A Critical Review of Noninvasive Brain Stimulation Technologies in Alzheimer's Dementia and Primary Progressive Aphasia.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin- and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed non-polypoid lesions. Seven (88%) showed multifocal GI disease, including five with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single-system), with the remaining 14 (36%) exhibiting multi-system disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multi-system LCH more frequently presented with GI symptoms (92%, P<0.001), non-colorectal GI site involvement (50%, P=0.02), multifocal GI lesions (43%, P=0.005), non-polypoid lesions (71%, P<0.001), infiltrative histologic growth pattern (78%, P=0.04), and persistent disease (57%, P<0.001). Adult multi-system LCH patients appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrate that adults with single-system LCH involving the GI tract have an excellent prognosis, while multi-system LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, non-colorectal GI involvement, multifocal GI disease, non-polypoid lesions, and infiltrative growth pattern.

SARS-CoV-2 wastewater surveillance at two university campuses: lessons learned and insights on intervention strategies for public health guidance.

Wastewater surveillance has been a tool for public health officials throughout the COVID-19 pandemic. Universities established pandemic response committees to facilitate safe learning for students, faculty, and staff. These committees met to analyze both wastewater and clinical data to propose mitigation strategies to limit the spread of COVID-19. This paper reviews the initial efforts of utilizing campus data inclusive of wastewater surveillance for SARS-CoV-2 RNA concentrations, clinical case data from university response teams, and mitigation strategies from Grand Valley State University in West Michigan (population 21,648 students) and Oakland University in East Michigan (population 18,552 students) from November 2020 to April 2022. Wastewater positivity rates for both universities ranged from 32.8 to 46.8%. Peak viral signals for both universities directly corresponded to variant points of entry within the campus populations from 2021 to 2022. It was found that the organization of clinical case data and variability of wastewater testing data were large barriers for both universities to effectively understand disease dynamics within the university population. We review the initial efforts of onboarding wastewater surveillance and provide direction for structuring ongoing surveillance workflows and future epidemic response strategies based on those that led to reduced viral signals in campus wastewater.

Histologic Features of Mycobacterial Spindle Cell Pseudotumors: A Multi-institutional Clinicopathologic Analysis of 14 Cases.

Mycobacterial spindle cell pseudotumors (MSPs) are a rare and diagnostically challenging manifestation of non-tuberculous mycobacterial (NTM) infections. Proper recognition of these pseudotumors is important because they are treatable and benign. In this study, we evaluated the morphologic patterns of MSPs to improve their pathologic identification. Clinical and morphologic features of 14 MSPs were analyzed. Histologic factors evaluated included the architectural growth pattern of spindled or epithelioid macrophages, granulomas and their location within the lesion, neutrophilic microabscesses, multinucleated giant cells, necrosis, and effacement of background tissue. The composition of inflammatory infiltrates, organism density by acid-fast staining, and stromal changes were also assessed. In addition, 8 of 14 cases underwent molecular microbiology identification by a clinical amplicon-sequencing assay for non-tuberculous mycobacteria. MSP sites included 2 bowel, 10 lymph nodes, 1 liver, and 1 extremity. Cases with available clinical history (n=10) all occurred in immunocompromised patients. All demonstrated effacement of normal structures with spindled cells arranged in a storiform or fascicular architectural pattern. In addition, all cases showed lymphocytic inflammation, with prominent concurrent neutrophilic inflammation in 50% (7/14) of cases. Other morphologic findings included foamy histiocytes (64%, 9/14), peripherally situated granulomas (21%, 3/14), and neutrophilic microabscesses (21%, 3/14). All tested cases were positive for NTM by PCR methods. Mycobacterium avium was the most commonly isolated pathogen (6/8). Mycobacterial spindle cell pseudotumors show predominantly spindled morphology that may be mistaken as a neoplasm. Surgical pathologists who evaluate lymph nodes, soft tissue, and gastrointestinal tissues should be aware of this spindled tumefactive phenomenon in the setting of immunocompromised patients. Recognition of key morphologic features of neutrophilic inflammation, peripheral granulomas, or foamy histiocytes within a spindled lesion can help guide the pathologist to a correct diagnosis of an inflammatory process secondary to infection rather than a spindle cell neoplasm. Accurate diagnosis to facilitate appropriate antimicrobial and/or surgical therapy requires a comprehensive evaluation combining clinical, histopathologic, and microbiological findings.

