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Background Skin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability. In order to develop a new histopathological outcome measure for SSc, we applied a computer vision technology called a deep neural network (DNN) to stained sections of SSc skin. We tested the hypotheses that DNN analysis could reliably assess mRSS and discriminate SSc from normal skin. Methods We analyzed biopsies from two independent (primary and secondary) cohorts. One investigator performed mRSS assessments and forearm biopsies, and trichrome-stained biopsy sections were photomicrographed. We used the AlexNet DNN to generate a numerical signature of 4096 quantitative image features (QIFs) for 100 randomly selected dermal image patches/biopsy. In the primary cohort, we used principal components analysis (PCA) to summarize the QIFs into a Biopsy Score for comparison with mRSS. In the secondary cohort, using QIF signatures as the input, we fit a logistic regression model to discriminate between SSc vs. control biopsy, and a linear regression model to estimate mRSS, yielding Diagnostic Scores and Fibrosis Scores, respectively. We determined the correlation between Fibrosis Scores and the published Scleroderma Skin Severity Score (4S) and between Fibrosis Scores and longitudinal changes in mRSS on a per patient basis. Results In the primary cohort (n = 6, 26 SSc biopsies), Biopsy Scores significantly correlated with mRSS (R = 0.55, p = 0.01). In the secondary cohort (n = 60 SSc and 16 controls, 164 biopsies; divided into 70% training and 30% test sets), the Diagnostic Score was significantly associated with SSc-status (misclassification rate = 1.9% [training], 6.6% [test]), and the Fibrosis Score significantly correlated with mRSS (R = 0.70 [training], 0.55 [test]). The DNN-derived Fibrosis Score significantly correlated with 4S (R = 0.69, p = 3 × 10− 17). Conclusions DNN analysis of SSc biopsies is an unbiased, quantitative, and reproducible outcome that is associated with validated SSc outcomes.

Purpose To characterize and provide population-based prevalence estimates of myopic degeneration (MD) among Chinese Americans, the fastest-growing minority population in the United States in the last decade. Design Population-based, cross-sectional study. Methods A total of 1523 Chinese-American adults with myopia, aged 50 years and older, residing in the city of Monterey Park, California, underwent an interview and comprehensive eye examination, including subjective and objective refraction and stereoscopic fundus photography. For each participant, the eye with the worse myopic refractive error was included in this analysis. MD was assessed in a masked manner by an expert grader. Results The prevalence of any MD was 44.9% among myopic subjects, based on the presence of any degenerative lesion secondary to myopia. The prevalence was 32.2% when MD was defined by a modified version of the Meta-Analysis for Pathologic Myopia. The prevalence of specific lesions included tessellation (31.7%), tilted disc (28.1%), peripapillary atrophy (7.0%), staphyloma (5.7%), diffuse atrophy (6.4%), lacquer cracks (2.6%), intrachoroidal cavitation (2.2%), patchy atrophy (0.9%), and end-stage MD (0.2%). The prevalence of MD was higher among older myopic subjects and among participants with more severe myopia and longer axial length ( P Conclusions These data provide the first population-based estimates of MD in Chinese Americans and indicate that a high proportion of Chinese Americans might be at risk for MD and associated visual complications. Prevalence of MD in this cohort of Chinese Americans was higher than that observed in other East Asian populations and in people of other ethnicities.

Background Brain metastases (BM) are frequently observed in advanced renal-cell carcinoma (RCC). Historically these individuals have been excluded from clinical trials, but recently, with better local control, many can receive aggressive therapy after treatment. We evaluate our single-institution experience over various treatment eras. Patients and Methods Patients undergoing evaluation for RCC BM from 2001 to 2018 were identified from our institutional database. Clinical notes, demographics, comorbidities, histology, central nervous system (CNS) treatments, systemic therapy, and outcomes were reviewed. Overall survival (OS) and CNS recurrence-free survival (RFS) were evaluated by the Kaplan-Meier method. Cumulative incidence was evaluated using a competing risk model. Results We identified 158 patients with RCC BM, of whom 94.4% had clear-cell RCC, and 90.6% had extracranial metastases at diagnosis. Of these patients, 94 (60%) developed RCC BM over time, while 46 (29.1%) had RCC BM at initial presentation. Clinical symptoms were noted in 81.9% of patients. The median OS after diagnosis of RCC BM was 8.4 months, with a 3-year OS of 28.2%. The median CNS RFS was 8.5 months overall; however, those with one and more than one lesion had median CNS RFS of 12.4 and 6 months, respectively (P Conclusion The majority of RCC patients with BM are symptomatic and had prior metastatic disease that progressed to the brain. Those with a solitary RCC BM are less likely to develop CNS recurrence after local therapy and are ideal candidates for enrollment onto clinical trials.

Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics.

Background and objectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methodsMale C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile , fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.

Background The impact of having an established dermatologist on melanoma depth at diagnosis is incompletely understood. Objective We sought to determine whether having had a previous dermatologic examination (an established dermatologist), the recency of the last examination, and the wait time for the dermatology appointment are associated with melanoma invasiveness and depth. Methods This was a retrospective cross-sectional study of 388 patients with primary melanoma at an academic dermatology department. Results Patients with an established dermatologist were more likely than patients without an established dermatologist to be given a diagnosis of melanoma in situ (103/162 [63.6%] vs 69/155 [44.5%], P = .001) and to have thinner invasive melanoma (0.48 [0.30-0.71] mm vs 0.61 [0.40-1.10] mm, respectively, P = .003). These trends were observed for patients with self-detected, but not dermatologist-detected, melanoma. Patient-detected melanomas made up 184/361 (51.0%) of all melanomas, 83/199 (41.7%) of in situ melanomas, and 101/162 (62.4%) invasive melanomas. Self-detected melanomas were in situ in 36 of 61 (59.0%) patients with an established dermatologist versus 40 of 108 (37.0%) patients without an established dermatologist, P = .006. Neither time from last dermatologic examination nor wait time for an appointment was associated with melanoma invasiveness or depth. Limitations Data are retrospective and from 1 large academic health care system. Conclusion Education obtained at the dermatology appointment may improve early self-detection of melanoma, and having an established dermatologist may facilitate earlier evaluation of concerning lesions.

To estimate the prevalence of refractive errors in adult Chinese Americans, and to evaluate factors associated with myopia and high myopia.A population-based, cross-sectional study.Chinese Americans 50 years and older residing in Monterey Park, California, were recruited. Noncycloplegic automated refraction with supplemental subjective refraction was performed. Myopia, high myopia, hyperopia, and high hyperopia were defined as a spherical equivalent of-0.5 diopter (D),-5.0 D,+0.5 D, and ≥+3.0 D, respectively. Astigmatism and high astigmatism were defined as a cylinder of0.5 D and2.25 D, respectively. Risk factor assessment was guided by a conceptual model.Data from 4144 participants were analyzed. The overall prevalence of myopia, high myopia, hyperopia, high hyperopia, astigmatism, and high astigmatism in the right eye was 35.1% (95% confidence interval, 33.6%-36.6%), 7.4% (6.6%-8.3%), 40.2% (38.7%-41.8%), 2.7% (2.2%-3.3%), 45.6% (44.1%-47.2%), and 3.7% (3.1%-4.3%), respectively. The prevalence of myopia and high myopia was lower among older individuals (P.05). Reversed age trends were observed for the other refractive errors (P.05). There was no sex difference in the prevalence of refractive errors, except for a higher prevalence of hyperopia among female subjects (P = .010). Age, acculturation, education, income, marital status, birth country, history of ocular disease, nonocular comorbidities, and recent eye examination were associated with prevalence of myopia. All of these factors, except for acculturation, were also associated with high myopia.Our data present the first population-based estimates of the prevalence of refractive errors among adult Chinese Americans. Compared with whites, Hispanics, and blacks, Chinese Americans have a higher burden of myopia, high myopia, and astigmatism.

