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.

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.

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.

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.

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.

Modifying pre-operative antibiotic overuse in gynecologic surgery.

Purpose Previous studies indicate adherence to pre-operative antibiotic prophylaxis guidelines has been inadequate. The purpose of this paper is to determine adherence rates to current perioperative antibiotic prophylaxis guidelines in gynecologic surgery at a tertiary care, academic institution. As a secondary outcome, improving guidelines after physician re-education were analyzed. Design/methodology/approach A retrospective chart review (2,463 patients) was completed. The authors determined if patients received perioperative antibiotic prophylaxis in accordance with current guidelines from the America College of Obstetricians and Gynecologists. Data were obtained before and after physician tutorials. Quality control was implemented by making guideline failures transparent. Statistical analysis used Fisher's exact and agreement tests. Findings In total, 23 percent of patients received antibiotics not indicated across all procedures. This decreased to 9 percent after physician re-education and outcome transparency ( p<0.0001). Laparoscopy was the procedure with the lowest guideline compliance prior to education. The compliance improved from 52 to 92 percent ( p<0.0001) after re-education. Practical implications Gynecologic surgeons overuse antibiotics for surgical prophylaxis. Physician re-education and transparency were shown to enhance compliance. Originality/value Educational tutorials are an effective strategy for encouraging physicians to improve outcomes, which, in turn, allows the healthcare system a non-punitive way to monitor quality and mitigate cost.

The role of biopsy in lacrimal gland inflammation: A clinicopathologic study.

PURPOSE: To determine the causes of lacrimal gland inflammation based on histopathology and systemic evaluation. METHODS: This is a retrospective case series study. From the University of British Columbia Orbit Clinic between January 1976 and December 2008, we reviewed the medical records of 60 patients who presented with inflammatory features of the lacrimal gland (i.e., erythema, edema, or tenderness) in which the diagnoses were not possible clinically and on imaging alone. As was our routine practice, all these patients underwent lacrimal gland biopsy before starting any treatment. RESULTS: The histopathologic findings of the 60 patients showed that 37 (61.7%) had identifiable types of lacrimal inflammation including 10 with Sjogren's syndrome, seven with sarcoidal reaction, six with feature of granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), five with lymphoma, two with sclerosing inflammation, two with IgG4-related dacryoadenitis, and one patient each with infectious dacryoadenitis, myoepithelial carcinoma, xanthogranuloma, eosinophilic angiocentric fibrosis, and eosinophilic allergic granulomatous nodule. The histopathologic findings of the remaining 23 (38.3%) patients showed nonspecific inflammation of the lacrimal gland. 23 patients (38.3%) had associated systemic diseases. 48 patients (80%) were treated successfully and 10 (16.7%) had recurrence of inflammation. CONCLUSIONS: We recommend that in patients presenting with lacrimal gland inflammation (i.e., erythema, edema, tenderness) in which the specific diagnosis cannot be made clinically and on imaging, biopsy is warranted for accurate diagnosis and appropriate treatment. We found that the majority of these patients (61.7%) had specific histopathology, and 38% had systemic diseases.

LAMELLAR HOLE-ASSOCIATED EPIRETINAL PROLIFERATION: A Clinicopathologic Correlation.

PURPOSE: To correlate clinical and optical coherence tomographic features with histopathological and immunohistochemical findings in an eye undergoing surgical excision of lamellar hole-associated epiretinal proliferation (LHEP). METHODS: An eye with a lamellar macular hole and LHEP without a tractional epiretinal membrane component was identified with spectral-domain optical coherence tomographic imaging and underwent pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. The surgically excised LHEP specimen was analyzed with histopathological and immunohistochemical staining using flat-mount preparation techniques. Postsurgical outcomes including visual acuity and optical coherence tomographic imaging were reviewed. RESULTS: With spectral-domain optical coherence tomography, the lamellar macular hole was found to be closed with no residual LHEP after the surgery. Visual acuity improved from 20/200 preoperatively to 20/40 at 6 months after the surgery. Histopathological and immunohistochemical analyses of the LHEP specimen revealed retinal glial cells that reacted positively with anti-glial fibrillary acidic protein and anti-glutamine synthetase, a Müller cell-specific antibody. CONCLUSION: Lamellar macular hole with LHEP may demonstrate closure after pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. There was considerable improvement in visual acuity. It is possible that LHEP originates from middle retinal layers of the lamellar hole defect because it contains retinal glial cells, specifically Müller cells.

Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of malawian children with fatal cerebral malaria.

