P = 0.604), psychosocial well-being (P = 0.146), physical well-being (P = 0.121), and satisfaction with surgeon (P = 0.170). Sexual well-being was significantly higher in NSM patients (P = 0.011)., Conclusion: NSM provides patients with favorable results in psychosocial, sexual, and physical well-being and overall satisfaction. Sexual well-being showed significant improvement for NSM., (© 2018 Wiley Periodicals, Inc.)

Objective: The ability to use electronic medical records (EMR) is an essential skill for surgical residents. However, frustration and anxiety surrounding EMR tasks may detract from clinical performance. We created a series of brief, 1-3 minutes "how to" videos demonstrating 7 key perioperative EMR tasks: booking OR cases, placing preprocedure orders, ordering negative-pressure wound dressing supplies, updating day-of-surgery history and physical notes, writing brief operative notes, discharging patients from the postanesthesia care unit, and checking vital signs. Additionally, we used "Cutting Insights"-a locally developed responsive mobile application for surgical trainee education-as a platform for providing interns with easy access to these videos. We hypothesized that exposure to these videos would lead to increased resident efficiency and confidence in performing essential perioperative tasks, ultimately leading to improved clinical performance., Methods: Eleven surgery interns participated in this initiative. Before watching the "how to" videos, each intern was timed performing the aforementioned 7 key perioperative EMR tasks. They also underwent a simulated perioperative emergency requiring the performance of 3 of these EMR tasks in conjunction with 5 other required interventions (including notifying the chief resident, the anesthesia team, and the OR coordinator; and ordering fluid boluses, appropriate laboratories, and blood products). These simulations were scored on a scale from 0 to 8. The interns were then directed to watch the videos. Two days later, their times for performing the 7 tasks and their scores for a similar perioperative emergency simulation were once again recorded. Before and after watching the videos, participants were surveyed to assess their confidence in performing each EMR task using a 5-point Likert scale. We also elicited their opinions of the videos and web-based mobile application using a 5-point scale. Statistical analyses to assess for statistical significance (p ≤ 0.05) were conducted using paired t-test for parametric variables and a Wilcoxon matched-pair test for nonparametric variables., Setting: Hospital of the University of Pennsylvania, Philadelphia, PA (a quaternary teaching hospital within the University of Pennsylvania Health System)., Participants: Eleven out of 15 interns (12 entered and 11 completed the study) from our categorical and preliminary general surgery residency programs during the 2016 academic year., Results: Before exposure to the brief "how to" videos, 6 of 11 interns were unable to complete all 7 EMR tasks; after exposure, all 11 interns were able to complete all 7 EMR tasks. Moreover, interns' times for each task improved following exposure. Interns self-reported improved confidence in booking an OR case (4 ± 0.9 vs. 4.7 ± 0.6, p = 0.05), ordering negative-pressure wound therapy supplies (3.1 ± 1.6 vs. 4.5 ± 0.7, p < 0.05), writing a brief operative note (3.7 ± 1.2 vs. 4.6 ± 0.7, p = 0.05), discharging patients from the postanesthesia care unit (3.3 ± 1.0 vs. 4.4 ± 0.8, p < 0.05), checking vital signs (2.5 ± 1.4 vs. 4.5 ± 0.8, p ≤ 0.01), and performing necessary EMR tasks during an emergency situation (2.4 ± 0.8 vs. 4.6 ± 0.7, p ≤ 0.0001). Participants also demonstrated a significant improvement in average clinical score on the emergency simulations (5.2 ± 1.7 vs. 6.6 ± 0.9, p < 0.05). Interns' opinions of the videos and the mobile phone application were favorable., Conclusions: In our group of 11 surgery interns, exposure to a series of short "how to" videos led to increased confidence and shortened times in performing 7 essential EMR tasks. Additionally, during a simulated perioperative emergency, EMR tasks were performed significantly faster. Clinical performance also improved significantly following exposure to the videos. This just-in-time educational intervention could improve workflow efficiency and clinical performance, both of which may ultimately enhance perioperative patient safety., (Copyright © 2017. Published by Elsevier Inc.)

