Multi-pilot implementation experiences of patient-centered pathology reports: lessons learned for the advancement of patient-centered tools for cancer decision-making.

PURPOSE: New federal legislation in the United States grants patients expanded access to their medical records, making it critical that medical records information is understandable to patients. Provision of informational summaries significantly increase patient perceptions of patient-centered care and reduce feelings of uncertainty, yet their use for cancer pathology is limited. METHODS: Our team developed and piloted patient-centered versions of pathology reports (PCPRs) for four cancer organ sites: prostate, bladder, breast, and colorectal polyp. The objective of this analysis was to identify common barriers and facilitators to support dissemination of PCPRs in care delivery settings. We analyzed quantitative and qualitative data from pilot PCPR implementations, guided by the RE-AIM framework to explore constructs of reach, effectiveness, adoption, implementation, and maintenance. RESULTS: We present two case studies of PCPR implementation - breast cancer and colorectal polyps-that showcase diverse workflows for pathology reporting. Cross-pilot learnings emphasize the potential for PCPRs to improve patient satisfaction, knowledge, quality of shared decision-making activities, yet several barriers to dissemination exist. CONCLUSION: While there is promise in expanding patient-centered cancer communication tools, more work is needed to expand the technological capacity for PCPRs and connect PCPRs to opportunities to reduce costs, improve quality, and reduce waste in care delivery systems.

STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata.

Human asthma is a heterogeneous disease characterized by the expression of both Th2 and Th17 cytokines. In vitro and in vivo studies have shown a reciprocal regulation between Th2 and Th17 pathways, suggesting a potential induction of neutrophil-promoting Th17 inflammation in the absence of a Th2 response. Alternaria alternata is a clinically relevant allergen that is associated with severe and fatal asthma exacerbations. Exposure to A. alternata is characterized by a predominant Th2 response, but can also induce the production of factors associated with Th17 responses (e.g., CXCL8) from epithelial cells. Using a mouse model, we found that wild-type mice develop an eosinophilic Th2 airway disease in response to A. alternata exposure, whereas IL-4-, IL-13-, and STAT6-deficient mice exhibit a primarily neutrophilic response. Neutrophilic asthma in STAT6-/- mice was accompanied by elevated lung levels of TNF-α, CXCL1, CXCL2, and CXCL5, and was steroid resistant. Neutralization of Th17 signaling only partially reduced neutrophil numbers and total airway inflammation. Airway neutrophilia developed in RAG-deficient and CD4-depleted BALB/c mice, suggesting that the suppression of neutrophil responses is dependent on Th2 cytokine production by T cells and that airway neutrophilia is primarily an innate response to allergen. These results highlight the importance of combination therapies for treatment of asthma and establish a role for factors other than IL-17 as targets for neutrophilic asthma.

Nonalcoholic fatty liver disease (NAFLD): Diagnosis, pitfalls, and staging.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with obesity, diabetes and the metabolic syndrome, not only in the Western societies, but also in most regions of the world in the 21st century. The spectrum of its histopathology ranges from steatosis to nonalcoholic steatohepatitis (NASH), with risk for progressive fibrosis that may lead to cirrhosis and hepatocellular carcinoma (HCC). Benign and malignant liver tumors have also been more frequently reported with the increasing prevalence of obesity and diabetes. This review addresses the pathology of NAFLD and NASH, and their diagnostic features, diagnostic pitfalls, grading and staging, and clinical correlation.

IFNαR signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease.

Type I IFNs are a family of proinflammatory cytokines that are essential for antiviral immunity but whose overexpression is associated with several autoimmune disorders. In this study, we asked how chronic IFN overexpression regulates the activity of different cell types and how this contributes to immune dysfunction during IFN-associated inflammatory diseases. We show that in mice that chronically overproduce type I IFNs owing to loss of the DNA exonuclease Trex1, inflammatory disease completely depends on IFNαR signaling in T cells. Although IFNs directly inhibited the proliferation and activation of Foxp3(+) regulatory T cells, this was neither required nor sufficient for development of inflammatory disease. Rather, chronic IFN expression directly promoted the expansion and activation of effector T cells, and disease development was completely dependent on IFNαR signaling in these cells. Thus, chronic IFN expression can drive inflammatory disease via its direct effects on effector, but not regulatory, T cells.

