Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Machine learning-augmented interventions in perioperative care: a systematic review and meta-analysis.

BACKGROUND: We lack evidence on the cumulative effectiveness of machine learning (ML)-driven interventions in perioperative settings. Therefore, we conducted a systematic review to appraise the evidence on the impact of ML-driven interventions on perioperative outcomes. METHODS: Ovid MEDLINE, CINAHL, Embase, Scopus, PubMed, and ClinicalTrials.gov were searched to identify randomised controlled trials (RCTs) evaluating the effectiveness of ML-driven interventions in surgical inpatient populations. The review was registered with PROSPERO (CRD42023433163) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was conducted for outcomes with two or more studies using a random-effects model, and vote counting was conducted for other outcomes. RESULTS: Among 13 included RCTs, three types of ML-driven interventions were evaluated: Hypotension Prediction Index (HPI) (n=5), Nociception Level Index (NoL) (n=7), and a scheduling system (n=1). Compared with the standard care, HPI led to a significant decrease in absolute hypotension (n=421, P=0.003, I2=75%) and relative hypotension (n=208, P<0.0001, I2=0%); NoL led to significantly lower mean pain scores in the post-anaesthesia care unit (PACU) (n=191, P=0.004, I2=19%). NoL showed no significant impact on intraoperative opioid consumption (n=339, P=0.31, I2=92%) or PACU opioid consumption (n=339, P=0.11, I2=0%). No significant difference in hospital length of stay (n=361, P=0.81, I2=0%) and PACU stay (n=267, P=0.44, I2=0) was found between HPI and NoL. CONCLUSIONS: HPI decreased the duration of intraoperative hypotension, and NoL decreased postoperative pain scores, but no significant impact on other clinical outcomes was found. We highlight the need to address both methodological and clinical practice gaps to ensure the successful future implementation of ML-driven interventions. SYSTEMATIC REVIEW PROTOCOL: CRD42023433163 (PROSPERO).

Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression.

Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary, our results identify CUL3-KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis and demonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.

A Resident-as-Leader Curriculum for Managing Inpatient Teams.

PROBLEM: Leading inpatient teams is a foundational clinical responsibility of resident physicians and leadership is a core competency for inpatient physicians, yet few training programs have formal leadership curricula to realize this clinical skill. INTERVENTION: We implemented a 4-module curriculum for PGY1 internal medicine residents. The program focused on the managerial skills necessary for daily clinical leadership, followed by clinical coaching. Interns were first introduced to foundational concepts and then given the opportunity to apply those concepts to real-world practice followed by clinical coaching. CONTEXT: Using direct-observations and a previously published checklist for rounds leadership, this study sought to evaluate the workplace behavior change for novice residents leading inpatient teams for the first time. We conducted a prospective cohort study (March 2016 and August 2018) of internal medicine residents at a large tertiary academic medical center in Boston, MA. Trained faculty raters performed direct observations of clinical rounding experiences using the checklist and compared the findings to historical and internal controls. Questionnaires were distributed pre- and post- curriculum to assess satisfaction and readiness to lead a team. IMPACT: We trained 65 PGY1 residents and raters conducted 140 direct observations - 36 in the intervention group and 104 among historical controls. The unadjusted mean score in rounds leadership skills for the intervention group was 19.0 (SD = 5.1) compared to 16.2 (SD = 6.2) for historical controls. Adjusting for repeated measures, we found significant improvement in mean scores for behaviors linked to the curricular objectives (p = 0.008) but not for general behaviors not covered by the curriculum (p = 0.2). LESSONS LEARNED: A formal curriculum to train residents as leaders led to behavior change in the workplace in domains essential to rounds leadership. We also found that the curriculum was highly regarded in that all interns indicated they would recommend the curriculum to a peer. Moreover, the program may have assuaged some anxiety during the transition to junior year as 90% of interns surveyed felt more ready to start PGY2 year than historical trainings. We learned that while a robust, multi-faceted modular curriculum and clinical coaching successfully resulted in behavior change, the resources required to manage this program are significant and difficult to sustain. Future iterations could include asynchronous material and potentially peer-observation of rounds leadership to reduce the burden on faculty and program curricular time.

Diving deeper into distress screening implementation in oncology care.

