The impact of resident training on robotic operative times: is there a July Effect?

It is unknown whether the July Effect (a theory that medical errors and organizational inefficiencies increase during the influx of new surgical residents) exists in urologic robotic-assisted surgery. The aim of this study was to investigate the impact of urology resident training on robotic operative times at the beginning of the academic year. A retrospective chart review was conducted for urologic robotic surgeries performed at a single institution between 2008 and 2019. Univariate and multivariate mix model analyses were performed to determine the association between operative time and patient age, estimated blood loss, case complexity, robotic surgical system (Si or Xi), and time of the academic year. Differences in surgery time and non-surgery time were assessed with/without resident presence. Operative time intervals were included in the analysis. Resident presence correlated with increased surgery time (38.6 min (p < 0.001)) and decreased non-surgery time (4.6 min (p < 0.001)). Surgery time involving residents decreased by 8.7 min after 4 months into the academic year (July-October), and by an additional 5.1 min after the next 4 months (p = 0.027, < 0.001). When compared across case types stratified by complexity, surgery time for cases with residents significantly varied. Cases without residents did not demonstrate such variability. Resident presence was associated with prolonged surgery time, with the largest effect occurring in the first 4 months and shortening later in the year. However, resident presence was associated with significantly reduced non-surgery time. These results help to understand how new trainees impact operating room times.

Dysregulated NUB1 and neddylation enhances rheumatoid arthritis fibroblast-like synoviocyte inflammatory responses.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) contribute to the pathogenesis of rheumatoid arthritis (RA), in part due to activation of the pro-inflammatory transcription factor NF-κB. Neddylation is modulated by the negative regulator of ubiquitin-like proteins-1 (NUB1). We determined whether NUB1 and neddylation are aberrant in RA FLS thereby contributing to their aggressive phenotype. METHODS: RA or osteoarthritis (OA) FLS were obtained from arthroplasty synovia. RT-qPCR and Western blot analysis assessed gene and protein expression, respectively. NUB1 was overexpressed using an expression vector. NF-κB activation was assessed by stimulating FLS with IL-1ß. Neddylation inhibitor (MLN4924) and proteasome inhibitor were used in migration and gene expression assays. MLN4924 was used in the K/BxN serum transfer arthritis model. RESULTS: Enhanced H3K27ac and H3K27me3 peaks were observed in the NUB1 promoter in OA FLS compared with RA FLS. NUB1 was constitutively expressed by FLS but induction by IL-1ß was significantly greater in OA FLS. The ratio of neddylated CUL1 to non-neddylated CUL1 was lower in OA FLS than RA FLS. NUB1 overexpression decreased NF-κB nuclear translocation and IL-6 mRNA in IL-1ß-stimulated RA FLS. MLN4924 decreased CUL1 neddylation, NF-κB nuclear translocation and IL-6 mRNA in IL-1ß-stimulated RA FLS. MLN4924 significantly decreased arthritis severity in K/BxN serum-transfer arthritis. CONCLUSION: CUL1 neddylation and NUB1 induction is dysregulated in RA, which increases FLS activation. Inhibition of neddylation is an effective therapy in an animal model of arthritis. These data suggest that neddylation system contributes to the pathogenesis of RA and that regulation of neddylation could be a novel therapeutic approach.

Complex adaptive systems-based framework for modeling the health impacts of climate change.

