Sustained wet-dry cycling on early Mars.

The presence of perennially wet surface environments on early Mars is well documented1,2, but little is known about short-term episodicity in the early hydroclimate3. Post-depositional processes driven by such short-term fluctuations may produce distinct structures, yet these are rarely preserved in the sedimentary record4. Incomplete geological constraints have led global models of the early Mars water cycle and climate to produce diverging results5,6. Here we report observations by the Curiosity rover at Gale Crater indicating that high-frequency wet-dry cycling occurred in early Martian surface environments. We observe exhumed centimetric polygonal ridges with sulfate enrichments, joined at Y-junctions, that record cracks formed in fresh mud owing to repeated wet-dry cycles of regular intensity. Instead of sporadic hydrological activity induced by impacts or volcanoes5, our findings point to a sustained, cyclic, possibly seasonal, climate on early Mars. Furthermore, as wet-dry cycling can promote prebiotic polymerization7,8, the Gale evaporitic basin may have been particularly conducive to these processes. The observed polygonal patterns are physically and temporally associated with the transition from smectite clays to sulfate-bearing strata, a globally distributed mineral transition1. This indicates that the Noachian-Hesperian transition (3.8-3.6 billion years ago) may have sustained an Earth-like climate regime and surface environments favourable to prebiotic evolution.

Evaluation and comparison of risk-based and universal prenatal HCV screening programs in Alberta, Canada.

BACKGROUND & AIMS: Canadian clinical practice guidelines currently recommend risk-based screening for HCV in pregnant individuals. However, no provinces or territories have ever compared the effectiveness of risk-based vs. universal screening for the prenatal diagnosis of HCV. We aimed to evaluate and compare HCV screening programs after implementing a universal population-level pilot program among prenatal patients in Alberta, Canada. METHODS: The Alberta Prenatal Screening Program for Select Communicable Diseases was amended to include universal HCV antibody screening. Cohorts of pregnant individuals screened for HCV through risk-based or universal programs were generated over 1-year periods. HCV screening rates and prevalence were analyzed and compared between cohorts to evaluate the effectiveness of screening methods. Social and demographic risk factors for HCV-positive individuals were compared between screening cohorts to identify which populations may be overlooked with risk-based guidelines. RESULTS: HCV antibody screening rates were 11.9% and 99.9% among pregnant individuals in the risk-based and universal cohorts, respectively. HCV prevalence among the cohorts was 0.07% and 0.11% (difference = 0.04%, p = 0.032), with an average of 21 additional HCV-positive pregnant individuals identified annually with universal screening. HCV-positive pregnant patients diagnosed through universal screening were more likely to engage in high-risk sexual behaviours/sex work compared to those diagnosed through risk-based screening (47.6% vs. 12.5%, respectively p = 0.035), suggesting that these high-risk cases are being missed by risk-based screening. CONCLUSIONS: Universal HCV screening diagnoses significantly higher numbers of pregnant individuals infected with HCV compared to risk-based screening. Universal HCV screening or amending risk-based guidelines to incorporate more proxy variables for risk factors should be considered to improve prenatal HCV screening guidelines in Canada and help achieve HCV elimination in the next decade. IMPACT AND IMPLICATIONS: HCV is a bloodborne pathogen that can cause severe liver disease and be vertically transmitted from a mother to her baby during pregnancy. Pregnant individuals in Alberta are currently only tested for HCV if they disclose engaging in activities that put them at risk of acquiring the infection (risk-based screening). Using a population-wide universal prenatal HCV screening program, our work shows that testing based on patient disclosed risk alone leads to the significant underdiagnosis of HCV in pregnant individuals and suggests individuals engaging in sex work or risky sexual behaviours are being overlooked by the current risk-based program. Our outcomes represent the first province-wide study to evaluate and compare prenatal HCV risk-based and universal screening programs in Canada and provide evidence to support the update of prenatal HCV screening policies across the country and in similar jurisdictions.

Outcomes and cost analysis of patients with dementia in the intensive care unit: a population-based cohort study.