BACKGROUND: Responding to calls for additional research that identifies effective distress screening (DS) processes, including referral practices subsequent to screening and receipt of recommended care, we engaged in qualitative research as part of a larger (mixed methods) study of distress screening. This qualitative inquiry of oncology professionals across different facilities in the United States examined routine DS implementation, facilitators and challenges staff encounter with DS processes, and staff members' perceived value of DS. PARTICIPANTS AND METHODS: We conducted key informant interviews and focus groups with staff in 4 Commission on Cancer (CoC)-accredited oncology facilities (a total of 18 participants) to understand implementation of routine DS within oncology care. We used a rigorous data analysis design, including inductive and deductive approaches. RESULTS: Respondents believe DS enhances patient care and described ways to improve DS processes, including administering DS at multiple points throughout oncology care, using patient-administrated DS methods, and enhancing electronic health records infrastructure to better collect, record, and retrieve DS data. Respondents also identified the need for additional psychosocial staff at their facilities to provide timely psychosocial care. CONCLUSIONS: Results reinforce the value of DS in cancer care, including the importance of follow-up to screening with psychosocial oncology providers. Understanding and resolving the barriers and facilitators to implementing DS are important to ensure appropriate psychosocial care for people with cancer. Insights from oncology staff may be used to enhance the quality of DS and subsequent psychosocial care, which is an essential component of oncology care.

A Call for Reform: Variability and Insufficiency in Radiation Oncology Resident Didactics-a Brief Report and National Survey of Program Directors.

An informal needs assessment and lack of a national standardized curriculum suggest that there is tremendous variability in the formal teaching of radiation oncology resident throughout the USA. The goal of this study was to characterize formal radiation oncology resident education, in order to identify knowledge gaps and areas for improvement. We developed a 14-item survey consisting of the following domains: program characteristics, teaching faculty, formal teaching time, instructional approaches for formal teaching, curricular topics, and satisfaction with didactics. All 91 accredited US-based radiation oncology program directors received an invitation to complete the survey anonymously by email. Twenty-four (26% response rate) program directors responded. Programs used a variety of instructional methods; all programs reported using lecture-based teaching and only a minority using simulation (38%) or flipped classroom techniques (17%). Other than PowerPoint, the most common electronic resource utilized was quizzing/polling (67%), webinar (33%), and econtour.org (13%). The lack of a national, standardized, radiation oncology residency didactic curriculum promotes variability and insufficiency in resident training. Themes for improvement were diversity in didactic topics, incorporation of evidence-based teaching practices, increased faculty involvement, and sharing of resources across programs. Development of a national curriculum and increased electronic resource sharing may help address some of these areas of improvement.

Childhood Cancer Information-Seeking: Findings from the National Cancer Institute's Cancer Information Service.

The benefits of cancer information-seeking may be particularly salient to individuals impacted by childhood cancer, including patients, caregivers, health professionals, and advocates. The purpose of this study was to explore information-seeking patterns for childhood cancer through the National Cancer Institute's Cancer Information Service (CIS), a multi-channel, bilingual resource for cancer information. The study team conducted descriptive analyses on secondary data characterizing 1820 caregivers, health professionals, organizations, and members of the general public who contacted the CIS about childhood cancer between September 2018 and June 2022. Almost 80% of inquiries about childhood cancer were initiated by caregivers, followed by the public, health professionals, and organizations. Although English was the primary language used by individuals to reach the CIS when discussing childhood cancer, there were variations in points of access (i.e., telephone, instant messaging, email, social media) across the four user groups. Most childhood cancer inquiries were about staging and treatment, and the primary cancer sites discussed by CIS users were neurologic or brain, hematologic, and musculoskeletal cancers. Discussion topics included managing and coping with cancer, clinical trials, and treatment side effects. Just over half (54%) of CIS contacts about childhood cancer resulted in a health professional referral. Findings provide direction for the CIS and other public health organizations to deliver, prioritize, and tailor their services to support the information needs of childhood cancer survivors and their families-as well as those who care and advocate for them-who may have a significant need for credible cancer information.

Interleukin-10 Deficiency Alters Endothelial Progenitor Cell-Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment.

Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC-derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell-derived exosomes (TNFα inflamed mouse cardiac endothelial cell-derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB-dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome-mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.

Establishing construct validity of neuropsychological tests in cancer survivors.

OBJECTIVE: Cancer-related cognitive impairments (CRCI) are frequently reported among cancer survivors, and attention is the most frequently assessed cognitive domain in CRCI. However, there is no consensus as to whether attention is impaired. We suggest that a major reason for this lack of agreement is a lack of construct validity for neuropsychological attention tests. We propose to assess the construct validity of neuropsychological attention tests with respect to experimental paradigms from cognitive psychology. METHODS: Self-reported cancer survivors (N = 314) completed an online battery comprising six experimental attention paradigms and eight neuropsychological tests. Confirmatory factor analysis was used to evaluate the fit of five models derived from a general population sample (N = 636) in a previous study (M. Treviño, Cogn Res Princ Implic, in press). We then subjected the best-fitting model to a measurement invariance analysis. RESULTS: The best-fitting model was a six intercorrelated factor structure, comprising Capacity, Search, Digit Span, Arithmetic, Sustained Attention, and Flanker Interference factors. Configural and weak invariance held, indicating that the factor loadings were invariant across groups. Strong invariance, indicating that intercepts were also invariant, held except for the Approximate Number Sense test. CONCLUSIONS: According to our factor model, Spatial Span and Digit Symbol Coding measure attentional capacity, while the Trail Making Test (A&B) and Letter Cancellation tests measure visual search ability. However, Digit Span and Arithmetic tests do not measure attention. We hope that these results will lead to better scientific models, better patient education, and, ultimately, improved outcomes for survivors.

Partnering with healthcare facilities to understand psychosocial distress screening practices among cancer survivors: pilot study implications for study design, recruitment, and data collection.

BACKGROUND: We sought to understand barriers and facilitators to implementing distress screening (DS) of cancer patients to inform and promote uptake in cancer treatment facilities. We describe the recruitment and data collection challenges and recommendations for assessing DS in oncology treatment facilities. METHODS: We recruited CoC-accredited facilities and collected data from each facility's electronic health record (EHR). Collected data included cancer diagnosis and demographics, details on DS, and other relevant patient health data. Data were collected by external study staff who were given access to the facility's EHR system, or by facility staff working locally within their own EHR system. Analyses are based on a pilot study of 9 facilities. RESULTS: Challenges stemmed from being a multi-facility-based study and local institutional review board (IRB) approval, facility review and approval processes, and issues associated with EHR systems and the lack of DS data standards. Facilities that provided study staff remote-access took longer for recruitment; facilities that performed their own extraction/abstraction took longer to complete data collection. CONCLUSION: Examining DS practices and follow-up among cancer survivors necessitated recruiting and working directly with multiple healthcare systems and facilities. There were a number of lessons learned related to recruitment, enrollment, and data collection. Using the facilitators described in this manuscript offers increased potential for working successfully with various cancer centers and insight into partnering with facilities collecting non-standardized DS clinical data.

Cancer Information-seeking in an Age of COVID-19: Findings from the National Cancer Institute's Cancer Information Service.

Seeking cancer information is recognized as an important, life-saving behavior under normal circumstances. However, given the significant impact of COVID-19 on society, the healthcare system, and individuals and their families, it is important to understand how the pandemic has affected cancer information needs in a crisis context and, in turn, how public health agencies have responded to meeting the information needs of various audiences. Using data from the National Cancer Institute's Cancer Information Service (CIS) - a long-standing, multi-channel resource for trusted cancer information in English and Spanish - this descriptive analysis explored differences in cancer information-seeking among cancer survivors, caregivers, tobacco users, and members of the general public during the onset and continuation of the COVID-19 pandemic (February - September 2020), specifically comparing interactions that involved a discussion of COVID-19 to those that did not. During the study period, COVID-19 discussions were more likely to involve survivors or caregivers compared to tobacco users and the general public. Specific patterns emerged across the four user types and their respective discussions of COVID-19 related to language of service, point of CIS access, stage on the cancer continuum, subject of interaction, cancer site discussed, and referrals provided by the CIS. These results provide insights that may help public health agencies deliver, prioritize, and tailor their messaging and response to specific audiences based on heightened health information needs during a crisis.