Introduction: Climate change is a global phenomenon with far-reaching consequences, and its impact on human health is a growing concern. The intricate interplay of various factors makes it challenging to accurately predict and understand the implications of climate change on human well-being. Conventional methodologies have limitations in comprehensively addressing the complexity and nonlinearity inherent in the relationships between climate change and health outcomes. Objectives: The primary objective of this paper is to develop a robust theoretical framework that can effectively analyze and interpret the intricate web of variables influencing the human health impacts of climate change. By doing so, we aim to overcome the limitations of conventional approaches and provide a more nuanced understanding of the complex relationships involved. Furthermore, we seek to explore practical applications of this theoretical framework to enhance our ability to predict, mitigate, and adapt to the diverse health challenges posed by a changing climate. Methods: Addressing the challenges outlined in the objectives, this study introduces the Complex Adaptive Systems (CAS) framework, acknowledging its significance in capturing the nuanced dynamics of health effects linked to climate change. The research utilizes a blend of field observations, expert interviews, key informant interviews, and an extensive literature review to shape the development of the CAS framework. Results and discussion: The proposed CAS framework categorizes findings into six key sub-systems: ecological services, extreme weather, infectious diseases, food security, disaster risk management, and clinical public health. The study employs agent-based modeling, using causal loop diagrams (CLDs) tailored for each CAS sub-system. A set of identified variables is incorporated into predictive modeling to enhance the understanding of health outcomes within the CAS framework. Through a combination of theoretical development and practical application, this paper aspires to contribute valuable insights to the interdisciplinary field of climate change and health. Integrating agent-based modeling and CLDs enhances the predictive capabilities required for effective health outcome analysis in the context of climate change. Conclusion: This paper serves as a valuable resource for policymakers, researchers, and public health professionals by employing a CAS framework to understand and assess the complex network of health impacts associated with climate change. It offers insights into effective strategies for safeguarding human health amidst current and future climate challenges.

Joint-specific rheumatoid arthritis fibroblast-like synoviocyte regulation identified by integration of chromatin access and transcriptional activity.

The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific FLS biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors (TFs) and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an 'activated' state relative to the 'resting' state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

Responsiveness to Vedolizumab Therapy in Ulcerative Colitis is Associated With Alterations in Immune Cell-Cell Communications.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses to intestinal microbes. Although changes in the composition of immune cell subsets in the context of IBD have been previously described, the interactions and communication among cells are less well understood. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-α4ß7 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts. METHODS: We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on peripheral blood and colon immune cells derived from patients with ulcerative colitis treated with the anti-α4ß7 integrin antagonist vedolizumab. We applied a previously published computational approach, NicheNet, to predict immune cell-cell interactions, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications (CCC). RESULTS: We observed decreased proportions of T helper 17 (TH17) cells in UC patients who responded to vedolizumab and therefore focused the study on identifying cell-cell communications and signals of TH17 cells with other immune cells. For example, we observed that colon TH17 cells from vedolizumab nonresponders were predicted to have a greater degree of interactions with classical monocytes compared with responders, whereas colon TH17 cells from vedolizumab responders exhibited more interactions with myeloid dendritic cells compared with nonresponders. CONCLUSIONS: Overall, our results indicate that efforts to elucidate cell-cell communications among immune and nonimmune cell types may increase the mechanistic understanding of current and investigational therapies for IBD.

Compared to ulcerative patients unresponsive to vedolizumab, immune cell networks of ulcerative colitis patients responsive to vedolizumab have decreased proportion of TH17 and less pro-inflammatory signaling in the gut. Decreased pro-TH17 and interleukin (IL)-1 signaling from classical monocytes and innate immunocytes may mediate this phenotype.

Female sexual health digital resources: women and health care providers need more options.

INTRODUCTION: Female sexual health and female sexual dysfunction (FSD) are usually poorly diagnosed and treated because of the numerous barriers providers and patients face. Internet platforms, such as mobile applications (apps) are potential tools that help overcome these barriers and improve patient access to education and management options for FSD. OBJECTIVES: The aim of this review was to identify existing applications on female sexual health and evaluate their educational content and services. METHODS: We searched the internet and Apple App Store using multiple keywords. A panel of physicians specialized in the treatment of FSD reviewed the apps for content quality, the scientific basis of provided information, interactivity, usability, and whether they would recommend it as a reference tool for patients. RESULTS: Of the 204 apps identified, 17 met the inclusion criteria and were reviewed further. The selected apps were organized into groups based on common themes such as educational (n = 6), emotions and communication (n = 2), relaxation and meditation (n = 4), general sexual health (n = 2), and social and fun (n = 3). All apps from the educational category provided scientific information in collaboration with health experts. When assessed for usability, 1 app received good and 5 received excellent scores based on the System Usability Scale. Most apps (n = 5) provided information on pathology and treatments of orgasmic dysfunction, but only 1 app, created by a physician, provided comprehensive information on all the types of FSD. CONCLUSION: Digital technology could be an effective way to overcome barriers to accessing information and ultimately care for female sexual health. Our review demonstrated that there is still a need for more accessible educational resources addressing female sexual health and FSD for patients and providers.

