The Skin and Inflamm-Aging.

With its unique anatomical location facing both the external and internal environment, the skin has crucial functions, including shielding the body from damage caused by ultraviolet radiation and chemicals, preventing water loss, acting as a primary barrier against pathogens, participating in metabolic processes like vitamin D production and temperature control and relaying information to the body through sensory and proprioceptor nerves. Like all organ systems, skin is known to undergo multiple changes with aging. A better understanding of the mechanisms that mediate aging-related skin dysfunction may allow the creation of targeted therapeutics that have beneficial effects not only on aged skin but also on other organs and tissues that experience a loss of or decline in function with aging. The skin is the largest organ of the body and can contribute to serum inflammatory mediator levels. One alteration known to occur with age is an impairment of skin barrier function; since disruption of the barrier is known to induce inflammation, skin may be a major contributor to the sustained, sub-clinical systemic inflammation associated with aging. Such "inflamm-aging" may underlie many of the deleterious changes observed in aged individuals. This review explores the role of age-related skin changes, skin inflammation and inflamm-aging.

simKAP: simulation framework for the kidney allocation process with decision making model.

Organ shortage is a major barrier in transplantation and rules guarding organ allocation decisions should be robust, transparent, ethical and fair. Whilst numerous allocation strategies have been proposed, it is often unrealistic to evaluate all of them in real-life settings. Hence, the capability of conducting simulations prior to deployment is important. Here, we developed a kidney allocation simulation framework (simKAP) that aims to evaluate the allocation process and the complex clinical decision-making process of organ acceptance in kidney transplantation. Our findings have shown that incorporation of both the clinical decision-making and a dynamic wait-listing process resulted in the best agreement between the actual and simulated data in almost all scenarios. Additionally, several hypothetical risk-based allocation strategies were generated, and we found that these strategies improved recipients' long-term post-transplant patient survival and reduced wait time for transplantation. The importance of simKAP lies in its ability for policymakers in any transplant community to evaluate any proposed allocation algorithm using in-silico simulation.

Periodic Colonoscopies Are Associated with Improved Survival and Prognosis of Colorectal Cancer in Ulcerative Colitis.

BACKGROUND AND STUDY AIMS: This study aimed to identify whether ulcerative colitis (UC) patients who develop colorectal cancer (CRC) present at earlier stages of CRC and have improved survival if prior to their CRC diagnosis, they underwent intermittent follow-up colonoscopies compared to those who have no follow-up colonoscopies. METHODS: Patients with UC who developed primary CRC were identified using data provided by the Institute for Clinical Evaluative Sciences. We defined low-risk CRC stage as estimated 5-year survival ≥ 80% compared to high-risk CRC as 5-year survival < 80%. RESULTS: A total of 421 patients were identified with UC and CRC. The 15-year mortality rate was significantly higher in those who did not have follow-up colonoscopy (33/74; 44.6%) compared to the follow-up group (105/347; 30.3%) (p = 0.0172). Among the 219 patients with UC with staging information available, patients who did not have follow-up colonoscopy were more likely to present with high-risk CRC (24/31; 77.4%) compared with patients who had follow-up colonoscopies (88/188; 44.4%) (p = 0.0016). Those who underwent follow-up colonoscopies at average intervals ≤ 3 years presented with high-risk CRC 41.3% of the time, which was less than the 48.6% in those with less frequent colonoscopies and 77.4% in those with no follow-up (p = 0.0048). CONCLUSIONS: Patients with UC who underwent intermittent follow-up colonoscopies had CRC detected at earlier stages and improvement in all-cause mortality, compared to those who with no follow-up colonoscopies. This may support regular surveillance colonoscopies for patients with UC.

Longitudinal cognitive and functional changes in primary progressive aphasia.

OBJECTIVE: The variants of primary progressive aphasia (PPA) are predominantly diagnosed on the basis of specific profiles of language impairments. Deficits in other cognitive domains and their evolution over time are less well documented. This study examined the cognitive profiles of the PPA variants over time and determined the contribution of cognition on functional capacity. METHODS: Longitudinal performance on the Addenbrooke's Cognitive Examination-III (ACE-III) total and cognitive subdomains were investigated in 147 PPA individuals (41 logopenic [lv-PPA], 44 non-fluent [nfv-PPA], and 62 semantic variants [sv-PPA]). The relative contribution of ACE-III subdomain scores to overall functional capacity over time was identified using mixed and hierarchical regression modelling. RESULTS: The annual rate of global ACE-III decline was twice that in lv-PPA than in nfv-PPA and sv-PPA, despite lv-PPA performing intermediate to the other variants at baseline assessment. Notably, attention and visuospatial subdomains declined faster in lv-PPA than in nfv-PPA and sv-PPA; and memory impairment was more severe in lv-PPA than in nfv-PPA at all time points. Functional decline was comparable across PPA variants; however, the contribution of cognition on functional capacity varied across variants and over time. CONCLUSION: The cognitive profiles of the PPA variants are distinct at baseline and over time. Crucially, cognitive decline in lv-PPA was more widespread and pervasive than in nfv-PPA and sv-PPA. Our findings also demonstrate the complex interplay between cognition and functional capacity. This study underscores the importance of routinely assessing cognition and functional capacity in PPA to improve diagnostic accuracy and provide targeted support services.