Objective: The American College of Surgeons/Association of Program Directors in Surgery is a comprehensive, simulation-based curriculum for General Surgery residents which exists in 3 phases. While phases 1 and 2 deal with core skills and advanced procedures respectively, phase 3 targets team-based skills. To date, the 3rd phase of this curriculum has not seen wide scale implementation. This is a pilot study to verify the feasibility of implementing the phase 3 curriculum in the in-situ setting., Design: In our initial attempt to implement Phase 3 at our institution, we chose to perform the training in an in-situ setting within an operating room (OR) at our main hospital, despite our having a separate simulation center. By choosing the in-situ OR environment for this training we were able to minimize concerns regarding resident and faculty availability and able to successfully complete 8 separate sessions during the academic year. During 7 sessions, 2 separate scenarios were performed while a single scenario was performed in 1 session. This single session was excluded from analysis, leaving a total of 14 scenarios to evaluate. The unique scenarios included laparoscopic crisis, postoperative myocardial infarction, anaphylaxis, and postoperative hypotension. All sessions were audiovisually recorded. In order to evaluate the effect of the training, the videos were viewed by 3 independent reviewers and all surgery, anesthesia and nursing participants were rated using the NOTECHs II scale. Degree of inter-rater agreement was established. The difference between the first and second simulations on the same day was then assessed. In addition, participant opinions of the simulations were assessed through electronic surveys following the training., Setting: Tertiary Care University Hospital., Participants: We performed a total of 8 sessions, for a total of 15 scenarios. Eight surgery residents at the postgraduate year 1 (PGY1)-PGY3 level, 16 anesthesia residents at the PGY3-PGY4 level, 16 nurses and 13 ancillary staff participated., Results: From the first to the second scenario, the total team NOTECHs II score increased from 69.4 ± 1.4 to 77.3 ± 0.5 (p = 0.007). The NOTECHs II scores for each subteam also improved, from 24.2 ± 0.6 to 26.4 ± 0.5 (p = 0.007) for surgery residents, 23.7 ± 0.9 to 26.7 ± 0.4 (p = 0.03) for anesthesia, and 21.6 ± 0.3 to 24.3 ± 0.5 (p = 0.01) for nursing. The inter-rater reliability as measured by Kendall's coefficient of concordance was modest for the whole team score. Most of the participant responses were either favorable or strongly favorable., Conclusion: The in-situ OR environment is both a unique and effective setting to perform team-based training. Furthermore, training in the in-situ setting minimizes or removes many of the logistic issues involved in designing and implementing team-based training curricula for general surgery residency programs. However, we found that administrative and departmental (surgery, anesthesia, and nursing) "buy in" as well as protected faculty time for education were all necessary for in-situ training to be successful. NOTECHs II is an established scale for the evaluation of teams in this simulation setting and appears to be a valid tool based on the results of this study. However, further assessment of inter-rater reliability as well as improved training of evaluators are necessary to determine if inter-rater reliability can improve., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Nontechnical skills are an essential component of surgical education and a major competency assessed by the ACGME milestones project. However, the optimal way to integrate nontechnical skills training into existing curricula and then objectively evaluate the outcome is still unknown. The aim of this study was to determine the effect laparoscopic team-based task training would have on the nontechnical skills needed for laparoscopic surgery., Design: 9 PGY-1 residents underwent an established training curriculum for teaching the knowledge and technical skills involved in laparoscopic cholecystectomy. Initial training involved a didactic session, expert-led practice on a porcine model in a simulated operating room and laparoscopic skills practice on a virtual reality trainer. Residents then performed a laparoscopic cholecystectomy on the same porcine model as a preintervention test. Three to four months following this, residents were subjected to specific nontechnical skills training involving 2 simple team-based laparoscopic tasks. They then practiced a further 4 to 6 hours on the virtual reality trainer. A repeat postintervention laparoscopic cholecystectomy was then performed 3 to 4 months after nontechnical skills training. Both the preintervention and postintervention laparoscopic cholecystectomies were audiovisually recorded and then evaluated by 2 independent surgeons in a blinded fashion. Technical skills were assessed using objective structured assessment of technical skills (OSATS) and a technique specific rating scale (TRS) that we developed for laparoscopic cholecystectomy. Nontechnical skills were assessed using nontechnical skills for surgeons (NOTSS). Residents also completed a survey at the beginning and end of the training., Setting: Tertiary care, university based teaching institution., Participants: A total of 9 general surgery residents at the intern level., Results: The mean OSATS score improved from 13.7 ± 1.24 to 26.7 ± 0.31 (p < 0.001), the mean TRS score improved from 6 ± 0.46 to 13.1 ± 0.36 (p < 0.001) and the mean NOTSS score improved from 21.7 ± 1.83 to 36.3 ± 0.87 (p < 0.001) following the training. There was a strong correlation between OSATS and NOTSS scores (Pearson's R = 0.98) and TRS and NOTSS (R = 0.94). The inter-rater agreement was 0.79 for NOTSS, 0.9 for OSATS, and 0.82 for TRS. Following completion of the training, residents self-reported improvements in exchanging information (p < 0.01), coordinating activities (p < 0.01) and coping with pressure in the operating room (p < 0.001)., Conclusion: Simple, team-based nontechnical skills training for laparoscopic cholecystectomy that was separate from technical skills training led to a sustained increase in residents' nontechnical skills 3 to 4 months after training. This was associated with a self-reported improvement in many nontechnical skills based on resident survey. Based on these results, we recommend that such designated nontechnical skills training is a valid alternative to other methods such as coaching and debriefing. We, therefore, plan to continue our efforts to develop team-based simulation tasks aimed at improving nontechnical skills for multiple surgical modalities., (Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Fibrocystic Breast Disease (FBD) or Fibrocystic change (FC) affects about 60% of women at some time during their life. Although usually benign, it is often associated with pain and tenderness (mastalgia). The synthetic steroid danazol has been shown to be effective in reducing the pain associated with FBD, but the cellular and molecular mechanisms for its action have not been elucidated. We investigated the hypothesis that danazol acts by affecting energy metabolism. Effects of danazol on Mcf10A cells homeostasis, including mechanisms of oxidative phosphorylation, cytosolic calcium signaling and oxidative stress, were assessed by high-resolution respirometry and flow cytometry. In addition to fast physiological responses the associated genomic modulations were evaluated by Affimetrix microarray analysis. The alterations of mitochondria membrane potential and respiratory activity, downregulation of energy metabolism transcripts result in suppression of energy homeostasis and arrest of Mcf10A cells growth. The data obtained in this study impacts the recognition of direct control of mitochondria by cellular mechanisms associated with altered energy metabolism genes governing the breast tissue susceptibility and response to medication by danazol., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: The objectives of this project are 1) to describe aspirin use for primary prevention in an underserved, minority population; 2) to determine the impact of a pharmacist-led intervention on the prevalence of aspirin use for primary prevention; and 3) to compare aspirin indications based on Framingham Risk Score (FRS) and atherosclerotic cardiovascular disease (ASCVD) risk score., Methods: Men and women age 45-79 and 55-79 years, respectively, without ASCVD were screened for aspirin use. An FRS of 10% or greater and low risk for a serious bleed were considered indications for primary prevention aspirin on the basis of guideline-directed medical therapy recommendations. When treatment with aspirin was indicated, providers were notified with patient-specific messages. Patients' FRS and ASCVD risk score distributions were plotted and compared. Primary prevention aspirin indications were identified using both risk stratification tools., Results: One hundred sixteen patients were evaluated for aspirin use in a predominantly black (80%), middle-aged (mean age, 58 years), and indigent population. Thirty-one patients (27%) had an FRS of 10% or greater and low risk for bleeding, and 10 patients (9%) were taking aspirin at baseline. Providers approved recommendations to start administering aspirin in 19 of 31 patients (61%), which significantly increased the overall proportion receiving aspirin compared to baseline (9%-25%; P < 0.01). Patients were more than twice as likely to meet the minimum risk score threshold (≥10%) for a primary prevention aspirin indication using ASCVD risk scores versus FRS (70% vs. 30%; P < 0.01)., Conclusions: Baseline utilization of primary prevention aspirin was low in an indigent, minority population. A provider-focused pharmacist intervention improved the prevalence of aspirin use for primary prevention, while minimizing risk for serious bleeding events. Among our cohort, more patients had indications for primary prevention aspirin using ASCVD risk scores versus FRS., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Investigation of aeroponically grown Physalis peruviana resulted in the isolation of 11 new withanolides, including perulactones I-L (1-4), 17-deoxy-23β-hydroxywithanolide E (5), 23β-hydroxywithanolide E (6), 4-deoxyphyperunolide A (7), 7β-hydroxywithanolide F (8), 7β-hydroxy-17-epi-withanolide K (9), 24,25-dihydro-23β,28-dihydroxywithanolide G (10), and 24,25-dihydrowithanolide E (11), together with 14 known withanolides (12-25). The structures of 1-11 were elucidated by the analysis of their spectroscopic data, and 12-25 were identified by comparison of their spectroscopic data with those reported. All withanolides were evaluated for their cytotoxic activity against a panel of tumor cell lines including LNCaP (androgen-sensitive human prostate adenocarcinoma), 22Rv1 (androgen-resistant human prostate adenocarcinoma), ACHN (human renal adenocarcinoma), M14 (human melanoma), SK-MEL-28 (human melanoma), and normal human foreskin fibroblast cells. Of these, the 17β-hydroxywithanolides (17-BHWs) 6, 8, 9, 11-13, 15, and 19-22 showed selective cytotoxic activity against the two prostate cancer cell lines LNCaP and 22Rv1, whereas 13 and 20 exhibited selective toxicity for the ACHN renal carcinoma cell line. These cytotoxicity data provide additional structure-activity relationship information for the 17-BHWs.