The Mindful Manager: Validation of a Rounding Leadership Instrument for Residents.

BACKGROUND: In the context of inpatient general medicine, "rounding" refers to the process of seeing, assessing, and caring for patients as a team. The clinical leadership skills required of residents to lead rounds are essential to inpatient care and clinical education. Assessment of these skills has relevance to developing competent physicians; however, there is an absence of widely accepted tools to specifically measure this competency. OBJECTIVE: To develop and collect validity evidence for a direct observation instrument of internal medicine residents' leadership skills during daily inpatient care rounds for future formative assessment. DESIGN: Prospective observational study. PARTICIPANTS: PGY2 and PGY3 internal medicine residents. MAIN MEASURES: The authors collected inferences of validity evidence according to Kane's validity model. They performed direct observations of PGY2 and PGY3 residents by individual faculty and trained raters and measured inter-rater reliability, using the kappa statistic. Mixed linear regression models were used to compare PGY2 and PGY3 residents. Surveys captured faculty perceptions about value of the instrument. KEY RESULTS: A total of 223 observations were performed in 92 unique individuals. Twenty-four faculty used the observation instrument, of which 18 (75%) completed the post-survey, and 100% agreed that the instrument represented the resident's global leadership abilities. Inter-rater reliability was strong, with an overall kappa statistic equaling 0.82. The mean performance for PGY2 and PGY3 residents was 15.9 (SD 5.1) and 17.7 (SD 4.1), respectively. Adjusting for repeated measures, there was no statistically significant difference between groups. CONCLUSIONS: The authors reported evidence for all four stages of validity and use of the instrument in clinical practice. Their work provides a codification of best practices of rounding leadership, which directly impacts the education of trainees, care of hospitalized patients, and use for formative assessment. The instrument also has the potential to be used for summative assessment.

Adapting Maslow's Hierarchy of Needs as a Framework for Resident Wellness.

ISSUE: Burnout in graduate medical education is pervasive and has a deleterious impact on career satisfaction, personal well-being, and patient outcomes. Interventions in residency programs have often addressed isolated contributors to burnout; however, a more comprehensive framework for conceptualizing wellness is needed. EVIDENCE: In this article the authors propose Maslow's hierarchy of human needs (physiologic, safety, love/belonging, esteem, and self-actualization) as a potential framework for addressing wellness initiatives. There are numerous contributors to burnout among physician-trainees, and programs to combat burnout must be equally multifaceted. A holistic approach, considering both the trainees personal and professional needs, is recommended. Maslow's Needs can be adapted to create such a framework in graduate medical education. The authors review current evidence to support this model. IMPLICATIONS: This work surveys current interventions to mitigate burnout and organizes them into a scaffold that can be used by residency programs interested in a complete framework to supporting wellness.

Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer.

Androgen deprivation therapy (ADT) is a mainstay of treatment for prostate cancer (PCa). As androgens stimulate erythropoiesis, ADT is associated with a reduction in hematocrit, which in turn contributes to fatigue and related morbidity. However, the mechanisms involved in ADT-induced reduction in erythropoiesis remain unclear. We conducted a 6-mo prospective cohort study and enrolled men with PCa about to undergo ADT (ADT-Group) and a control group of men who had previously undergone prostatectomy for localized PCa and were in remission (Non-ADT Group). All participants had normal testosterone levels at baseline. Fasting blood samples were collected at baseline, 12 wk, and 24 wk after initiation of ADT; samples were obtained at the same intervals from enrollment in the Non-ADT group. Blood count, iron studies, erythropoietin, erythroferrone, and hepcidin levels were measured. Seventy participants formed the analytical sample (31 ADT, 39 Non-ADT). ADT was associated with a significant reduction in erythrocyte count (estimated mean difference = -0.2×106 cells/µl, 95%CI = -0.3 to -0.1×106 cells/µl, P < 0.001), hematocrit (-1.9%, 95%CI = -2.7 to -1.1%, P < 0.001), and hemoglobin (-0.6 g/dl, 95%CI = -0.8 to -0.3 g/dl, P < 0.001). Serum hepcidin concentration increased in the ADT-group (18 ng/ml, P < 0.001); however, iron concentrations did not change (-1.1 µg/dl, P = 0.837). Ferritin levels increased in men on ADT (60 ng/ml, P < 0.001). Iron binding capacity, transferrin saturation, erythroferrone, and erythropoietin did not change. Nine men undergoing ADT developed new-onset anemia. In conclusion, reduced proliferation of marrow erythroid progenitors leads to ADT-induced reduction in erythropoiesis. Future studies should evaluate the role of selective androgen receptor modulators in the treatment of ADT-induced anemia.

miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6.