Ileal or Colonic Histologic Activity Is Not Associated With Clinical Relapse in Patients With Crohn's Disease in Endoscopic Remission.

BACKGROUND & AIMS: Goals of treatment for Crohn's disease (CD) are clinical and endoscopic remission. It is not clear whether histologic markers of healing associate with endoscopic remission in patients with CD. METHODS: We identified patients with CD from a single institutional registry, and collected data from 129 patients (46.5% female; mean age 25 y; mean CD duration 14.5 y) who underwent colonoscopy evaluation and had simple endoscopic scores for CD below 3 (the definition of endoscopic remission). Histologic signs of CD activity were graded in 192 biopsies (90 ileum and 102 colon), and disease was classified as active (presence of crypt destruction, neutrophils, erosions or ulcerations), quiescent (presence of architectural distortion and chronic inflammatory infiltrate), or normal histology (none of these). The primary outcome was clinical relapse within 2 y (dose escalation, change in therapy, need for systemic steroids, or CD-related hospitalization or surgery). We performed multivariable regression adjusting for relevant confounders to examine the independent predictive value of histologic activity. RESULTS: Within 2 y of endoscopic evaluation, 42 patients (32.6%) had a clinical relapse. There were no significant differences in proportions of patients with active ileal CD (23.8%), quiescent CD (28.6%), or normal histology (37%) between those who relapsed and those remaining in remission (P = .43). There were no significant differences in proportions of relapses among patients with active colonic disease (38.1%), quiescent disease (35.0%), or normal histology (27.9%, P = .73). A linear regression analysis found no association between histologic features of active disease in ileal histology biopsies and symptom scores (Harvey Bradshaw index and simple inflammatory bowel disease questionnaire scores). CONCLUSIONS: In an analysis of biopsies from patients with CD who had achieved clinical and endoscopic remission, histologic remission was not associated with clinical relapse within 2 years.

Combination Therapy Does Not Improve Rate of Clinical or Endoscopic Remission in Patients with Inflammatory Bowel Diseases Treated With Vedolizumab or Ustekinumab.

BACKGROUND & AIMS: Patients with Crohn's disease (CD) or ulcerative colitis (UC) often receive combination therapy with an immunomodulator and tumor necrosis factor antagonists, especially infliximab. However, the benefits of combination therapy with vedolizumab and ustekinumab are unclear. METHODS: We performed a retrospective study of patients with CD or UC initiating vedolizumab or ustekinumab therapy at Massachusetts General Hospital (USA), Alberta Health Sciences (Canada), or Nancy University Hospital (France) with at least 1 year of follow up. The primary outcome was clinical remission or response at week 14, based on the Harvey Bradshaw index for CD or simple clinical colitis index or partial Mayo score for UC. We separately examined week 30 and week 54 clinical outcomes, endoscopic response, and durability of therapy using multivariable regression models and adjusting for relevant confounders. RESULTS: Our study included 549 patients (263 with UC, 286 with CD) receiving maintenance therapy with vedolizumab and 363 patients (4 with UC, 359 with CD) receiving maintenance therapy with ustekinumab with 1 year of follow up. The mean disease duration was 13-15 years. One-hundred thirty-one patients receiving vedolizumab (23.9%; 78 receiving thiopurine, 53 receiving methotrexate) and 120 patients receiving ustekinumab (33.1%, 57 receiving thiopurine, 63 receiving methotrexate) were receiving combination therapy. For vedolizumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (68.2% vs 74.1%; P = .22), week 30 (74.3% vs 75.6%; P = .78) or week 54 (78.3% vs 72.9%, P = .33). For ustekinumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (54.6% vs 65.8%; P = .08), week 30 (71.6% vs 77.4%; P = .33) or week 54 (62.1% vs 67.0%; P = .52). There were similar proportions of patients remaining on treatment or with endoscopic response at 1 year among patients receiving combination or monotherapy with vedolizumab or ustekinumab. CONCLUSIONS: In patients with CD or UC initiating ustekinumab or vedolizumab therapy, combination therapy with immunomodulators did not increase rates of clinical remission or response, endoscopic remission, or persistence of therapy at 1 year.

Yield of Random Biopsies During Colonoscopies in Inflammatory Bowel Disease Patients Undergoing Dysplasia Surveillance.