Modeling the habitat suitability for the arbovirus vector Aedes albopictus (Diptera: Culicidae) in Germany.

Climatic changes raise the risk of re-emergence of arthropod-borne virus outbreaks globally. These viruses are transmitted by arthropod vectors, often mosquitoes. Due to increasing worldwide trade and tourism, these vector species are often accidentally introduced into many countries beyond their former distribution range. Aedes albopictus, a well-known disease vector, was detected for the first time in Germany in 2007, but seems to have failed establishment until today. However, the species is known to occur in other temperate regions and a risk for establishment in Germany remains, especially in the face of predicted climate change. Thus, the goal of the study was to estimate the potential distribution of Ae. albopictus in Germany. We used ecological niche modeling in order to estimate the potential habitat suitability for this species under current and projected future climatic conditions. According to our model, there are already two areas in western and southern Germany that appear suitable for Ae. albopictus under current climatic conditions. One of these areas lies in Baden-Wuerttemberg, the other in North-Rhine Westphalia in the Ruhr region. Furthermore, projections under future climatic conditions show an increase of the modeled habitat suitability throughout Germany. Ae. albopictus is supposed to be better acclimated to colder temperatures than other tropical vectors and thus, might become, triggered by climate change, a serious threat to public health in Germany. Our modeling results can help optimizing the design of monitoring programs currently in place in Germany.

Short-term benefits, but transgenerational costs of maternal loss in an insect with facultative maternal care.

A lack of parental care is generally assumed to entail substantial fitness costs for offspring that ultimately select for the maintenance of family life across generations. However, it is unknown whether these costs arise when parental care is facultative, thus questioning their fundamental importance in the early evolution of family life. Here, we investigated the short-term, long-term and transgenerational effects of maternal loss in the European earwig Forficula auricularia, an insect with facultative post-hatching maternal care. We showed that maternal loss did not influence the developmental time and survival rate of juveniles, but surprisingly yielded adults of larger body and forceps size, two traits associated with fitness benefits. In a cross-breeding/cross-fostering experiment, we then demonstrated that maternal loss impaired the expression of maternal care in adult offspring. Interestingly, the resulting transgenerational costs were not only mediated by the early-life experience of tending mothers, but also by inherited, parent-of-origin-specific effects expressed in juveniles. Orphaned females abandoned their juveniles for longer and fed them less than maternally-tended females, while foster mothers defended juveniles of orphaned females less well than juveniles of maternally-tended females. Overall, these findings reveal the key importance of transgenerational effects in the early evolution of family life.

Hyperparasitism of mosquitoes by water mite larvae.

Hyperparasitism of ectoparasitic water mite larvae on mosquitoes is still a neglected relationship and was investigated only in a few studies. We analysed 2313 female mosquitoes from six different sampling localities with regard to their degree of parasitism with water mite larvae. In total, we found 38 mosquito individuals parasitized by 93 water mite larvae, ranging from 1 to 12 larvae per mosquito. Water mite larvae detected are members of the two species Parathyas cf. barbigera (n = 92) and Arrenurus cf. globator (n = 1). Out of the analysed mosquitoes, individuals out of the species Aedes vexans, Anopheles claviger, Ochlerotatus communis, the Ochlerotatus cantans/annulipes group, Ochlerotatus cataphylla and Ochlerotatus sticticus were tested to be parasitized by water mite larvae. The highest prevalence was found within the species Oc. cataphylla (28.6 %) and Oc. cantans/annulipes (21.7 %). No water mite larvae were found, e.g. on individuals of Aedes cinereus, Coquillettidia richiardii, the Culex pipiens/torrentium group, Ochlerotatus caspius, Ochlerotatus dorsalis or Ochlerotatus punctor. All of the attachment sites were located between the neck and abdomen with the ventral thorax site being the most frequent one.

Modeling of the putative distribution of the arbovirus vector Ochlerotatus japonicus japonicus (Diptera: Culicidae) in Germany.