It has been suggested that microRNAs (miRs) are involved in the immune regulation of periodontitis. However, it is unclear whether and how miRs regulate the function of B cells in the context of periodontitis. This study is to explore the role of miR-146a on the inflammatory cytokine production of B cells challenged by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). Primary B cells were harvested from mouse spleen. Quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of inflammatory cytokines in B cells in the presence or absence of P. gingivalis LPS and/or miR-146a. Bioinformatics, luciferase reporter assay and overexpression assay were used to explore the binding target of miR-146a. Our results showed that miR-146a level in B cells was elevated by P. gingivalis LPS stimulation, and the mRNA expressions of interleukin (IL)-1ß, 6 and 10, and IL-1 receptor associated kinase-1 (IRAK1), but not TNF receptor associated factor 6 (TRAF6), were also upregulated. The expression levels of IL-1ß, 6, 10 and IRAK1 were reduced in the presence of miR-146a mimic, but were elevated by the addition of miR-146a inhibitor. MiR-146a could bind with IRAK1 3' untranslated region (UTR) but not TRAF6 3'-UTR. Overexpression of IRAK1 reversed the inhibitory effects of miR-146a on IL-1ß, 6 and 10. In summary, miR-146a inhibits inflammatory cytokine production in B cells through directly targeting IRAK1, suggesting a regulatory role of miR-146a in B cell-mediated periodontal inflammation.

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection.

Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155.

Stabilizing displayed proteins on vegetative Bacillus subtilis cells.

Microbes engineered to display heterologous proteins could be useful biotechnological tools for protein engineering, lignocellulose degradation, biocatalysis, bioremediation, and biosensing. Bacillus subtilis is a promising host to display proteins, as this model Gram-positive bacterium is genetically tractable and already used industrially to produce enzymes. To gain insight into the factors that affect displayed protein stability and copy number, we systematically compared the ability of different protease-deficient B. subtilis strains (WB800, BRB07, BRB08, and BRB14) to display a Cel8A-LysM reporter protein in which the Clostridium thermocellum Cel8A endoglucanase is fused to LysM cell wall binding modules. Whole-cell cellulase measurements and fractionation experiments demonstrate that genetically eliminating extracytoplasmic bacterial proteases improves Cel8A-LysM display levels. However, upon entering stationary phase, for all protease-deficient strains, the amount of displayed reporter dramatically decreases, presumably as a result of cellular autolysis. This problem can be partially overcome by adding chemical protease inhibitors, which significantly increase protein display levels. We conclude that strain BRB08 is well suited for stably displaying our reporter protein, as genetic removal of its extracellular and cell wall-associated proteases leads to the highest levels of surface-accumulated Cel8A-LysM without causing secretion stress or impairing growth. A two-step procedure is presented that enables the construction of enzyme-coated vegetative B. subtilis cells that retain stable cell-associated enzyme activity for nearly 3 days. The results of this work could aid the development of whole-cell display systems that have useful biotechnological applications.

Identification of perioperative pulmonary aspiration in children using quality assurance and hospital administrative billing data.