Identification of CD8 + T-Cell-Immune Cell Communications in Ileal Crohn's Disease.

INTRODUCTION: Crohn's disease (CD) is a major subtype of inflammatory bowel disease (IBD), a spectrum of chronic intestinal disorders caused by dysregulated immune responses to gut microbiota. Although transcriptional and functional changes in a number of immune cell types have been implicated in the pathogenesis of IBD, the cellular interactions and signals that drive these changes have been less well-studied. METHODS: We performed Cellular Indexing of Transcriptomes and Epitopes by sequencing on peripheral blood, colon, and ileal immune cells derived from healthy subjects and patients with CD. We applied a previously published computational approach, NicheNet, to predict immune cell types interacting with CD8 + T-cell subsets, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications. RESULTS: As a number of recent studies have revealed a potential role for CD8 + T-cell subsets in the pathogenesis of IBD, we focused our analyses on identifying the interactions of CD8 + T-cell subsets with other immune cells in the intestinal tissue microenvironment. We identified ligands and signaling pathways that have implicated in IBD, such as interleukin-1ß, supporting the validity of the approach, along with unexpected ligands, such as granzyme B, which may play previously unappreciated roles in IBD. DISCUSSION: Overall, these findings suggest that future efforts focused on elucidating cell-cell communications among immune and nonimmune cell types may further our understanding of IBD pathogenesis.

Outcomes of the Supris Sling in an Urban Latina Population.

OBJECTIVE: To analyze patient reported outcomes, safety, and efficacy of the Supris mid-urethral sling in a diverse population. METHODS: A retrospective chart review of 101 women who underwent a mid-urethral Suprissling procedure was conducted. Baseline characteristics and perioperative parameters were collected. Post-operative results and patient reported outcomes were collected at an average follow-up time of 19 months using the Urogenital Distress Inventory-6 (UDI-6) and Patient Global Impression of Improvement (PGI-I) validated questionnaires. Subjective cure rates were compared using the nonparametric Wilcoxon Rank Sum Test. RESULTS: The median age of women was 57 years old, and 86.1% identified as Latina. 28% and 72% of women had a SUI and MUI diagnosis, respectively. Women, on average, used 2 pads pre-operatively and none post-operatively. There was a 3% surgical revision rate. 80 women completed the questionnaires. 82% of the MUI group reported being very much improved or much better. The SUI group reported being 94% very much improved or much better. The UDI-6 questions related to urgency and leakage of small amounts of urine were significantly different between the MUI and SUI groups (P = .002 and P = .044). CONCLUSION: In our primarily Latina patient population, the majority of whom had MUI, the Supris retropubic sling greatly improved symptoms. Although reported outcomes were excellent in both groups, those with pre-operative urge incontinence were more likely to experience urge symptoms post-operatively. Despite persistent urge symptoms, patients reported improvement of their overall symptoms.

Barriers to safety and efficiency in robotic surgery docking.

BACKGROUND: The introduction of new technology into the operating room (OR) can be beneficial for patients, but can also create new problems and complexities for physicians and staff. The observation of flow disruptions (FDs)-small deviations from the optimal course of care-can be used to understand how systems problems manifest. Prior studies showed that the docking process in robotic assisted surgery (RAS), which requires careful management of process, people, technology and working environment, might be a particularly challenging part of the operation. We sought to explore variation across multiple clinical sites and procedures; and to examine the sources of those disruptions. METHODS: Trained observers recorded FDs during 45 procedures across multiple specialties at three different hospitals. The rate of FDs was compared across surgical phases, sites, and types of procedure. A work-system flow of the RAS docking procedure was used to determine which steps were most disrupted. RESULTS: The docking process was significantly more disrupted than other procedural phases, with no effect of hospital site, and a potential interaction with procedure type. Particular challenges were encountered in room organization, retrieval of supplies, positioning the patient, and maneuvering the robot. CONCLUSIONS: Direct observation of surgical procedures can help to identify approaches to improve the design of technology and procedures, the training of staff, and configuration of the OR environment, with the eventual goal of improving safety, efficiency and teamwork in high technology surgery.