Today, international travel and global freight transportation are increasing and have a direct influence on the introduction and establishment of non-native mosquito species as well as on the spread of arthropod (mosquito)-borne diseases inside Europe. One of the mosquito species that has become invasive in many areas is the Asian rock pool or bush mosquito Ochlerotatus japonicus japonicus (synonyms: Aedes japonicus japonicus or Hulecoeteomyia japonica japonica). This species was detected in Germany in 2008 for the first time. Until today, three different Oc. j. japonicus populations have been documented. Laboratory studies have shown that Oc. j. japonicus can act as a vector for a variety of disease agents. Thus, the knowledge on its current distribution is essential for different measurements. In the present study, ecological niche models were used to estimate the potential distribution of Oc. j. japonicus in Germany. The aim was to detect areas within Germany that could potentially function as habitats for this species. According to our model, areas in western, southern, and central Germany offer suitable conditions for the mosquito and may therefore be at risk for an invasion of the species. We strongly suggest that those areas should be monitored more intensively in the future. For this purpose, it would also be essential to search for possible dispersal routes as well as for natural barriers.

Mother and offspring fitness in an insect with maternal care: phenotypic trade-offs between egg number, egg mass and egg care.

BACKGROUND: Oviparous females have three main options to increase their reproductive success: investing into egg number, egg mass and/or egg care. Although allocating resources to either of these three components is known to shape offspring number and size, potential trade-offs among them may have key impacts on maternal and offspring fitness. Here, we tested the occurrence of phenotypic trade-offs between egg number, egg mass and maternal expenditure on egg care in the European earwig, Forficula auricularia, an insect with pre- and post-hatching forms of maternal care. In particular, we used a series of laboratory observations and experiments to investigate whether these three components non-additively influenced offspring weight and number at hatching, and whether they were associated with potential costs to females in terms of future reproduction. RESULTS: We found negative associations between egg number and mass as well as between egg number and maternal expenditure on egg care. However, these trade-offs could only be detected after statistically correcting for female weight at egg laying. Hatchling number was not determined by single or additive effects among the three life-history traits, but instead by pairwise interactions among them. In particular, offspring number was positively associated with the number of eggs only in clutches receiving high maternal care or consisting of heavy eggs, and negatively associated with mean egg mass in clutches receiving low care. In contrast, offspring weight was positively associated with egg mass only. Finally, maternal expenditure on egg care reduced their future reproduction, but this effect was only detected when mothers were experimentally isolated from their offspring at egg hatching. CONCLUSIONS: Overall, our study reveals simultaneous trade-offs between the number, mass and care of eggs. It also demonstrates that these factors interact in their impact on offspring production, and that maternal expenditure on egg care possibly shapes female future reproduction. These findings emphasize that studying reproductive success requires consideration of phenotypic trade-offs between egg-number, egg mass and egg care in oviparous species.

Prospective randomized pilot study of a novel patient-centered pathology report for colorectal polyps.

Objective: US patients have increased access to their medical records, yet the information is not always understandable. To improve patient understanding, we tested a patient-centered pathology report (PCPR) containing results for recent colon cancer screening or surveillance colonoscopy. Methods: A pilot randomized trial assessed the impact of addition of the PCPR to a standard pathology report on knowledge accuracy, decisional self-efficacy and control, and therapeutic alliance. Results: 55 participants were enrolled; 20 participants in the intervention group and 24 controls completed follow-up. There was no significant difference in polyp knowledge between groups at baseline or 30-days, with similar confidence in understanding their diagnoses, decisional self-efficacy, and therapeutic alliance. Most participants receiving a PCPR felt that it helped them understand their diagnosis better and should always be provided with the standard pathology report. Conclusion: Although patient attitudes toward the PCPR were positive, receiving it did not significantly improve knowledge accuracy or measures of self-efficacy. Further iterations should be explored to communicate key knowledge about colorectal polyp results. Innovation: A stakeholder-driven approach to PCPR development facilitated construction of a personalized document that has potential to increase patient's understanding for their results and needed follow-up.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future.

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.

Overexpression of a constitutively active form of Stat5b (Stat5b-CA) increases regulatory T cells (Tregs). We show that Stat5b-CA transgenic (TG) CD4(+) T cells had a markedly reduced graft-versus-host disease (GVHD) capacity versus wild-type (WT) T cells. Stat5b-CA TG versus WT CD4(+) T cells had a higher proportion of Tregs, which were superior in suppressing alloresponses mediated by CD4(+)CD25(-) effector T cells (Teffs). By day 5 after transplantation, Stat5b-CA TG Tregs had expanded approximately 3-fold more than WT Tregs. Purified Stat5b-CA TG Tregs added to WT CD4(+)CD25(-) Teffs were superior on a per-cell basis for inhibiting GVHD versus WT Tregs. Surprisingly, rigorously Treg-depleted Stat5b-CA TG versus WT CD4(+)CD25(-) Teffs caused less GVHD lethality associated with diminished Teff proinflammatory and increased Th2 anti-inflammatory cytokine responses. Reduced GVHD by Stat5b-CA TG versus WT Teffs could not be explained by conversion into Tregs in day 10 posttransplantation spleen or small intestine. In addition, Stat5b-CA TG Teffs retained a graft-versus-leukemia response. These results indicate a major role for Stat5 in Treg expansion and potency along with a lesser but significant role in Teff activation and suggest a strategy of pharmacologic Stat5b up-regulation as a means of decreasing GVHD while retaining a graft-versus-leukemia effect.