Objective: To systematically review the literature surrounding operating room-based in situ training in surgery., Methods: A systematic review was conducted of MEDLINE. The review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, and employed the Population, Intervention, Comparator, Outcome (PICO) structure to define inclusion/exclusion criteria. The Kirkpatrick model was used to further classify the outcome of in situ training when possible., Results: The search returned 308 database hits, and ultimately 19 articles were identified that met the stated PICO inclusion criteria. Operating room-based in situ simulation is used for a variety of purposes and in a variety of settings, and it has the potential to offer unique advantages over other types of simulation. Only one randomized controlled trial was conducted comparing in situ simulation to off-site simulation, which found few significant differences. One large-scale outcome study showed improved perinatal outcomes in obstetrics., Conclusions: Although in situ simulation theoretically offers certain advantages over other types of simulation, especially in addressing system-wide or environmental threats, its efficacy has yet to be clearly demonstrated., (Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma (RCC) is a cancer with poor prognosis, and the 5-year survival rate of patients with metastatic RCC is 5-10%. Consequently, treatment of metastatic RCC represents an unmet clinical need. Screening of a 50 000-member library of natural and synthetic compounds for sensitizers of RCC cells to TRAIL-mediated apoptosis led to identification of the 17β-hydroxywithanolide (17-BHW), withanolide E (1), as a promising lead. To explore structure-activity relationships, we obtained natural and semisynthetic withanolides 1, 2a, 2c, and 3-36 and compared their ability to sensitize TRAIL-mediated apoptosis in a panel of renal carcinoma cells. Our findings revealed that 17-BHWs with a α-oriented side chain are superior to known TRAIL-sensitizing withanolides belonging to withaferin A class with a β-oriented side chain and demonstrated that the 17-BHW scaffold can be modified to enhance sensitization of RCCs to TRAIL-mediated apoptosis, thereby assisting development of natural-product-inspired drugs to treat metastatic RCC.