The Impact of Provider Sex and Experience on the Quality of Care Provided for Women with Urinary Incontinence.

BACKGROUND: Although specialists are skilled in the management of urinary incontinence, primary care clinicians are integral in early diagnosis and initiation of management in order to decrease overuse of specialty care and improve the quality of specialist visits. We measured the quality of incontinence care provided by primary care clinicians prior to referral to a specialist and evaluated the impact of provider variables on quality of care. METHODS: We performed a retrospective review of 200 women referred for urinary incontinence to a Female Pelvic Medicine and Reconstructive Surgery specialist between March 2017 and July 2018. We measured primary care adherence to 12 quality indicators in the 12 months prior to specialist consultation. We stratified adherence to quality indicators by clinician sex and years of experience. RESULTS: Half of women with incontinence underwent a pelvic examination or had a urinalysis ordered. Few patients with urge urinary incontinence were recommended behavioral therapy (14%) or prescribed medication (8%). When total aggregate scores were compared, female clinicians performed the recommended care 47% ± 25% of the time, compared with 35% ± 23% for male clinicians (P = .003). Increasing years of experience was associated with worse overall urinary incontinence care (r -0.157, P = .02). CONCLUSIONS: We found low rates of adherence to a set of quality indicators for women with urinary incontinence, with male clinicians performing significantly worse than female clinicians. Improvement of incontinence care in primary care could significantly reduce costs of care and preserve outcomes.

Characteristics and Long Term Follow up of Men Who Suffer Ischemic Priapism Secondary to Recreational Use of Intracavernosal Injectable Medications.

OBJECTIVE: To better understand patient experience, risk factors, culture, and ED outcomes surrounding recreational ICI use that led to ischemic priapism. METHODS: After IRB approval, men presenting for ischemic priapism secondary to recreational ICI use from January 2010 to December 2018 were contacted by mail and then via telephone. Standardized questions were asked of all study participants on the topics of erectile function (IIEF-5), sexual practices, and at-risk behavior at the time of priapism. Qualitative data analysis was performed using grounded theory methodology. RESULTS: 14 men age 24-59 were successfully recruited. All men described themselves as men having sex with men (MSM) and one (7.1%) as having both male and female sexual partners. Average follow up IIEF-5 among participants was 13 (SD 4.0). Eleven men (78.6 %) described illicit drug use at the time of priapism. Qualitative data analysis yielded several preliminary themes: concomitant drug use, naivety, peer pressure, and delay in seeking treatment. Men frequently reported illicit drug use in group sex scenarios and ICI use under pressure to perform sexually or to counteract effects of illicit substances. CONCLUSIONS: Recreational ICI in this cohort was part of a lifestyle of risky behavior. Methamphetamine use and group sex encounters strongly motivate recreational ICI use. Substance abuse centers may offer an entry point into this population for counseling and primary prevention.

IMACTIV: A Pilot Study of the Impact of Unrestricted Activity Following Urethral Sling Surgery.

OBJECTIVES: To compare continence outcomes and health-related quality of life (HRQOL) among women with limited activity restrictions vs traditional restrictions following mid-urethral sling (MUS) surgery. METHODS: Thirty-six women who underwent MUS surgery were randomized: (1) the Restrictions group was given traditional postoperative restrictions for 6 weeks while (2) the Limited Restrictions group was instructed to resume normal activities other than pelvic rest. Patients undergoing concomitant surgery for Stage III and IV prolapse were excluded. Participants completed questionnaires related to urinary symptoms (UDI-6, IIQ-7) for continence outcomes and HRQOL (SF-12) at baseline, 1 to 6 weeks, 3 months, 6 months, and at least 1 year after surgery. RESULTS: There was no difference in mean scores on the UDI-6 or IIQ-7 between groups at baseline or any time after surgery. The Limited Restrictions group reported better scores than the Restrictions group on the SF-12 mental health component at 1 week (56.7 vs 50.2, P = .01) and 4 weeks (58.4 vs 53.3, P = .04). The Restrictions group reported better SF-12 physical health scores at 5 weeks (55.7 vs 53.0, P = .02) but there was no difference in HRQOL scores between the two groups at any other time. CONCLUSION: In this pilot study, there was no difference in continence outcomes for women with traditional vs limited activity restrictions following MUS surgery. There were differences in HRQOL in the early post-operative period, but these differences were not sustained. Larger prospective studies are needed, but it appears that activity restrictions after MUS surgery may not be necessary.