A modified neural circuit framework for semantic memory retrieval with implications for circuit modulation to treat verbal retrieval deficits.

Word finding difficulty is a frequent complaint in older age and disease states, but treatment options are lacking for such verbal retrieval deficits. Better understanding of the neurophysiological and neuroanatomical basis of verbal retrieval function may inform effective interventions. In this article, we review the current evidence of a neural retrieval circuit central to verbal production, including words and semantic memory, that involves the pre-supplementary motor area (pre-SMA), striatum (particularly caudate nucleus), and thalamus. We aim to offer a modified neural circuit framework expanded upon a memory retrieval model proposed in 2013 by Hart et al., as evidence from electrophysiological, functional brain imaging, and noninvasive electrical brain stimulation studies have provided additional pieces of information that converge on a shared neural circuit for retrieval of memory and words. We propose that both the left inferior frontal gyrus and fronto-polar regions should be included in the expanded circuit. All these regions have their respective functional roles during verbal retrieval, such as selection and inhibition during search, initiation and termination of search, maintenance of co-activation across cortical regions, as well as final activation of the retrieved information. We will also highlight the structural connectivity from and to the pre-SMA (e.g., frontal aslant tract and fronto-striatal tract) that facilitates communication between the regions within this circuit. Finally, we will discuss how this circuit and its correlated activity may be affected by disease states and how this circuit may serve as a novel target engagement for neuromodulatory treatment of verbal retrieval deficits.

Verbal retrieval deficits due to traumatic brain injury are associated with changes in event related potentials during a Go-NoGo task.

OBJECTIVE: Verbal retrieval (VR) deficits often occur after traumatic brain injury (TBI), but the mechanisms remain unclear. We examined how event-related potentials (ERPs) during a Go-NoGo task were associated with VR deficits. METHODS: Sixty veterans with a history of TBI underwent a neuropsychological battery and a Go-NoGo task with concurrent EEG recording. We compared task performance and ERP measures (N2, P3) between those with and those without persistent injury-related VR deficits. We then used generalized linear modeling to examine the relationship between ERP measures and scores on measures of executive function and processing speed. RESULTS: Go-NoGo task performance was comparable between the groups. Those with VR deficits had larger N2 amplitude in NoGo than in Go conditions. In participants with VR deficits, larger NoGo N2/P3 amplitude predicted faster processing speed. Furthermore, larger P3 amplitude and shorter P3 latency of the difference wave (NoGo - Go) predicted faster processing speed in those with VR deficits. CONCLUSIONS: Despite no difference in Go-NoGo task performance, ERP amplitude and latency measures associated with cognitive control during Go-NoGo distinguished TBI individuals with VR deficits from those without. SIGNIFICANCE: This study furthers our understanding of VR deficits in TBI and implicates potential application of ERP measures in monitoring and treating such deficits.

Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.

Analyzing direct effects of education level and estimated IQ between cognitively intact Mexican Americans and Non-Hispanic whites on a confrontational naming task.

Confrontational naming is widely used in diagnosing neurodegenerative disorders like MCI and dementia, and previous research indicates that healthy Non-Hispanic Whites outperform Hispanics in such tasks. However, understanding the factors contributing to score differences among ethnic groups remains limited. This study focuses on cognitively intact Mexican Americans and Non-Hispanic White older adults from the TARCC Hispanic Cohort project. Hierarchical regression analyses reveal that sex, age, ethnicity, education level, and estimated IQ significantly predict performance on the Boston Naming Test (BNT). Notably, education level and estimated IQ more strongly influence BNT performance in Mexican Americans than in Non-Hispanic Whites. When controlling for education level, estimated IQ has a more pronounced impact on BNT performance in aging Mexican Americans compared to Non-Hispanic Whites. Conversely, after controlling for estimated IQ, the influence of education level is weaker for Mexican Americans than Non-Hispanic Whites. These findings emphasize the need for careful evaluation of confrontational naming task scores in diverse ethnic groups, emphasizing the critical role of education and estimated IQ in understanding performance disparities.