Implementation and Effectiveness of a Completely Virtual Pathology Rotation for Visiting Medical Students.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) upended in-person medical education, relocating many activities online. We designed a completely virtual pathology rotation to replace our traditional visiting rotation. METHODS: The virtual away rotation was listed in the Visiting Student Application Service (VSAS) and advertised on social media as well as various medical student mailing lists. Nine students were selected to participate in three month-long rotations. The virtual curriculum mirrored our typical in-person clerkship with didactic lectures and daily signout but also included activities exclusive to the virtual rotation such as digitally scanned slide trays and small-group problem-based learning. Anonymous surveys were conducted in which both participants and instructors rated their experiences. RESULTS: Postrotation feedback was overwhelmingly positive from both participants and instructors. Students considered virtual slide sessions as the most effective teaching tool and did not feel hindered overall by lack of in-person experiences. Volunteer trainee instructors indicated the experience improved their teaching and diagnostic skills and expressed interest in teaching future virtual courses. CONCLUSIONS: The success of the virtual away rotation raises consideration for applications beyond the pandemic era and may provide a more level playing field for medical students from underrepresented groups.

Medical Education in Pathology: General Concepts and Strategies for Implementation.

CONTEXT.­: Pathology education must evolve as medical knowledge expands and disruptive technologies emerge. The evolution in pathology teaching practices accelerated as traditional teaching modalities were suspended in March 2020 during the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVES.­: To provide pathologists an overview of established teaching paradigms and practical examples of how these paradigms may be applied to pathology education, emphasizing differences in graduate and undergraduate medical education as well as the challenges and promises of remote learning, as revealed by the COVID-19 pandemic. DATA SOURCES.­: Selected peer-reviewed publications representing the field of educational social science. CONCLUSIONS.­: Evidence-based methods described in education and social sciences can be effectively deployed in pathology education and especially remote learning, as necessitated by the current COVID-19 pandemic. Understanding established principles, such as cognitive load, competency-based learning, peer-assisted learning, and flipped classrooms may prove useful in developing effective, learner-centric content for pathology education.

Bats as putative Zaire ebolavirus reservoir hosts and their habitat suitability in Africa.

The genus Ebolavirus comprises some of the deadliest viruses for primates and humans and associated disease outbreaks are increasing in Africa. Different evidence suggests that bats are putative reservoir hosts and play a major role in the transmission cycle of these filoviruses. Thus, detailed knowledge about their distribution might improve risk estimations of where future disease outbreaks might occur. A MaxEnt niche modelling approach based on climatic variables and land cover was used to investigate the potential distribution of 9 bat species associated to the Zaire ebolavirus. This viral species has led to major Ebola outbreaks in Africa and is known for causing high mortalities. Modelling results suggest suitable areas mainly in the areas near the coasts of West Africa with extensions into Central Africa, where almost all of the 9 species studied find suitable habitat conditions. Previous spillover events and outbreak sites of the virus are covered by the modelled distribution of 3 bat species that have been tested positive for the virus not only using serology tests but also PCR methods. Modelling the habitat suitability of the bats is an important step that can benefit public information campaigns and may ultimately help control future outbreaks of the disease.

Vector distribution and transmission risk of the Zika virus in South and Central America.