BACKGROUND: The development of chromoendoscopy (CE) and high definition endoscopy (HDE) has improved detection of subtle colonic dysplasia in patients with inflammatory bowel diseases (IBDs). The role of random biopsies for dysplasia surveillance is unclear. METHODS: We reviewed patients with IBD who underwent a CE or HDE colonoscopy and had colonic dysplasia detected. Detection of dysplasia was classified as either visible or random and graded as low grade dysplasia (LGD), high grade dysplasia (HGD), or indefinite for dysplasia. Multivariable regression adjusted for relevant confounders examined the predictors of dysplasia detectable on random biopsies alone. RESULTS: The study included 300 patients (203 ulcerative colitis, 97 Crohn's disease with colonic involvement) contributing 442 colonoscopies; the mean disease duration was 24.5 years; 7.2% had primary sclerosing cholangitis (PSC). Three hundred sixty-two colonoscopies (82%) had only visible dysplasia, 52 (12%) had only random dysplasia, and 28 (6%) had both visible and random dysplasia. Longer disease duration (odds ratio, 1.04; 95% CI, 1.01-1.07), active inflammation (odds ratio, 2.89; 95% CI, 1.26-6.67), and concomitant PSC (odds ratio, 3.66; 95% CI, 1.21-11.08) were associated with detecting dysplasia on random biopsies compared with visible lesions. Patients with random dysplasia (21%) or both random and visible dysplasia (21%) were more likely to undergo surgical resection compared with those with only visible dysplasia (5%; P < 0.001) and have subsequent development of colorectal cancer (15%, 7%, 1%, respectively; P < 0.0001). CONCLUSION: Nearly one fifth of dysplasia detected in patients with IBD was found on random biopsies. Patients with high risk characteristics may benefit from continuing the practice of random biopsies during surveillance examinations.

A 'culture' shift: Application of molecular techniques for diagnosing polymicrobial infections.

With the advancement of microbiological discovery, it is evident that many infections, particularly bloodstream infections, are polymicrobial in nature. Consequently, new challenges have emerged in identifying the numerous etiologic organisms in an accurate and timely manner using the current diagnostic standard. Various molecular diagnostic methods have been utilized as an effort to provide a fast and reliable identification in lieu or parallel to the conventional culture-based methods. These technologies are mostly based on nucleic acid, proteins, or physical properties of the pathogens with differing advantages and limitations. This review evaluates the different molecular methods and technologies currently available to diagnose polymicrobial infections, which will help determine the most appropriate option for future diagnosis.

A "Culture" Shift: Broad Bacterial Detection, Identification, and Antimicrobial Susceptibility Testing Directly from Whole Blood.

BACKGROUND: The time required for bloodstream pathogen detection, identification (ID), and antimicrobial susceptibility testing (AST) does not satisfy the acute needs of disease management. Conventional methods take up to 3 days for ID and AST. Molecular diagnostics have reduced times for ID, but their promise to supplant culture is unmet because AST times remain slow. We developed a combined quantitative PCR (qPCR)-based ID+AST assay with sequential detection, ID, and AST of leading nosocomial bacterial pathogens. METHODS: ID+AST was performed on whole blood samples by (a) removing blood cells, (b) brief bacterial enrichment, (c) bacterial detection and ID, and (d) species-specific antimicrobial treatment. Broad-spectrum qPCR of the internal transcribed spacer between the 16S and 23S was amplified for detection. High-resolution melting identified the species with a curve classifier. AST was enabled by Ct differences between treated and untreated samples. RESULTS: A detection limit of 1 CFU/mL was achieved for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. All species were accurately identified by unique melting curves. Antimicrobial minimum inhibitory concentrations were identified with Ct differences of ≥1 cycle. Using an RNA target allowed reduction of AST incubation time from 60 min to 5 min. Rapid-cycle amplification reduced qPCR times by 83% to 30 min. CONCLUSIONS: Combined, sequential ID+AST protocols allow rapid and reliable detection, ID, and AST for the diagnosis of bloodstream infections, enabling conversion of empiric to targeted therapy by the second dose of antimicrobials.

Microbial Typing by Machine Learned DNA Melt Signatures.

There is still an ongoing demand for a simple broad-spectrum molecular diagnostic assay for pathogenic bacteria. For this purpose, we developed a single-plex High Resolution Melt (HRM) assay that generates complex melt curves for bacterial identification. Using internal transcribed spacer (ITS) region as the phylogenetic marker for HRM, we observed complex melt curve signatures as compared to 16S rDNA amplicons with enhanced interspecies discrimination. We also developed a novel Naïve Bayes curve classification algorithm with statistical interpretation and achieved 95% accuracy in differentiating 89 bacterial species in our library using leave-one-out cross-validation. Pilot clinical validation of our method correctly identified the etiologic organisms at the species-level in 59 culture-positive mono-bacterial blood culture samples with 90% accuracy. Our findings suggest that broad bacterial sequences may be simply, reliably and automatically profiled by ITS HRM assay for clinical adoption.

Course evaluation and assessment: examples of a learner-centered approach.

Teaching in higher education increasingly requires greater accountability, the utilization of contemporary learner-focused teaching models, and transparent grading methods for nonstandardized learning products. This article describes learner-centered evaluation and assessment strategies and illustrates how these approaches emphasize learners' responsibility for their own learning, foster students' commitment to learning and provide useful information for continuous curriculum improvement. In addition, the article discusses the components of learner-centered assessment models including the course assessment and enhancement model, the Personal Action Plan, and the Gedanken Experiment. Further, a rubric is presented as a tool for systematic and transparent grading of learner-centered assessment products. The need for further validation of these strategies is being discussed.