Immunogenicity, safety, and reactogenicity of a half- versus full-dose BNT162b2 (Pfizer-BioNTech) booster following a two-dose ChAdOx1 nCoV-19, BBIBP-CorV, or Gam-COVID-Vac priming schedule in Mongolia: a randomised, controlled, non-inferiority trial.

Background: COVID-19 vaccine booster doses restore vaccine effectiveness lost from waning immunity and emerging variants. Fractional dosing may improve COVID-19 booster acceptability and uptake and will reduce the per-dose cost of COVID-19 booster programmes. We sought to quantify the immunogenicity, reactogenicity, and safety of a half-dose BNT162b2 (Pfizer-BioNTech) booster relative to the standard formulation. Methods: This randomised, controlled, non-inferiority trial recruited adults in Mongolia primed with a two-dose homologous ChAdOx1 nCov-19 (Oxford-AstraZeneca, n = 129 participants), BBIBP-CorV (Sinopharm (Beijing), n = 399), or Gam-COVID-Vac (Gamaleya, n = 70) schedule. Participants were randomised (1:1) to receive a 15 µg (half-dose) or 30 µg (full-dose) BNT162b2 booster. Participants and study staff assessing reactogenicity were blinded up to day 28. Co-primary endpoints were Wuhan-Hu-1 anti-spike S1 IgG seroresponse 28 days post-boosting and reactogenicity within 7 days of boosting. The non-inferiority margin for the absolute difference in seroresponse was -10%. Differences in seroresponse were estimated from logistic regression with marginal standardisation. Geometric mean ratios of IgG were also estimated. ClinicalTrials.gov Identifier: NCT05265065. Findings: Between May 27th and September 30th, 2022, 601 participants were randomized to full-dose BNT162b2 (n = 300) or half-dose (n = 301). 598 were included in safety analyses, and 587 in immunological analyses. The frequency of grade 3-4 reactions was similar between arms (half-dose: 4/299 [1.3%]; full-dose: 6/299 [2.0%]). Across all severity grades, half-dose recipients reported fewer local and systemic reactions (60% versus 72% and 25% versus 32%, respectively). Seroresponse was 84.7% (250/295) and 86.6% (253/292) in the half-dose and full-dose arms, respectively (Difference: -2.8%; 95% CI -7.7, 2.1). Geometric mean IgG titres were similar in those receiving full and half-dose boosters for the ChAdOx1 and BBIBP-CorV primed groups, but lower in the half-dose arm in Gam-COVID-Vac-primed participants (GMR: 0.71; 95% CI 0.54, 0.93). Interpretation: Half-dose BNT162b2 boosting elicited an immune response that was non-inferior to a full-dose, with fewer reactions, in adults primed with ChAdOx1 nCov-19 or BBIBP-CorV. Half-dose boosting may not be suitable in adults primed with Gam-COVID-Vac. Half-dose BNT162b2 boosting may be considered in populations primed with ChAdOx1 nCov-19 or BBIBP-CorV. Funding: Coalition for Epidemic Preparedness Innovations (CEPI).

Traumatic Brain Injury Characteristics Are Not Related to Neurocognitive Decline in Older Adults: A Nationwide Longitudinal Cohort Study.

OBJECTIVE: Evaluate whether traumatic brain injury (TBI) characteristics, age of injury, or recency of injury predicts the course of neurocognitive decline and/or increases conversion rates to mild cognitive impairment (MCI) or dementia. METHODS: Data were obtained from the National Alzheimer's Coordinating Center for participants 50-85 years old with 3-5 visits from 2015 to 2022, with or without TBI history (TBI+ = 508; TBI- = 2,382). Groups were stratified by self-reported TBI history (i.e., single TBI without loss of consciousness [LOC], single TBI with LOC, multiple TBI without LOC, and multiple TBI with LOC), age of most recent TBI, and recency of TBI. Mixed linear models compared neuropsychological composite trajectories (executive functioning/attention/speed, language, memory, and global), co-varying for age, gender, education, apolipoprotein E4 status, race/ethnicity, and baseline diagnosis (normal aging n = 1,720, MCI n = 749, or dementia n = 417). Logistic binary regression examined MCI/dementia conversion rates. RESULTS: There was a slightly higher frequency of MCI/dementia in those with multiple TBIs (50% to 60% with and without LOC, compared to 39% with no TBI) at baseline, but longitudinal trajectories were similar. TBI history, age of injury, or recency of injury did not impact neurocognitive trajectories or conversion rates to MCI/dementia (all p's > .01). CONCLUSIONS: TBI history, regardless of injury characteristics, age of injury, or recency of injury, did not worsen neurocognitive decline or MCI/dementia conversion. Additional longitudinal research in more diverse cohorts with a wider range of TBI severity is needed to evaluate the specific factors and possible mechanisms in which TBI may increase dementia risk.

