A crisis planning and monitoring intervention to reduce compulsory hospital readmissions (FINCH study): protocol for a randomised controlled feasibility study.

BACKGROUND: Rates of compulsory (also known as involuntary) detention under mental health legislation have been rising over several decades in countries including England. Avoiding such detentions should be a high priority given their potentially traumatic nature and departure from usual ethical principles of consent and collaboration. Those who have been detained previously are at high risk of being detained again, and thus a priority group for preventive interventions. In a very sparse literature, interventions based on crisis planning emerge as having more supporting evidence than other approaches to preventing compulsory detention. METHOD: We have adapted and manualised an intervention previously trialled in Zürich Switzerland, aimed at reducing future compulsory detentions among people being discharged following a psychiatric admission that has included a period of compulsory detention. A co-production group including people with relevant lived and clinical experience has co-designed the adaptations to the intervention, drawing on evidence on crisis planning and self-management and on qualitative interviews with service users and clinicians. We will conduct a randomised controlled feasibility trial of the intervention, randomising 80 participants to either the intervention in addition to usual care, or usual care only. Feasibility and acceptability of the intervention and trial procedures will be assessed through process evaluation (including rates of randomisation, recruitment, and retention) and qualitative interviews. We will also assess and report on planned trial outcomes. The planned primary outcome for a full trial is repeat compulsory detention within one year of randomisation, and secondary outcomes include compulsory detention within 2 years, and symptoms, service satisfaction, self-rated recovery, self-management confidence, and service engagement. A health economic evaluation is also included. DISCUSSION: This feasibility study, and any subsequent full trial, will add to a currently limited literature on interventions to prevent involuntary detention, a goal valued highly by service users, carers, clinicians, and policymakers. There are significant potential impediments to recruiting and retaining this group, whose experiences of mental health care have often been negative and traumatising, and who are at high risk of disengagement. TRIAL REGISTRATION: ISRCTN, ISRCTN11627644. Registered 25th May 2022, https://www.isrctn.com/ISRCTN11627644 .

Genomic epidemiology reveals the dominance of Hennepin County in the transmission of SARS-CoV-2 in Minnesota from 2020 to 2022.

IMPORTANCE: We analyzed over 22,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes of patient samples tested at Mayo Clinic Laboratories during a 2-year period in the COVID-19 pandemic, which included Alpha, Delta, and Omicron variants of concern to examine the roles and relationships of Minnesota virus transmission. We found that Hennepin County, the most populous county, drove the transmission of SARS-CoV-2 viruses in the state after including the formation of earlier clades including 20A, 20C, and 20G, as well as variants of concern Alpha and Delta. We also found that Hennepin County was the source for most of the county-to-county introductions after an initial predicted introduction with the virus in early 2020 from an international source, while other counties acted as transmission "sinks." In addition, major policies, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, did not appear to have an impact on virus diversity across individual counties.

Telomere length assessment and molecular characterization of TERT gene promoter in periampullary carcinomas.

Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P = 0.01) and lower TERT protein expression (p = 0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T > C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δß 7%; cg02545192 with Δß 9%; cg03323598 with Δß 19%; and cg07285213 with Δß 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.

Genomic epidemiology reveals the dominance of Hennepin County in transmission of SARS-CoV-2 in Minnesota from 2020-2022.

SARS-CoV-2 has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of virus evolution and spread, and to inform policy decisions. We sequenced viral genomes from over 22,000 patient samples tested at Mayo Clinic Laboratories between 2020-2022 and use Bayesian phylodynamics to describe county and regional spread in Minnesota. The earliest introduction into Minnesota was to Hennepin County from a domestic source around January 22, 2020; six weeks before the first confirmed case in the state. This led to the virus spreading to Northern Minnesota, and eventually, the rest of the state. International introductions were most abundant in Hennepin (home to the Minneapolis/St. Paul International (MSP) airport) totaling 45 (out of 107) over the two-year period. Southern Minnesota counties were most common for domestic introductions with 19 (out of 64), potentially driven by bordering states such as Iowa and Wisconsin as well as Illinois which is nearby. Hennepin also was, by far, the most dominant source of in-state transmissions to other Minnesota locations (n=772) over the two-year period. We also analyzed the diversity of the location source of SARS-CoV-2 viruses in each county and noted the timing of state-wide policies as well as trends in clinical cases. Neither the number of clinical cases or major policy decisions, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, appeared to have impact on virus diversity across each individual county.

Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC), the same or different entities?

Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC) have overlapping histopathological appearances and sites of occurrence, which may cause diagnostic difficulty impacting subsequent treatment. We conducted a systematic review of the scientific literature to determine whether molecular alterations were sufficiently different in MEC and ASC to aid in classifying the two entities. We searched Medline, Embase and Web of Science for studies reporting molecular determinations of ASC and/or MEC and screened retrieved records for eligibility. Two independent researchers reviewed included studies, assessed methodological quality and extracted data. Of 8623 identified records, 128 articles were included for analysis: 5 which compared the two tumors in the same investigation using the same methods and 123 which examined the tumors separately. All articles, except one were case series of moderate to poor methodological quality. The 5 publications examining both tumors showed that 52/88 (59%) MEC and 0% of 110 ASC had rearrangement of the MAML2 gene as detected by FISH and/or RT-PCR, but did not investigate other genes. In the entire series MEC had MAML2 gene rearrangement in 1337/2009 (66.6%) of tumors studied. The articles examining tumors separately found that MEC had mutations in EGFR (11/329 cases, 3.3%), KRAS (11/266, 4.1%) and ERBB2 (9/126, 7.1%) compared with ASC that had mutations in EGFR (660/1705, 38.7%), KRAS (143/625, 22.9%) and ERBB2 (6/196, 3.1%). The highest level of recurrent mutations was in pancreatic ASC where (108/126, 85.7%) reported mutations in KRAS. The EGFR mutations in ASC were similar in number and kind to those in lung adenocarcinoma. By standards of systematic review methodology and despite the large number of retrieved studies, we did not find adequate evidence for a distinctive molecular profile of either MEC or ASC that could definitively aid in its classification, especially in histologically difficult cases that are negative for MAML2 rearrangement. The case series included in this review indicate the relevance of MAML2 rearrangement to support the diagnosis of MEC, findings that should be confirmed by additional research with adequate study design.

Ocular Pathology of Cerebral Malaria.

Investigation of post-mortem eyes from children with malarial retinopathy has helped to explain the retinal pathology of cerebral malaria, and also demonstrated histological associations between evolving retinal pathogenesis-visible clinically-and similar cerebral features which can only be examined at autopsy. The pathology of malarial retinopathy has been well-described and correlates with brain pathology. Some clinical and pathological features are associated with outcome. This chapter describes the materials and methods needed to study the pathological features of malarial retinopathy. Some are common to histopathology in general, but accurate spatial correlation between retinal features observed in life and their associated pathology in post-mortem specimens requires special techniques.

Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for "confirmatory MAML2 testing" in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic.

Clonality, Mutation and Kaposi Sarcoma: A Systematic Review.

BACKGROUND: It remains uncertain whether Kaposi sarcoma (KS) is a true neoplasm, in that it regresses after removal of the stimulus to growth (as HHV8) when immunosuppression is reduced. We aimed to summarize the available evidence on somatic mutations and clonality within KS to assess whether KS is a neoplasm or not. METHODS: Medline and Web of Science were searched until September 2020 for articles on clonality or mutation in KS. Search strings were supervised by expert librarians, and two researchers independently performed study selection and data extraction. An adapted version of the QUADAS2 tool was used for methodological quality appraisal. RESULTS: Of 3077 identified records, 20 publications reported on relevant outcomes and were eligible for qualitative synthesis. Five studies reported on clonality, 10 studies reported on various mutations, and 5 studies reported on chromosomal aberrations in KS. All studies were descriptive and were judged to have a high risk of bias. There was considerable heterogeneity of results with respect to clonality, mutation and cytogenetic abnormalities as well as in terms of types of lesions and patient characteristics. CONCLUSIONS: While KS certainly produces tumours, the knowledge is currently insufficient to determine whether KS is a clonal neoplasm (sarcoma), or simply an aggressive reactive virus-driven lesion.

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

BACKGROUND: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. METHODS: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. RESULTS: Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21-33.78 and OR = 8.58, 95% CI = 2.56-29.08, respectively) and brain swelling (P < .05). Vessel leak and macular nonperfusion were associated with neurological disability (OR = 3.71, 95% CI = 1.26-11.02 and OR = 9.06, 95% CI = 1.79-45.90). Large focal leak was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. CONCLUSIONS: Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

Counting mitoses: SI(ze) matters!

Mitoses are often assessed by pathologists to assist the diagnosis of cancer, and to grade malignancy, informing prognosis. Historically, this has been done by expressing the number of mitoses per n high power fields (HPFs), ignoring the fact that microscope fields may differ substantially, even at the same high power (×400) magnification. Despite a requirement to define HPF size in scientific papers, many authors fail to address this issue adequately. The problem is compounded by the switch to digital pathology systems, where ×400 equivalent fields are rectangular and also vary in the area displayed. The potential for error is considerable, and at times this may affect patient care. This is easily solved by the use of standardized international (SI) units. We, therefore, recommend that features such as mitoses are always counted per mm2, with an indication of the area to be counted and the method used (usually "hotspot" or "average") to obtain the results.

Misleading terminology in pathology: lack of definitions hampers communication.