BACKGROUND: Dementia is a neurological syndrome affecting the growing elderly population. While patients with dementia are known to require significant hospital resources, little is known regarding the outcomes and costs of patients admitted to the intensive care unit (ICU) with dementia. METHODS: We conducted a population-based retrospective cohort study of patients with dementia admitted to the ICU in Ontario, Canada from 2016 to 2019. We described the characteristics and outcomes of these patients alongside those with dementia admitted to non-ICU hospital settings. The primary outcome was hospital mortality but we also assessed length of stay (LOS), discharge disposition, and costs. RESULTS: Among 114,844 patients with dementia, 11,341 (9.9%) were admitted to the ICU. ICU patients were younger, more comorbid, and had less cognitive impairment (81.8 years, 22.8% had ≥ 3 comorbidities, 47.5% with moderate-severe dementia), compared to those in non-ICU settings (84.2 years, 15.0% had ≥ 3 comorbidities, 54.1% with moderate-severe dementia). Total mean LOS for patients in the ICU group was nearly 20 days, compared to nearly 14 days for the acute care group. Mortality in hospital was nearly three-fold greater in the ICU group compared to non-ICU group (22.2% vs. 8.8%). Total healthcare costs were increased for patients admitted to ICU vs. those in the non-ICU group ($67,201 vs. $54,080). CONCLUSIONS: We find that patients with dementia admitted to the ICU have longer length of stay, higher in-hospital mortality, and higher total healthcare costs. As our study is primarily descriptive, future studies should investigate comprehensive goals of care planning, severity of illness, preventable costs, and optimizing quality of life in this high risk and vulnerable population.

Wildlife health surveillance: gaps, needs and opportunities.

Disease emergence represents a global threat to public health, economy and biological conservation. Most emerging zoonotic diseases have an animal origin, most commonly from wildlife. To prevent their spread and to support the implementation of control measures, disease surveillance and reporting systems are needed, and due to globalisation, these activities should be carried out at the global level. To define the main gaps affecting the performance of wildlife health surveillance and reporting systems globally, the authors analysed data from a questionnaire sent to National Focal Points of the World Organisation for Animal Health that inquired on structure and limits of wildlife surveillance and reporting systems in their territories. Responses from 103 Members, covering all areas of the globe, revealed that 54.4% have a wildlife disease surveillance programme and 66% have implemented a strategy to manage disease spread. The lack of dedicated budget affected the possibility of outbreak investigations, sample collection and diagnostic testing. Although most Members maintain records relating to wildlife mortality or morbidity events in centralised databases, data analysis and disease risk assessment are reported as priority needs. The authors' evaluation of surveillance capacity found an overall low level, with marked variability among Members that was not restricted to a specific geographical area. Increased wildlife disease surveillance globally would help in understanding and managing risks to animal and public health. Moreover, consideration of the influence of socio-economic, cultural and biodiversity aspects could improve disease surveillance under a One Health approach.

L'émergence de maladies représente une menace pour la santé publique, l'économie et la conservation de la biodiversité au niveau mondial. La plupart des maladies émergentes sont d'origine animale et proviennent de la faune sauvage. Afin de prévenir leur propagation et de soutenir la mise en oeuvre de mesures de contrôle, une surveillance des maladies et des systèmes de notification sont nécessaires - et ce à l'échelle internationale, en raison de la mondialisation. En vue de définir les lacunes principales affectant les performances de la surveillance et de la notification sanitaire relative à la faune sauvage au niveau mondial, les auteurs ont analysé les données d'un questionnaire envoyé aux Points focaux nationaux de l'Organisation mondiale de la santé animale et traitant de la structure et des limites des systèmes de surveillance et de notification applicables à la faune sauvage sur leur territoire. Selon les réponses des 103 Membres, qui représentaient toutes les régions du monde, 54,4 % disposent d'un programme de surveillance et 66 % ont mis en oeuvre une stratégie visant à gérer la propagation de maladies. L'absence de budgets dédiés affecte la possibilité d'enquêter sur l'apparition d'épidémies, de prélever des échantillons et d'effectuer des tests diagnostiques. Bien que la majorité des Membres consignent dans des bases de données centralisées les événements de mortalité et de morbidité affectant la faune sauvage, l'analyse des données et l'évaluation des risques sanitaires ont été mentionnées comme étant des besoins prioritaires. Les auteurs ont évalué les capacités de surveillance qui se situent, selon eux, à un niveau faible et se caractérisent par une grande variabilité entre les Membres, indépendamment des zones géographiques dont il s'agit. Une meilleure surveillance sanitaire de la faune sauvage au niveau mondial permettrait d'améliorer la compréhension et la gestion des risques pour la santé animale et publique. Par ailleurs, une réflexion sur l'influence des aspects socio-économiques, culturels et liés à la biodiversité améliorerait la surveillance sanitaire mise en place dans le cadre de l'approche Une seule santé.

