Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk.

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8(+) gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction

Statistical feature training improves fingerprint-matching accuracy in novices and professional fingerprint examiners

AbstractForensic science practitioners compare visual evidence samples (e.g. fingerprints) and decide if they originate from the same person or different people (i.e. fingerprint ‘matching’). These tasks are perceptually and cognitively complex—even practising professionals can make errors—and what limited research exists suggests that existing professional training is ineffective. This paper presents three experiments that demonstrate the benefit of perceptual training derived from mathematical theories that suggest statistically rare features have diagnostic utility in visual comparison tasks. Across three studies (N = 551), we demonstrate that a brief module training participants to focus on statistically rare fingerprint features improves fingerprint-matching performance in both novices and experienced fingerprint examiners. These results have applied importance for improving the professional performance of practising fingerprint examiners, and even other domains where this technique may also be helpful (e.g. radiology or banknote security).</jats:p

Heterogeneity of Multifunctional IL-17A Producing S. Typhi-Specific CD8+ T Cells in Volunteers following Ty21a Typhoid Immunization

Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to cause significant morbidity and mortality world-wide. CD8+ T cells are an important component of the cell mediated immune (CMI) response against S. Typhi. Recently, interleukin (IL)-17A has been shown to contribute to mucosal immunity and protection against intracellular pathogens. To investigate multifunctional IL-17A responses against S. Typhi antigens in T memory subsets, we developed multiparametric flow cytometry methods to detect up to 6 cytokines/chemokines (IL-10, IL-17A, IL-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1β (MIP-1β)) simultaneously. Five volunteers were immunized with a 4 dose regimen of live-attenuated S. Typhi vaccine (Ty21a), peripheral blood mononuclear cells (PBMC) were isolated before and at 11 time points after immunization, and CMI responses were evaluated. Of the 5 immunized volunteers studied, 3 produced detectable CD8+ T cell responses following stimulation with S. Typhi-infected autologous B lymphoblastoid cell lines (B-LCL). Additionally, 2 volunteers had detectable levels of intracellular cytokines in response to stimulation with S. Typhi-infected HLA-E restricted cells. Although the kinetics of the responses differed among volunteers, all of the responses were bi- or tri-phasic and included multifunctional CD8+ T cells. Virtually all of the IL-17A detected was derived from multifunctional CD8+ T cells. The presence of these multifunctional IL-17A+ CD8+ T cells was confirmed using an unsupervised analysis program, flow cytometry clustering without K (FLOCK). This is the first report of IL-17A production in response to S. Typhi in humans, indicating the presence of a Tc17 response which may be important in protection. The presence of IL-17A in multifunctional cells co-producing Tc1 cytokines (IL-2, IFN-γ and TNF-α) may also indicate that the distinction between Tc17 and Tc1 responses in humans is not as clearly delineated as suggested by in vitro experiments and animal models

Long-term clinical, immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection

BACKGROUND: To test the hypothesis of down-regulating the increased immune system activation/destruction process associated with chronic HIV infection, we focused our interest on prednisolone (PDN), because we had showed that, in vitro, PDN had a strong anti-apoptotic activity on activated T cells of HIV-infected patients and no effect on viral replication. We thus designed in 1992 a pilot study to evaluate the clinical, immunologic and virologic effects of PDN. The drug was given to a group of 44 patients with CD4 T cells over 200/μl. After one year, no patient had developed clinical AIDS and the mean CD4 T cell count of the group had increased from 441 ± 21 cells/μl to 553 ± 43 cells/μl. Moreover, markers of immune activation had dropped back to normal levels while the mean viral load of the group had remained unchanged. Here we explore the long-term clinical, immunologic, and virologic impact of prednisolone on the chronic phase of HIV infection. METHODS: Retrospective study over 10 years starting between July 1992 and February 1993. A total of 44 patients with CD4 cells/μl ranging from 207 to 775 were treated with prednisolone, 0.5 mg/kg/d, over 6 months and 0.3 mg/kg/d thereafter. RESULTS: No clinical AIDS developed under prednisolone; side effects of the drug were mild. CD4 cells which increased from 421 cells/μl at entry to 625 cells/μl at day 15, slowly decreased to reach 426 cells/μl after two years; T cell apoptosis and activation markers dropped within 15 days to normal levels and reincreased slowly thereafter. Serum viral loads remained stable. The percentage of patients maintaining CD4 cells over entry was 43.2% at two years, 11.4% at five years and 4.6% at 10 years. Initial viral load was highly predictive of the rate of CD4 decrease under prednisolone. CONCLUSIONS: Prednisolone postponed CD4 cell decrease in a viral load dependent manner for a median of two years and for up to 10 years in a fraction of the patients with a low viral load. These findings might stimulate clinical trials as well as biological research on the role of antiapoptotic drugs in HIV infection

Puzzle based teaching versus traditional instruction in electrocardiogram interpretation for medical students – a pilot study