Using Flow Disruptions to Examine System Safety in Robotic-Assisted Surgery: Protocol for a Stepped Wedge Crossover Design.

BACKGROUND: The integration of high technology into health care systems is intended to provide new treatment options and improve the quality, safety, and efficiency of care. Robotic-assisted surgery is an example of high technology integration in health care, which has become ubiquitous in many surgical disciplines. OBJECTIVE: This study aims to understand and measure current robotic-assisted surgery processes in a systematic, quantitative, and replicable manner to identify latent systemic threats and opportunities for improvement based on our observations and to implement and evaluate interventions. This 5-year study will follow a human factors engineering approach to improve the safety and efficiency of robotic-assisted surgery across 4 US hospitals. METHODS: The study uses a stepped wedge crossover design with 3 interventions, introduced in different sequences at each of the hospitals over four 8-month phases. Robotic-assisted surgery procedures will be observed in the following specialties: urogynecology, gynecology, urology, bariatrics, general, and colorectal. We will use the data collected from observations, surveys, and interviews to inform interventions focused on teamwork, task design, and workplace design. We intend to evaluate attitudes toward each intervention, safety culture, subjective workload for each case, effectiveness of each intervention (including through direct observation of a sample of surgeries in each observational phase), operating room duration, length of stay, and patient safety incident reports. Analytic methods will include statistical data analysis, point process analysis, and thematic content analysis. RESULTS: The study was funded in September 2018 and approved by the institutional review board of each institution in May and June of 2019 (CSMC and MDRH: Pro00056245; VCMC: STUDY 270; MUSC: Pro00088741). After refining the 3 interventions in phase 1, data collection for phase 2 (baseline data) began in November 2019 and was scheduled to continue through June 2020. However, data collection was suspended in March 2020 due to the COVID-19 pandemic. We collected a total of 65 observations across the 4 sites before the pandemic. Data collection for phase 2 was resumed in October 2020 at 2 of the 4 sites. CONCLUSIONS: This will be the largest direct observational study of surgery ever conducted with data collected on 680 robotic surgery procedures at 4 different institutions. The proposed interventions will be evaluated using individual-level (workload and attitude), process-level (perioperative duration and flow disruption), and organizational-level (safety culture and complications) measures. An implementation science framework is also used to investigate the causes of success or failure of each intervention at each site and understand the potential spread of the interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25284.

Work-system interventions in robotic-assisted surgery: a systematic review exploring the gap between challenges and solutions.

BACKGROUND: The introduction of a robot into the surgical suite changes the dynamics of the work-system, creating new opportunities for both success and failure. An extensive amount of research has identified a range of barriers to safety and efficiency in Robotic Assisted Surgery (RAS), such as communication breakdowns, coordination failures, equipment issues, and technological malfunctions. However, there exists very few solutions to these barriers. The purpose of this review was to identify the gap between identified RAS work-system barriers and interventions developed to address those barriers. METHODS: A search from three databases (PubMed, Web of Science, and Ovid Medline) was conducted for literature discussing system-level interventions for RAS that were published between January 1, 1985 to March 17, 2020. Articles describing interventions for systems-level issues that did not involve technical skills in RAS were eligible for inclusion. RESULTS: A total of 30 articles were included in the review. Only seven articles (23.33%) implemented and evaluated interventions, while the remaining 23 articles (76.67%) provided suggested interventions for issues in RAS. Major barriers identified included disruptions, ergonomic issues, safety and efficiency, communication, and non-technical skills. Common solutions involved team training, checklist development, and workspace redesign. CONCLUSION: The review identified a significant gap between issues and solutions in RAS. While it is important to continue identifying how the complexities of RAS affect operating room (OR) and team dynamics, future work will need to address existing issues with interventions that have been tested and evaluated. In particular, improving RAS-associated non-technical skills, task management, and technology management may lead to improved OR dynamics associated with greater efficiency, reduced costs, and better systems-level outcomes.