La aparición de enfermedades representa una amenaza de dimensión mundial para la salud pública, la economía y la conservación de los recursos biológicos. La mayor parte de las enfermedades zoonóticas tienen un origen animal, por lo general localizado en la fauna silvestre. Para evitar que estas enfermedades se propaguen y apoyar la aplicación de medidas de lucha hacen falta sistemas de vigilancia y notificación de enfermedades, sistemas que, teniendo en cuenta las dinámicas de la mundialización, deben declinarse a escala planetaria. Con objeto de determinar las principales carencias que lastran el buen funcionamiento de los sistemas de vigilancia y notificación de enfermedades de la fauna silvestre a escala mundial, los autores analizaron datos extraídos de un cuestionario distribuido entre los puntos focales nacionales de la Organización Mundial de Sanidad Animal, en el cual se les preguntaba por la estructura y los límites que presentaban en su territorio dichos sistemas. Las respuestas recibidas de 103 Miembros de todas las zonas del globo pusieron de relieve que un 54,4% de ellos cuenta con un programa de vigilancia sanitaria de la fauna silvestre y que un 66% tiene implantada una estrategia para contener la propagación de enfermedades. La falta de un presupuesto asignado específicamente a estas tareas limita la posibilidad de investigar eventuales brotes, obtener muestras y practicar pruebas de diagnóstico. Aunque la mayoría de los Miembros lleva un registro de los episodios de mortalidad y morbilidad de animales salvajes en bases de datos centralizadas, el análisis de datos y la determinación del riesgo de enfermedad son dos de los aspectos mencionados como necesidad prioritaria. La evaluación de la capacidad de vigilancia realizada por los autores puso de manifiesto un nivel en general bajo, con una marcada heterogeneidad entre los Miembros que no se circunscribía a una zona geográfica en particular. Una mayor vigilancia de las enfermedades de la fauna silvestre a escala mundial ayudaría a aprehender y manejar mejor los riesgos que estas presentan para la sanidad animal y la salud pública. Además, el hecho de tener en cuenta la influencia de factores socioeconómicos, culturales y ligados a la diversidad biológica podría traducirse en una más eficaz vigilancia sanitaria en clave de Una sola salud.

Adrenalectomy for incidental and symptomatic phaeochromocytoma: retrospective multicentre study based on the Eurocrine® database.

BACKGROUND: Phaeochromocytoma is sometimes not diagnosed before surgery and may present as an adrenal incidentaloma. The aim of this study was to investigate differences in clinical presentation and perioperative outcome in patients with subclinical and symptomatic phaeochromocytoma, and in patients operated with and without preoperative α-blockade. METHODS: This was a retrospective observational study of patients with a histopathological diagnosis of phaeochromocytoma registered in Eurocrine®, the European registry for endocrine tumours, between 1 January 2015 and 31 March 2020. Patient characteristics, clinical presentation, tumour detection, and perioperative variables were analysed. RESULTS: Some 551 patients were included. Of these, 486 patients (88.2 per cent) had a preoperative diagnosis of phaeochromocytoma. Tumours were detected as incidentalomas in 239 patients (43.4 per cent) and 265 (48.1 per cent) had a preoperative diagnosis of hypertension. Preoperative α-blockade was more frequently used in patients with a known phaeochromocytoma (350, 90.9 per cent) than in patients with other indications for adrenalectomy (16, 31 per cent). Complications did not differ between patients who had surgery because of catecholamine excess compared with those who had other indications for surgery (19 (3.9 per cent) versus 2 (3 per cent); P = 0.785), nor did the conversion rate from minimally invasive to open surgery differ between the groups. There were no obvious differences in complications, according to the Clavien-Dindo classification, based on preoperative α-blockade or not. CONCLUSION: Subclinical phaeochromocytoma detected incidentally is common. A significant proportion of patients with phaeochromocytoma did not have α-blockade before surgery, without an apparent effect on complications.