Accurate terminology is the basis for clear communication among specialists and relies upon precise definitions, indispensable for the WHO Classification of Tumours. We identified a number of potentially misleading terms in use in the recently published WHO Classification of Tumours, 5th edition. From a list of common sources that might be consulted by specialists in the pathology field, we searched for definitions of the terms. Where at least two sources provided definitions for a term, we assessed their level of agreement using an ad hoc developed scale. We identified 26 potentially misleading terms from the 5th edition Digestive System and Breast Tumour Books, and 16 sources. The number of definitions provided by the sources ranged from no definition (for four terms) to ten (for two terms). No source had definitions for all terms. We found only 111 (27%) of a possible 416 definitions. Where two or more definitions were present for a term, the level of agreement between them was judged to be high. There was a paucity of definitions for potentially misleading terms in the sources consulted, but there was a good agreement when two or more definitions were present. In a globalized world where healthcare workers and learners in many fields may access these sources to learn about terminology with which they are unfamiliar, the lack of definitions is a hindrance to a precise understanding of classification in the speciality of pathology and to clear communication between specialist groups.

Differences in 7th and 8th edition American Joint Committee on Cancer staging for periocular sebaceous carcinoma.

OBJECTIVE: To examine the clinicopathological features of periocular sebaceous carcinoma and describe the differences in T category between the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging system for eyelid carcinoma in a Canadian population. METHODS: This study is a single-centre retrospective review of consecutive patients diagnosed with periocular sebaceous carcinoma at Vancouver General Hospital over a 24-year period. Medical records and pathological slides were reviewed. Clinicopathological features, management, and outcomes were recorded. Each carcinoma was staged as per both the seventh and eighth editions AJCC staging system for eyelid carcinoma. RESULTS: Forty-five patients (25 women, 20 men) were identified with a median age of 74 years (range 42-91 years). Tumour size was with a median of 4 mm (range 1-30 mm) and a mean of 6.7 mm. Using the seventh edition, patients were assigned the following T categories: Tis = 10, T1 = 9, T2 = 11, T3 = 8, T4 = 0. Under the eighth edition, 18 of 45 patients (40%) were restaged, with the majority of these (15 patients, 33%) being downstaged. The eighth edition categories were as follows: Tis = 10, T1 = 22, T2 = 3, T3 = 0, T4 = 3. Three patients developed disease recurrence, 2 of whom (staged T2c and T4b) died of disease. CONCLUSIONS: There were substantial differences in the seventh and eighth editions of AJCC for the staging of periocular sebaceous carcinoma. Our series had small tumours at presentation with infrequent recurrences or metastases. We found a high number of patients with in-situ-only disease.

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Revising the WHO classification: female genital tract tumours.

The upcoming revision of the World Health Organisation (WHO) classification of tumours of the female genital tract is scheduled for release in the second quarter of 2020. It will feature significant changes compared to earlier editions. In this review, we outline the process of revising this important reference source for those diagnosing tumours or engaged in cancer research and describe the significant changes. The WHO classification of tumours is increasingly evidence-based, with a clear update cycle, improved quality of illustrations and content, led by an editorial board comprised mainly of pathologists, but increasingly incorporating input from other disciplines. The advent of the new website allows the use of whole-slide images and hyperlinks to evidence or external bodies that produce guidance on staging or reporting.

Understanding and Classification of Ocular Lymphomas.

BACKGROUND: Lymphomas that involve the tissues of the ocular adnexae and the eye itself can be confusing for both the new and seasoned learner alike. In this review, I present a simple way of classifying these disorders that will help to facilitate understanding of these myriad entities. SUMMARY: Classifications of lymphomas have changed significantly over the last 40 years, but in recent decades, the basic structure of the WHO classification has remained the same, facilitating understanding. KEY MESSAGES: The ocular lymphomas can be divided into those that are external to the eye (ocular adnexae) and those that are internal (vitreoretinal and uveal). At each of these sites specific subtypes of lymphoma are common. Focusing on these common subtypes can aid the learner to create a scaffold that enables current understanding and upon which they can build for the future.

Unsupervised tumor detection in Dynamic PET/CT imaging of the prostate.

Early detection and localization of prostate tumors pose a challenge to the medical community. Several imaging techniques, including PET, have shown some success. But no robust and accurate solution has yet been reached. This work aims to detect prostate cancer foci in Dynamic PET images using an unsupervised learning approach. The proposed method extracts three feature classes from 4D imaging data that include statistical, kinetic biological and deep features that are learned by a deep stacked convolutional autoencoder. Anomalies, which are classified as tumors, are detected in feature space using density estimation. The proposed algorithm generates promising results for sufficiently large cancer foci in real PET scans imaging where the foci is not viewed by the tomographic devices used for detection.