Using optical coherence tomography to optimize Mohs micrographic surgery.

Mohs micrographic surgery (MMS) is considered the gold standard for treating high-risk cutaneous basal cell carcinoma (BCC), but is expensive, time-consuming, and can be unpredictable as to how many stages will be required or how large the final lesion and corresponding surgical defect will be. This study is meant to investigate whether optical coherence tomography (OCT), a highly researched modality in dermatology, can be used preoperatively to map out the borders of BCC, resulting in fewer stages of MMS or a smaller final defect. In this prospective study, 22 patients with BCC undergoing surgical excision were enrolled at a single institution. All patients had previously received a diagnostic biopsy providing confirmation of BCC and had been referred to our center for excision with MMS. Immediately prior to performing MMS, OCT was used to map the borders of the lesion. MMS then proceeded according to standard protocol. OCT images were compared to histopathology for agreement. Histopathologic analysis of 7 of 22 MMS specimens (32%) revealed a total absence of BCC, indicating resolution of BCC after previous diagnostic biopsy. This outcome was correctly predicted by OCT imaging in 6 of 7 cases (86%). Nine tumors (9/22, 41%) had true BCC and required a single MMS stage, which was successfully predicted by pre-operative OCT analysis in 7 of 9 cases (78%). The final six tumors (27%) had true BCC and required two MMS stages for complete excision; preoperative OCT successfully predicted the need for a second stage in five cases (5/6, 83.3%). Overall, OCT diagnosed BCC with 95.5% accuracy (Cohen's kappa, κ = 0.89 (p-value = < 0.01) in the center of the lesion. Following a diagnostic biopsy, OCT can be used to verify the existence or absence of residual basal cell carcinoma. When residual tumor is present that requires excision with MMS, OCT can be used to predict tumor borders, optimize surgery and minimize the need for additional surgical stages.

Rapid measurement of epidermal thickness in OCT images of skin.

Epidermal thickness (ET) changes are associated with several skin diseases. To measure ET, segmentation of optical coherence tomography (OCT) images is essential; manual segmentation is very time-consuming and requires training and some understanding of how to interpret OCT images. Fast results are important in order to analyze ET over different regions of skin in rapid succession to complete a clinical examination and enable the physician to discuss results with the patient in real time. The well-known CNN-graph search (CNN-GS) methodology delivers highly accurate results, but at a high computational cost. Our objective was to build a computational core, based on CNN-GS, able to accurately segment OCT skin images in real time. We accomplished this by fine-tuning the hyperparameters, testing a range of speed-up algorithms including pruning and quantization, designing a novel pixel-skipping process, and implementing the final product with efficient use of core and threads on a multicore central processing unit (CPU). We name this product CNN-GS-skin. The method identifies two defined boundaries on OCT skin images in order to measure ET. We applied CNN-GS-skin to OCT skin images, taken from various body sites of 63 healthy individuals. Compared with CNN-GS, our described method reduced computation time by 130 [Formula: see text] with minimal reduction in ET determination accuracy (from 96.38 to 94.67%).

Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1-deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1-deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.

Climate change and malaria: some recent trends of malaria incidence rates and average annual temperature in selected sub-Saharan African countries from 2000 to 2018.

BACKGROUND: Malaria is still a disease of massive burden in Africa, also influenced by climate change. The fluctuations and trends of the temperature and precipitation are well-known determinant factors influencing the disease's vectors and incidence rates. This study provides a concise account of malaria trends. It describes the association between average temperature and malaria incidence rates (IR) in nine sub-Saharan African countries: Nigeria, Ethiopia, South Africa, Kenya, Uganda, Ghana, Mozambique, Zambia and Zimbabwe. The incidence of malaria can vary both in areas where the disease is already present, and in regions where it is present in low numbers or absent. The increased vulnerability to the disease under increasing average temperatures and humidity is due to the new optimal level for vector breeding in areas where vector populations and transmission are low, and populations are sensitive due to low acquired immunity. METHODS: A second source trend analysis was carried out of malaria cases and incidence rates (the number of new malaria cases per 1000 population at risk per year) with data from the World Health Organization (WHO) and average annual mean temperature from 2000 to 2018 from the World Bank's Climate Change Knowledge Portal (CCKP). Additionally, descriptive epidemiological methods were used to describe the development and trends in the selected countries. Furthermore, MS Excel was chosen for data analysis and visualization. RESULTS: Findings obtained from this article align with the recent literature, highlighting a declining trend (20-80%) of malaria IR (incidence rate) from 2000 to 2018. However, malaria IR varies considerably, with high values in Uganda, Mozambique, Nigeria and Zambia, moderate values in Ghana, Zimbabwe, and Kenya, and low values in South Africa and Ethiopia in 2018. Evidence suggests varying IRs after average temperature fluctuations in several countries (e.g., Zimbabwe, Ethiopia). Also, an inverse temperature-IR relationship occurs, the sharp decrease of IR during 2012-2014 and 2000-2003, respectively, occurred with increasing average temperatures in Ghana and Nigeria. The decreasing trends and fluctuations, partly accompanying the temperature, should result from the intervention programmes and rainfall variability. The vulnerability and changing climate could arrest the recent trends of falling IR. CONCLUSION: Thus, malaria is still a crucial public health issue in sub-Saharan Africa, although a robust decreasing IR occurred in most studied countries.