Patient and Provider Experience with Telemedicine in a Urology Practice: Identifying Opportunities for Improvement.

INTRODUCTION: As a result of COVID-19, several clinics have adopted telemedicine to safely deliver care. However, the introduction of a new technology into an already complex system creates new challenges that have the potential to negatively impact patient and provider experience. We aimed to use a human factors approach (the science concerned with understanding the interactions between humans and other elements in a complex system) to identify where systemic vulnerabilities may exist throughout the patient/provider experience with telemedicine. METHODS: A total of 23 patients scheduled for telemedicine consults were observed during visits with providers. A trained human factors observer documented disruptions to system efficiency (eg communication breakdowns, connectivity problems and interruptions) and invited patients and providers to take a survey investigating perceptions of telemedicine technology usability, satisfaction with the experience and opportunities to improve the process. RESULTS: Visits lasted an average of 17 minutes, 20 seconds and each visit had an average of 6 disruptions. Inefficiencies were categorized into 13 categories consisting mainly of interruptions (21, 15.22%), Internet connectivity issues (21, 15.22%), nonoptimal device setup (19, 13.77%) and repeat communication (18, 13.04%). Provider satisfaction with the system was 3.72/5.00 and perceived usability was 63.15 (68 is considered acceptable). Patient satisfaction was 4.80/5.00 and perceived usability was 85. CONCLUSIONS: These findings highlight opportunities for a multifaceted intervention, including the development of an informational sheet/video for patients, a telemedicine "best practices" guideline for physicians, a standardized training process and checklist for front office staff and an in-service training for the entire care team.

Immunostaining Patterns of Posttransplant Liver Biopsies Using 2 Anti-C4d Antibodies.

Histopathologic diagnosis of antibody-mediated rejection in posttransplant liver biopsies is challenging. The recently proposed diagnostic criteria by the Banff Working Group on Liver Allograft Pathology require positive C4d immunohistochemical staining to establish the diagnosis. However, the reported C4d staining patterns vary widely in different studies. One potential explanation may be due to different antibody preparations used by different investigators. In this study, posttransplant liver biopsies from 69 patients histopathologically diagnosed with acute cellular rejection, chronic rejection, or recurrent hepatitis C were immunohistochemically stained using 2 polyclonal anti-C4d antibodies. On the basis of the distribution of C4d immunoreactivity, 5 different staining patterns were observed: portal vein and capillary, hepatic artery, portal stroma, central vein, and sinusoids. The frequency, extent, and intensity of positive C4d staining with the 2 antibody preparations differed significantly for portal veins/capillaries and central veins, but not for hepatic arteries and portal stroma. Positive sinusoidal staining was seen in only 1 case. There were no significant differences in the frequency, extent, and intensity of positive C4d staining among the acute cellular rejection, chronic rejection, and recurrent hepatitis C groups with the 2 anti-C4d antibodies. These data show that different anti-C4d antibodies can show different staining patterns, which may lead to different interpretation. Caution is thus needed when selecting C4d antibodies for clinical use to aid in the diagnosis of antibody-mediated rejection.

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas.

CONTEXT: - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES: - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES: - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS: - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

Inflamed conjunctival nevi: histopathological criteria.

Inflamed conjunctival nevi (ICN) may suggest malignancy because of their rapid growth and atypical histology. The objective of this study was to characterize the diagnostic features of ICN. A retrospective, nonrandomized study of 13 patients with ICN was conducted. A scoring method was developed based on histology and immunopathological parameters. The presence of epithelial solid or cystic inclusions and the preservation of goblet cells are consistent with a benign melanocytic lesion. Periodic acid-Schiff stain and immunohistochemistry to identify the epithelial component prove helpful in the differential diagnosis for melanoma. Polyclonal lymphoid infiltrate and benign cytological features of ICN exclude a diagnosis of lymphoma. Despite the presence of immunoglobulin 4-positive plasma cells in the lesions, ICN does not meet the diagnostic criteria for immunoglobulin 4-related disease. Most patients with ICN are young. The treatment for ICN is complete excision, and the prognosis is excellent.