BACKGROUND: Malarial retinopathy (MR) has diagnostic and prognostic value in children with Plasmodium falciparum cerebral malaria (CM). A clinicopathological correlation between observed retinal changes during life and the degree of sequestration of parasitized red blood cells was investigated in ocular and cerebral vessels at autopsy. METHODS: In 18 Malawian children who died from clinically defined CM, we studied the intensity of sequestration and the maturity of sequestered parasites in the retina, in nonretinal ocular tissues, and in the brain. RESULTS: Five children with clinically defined CM during life had other causes of death identified at autopsy, no MR, and scanty intracerebral sequestration. Thirteen children had MR and died from CM. MR severity correlated with percentage of microvessels parasitized in the retina, brain, and nonretinal tissues with some neuroectodermal components (all P < .01). In moderate/severe MR cases (n = 8), vascular congestion was more intense (ρ = 0.841; P < .001), sequestered parasites were more mature, and the quantity of extraerythrocytic hemozoin was higher, compared with mild MR cases (n = 5). CONCLUSIONS: These data provide a histopathological basis for the known correlation between degrees of retinopathy and cerebral dysfunction in CM. In addition to being a valuable tool for clinical diagnosis, retinal observations give important information about neurovascular pathophysiology in pediatric CM.

Orbital pseudotumor can be a localized form of granulomatosis with polyangiitis as revealed by gene expression profiling.

Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n=20) and patients with GPA (n=6), NSOI (n=25), sarcoidosis (n=7), or thyroid eye disease (TED) (n=20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays. Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>1.5-fold difference, false discovery rate adjusted p<0.05). The immunoglobulin family of genes had the most dramatic increase in expression. Although gene expression in GPA could be readily distinguished from gene expression in TED, sarcoidosis, or controls, a comparison of gene expression in GPA versus NSOI found no statistically significant differences. Thus, forms of orbital inflammation can be distinguished based on gene expression. NSOI/pseudotumor is heterogeneous but often may be an unrecognized, localized form of GPA.

Cerebral malaria in children: using the retina to study the brain.

Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes.

Comparison of American Joint Committee on Cancer TNM-based staging system (7th edition) and Ann Arbor classification for predicting outcome in ocular adnexal lymphoma.

OBJECTIVE: To compare the TNM and Ann Arbor staging systems in predicting outcome in ocular adnexal lymphoma (OAL). METHODS: Retrospective review of the clinical, imaging and histopathologic records of OALs between 1986 and 2009. Outcome measures included local recurrence and progression. RESULTS: One hundred and sixty patients of OAL were included. Mean age was 65 ± 15 years (range 20-97) and 68 (43%) were male. The median follow-up of all OAL patients was 65 months (range 2.5-238). Histopathology identified low-grade, indolent B-cell lymphomas in 140 patients (87.5%) and rest had aggressive grades. Of 134 indolent OAL patients, those with unilateral disease had a 10-year progression free survival of 72% versus 48% in their bilateral counterparts (p = 0.001). Amongst unilateral OAL patients staged within the T1-2 group, a significantly better outcome was noted for patients without nodal or metastatic involvement compared to those with such involvement (p = 0.0001). The above observations helped to formulate a simple scoring system to prognosticate OALs based on their laterality and node/metastatic status. Amongst the 3 groups identified, group 1 with a score of 0 (unilateral OALs with no nodes or metastasis) had a 10-year progression free survival of 75%; group 2 with score 1 (either bilateral or positive nodes/metastasis) 50% and group 3 with score 2 (both bilateral OAL with positive nodes/metastasis) zero at 10 years (p < 0.00001). CONCLUSIONS: The TNM-based staging system better predicts outcome in OAL than the Ann Arbor system primarily by delineation of bilateral disease and nodal/metastatic involvement at presentation.

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 .

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye.

Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD eye. The pathways and novel genes identified here highlight inflammation as a key response to AGE stimulation in primary culture of human RPE, and identify chemokine CXCL11 as putative novel agent associated with the pathogenesis of AMD.

IgG4-related disease with hypergammaglobulinemic hyperviscosity and retinopathy.

Immunoglobulin G4-related disease (IgG4-RD) is a recently described entity with protean manifestations. We describe a novel case of IgG4-RD with hypergammaglobulinemic hyperviscosity responsive to fludarabine and rituximab. A 33-year-old Asian man developed bilateral lacrimal gland and submandibular salivary gland swelling with cervical lymphadenopathy. Biopsies of the affected tissues revealed reactive follicular hyperplasia. Seven years later, he presented with bilateral retinal hemorrhages due to hyperviscosity syndrome from profound polyclonal increase in IgG, including marked IgG4 elevation. Despite plasmapheresis, overproduction of IgG continued and he was refractory to systemic steroids, azathioprine, interferon alpha, and cyclophosphamide. IgG4-RD was suspected following a myocardial infarction and detection of aneurysmal coronary arteries indicating large vessel vasculitis. Review of the cervical lymph node and lacrimal gland biopsies with immunohistochemical staining for IgG4-positive plasma cells confirmed IgG4-RD. B-cell depletion with rituximab produced a partial response, but clinical symptoms and elevated protein levels persisted. Fludarabine was added to rituximab to suppress T-cell activity, and this resulted in an excellent clinical and biochemical response. Combination therapy with fludarabine and rituximab in IgG4-RD has not previously been reported and can be considered in patients with severe refractory disease.

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.

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.