Sex differences in peripheral immune cell activation: Implications for pain and pain resolution.

Decades of research into chronic pain has deepened our understanding of the cellular mechanisms behind this process. However, a failure to consider the biological variable of sex has limited the application of these breakthroughs into clinical application. In the present study, we investigate fundamental differences in chronic pain between male and female mice resulting from inflammatory activation of the innate immune system. We provide evidence that female mice are more sensitive to the effects of macrophages. Injecting small volumes of media conditioned by either unstimulated macrophages or macrophages stimulated by the inflammatory molecule TNFα lead to increased pain sensitivity only in females. Interestingly, we find that TNFα conditioned media leads to a more rapid resolution of mechanical hypersensitivity and altered immune cell recruitment to sites of injury. Furthermore, male and female macrophages exhibit differential polarization characteristics and motility after TNFα stimulation, as well as a different profile of cytokine secretions. Finally, we find that the X-linked gene Tlr7 is critical in the facilitating the adaptive resolution of pain in models of acute and chronic inflammation in both sexes. Altogether, these findings suggest that although the cellular mechanisms of pain resolution may differ between the sexes, the study of these differences may yield more targeted approaches with clinical applications.

Noninvasive imaging exploration of phacomatosis pigmentokeratotica using high-frequency ultrasound and optical coherence tomography: Can biopsy of PPK patients be avoided?

BACKGROUND: Phacomatosis pigmentokeratotica (PPK) is a distinct and rare type of epidermal nevus syndrome characterized by coexisting nonepidermolytic organoid sebaceous nevus (SN) with one or more speckled lentiginous nevi (SLN). Atypical nevi including compound Spitz and compound dysplastic may manifest within regions of SLN. Patients with PPK, or similar atypical nevus syndromes, may be subject to a significant lifetime number of biopsies, leading to pain, scarring, anxiety, financial burden, and decreased quality of life. The current literature includes case reports, genetics, and associated extracutaneous symptoms of PPK, but use of noninvasive imaging techniques have not been explored. We aim to investigate the value of high-frequency ultrasound (HFUS) and optical coherence tomography (OCT) in discriminating morphological features of pigmented lesions and nevus sebaceous within one patient with PPK. MATERIALS AND METHODS: Two modalities, (1) HFUS imaging, based on acoustic properties and (2) OCT imaging, based on optical properties, were used to image a patient with PPK. Benign pigmented lesions, which may raise clinical suspicion for significant atypia, and nevus sebaceous, were selected on different areas of the body to be studied. RESULTS: Five pigmented lesions and one area of nevus sebaceous were imaged and analyzed for noninvasive features. Distinct patterns of hypoechoic features were seen on HFUS and OCT. CONCLUSION: HFUS provides a deep view of the tissue, with ability to differentiate gross structures beneath the skin. OCT provides a smaller penetration depth and a higher resolution. We have described noninvasive features of atypical nevi and nevus sebaceous on HFUS and OCT, which indicate benign etiology.

γδ Thymocyte Maturation and Emigration in Adult Mice.

Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived γδ thymocytes in mice. In the Rag2pGFP model, immature (CD24+) γδ thymocytes expressed high levels of GFP whereas only a minority of mature (CD24-) γδ thymocytes were GFP+ Similarly, most peripheral GFP+ γδ T cells were immature. Analysis of γδ recent thymic emigrants (RTEs) indicated that most γδ T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature γδ thymocytes can mature outside the thymus. Mature γδ T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature γδ thymocytes that produced IFN-γ or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of γδ T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident γδ thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the γδ T cell compartment in adult mice.

Change in Health-Related Quality of Life Among Individuals With Cancer Undergoing Smoking Cessation Treatment Involving Varenicline.