Misattributions people make about their own affective reactions can be used to measure attitudes implicitly. Combining the logic of projective tests with advances in priming research, the affect misattribution procedure (AMP) was sensitive to normatively favorable and unfavorable evaluations (Experiments 1-4), and the misattribution effect was strong at both fast and slow presentation rates (Experiments 3 and 4). Providing further evidence of validity, the AMP was strongly related to individual differences in self-reported political attitudes and voting intentions (Experiment 5). In the socially sensitive domain of racial attitudes, the AMP showed in-group bias for Black and White participants. AMP performance correlated with explicit racial attitudes, a relationship that was moderated by motivations to control prejudice (Experiment 6). Across studies, the task was unaffected by direct warnings to avoid bias. Advantages of the AMP include large effect sizes, high reliability, ease of use, and resistance to correction attempts.

To understand the role of a gene in the development of colitis, we compared the responses of wild-type mice and gene-of-interest deficient knockout mice to colitis. If the gene-of-interest is expressed in both bone marrow derived cells and non-bone marrow derived cells of the host; however, it is possible to differentiate the role of a gene of interest in bone marrow derived cells and non- bone marrow derived cells by bone marrow transplantation technique. To change the bone marrow derived cell genotype of mice, the original bone marrow of recipient mice were destroyed by irradiation and then replaced by new donor bone marrow of different genotype. When wild-type mice donor bone marrow was transplanted to knockout mice, we could generate knockout mice with wild-type gene expression in bone marrow derived cells. Alternatively, when knockout mice donor bone marrow was transplanted to wild-type recipient mice, wild-type mice without gene-of-interest expressing from bone marrow derived cells were produced. However, bone marrow transplantation may not be 100% complete. Therefore, we utilized cluster of differentiation (CD) molecules (CD45.1 and CD45.2) as markers of donor and recipient cells to track the proportion of donor bone marrow derived cells in recipient mice and success of bone marrow transplantation. Wild-type mice with CD45.1 genotype and knockout mice with CD45.2 genotype were used. After irradiation of recipient mice, the donor bone marrow cells of different genotypes were infused into the recipient mice. When the new bone marrow regenerated to take over its immunity, the mice were challenged by chemical agent (dextran sodium sulfate, DSS 5%) to induce colitis. Here we also showed the method to induce colitis in mice and evaluate the role of the gene of interest expressed from bone-marrow derived cells. If the gene-of-interest from the bone derived cells plays an important role in the development of the disease (such as colitis), the phenotype of the recipient mice with bone marrow transplantation can be significantly altered. At the end of colitis experiments, the bone marrow derived cells in blood and bone marrow were labeled with antibodies against CD45.1 and CD45.2 and their quantitative ratio of existence could be used to evaluate the success of bone marrow transplantation by flow cytometry. Successful bone marrow transplantation should show a vast majority of donor genotype (in term of CD molecule marker) over recipient genotype in both the bone marrow and blood of recipient mice.

Drosophila melanogaster larvae have a remarkable capacity for regenerative growth: Damage to their imaginal discs, the larval precursors of adult structures, elicits a robust proliferative response from the surviving tissue [1–4]. However, as in other organisms, developmental progression and differentiation can restrict regenerative capacity of Drosophila tissues. Experiments in Drosophila and other holometabolous insects have demonstrated that either damage to imaginal tissues [5, 6] or transplantation of a damaged imaginal disc [7, 8] delays the onset of metamorphosis, a time when the imaginal discs undergo morphogenesis and differentiation into their adult structures. Therefore, in Drosophila there appears to be a mechanism that senses tissue damage and extends the larval phase to coordinate tissue regeneration with the overall developmental program of the organism. However, how such a pathway functions remains unknown. Here we demonstrate that a developmental checkpoint extends larval growth after imaginal disc damage by inhibiting the transcription of the gene encoding PTTH, a neuropeptide that promotes the release of the steroid hormone ecdysone. Using a genetic screen, we identify a previously unsuspected role for retinoid biosynthesis in regulating PTTH expression and delaying development in response to tissue damage. Retinoid signaling plays an important, but poorly defined role in several vertebrate regeneration models [9–11]. Our findings demonstrate that retinoid biosynthesis in Drosophila is important for the maintenance of a permissive condition for regenerative growth.