A lab-scale, tunable, single-filament, point-to-point nonthermal dieletric-barrier discharge (DBD) plasma device was built to study the mechanisms of inactivation of aerosolized bacterial pathogens. The system inactivates airborne antibiotic-resistant pathogens efficiently. Nebulization mediated pre-optimized (4 log and 7 log) bacterial loads were challenged to plasma-charged aerosols, and lethal and sublethal doses determined using colony assay, and cell viability assay; and the loss of membrane potential and cellular respiration were determined using cell membrane potential assay and XTT assay. Using the strategies of Escherichia coli wildtype, over-expression mutant, deletion mutants, and peroxide and heat stress scavenging, we analyzed activation of intracellular reactive oxygen species (ROS) and heat shock protein (hsp) chaperons. Superoxide dismutase deletion mutants (ΔsodA, ΔsodB, ΔsodAΔsodB) and catalase mutants ΔkatG and ΔkatEΔkatG did not show significant difference from wildtype strain, and ΔkatE and ΔahpC was found significantly more susceptible to cell death than wildtype. The oxyR regulon was found to mediate plasma-charged aerosol-induced oxidative stress in bacteria. Hsp deficient E. coli (ΔhtpG, ΔgroEL, ΔclpX, ΔgrpE) showed complete inactivation of cells at ambient temperature, and the treatment at cold temperature (4°C) significantly protected hsp deletion mutants and wildtype cells, and indicate a direct involvement of hsp in plasma-charged aerosol mediated E. coli cell death., Competing Interests: The authors have declared that no competing interests exist.