Phaeochromocytoma is an unusual adrenal tumour with hormonal overproduction of catecholamines leading to a severe condition, including extreme hypertension in some situations. It is treated with surgery. Medical treatment before surgery is used to minimize surgical complications related to high blood pressure. A large proportion of phaeochromocytomas are detected incidentally, without symptoms, on radiological examination for other reasons. The aim of this study was to investigate differences in patient characteristics and surgical results in patients operated with or without symptoms of phaeochromocytoma. Patients registered in the large, European database, Eurocrine®, between 2015 and 2020 were included in the study. The study showed that phaeochromocytoma without symptoms is common. Medical treatment before surgery does not seem to affect complications.

Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. OBJECTIVES: To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. METHODS: This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. RESULTS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P < 0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P = 0·001] and overall survival (HR 0·58, P = 0·007) compared with those who did not. CONCLUSIONS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.

A pan-apicomplexan phosphoinositide-binding protein acts in malarial microneme exocytosis.

Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is an essential step in the development of the disease. Consequently, the molecular players involved in host cell invasion represent important targets for inhibitor design and vaccine development. The process of merozoite invasion is a succession of steps underlined by the sequential secretion of the organelles of the apical complex. However, little is known with regard to how their contents are exocytosed. Here, we identify a phosphoinositide-binding protein conserved in apicomplexan parasites and show that it is important for the attachment and subsequent invasion of the erythrocyte by the merozoite. Critically, removing the protein from its site of action by knock sideways preferentially prevents the secretion of certain types of micronemes. Our results therefore provide evidence for a role of phosphoinositide lipids in the malaria invasion process and provide further insight into the secretion of microneme organelle populations, which is potentially applicable to diverse apicomplexan parasites.

Parental perception of a picture-based chronic asthma care management tool in an urban pediatric emergency department.

BACKGROUND: National asthma guidelines recommend use of an asthma action plan (AAP) as part of chronic asthma care. Unfortunately, AAPs have not been tailored for use in acute care settings, where many patients at risk for poor chronic asthma care are seen, including those who are non-English-speaking or have low literacy levels. We previously developed a picture-based medication plan (PBMP), a unique type of AAP for use in an ambulatory setting and designed to increase patient use and understanding. However, little is known about how parents seeking emergency department (ED) asthma care would perceive the PBMP. OBJECTIVE: To assess parental attitudes toward an asthma PBMP in the largest pediatric ED in Los Angeles County. METHODS: We surveyed a consecutive sample of English- or Spanish-speaking parents of children 2-17 years seeking ED asthma care. Parents used a 5-point Likert scale for various statements regarding their perceptions of the PBMP. Responses were analyzed by sociodemographics, asthma control, and health literacy using Chi-squared and t-tests. RESULTS: 90 parents provided feedback on the PBMP. The majority of parents endorsed the PBMP. Endorsement was 20%-30% higher among Spanish-speaking parents and those who did not complete high-school compared to English-speaking parents and parents with a high school education or higher (p < 0.05 for both comparisons). CONCLUSION: Spanish-speaking parents and parents with less than a high-school education overwhelmingly endorsed the PBMP. It may be useful to consider incorporating the PBMP as part of patient-centered chronic asthma care strategies for populations seen in ED settings.

Interpersonal trauma and its relation to childhood psychopathic traits: what does ADHD and ODD add to the equation?

BACKGROUND: Childhood trauma has demonstrated associations with callous-unemotional traits (e.g., reflecting lack of remorse and guilt, unconcern about own performance). Less is known about associations between trauma and multiple domains of child psychopathic traits. There has also been limited focus on the role of co-occurring disorders to psychopathy traits among children, namely, attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) and how they interact with childhood trauma. METHODS: We examined to what degree childhood interpersonal trauma can predict parent-rated psychopathic traits in a large population based Swedish twin sample (N = 5057), using a stringent definition of interpersonal trauma occurring before age 10. Two hundred and fifty-one participants met the interpersonal trauma criteria for analysis. The study explored the additional impact of traits of attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). RESULTS: Linear regressions demonstrated statistically significant but clinically negligible effects of interpersonal trauma on total and subscale scores of parent-rated psychopathic traits. When exploring interaction effects of ADHD and ODD into the model, the effect increased. There were interaction effects between ODD and trauma in relation to psychopathic traits, suggesting a moderating role of ODD. Having been exposed to trauma before age 10 was significantly associated with higher parent rated psychopathy traits as measured by The Child Problematic Traits Inventory-Short Version (CPTI-SV), however the explained variance was small (0.3-0.9%). CONCLUSIONS: The results challenge the notion of association between interpersonal trauma and youth psychopathic traits. They also highlight the need to gain an improved understanding of overlap between psychopathic traits, ADHD and ODD for clinical screening purposes and the underlying developmental mechanisms.

Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes.

Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.

Deep Neural Networks for Human's Fall-risk Prediction using Force-Plate Time Series Signal.

Early and accurate identification of the balance deficits could reduce falls, in particular for older adults, a prone population. Our work investigates deep neural networks' capacity to identify human balance patterns towards predicting fall-risk. Human balance ability can be characterized based on commonly-used balance metrics, such as those derived from the force-plate time series. We hypothesized that low, moderate, and high risk of falling can be characterized based on balance metrics, derived from the force-plate time series, in conjunction with deep learning algorithms. Further, we predicted that our proposed One-One-One Deep Neural Networks algorithm provides a considerable increase in performance compared to other algorithms. Here, an open source force-plate dataset, which quantified human balance from a wide demographic of human participants (163 females and males aged 18-86) for varied standing conditions (eyes-open firm surface, eyes-closed firm surface, eyes-open foam surface, eyes-closed foam surface) was used. Classification was based on one of the several indicators of fall-risk tied to the fear of falling: the clinically-used Falls Efficacy Scale (FES) assessment. For human fall-risk prediction, the deep learning architecture implemented comprised of: Recurrent Neural Network (RNN), Long-Short Time Memory (LSTM), One Dimensional Convolutional Neural Network (1D-CNN), and a proposed One-One-One Deep Neural Network. Results showed that our One-One-One Deep Neural Networks algorithm outperformed the other aforementioned algorithms and state-of-the-art models on the same dataset. With an accuracy, precision, and sensitivity of 99.9%, 100%, 100%, respectively at the 12th epoch, we found that our proposed One-One-One Deep Neural Network model is the most efficient neural network in predicting human's fall-risk (based on the FES measure) using the force-plate time series signal. This is a novel methodology for an accurate prediction of human risk of fall.

Human Health Risk from Consumption of Marine Fish Contaminated with DDT and Its Metabolites in Maputo Bay, Mozambique.

Many countries with incidence of malaria, including those surrounding Maputo Bay, use dichloro-diphenyl-trichloroethane (DDT) to reduce mosquitoes. This study is the first to estimate the human health risk associated with consumption of marine fish from Maputo Bay contaminated with DDTs. The median for ∑DDTs was 3.8 ng/g ww (maximum 280.9 ng/g ww). The overall hazard ratio for samples was 1.5 at the 75th percentile concentration and 28.2 at the 95th percentile. These calculations show increased potential cancer risks due to contamination by DDTs, data which will help policy makers perform a risk-benefit analysis of DDT use in malaria control programs in the region.

Determinants of longitudinal health-related quality-of-life change in children with asthma from low-income families: a report from the PROMIS® Pediatric Asthma Study.

BACKGROUND: How the longitudinal asthma control status and other socio-demographic factors influence the changes of health-related quality of life (HRQOL) among asthmatic children, especially from low-income families, has not been fully investigated. OBJECTIVES: This study aimed to describe the trajectories of asthma-specific HRQOL over 15 months and examine the effect of asthma control status on HRQOL by taking socio-demographic factors into consideration. METHODS: A total of 229 dyads of asthmatic children and their parents enroled in public insurance programs were recruited for assessing asthma control status and HRQOL over four time points of assessment. Asthma control status was measured using the Asthma Control and Communication Instrument, and asthma-specific HRQOL was assessed using the Patient-Reported Outcomes Measurement Information System's Pediatric Asthma Impact Scale. Latent growth models (LGMs) were applied to examine the trajectory of HRQOL and the factors contributing to the changes of HRQOL. RESULTS: Unconditional LGM revealed that HRQOL was improved over time. Conditional LGM suggested that accounting for asthma control and participants' socio-demographic factors, the variation in the initial level of HRQOL was significant, yet the rate of change was not. Conditional LGM also revealed that poorly controlled asthma status was associated with poor HRQOL at each time point (P's < 0.05). Lower parental education was associated with lower baseline HRQOL (P < 0.05). Hispanic children had a larger increase in HRQOL over time (P < 0.01) than non-Hispanic White children. CONCLUSIONS: Vulnerable socio-demographic characteristics and poorly controlled asthma status affect HRQOL in children. This finding encourages interventions to improve asthma control status and HRQOL in minority children.

Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

Salivary acinic cell carcinoma: reappraisal and update.

Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.