<p>Abstract</p> <p>Background</p> <p>Most medical professionals are expected to possess basic electrocardiogram (EKG) interpretation skills. But, published data suggests that residents' and physicians' EKG interpretation skills are suboptimal. Learning styles differ among medical students; individualization of teaching methods has been shown to be viable and may result in improved learning. Puzzles have been shown to facilitate learning in a relaxed environment. The objective of this study was to assess efficacy of teaching puzzle in EKG interpretation skills among medical students.</p> <p>Methods</p> <p>This is a reader blinded crossover trial. Third year medical students from College of Human Medicine, Michigan State University participated in this study. Two groups (n = 9) received two traditional EKG interpretation skills lectures followed by a standardized exam and two extra sessions with the teaching puzzle and a different exam. Two other groups (n = 6) received identical courses and exams with the puzzle session first followed by the traditional teaching. EKG interpretation scores on final test were used as main outcome measure.</p> <p>Results</p> <p>The average score after only traditional teaching was 4.07 ± 2.08 while after only the puzzle session was 4.04 ± 2.36 (p = 0.97). The average improvement after the traditional session was followed up with a puzzle session was 2.53 ± 1.94 while the average improvement after the puzzle session was followed with the traditional session was 2.08 ± 1.73 (p = 0.67). The final EKG exam score for this cohort (n = 15) was 84.1 compared to 86.6 (p = 0.22) for a comparable sample of medical students (n = 15) at a different campus.</p> <p>Conclusion</p> <p>Teaching EKG interpretation with puzzles is comparable to traditional teaching and may be particularly useful for certain subgroups of students. Puzzle session are more interactive and relaxing, and warrant further investigations on larger scale.</p

Electrophysiologic Studies and Radiofrequency Catheter Ablation of Ectopic Atrial Tachycardia in Children

Ectopic atrial tachycardia (EAT) often resists medical therapy, making radiofrequency catheter ablation (RFCA) the preferred treatment. This study reviewed the records of 35 patients who underwent electrophysiologic studies (EPS) and 39 RFCA procedures for EAT during a 10-year period. Of the 35 patients, 10 (28%) presented with decreased ventricular function and tachycardia-induced cardiomyopathy (TIC). The EAT originated on the right atrial side in 19 patients (54%) and on the left atrial side in the remaining 16 patients (46%). The right atrial sites included the right atrial appendage (RAA) (n = 9, 25%), the tricuspid annulus (n = 7, 20%), and the crista terminalis (n = 3). The left atrial sites included the left atrial appendage (LAA) (n = 6, 17%), the pulmonary veins (n = 5, 14%), the mitral annulus (n = 3), and the posterior wall of the left atrium (n = 2). The mechanism of all EAT probably is automaticity. All EATs could be abolished using RFCA. Follow-up data were available for all patients 2 to 8 years after RFCA. All 35 patients remained recurrence free, and ventricular function improved for all 10 patients with TIC. The origin of EAT in children differed from its origin in adults. The authors conclude that RFCA is a safe and effective treatment option for children with refractory EAT and should be considered early in the course of their illness

Teaching Feedback to First-year Medical Students: Long-term Skill Retention and Accuracy of Student Self-assessment

Giving and receiving feedback are critical skills and should be taught early in the process of medical education, yet few studies discuss the effect of feedback curricula for first-year medical students. To study short-term and long-term skills and attitudes of first-year medical students after a multidisciplinary feedback curriculum. Prospective pre- vs. post-course evaluation using mixed-methods data analysis. First-year students at a public university medical school. We collected anonymous student feedback to faculty before, immediately after, and 8 months after the curriculum and classified comments by recommendation (reinforcing/corrective) and specificity (global/specific). Students also self-rated their comfort with and quality of feedback. We assessed changes in comments (skills) and self-rated abilities (attitudes) across the three time points. Across the three time points, students’ evaluation contained more corrective specific comments per evaluation [pre-curriculum mean (SD) 0.48 (0.99); post-curriculum 1.20 (1.7); year-end 0.95 (1.5); p = 0.006]. Students reported increased skill and comfort in giving and receiving feedback and at providing constructive feedback (p &lt; 0.001). However, the number of specific comments on year-end evaluations declined [pre 3.35 (2.0); post 3.49 (2.3); year-end 2.8 (2.1)]; p = 0.008], as did students’ self-rated ability to give specific comments. Teaching feedback to early medical students resulted in improved skills of delivering corrective specific feedback and enhanced comfort with feedback. However, students’ overall ability to deliver specific feedback decreased over time

The epidemiology and management of severe hypertension

Hypertension guidelines stress that patients with severe hypertension (systolic blood pressure (BP)⩾180 or diastolic BP⩾110 mm Hg) require multiple drugs to achieve control and should have close follow-up to prevent adverse outcomes. However, little is known about the epidemiology or actual management of these patients. We retrospectively studied 59 207 veterans with hypertension. Patients were categorized based on their highest average BP over an 18-month period (1 July 1999 to 31 December 2000) as controlled (<140/90 mm Hg), mild (140–159/90–99 mm Hg), moderate (160–179/100–109 mm Hg) and severe hypertension. We examined severe hypertension prevalence, pattern, duration, associated patient characteristics, time to subsequent visit, percentage of visits with a medication increase, and final BP control and antihypertensive medication adequacy. Twenty-three per cent had ⩾1 visit with severe hypertension, 42% of whom had at least two such visits; median day with severe hypertension was 80 (range 1–548). These subjects were significantly older, more likely black, and with more comorbidities than other hypertension subjects. Medication increases occurred at 20% of visits with mild hypertension compared to 40% with severe hypertension; P<0.05). At study end, 76% of patients with severe hypertension remained uncontrolled; severe hypertension subjects with uncontrolled BP were less likely to be on adequate therapy than those with controlled BP (43.7 vs 45.4%). Among hypertensive veterans, severe hypertension episodes are common. Many subjects had relatively prolonged elevations, with older, sicker subjects at highest risk. Although, follow-up times are shorter and antihypertensive medication use greater in severe hypertension subjects, they are still not being managed aggressively enough. Interventions to improve providers' management of these high-risk patients are needed