We have investigated the development of a handheld 4 × 1 piezoelectric finger (PEF) array breast tumor detector system towards in vivo patient testing, particularly, on how the duration of the DC applied voltage, the depression depth of the handheld unit, and breast density affect the PEF detection sensitivity on 40 patients. The tests were blinded and carried out in four phases: with DC voltage durations 5, 3, 2, to 0.8 s corresponding to scanning a quadrant, a half, a whole breast, and both breasts within 30 min, respectively. The results showed that PEF detection sensitivity was unaffected by shortening the applied voltage duration from 5 to 0.8 s nor was it affected by increasing the depression depth from 2 to 6 mm. Over the 40 patients, PEF detected 46 of the 48 lesions (46/48)-with the smallest lesion detected being 5 mm in size. Of 28 patients (some have more than one lesion) with mammography records, PEF detected 31/33 of all lesions (94%) and 14/15 of malignant lesions (93%), while mammography detected 30/33 of all lesions (91%) and 12/15 of malignant lesions (80%), indicating that PEF could detect malignant lesions not detectable by mammography without significantly increasing false positives. PEF's detection sensitivity is also shown to be independent of breast density, suggesting that PEF could be a potential tool for detecting breast cancer in young women and women with dense breasts.

Objective: The purpose of this study was to understand the effect of a team-based surgical skills intervention on the technical and nontechnical skills of surgery residents., Design: This was a prospective cohort study with pretesting or posttesting. We designed basic tasks for the assessment and learning of nontechnical skills in the operating room (OR). A total of 15 postgraduate year 1 residents performed an open gastrojejunostomy in a simulated OR setting (pretest), followed by training in the 3 team-based tasks designed to teach communication and teamwork, followed by performance of a gastrojejunostomy in the simulated OR (posttest)., Setting: Tertiary care, university-based teaching institution., Participants: A total of 15 general surgery residents at the intern level., Results: The mean nontechnical skills for surgeons (NOTSS) score improved postteam task training (10.04 ± 0.33 vs. 12.14 ± 1.33). There was a concomitant increase in the objective structured assessment of technical skills (OSATS) score (18.56 ± 0.86 vs. 22.86 ± 0.15, p = 0.006). The percentage increases in OSATS and NOTSS score for each resident was similar (19.49 ± 4.8 % for NOTSS vs. 21.22 ± 4.92 % for OSATS, p = 0.502)., Conclusion: Nontechnical skills positively correlate with the technical performance of a surgeon. Simple, easily designed tasks can be used to improve NOTSS in the OR. These team tasks and development of curricula based on them can be used to explicitly address one of the most important components of ACGME core competencies for surgical residents, namely interpersonal skills and communication., (Copyright © 2016. Published by Elsevier Inc.)