BACKGROUND: Perioperative aspiration is a rare but potentially devastating complication, occurring in 1-10 per 10 000 anesthetics based on studies of quality assurance databases. Quality assurance reporting is known to underestimate the incidence of adverse outcomes, but few large studies use supplementary data sources. This study aims to identify the incidence of and risk factors for perioperative aspiration in children using quality assurance data supplemented by administrative billing records, and to examine the utility of billing data as a supplementary data source. METHODS: Aspiration events for children receiving anesthesia at a tertiary care pediatric hospital between 2008 and 2014 were identified using (i) a perioperative quality assurance database and (ii) hospital administrative billing records with International Classification of Diseases, Ninth Revision Clinical Modification coded diagnoses of aspiration. Records were subject to review by pediatric anesthesiologists. Following identification of all aspiration events, the incidence of perioperative aspiration was calculated and risk factors were assessed. RESULTS: 47 272 anesthetic cases were evaluated over 7 years. The quality assurance database identified 20 cases of perioperative aspiration occurring in surgical inpatients, same-day admissions, and outpatients. Using hospital administrative data (which excludes outpatients with shorter than a 24-hour stay), 9 cases of perioperative aspiration were identified of which 6 had not been found through quality assurance data. Overall, International Classification of Diseases, Ninth Revision coding demonstrated a positive predictive value of 94.5% for any aspiration event; however, positive predictive value was <4% for perioperative aspiration. A total incidence of 5.5 perioperative aspirations per 10 000 (95% CI: 3.7-8.0 per 10 000) anesthetics was found. CONCLUSION: Quality assurance data offer an efficient way to measure the incidence of rare events, but may underestimate perioperative complications. International Classification of Diseases, Ninth Revision codes for aspiration used as a secondary data source were nonspecific for perioperative aspiration, but when combined with record review yielded a 30% increase in identified cases of aspiration over quality assurance data alone. The use of administrative data therefore holds potential for supplementing quality assurance studies of rare complications.

Developing internal medicine subspecialty fellows' teaching skills: a needs assessment.

BACKGROUND: For academic physicians, teaching represents an essential skill. The proliferation of educator training programs aimed at residents and medical students signals the increasing commitment of training programs to develop teaching skills in their trainees as early as possible. However, clinical fellowships represent an important opportunity to advance training as educators. In addition to enriching the pipeline of future teachers, developing fellows as teachers augments the training experience for more junior trainees and may impact patient care. Fellows' needs for programs to improve teaching skills have been largely unexplored. METHODS: We conducted a multi-institutional needs assessment of internal medicine (IM) subspecialty fellows to gauge interest in teaching and improvement of teaching skills. We surveyed IM subspecialty fellows at three academic medical centers about their access to fellow-as-teacher programs and other mechanisms to improve their teaching skills during fellowship. We also elicited their attitudes towards teaching and interest in training related to teaching skills. RESULTS: One hundred eighty-three fellows representing 20 programs and nine different subspecialties responded to the survey (48% response rate). The majority of participants (67%) reported having no specific training focused on teaching skills and only 12% reported receiving regular feedback about their teaching during their fellowship. Seventy-nine percent of fellows anticipated teaching to be part of their careers, and 22% planned to participate in medical education scholarship. Fellows reported a strong interest in teaching and programs aimed at improving their teaching skills. CONCLUSIONS: The majority of fellows reported a lack of mechanisms to advance their teaching skills as fellows, despite anticipating teaching to be an important aspect of their future careers and having strong interest in such programs. Our findings at three academic medical centers confirm a lost opportunity among subspecialty fellowships to accelerate teaching skills development for future educators.

Development and Implementation of a Novel HIV Primary Care Track for Internal Medicine Residents.

BACKGROUND: Declining mortality has led to a rising number of persons living with HIV (PLWH) and concerns about a future shortage of HIV practitioners. AIM: To develop an HIV Primary Care Track for internal medicine residents. SETTING: Academic hospital and community health center with a history of caring for PLWH and lesbian, gay, bisexual, and transgender (LGBT) patients. PARTICIPANTS: Internal medicine residents. PROGRAM DESCRIPTION: We enrolled four residents annually in a 3-year track with the goal of having each provide continuity care to at least 20 PLWH. The curriculum included small group learning sessions, outpatient electives, a global health opportunity, and the development of a scholarly project. PROGRAM EVALUATION: All residents successfully accrued 20 or more PLWH as continuity patients. Senior residents passed the American Academy of HIV Medicine certification exam, and 75 % of graduates took positions in primary care involving PLWH. Clinical performance of residents in HIV care quality measures was comparable to those reported in published cohorts. DISCUSSION: We developed and implemented a novel track to train medical residents in the care of PLWH and LGBT patients. Our results suggest that a designated residency track can serve as a model for training the next generation of HIV practitioners.