OBJECTIVES: To determine whether health-related quality of life (HRQOL) among individuals with cancer is undermined by smoking cessation treatment involving varenicline. SAMPLE & SETTING: Participants (N = 103) were daily smokers with cancer (up to five years postdiagnosis) who completed a placebo-controlled trial of standard versus extended duration varenicline. METHODS & VARIABLES: For this secondary study, participants were selected based on having completed the SF-12® at weeks 0, 1, 12, and 24. Using separate repeated measures multivariate analysis of variance, change in SF-12 scores was evaluated by time and by cancer treatment, varenicline duration, and quit status at week 24. RESULTS: There was no change in any of the three HRQOL scores by time or by cancer treatment status, varenicline duration, or quit status. Average emotional HRQOL score across time was significantly higher for quitters versus smokers. IMPLICATIONS FOR NURSING: Varenicline, including long-term treatment, does not appear to adversely affect HRQOL, which is highly relevant to oncology nurses who are well positioned to assist with the pharmacologic treatment of tobacco dependence.

Leveraging Patient Reported Outcomes Measurement via the Electronic Health Record to Connect Patients with Cancer to Smoking Cessation Treatment.

Tobacco use negatively impacts cancer treatment outcomes, yet too few providers actively support their patients in quitting. Barriers to consistently addressing tobacco use and referring to treatment include time constraints and lack of knowledge surrounding treatment options. Patient Reported Outcomes (PRO) measurement is best practice in cancer care and has potential to help address these barriers to tobacco cessation treatment. This descriptive program evaluation study reports preliminary results following implementation of a novel automated PRO tobacco use screener and referral system via the electronic health record (EHR) patient portal (MyChart) that was developed and implemented as a part of a population-based tobacco treatment program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Between 25 June 2019 and 6 April 2020, 4589 unique patients completed the screener and 164 (3.6%) unique patients screened positive for recent (past month) cigarette smoking. All patients who screened positive were automatically referred to a smoking cessation treatment program integrated within the Lurie Cancer Center, and 71 (49.7%) patients engaged in treatment, as defined by completing at least one behavioral counseling session. Preliminary results indicate that the PRO/MyChart system may improve smoker identification and increase offering of treatment and, despite the "cold call" following a positive screen, may result in a treatment engagement rate that is higher than rates of treatment engagement previously documented in oncology settings. Longer term evaluation with formal statistical testing is needed before drawing conclusions regarding effectiveness, but PRO measurement via the EHR patient portal may serve a potentially important role in a multi-component approach to reaching and engaging cancer patients in comprehensive tobacco cessation treatment.

Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells.

Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.

Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology.

The nuclear orphan receptors NR4A1, NR4A2, and NR4A3 are immediate early genes that are induced by various signals. They act as transcription factors and their activity is not regulated by ligand binding and are thus regulated via their expression levels. Their expression is transiently induced in T cells by triggering of the T cell receptor following antigen recognition during both thymic differentiation and peripheral T cell responses. In this review, we will discuss how NR4A family members impact different aspects of the life of a T cell from thymic differentiation to peripheral response against infections and cancer.

A questionnaire-based study of gestation, parturition and neonatal mortality in pedigree breeding cats in the UK.

This study was based on a convenience-sampling questionnaire study of pedigree cat breeding in the UK. Data were collated for the births of 1,056 litters from 14 different pedigree breeds and 942 different households. Significant relationships between various outcomes and relevant predictors were assessed by multiple linear regression or logistic regression as appropriate. The overall mean gestation length of 65.1 days varied significantly between the breeds (P<0.0001), and larger litter sizes were associated with shorter gestation lengths (P=0.04). The mean litter size of 4.6 kittens also varied significantly according to breed (P<0.0001). The weight of kittens born alive (overall mean 93.5 g) increased with longer gestation lengths (P=0.0003), decreased with larger litter sizes (P<0.0001) and varied between the breeds (P<0.0001). A total of 8.0% of pregnancies resulted in a caesarean section, with a higher risk associated with smaller litter sizes (P=0.002). Although the frequency of caesarean sections varied from 0 to 18.5% between individual breeds, breed itself was not shown to have a significant independent effect on this likelihood. A mean of 7.2% of all the kittens were stillborn, which varied according to breed (P=0.0003), and the risk of a stillborn kitten increased with litter size (P=0.0001), and with the presence of congenital defects in the litter (P=0.0002). The mean kitten mortality between birth and 8 weeks of age was 9.1%, and the majority of these occurred in the first week of life. Parturition intervals varied widely. The duration of first stage of labour was less than 2h in 82.9% of cats. The interval between the birth of the first and last kitten was less than 6h in 85.7%, but more than 48 h in three cats. A maximum of 48 h was recorded between the births of individual kittens in unassisted deliveries.