Background: With the incidence of breast cancer rising worldwide, we are evaluating the iBreastExam (iBE) (UE LifeSciences Inc.), a handheld breast scanning device that can be utilized by community health workers to screen for breast abnormalities. The purpose of this study is to determine the sensitivity of the iBE in a population undergoing diagnostic breast imaging., Methods: Adult patients presenting to a breast imaging center for a diagnostic workup were eligible. Patients underwent an iBE exam performed by a trained ultrasound technician followed by their indicated imaging. Demographic, imaging, and biopsy data were recorded., Results: Seventy-eight iBE exams were completed, 77 females and one male with a mean age of 42 (21-79). All patients were evaluated by ultrasound, 52 had diagnostic mammography and 39 had biopsies. Imaging and/or biopsy confirmed a mass (fibroadenoma, cyst, papilloma, myofibroblastoma, fat necrosis, DCIS, or cancer) in 60 patients. Twelve patients had a cancer diagnosed. In total, 342 quadrants were scanned, 77 quadrants had lesions confirmed on imaging, and iBE correctly identified 66 lesions for a sensitivity of 86 % and specificity of 89 %., Conclusions: This validation study demonstrated excellent sensitivity of iBE for the identification of clinically significant lesions in patients presenting for diagnostic imaging., Trial Registration: A Cost-Effective Handheld Breast Scanner for Use in Low Resource Environments: A Validation Study: NCT02814292 .

Non-thermal atmospheric pressure plasma has attracted great interest due to its multiple potential biomedical applications with cancer treatment being among the most urgent. To realize the clinical potential of non-thermal plasma, the exact cellular and molecular mechanisms of plasma effects must be understood. This work aimed at studying the prostate cancer specific mechanisms of non-thermal plasma effects on energy metabolism as a central regulator of cell homeostasis and proliferation. It was found that cancer cells with higher metabolic rate initially are more resistant to plasma treated phosphate-buffered saline (PBS) since the respiratory and calcium sensitive signaling systems were not responsive to plasma exposure. However, dramatic decline of cancer oxidative phosphorylation developed over time resulted in significant progression of cell lethality. The normal prostate cells with low metabolic activity immediately responded to plasma treated PBS by suppression of respiratory functions and sustained elevation of cytosolic calcium. However, over time the normal cells start recovering their mitochondria functions, proliferate and restore the cell population. We found that the non-thermal plasma induced increase in intracellular ROS is of primarily non-mitochondrial origin. The discriminate non-thermal plasma effects hold a promise for clinical cancer intervention.

In continuation of our previous reports on the broad-spectrum antimicrobial activity of atmospheric non-thermal dielectric barrier discharge (DBD) plasma treated N-Acetylcysteine (NAC) solution against planktonic and biofilm forms of different multidrug resistant microorganisms, we present here the chemical changes that mediate inactivation of Escherichia coli. In this study, the mechanism and products of the chemical reactions in plasma-treated NAC solution are shown. UV-visible spectrometry, FT-IR, NMR, and colorimetric assays were utilized for chemical characterization of plasma treated NAC solution. The characterization results were correlated with the antimicrobial assays using determined chemical species in solution in order to confirm the major species that are responsible for antimicrobial inactivation. Our results have revealed that plasma treatment of NAC solution creates predominantly reactive nitrogen species versus reactive oxygen species, and the generated peroxynitrite is responsible for significant bacterial inactivation.

Cancer immunotherapy shows great promise but many patients fail to show objective responses, including in cancers that can respond well, such as melanoma and renal adenocarcinoma. The proteasome inhibitor bortezomib sensitizes solid tumors to apoptosis in response to TNF-family death ligands. Because T cells provide multiple death ligands at the tumor site, we investigated the effects of bortezomib on T-cell responses in immunotherapy models involving low-avidity antigens. Bortezomib did not affect lymphocyte or tissue-resident CD11c(+)CD8(+) dendritic cell counts in tumor-bearing mice, did not inhibit dendritic cell expression of costimulatory molecules, and did not decrease MHC class I/II-associated antigen presentation to cognate T cells. Rather, bortezomib activated NF-κB p65 in CD8(+) T cells, stabilizing expression of T-cell receptor CD3ζ and IL2 receptor-α, while maintaining IFNγ secretion to improve FasL-mediated tumor lysis. Notably, bortezomib increased tumor cell surface expression of Fas in mice as well as human melanoma tissue from a responsive patient. In renal tumor-bearing immunodeficient Rag2(-/-) mice, bortezomib treatment after adoptive T-cell immunotherapy reduced lung metastases and enhanced host survival. Our findings highlight the potential of proteasome inhibitors to enhance antitumor T-cell function in the context of cancer immunotherapy., (©2015 American Association for Cancer Research.)