BACKGROUND: Zika is of great medical relevance due to its rapid geographical spread in 2015 and 2016 in South America and its serious implications, for example, certain birth defects. Recent epidemics urgently require a better understanding of geographic patterns of the Zika virus transmission risk. This study aims to map the Zika virus transmission risk in South and Central America. We applied the maximum entropy approach, which is common for species distribution modelling, but is now also widely in use for estimating the geographical distribution of infectious diseases. METHODS: As predictor variables we used a set of variables considered to be potential drivers of both direct and indirect effects on the emergence of Zika. Specifically, we considered (a) the modelled habitat suitability for the two main vector species Aedes aegypti and Ae. albopictus as a proxy of vector species distributions; (b) temperature, as it has a great influence on virus transmission; (c) commonly called evidence consensus maps (ECM) of human Zika virus infections on a regional scale as a proxy for virus distribution; (d) ECM of human dengue virus infections and, (e) as possibly relevant socio-economic factors, population density and the gross domestic product. RESULTS: The highest values for the Zika transmission risk were modelled for the eastern coast of Brazil as well as in Central America, moderate values for the Amazon basin and low values for southern parts of South America. The following countries were modelled to be particularly affected: Brazil, Colombia, Cuba, Dominican Republic, El Salvador, Guatemala, Haiti, Honduras, Jamaica, Mexico, Puerto Rico and Venezuela. While modelled vector habitat suitability as predictor variable showed the highest contribution to the transmission risk model, temperature of the warmest quarter contributed only comparatively little. Areas with optimal temperature conditions for virus transmission overlapped only little with areas of suitable habitat conditions for the two main vector species. Instead, areas with the highest transmission risk were characterised as areas with temperatures below the optimum of the virus, but high habitat suitability modelled for the two main vector species. CONCLUSION: Modelling approaches can help estimating the spatial and temporal dynamics of a disease. We focused on the key drivers relevant in the Zika transmission cycle (vector, pathogen, and hosts) and integrated each single component into the model. Despite the uncertainties generally associated with modelling, the approach applied in this study can be used as a tool and assist decision making and managing the spread of Zika.

Leishmaniasis in Eurasia and Africa: geographical distribution of vector species and pathogens.

Leishmaniasis is a vector-borne disease with a broad global occurrence and an increasing number of recorded cases; however, it is still one of the world's most neglected diseases. We here provide climatic suitability maps generated by means of an ecological niche modelling approach for 32 Phlebotomus vector species with proven or suspected vector competence for five Leishmania pathogens occurring in Eurasia and Africa. A GIS-based spatial overlay analysis was then used to compare the distributional patterns of vectors and pathogens to help evaluate the vector species-pathogen relationship currently found in the literature. Based on this single factor of vector incrimination, that is, co-occurrence of both vector and pathogen, most of the pathogens occurred with at least one of the associated vector species. In the case of L. donovani, only a not yet confirmed vector species, P. rodhaini, could explain the occurrence of the pathogen in regions of Africa. Phlebotomus alexandri and P. longiductus on the other hand, proven vector species of L. donovani, do not seem to qualify as vectors for the pathogen. Their distribution is restricted to northern latitudes and does not match the pathogen's distribution, which lies in southern latitudes. Other more locally confined mismatches were discussed for each pathogen species. The comparative geographical GIS-overlay of vector species and pathogens functions as a first indication that testing and re-evaluation of some pathogen-vector relationships might be worthwhile to improve risk assessments of leishmaniasis.

Validation of a Congestive Hepatic Fibrosis Scoring System.

Congestive hepatopathy is a complication of right heart failure and chronically elevated right heart pressure. Histologic findings include sinusoidal dilatation, centrilobular hepatocellular plate atrophy, and fibrosis. We performed a validation study of a recently proposed scoring system (0 to 4 scale) for congestive hepatic fibrosis on 38 liver biopsies. Glutamine synthetase immunohistochemistry was also performed, and loss of centrizonal immunoreactivity correlated with increasing fibrosis score (P<0.01). Interobserver concordance for congestive hepatic fibrosis score based on Masson trichrome stain was initially fair (Fleiss κ=0.28, weighted concordance coefficient=0.60) and significantly improved (κ=0.40, weighted concordance coefficient=0.66) following a multiheaded microscope training session and inclusion of glutamine synthetase immunohistochemistry. Average congestive hepatic fibrosis score correlated with significantly higher right atrial pressure, severity of right atrial dilation, presence of right ventricular dilation, elevated serum alanine aminotransferase, platelet counts, prothrombin time, and model for end-stage liver disease score. In conclusion, the congestive hepatic fibrosis scoring system is reproducible among pathologists and correlates with clinical and laboratory markers of congestive hepatopathy.