A newly designed small molecule reagent provides both qualitative and quantitative readouts in assays that detect enzyme biomarkers. The qualitative readout enables rapid triaging of samples so that only samples that contain relevant concentrations of the target analyte must be quantified. The reagent is accessible in essentially three steps and 34% overall yield, is stable as a solid when heated to 44 °C for >1 month, and does not produce background signal when used in an assay. This paper describes the design and synthesis of the reagent, characterizes its response properties, and establishes the scope of its reactivity.

Rapid point-of-need assays are used to detect abundant biomarkers. The development of in situ signal amplification reactions could extend these assays to screening and triaging of patients for trace levels of biomarkers, even in resource-limited settings. We, and others, have developed small molecule-based in situ signal amplification reactions that eventually may be useful in this context. Herein we describe a design strategy for minimizing background signal that may occur in the absence of the target analyte, thus moving this in situ signal amplification approach one step closer to practical applications. Specifically, we describe allylic ethers as privileged connectors for linking detection and propagating functionality in a small molecule signal amplification reagent. Allylic ethers minimize background reactions while still enabling controlled release of a propagating signal in order to continue the signal amplification reaction. This paper characterizes the ability of allylic ethers to provide an amplified response, and offers insight into additional design considerations that are needed before in situ small molecule-based signal amplification becomes a viable strategy for point-of-need diagnostics.

Prostate cancer cells reprogram their metabolism, so that they support their elevated oxidative phosphorylation and promote a cancer friendly microenvironment. This work aimed to explore the mechanisms that cancer cells employ for fueling themselves with energy rich metabolites available in interstitial fluids. The mitochondria oxidative phosphorylation in metastatic prostate cancer DU145 cells and normal prostate epithelial PrEC cells were studied by high-resolution respirometry. An important finding was that prostate cancer cells at acidic pH 6.8 are capable of consuming exogenous succinate, while physiological pH 7.4 was not favorable for this process. Using specific inhibitors, it was demonstrated that succinate is transported in cancer cells by the mechanism of plasma membrane Na(+)-dependent dycarboxylic acid transporter NaDC3 (SLC13A3 gene). Although the level of expression of SLC13A3 was not significantly altered when maintaining cells in the medium with lower pH, the respirometric activity of cells under acidic condition was elevated in the presence of succinate. In contrast, normal prostate cells while expressing NaDC3 mRNA do not produce NaDC3 protein. The mechanism of succinate influx via NaDC3 in metastatic prostate cancer cells could yield a novel target for anti-cancer therapy and has the potential to be used for imaging-based diagnostics to detect non-glycolytic tumors.

Objective: To review evidence for dosing antihypertensives at bedtime and possible cardiovascular risk reduction., Data Sources: A PubMed, EMBASE, and Cochrane Controlled Trials database literature search (1990-September 2014) limited to human subjects was performed using the search terms hypertension, chronotherapy, ambulatory blood pressure, morning administration, evening administration, and antihypertensives. Additional references were identified from literature citations., Study Selection: All prospective studies assessing cardiovascular outcomes or comparing morning to evening administration of antihypertensives were selected., Data Synthesis: Compared with morning administration, dosing one or more antihypertensive medications at bedtime helps induce a normal circadian blood pressure pattern and reduces the risk of cardiovascular disease morbidity and mortality in individuals with hypertension. Similar results have been reported in high-risk individuals with diabetes, chronic kidney disease, and resistant hypertension. A lack of diversity among studied populations and reliance on subgroup analyses are among the limitations of these data. All antihypertensive medications have not been studied in chronotherapy and do not uniformly achieve desired results. The most substantial evidence exists for medications affecting the renin-angiotensin-aldosterone system., Conclusions: Despite growing evidence and promise as a cost-effective strategy for reducing cardiovascular risk, chronotherapy is not uniformly recommended in the treatment of hypertension. Careful selection of patients and antihypertensives for chronotherapy is required. Further investigation is needed to evaluate the definitive impact of chronotherapy on cardiovascular outcomes., (© The Author(s) 2014.)