Lymphoglandular Complex-Like Colorectal Carcinoma-A Series of 20 Colorectal Cases, Including Newly Reported Features of Malignant Behavior.

Distinguishing colon carcinoma that is surrounded by well-circumscribed lymphoid tissue from adenomas involving lymphoglandular complexes can be difficult. We assessed a multi-institutional international cohort of 20 colorectal carcinomas with associated prominent lymphoid infiltrates, which we referred to as lymphoglandular complex-like carcinoma (LGCC). We collected clinical and endoscopic features, including lesion size, endoscopic appearance, location, procedure, follow-up, AJCC stage, and mismatch repair status. We recorded the presence of the following histologic features: haphazard gland distribution, gland angulation, gland fusion, solid nest formation, single-cell formation, stromal desmoplasia, presence of lymphovascular invasion and perineural invasion, presence of lamina propria, cytologic atypia as low- or high-grade, presence of goblet cells in the invasive component, and the presence of a surface lesion. Most cases (9 of 13) were described endoscopically as sessile polyps with an average size of 1.56 cm. Most cases (90%) were associated with a surface lesion, of which the majority were tubular adenomas, though a subset was associated with sessile serrated lesions with dysplasia (3 of 18). All cases of LGCC demonstrated haphazard gland distribution and either gland angulation, fusion, or solid nest formation. A portion of cases demonstrated single-cell infiltration (35%) and desmoplasia (50%), and rarely lymphovascular invasion was present (5%). A subset (10%) of cases invaded beyond the submucosa. Deficient mismatch repair was present in 22% (2 of 9) of cases for which it was performed. In cases of colectomy or completion colectomy, nodal metastasis was present in 38% (3 of 8). No cases demonstrated disease recurrence or disease-specific mortality. Overall, LGCC represents an enigmatic subset of carcinomas that is important to distinguish from adenomas involving lymphoglandular complexes due to its varying prognostic outcomes.

Portosinusoidal Vascular Disorder: A Heretofore Unrecognized Manifestation of Sickle Cell Disease?

Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.

A novel telomere biology disease-associated gastritis identified through a whole exome sequencing-driven approach.

A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (POT1 and DCLRE1B). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.

Clinical Data Do Not Reliably Predict Duodenal Histology at Follow-up in Celiac Disease: A 13 Center Correlative Study.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

Fecal Impairment Framework, A New Conceptual Framework for Assessing Fecal Contamination in Recreational Waters.

Fecal pollution of surface water is a pervasive problem that negatively affects waterbodies concerning both public health and ecological functions. Current assessment methods monitor fecal indicator bacteria (FIB) to identify pollution sources using culture-based quantification and microbial source tracking (MST). These types of information assist stakeholders in identifying likely sources of fecal pollution, prioritizing them for remediation, and choosing appropriate best management practices. While both culture-based quantification and MST are useful, they yield different kinds of information, potentially increasing uncertainty in prioritizing sources for management. This study presents a conceptual framework that takes separate human health risk estimates based on measured MST and E. coli concentrations as inputs and produces an estimate of the overall fecal impairment risk as its output. The proposed framework is intended to serve as a supplemental screening tool for existing monitoring programs to aid in identifying and prioritizing sites for remediation. In this study, we evaluated the framework by applying it to two primarily agricultural watersheds and several freshwater recreational beaches using existing routine monitoring data. Based on a combination of E. coli and MST results, the proposed fecal impairment framework identified four sites in the watersheds as candidates for remediation and identified temporal trends in the beach application. As these case studies demonstrate, the proposed fecal impairment framework is an easy-to-use and cost-effective supplemental screening tool that provides actionable information to managers using existing routine monitoring data, without requiring specialized expertize.

Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was .08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy.

Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort.

BACKGROUND: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer's disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. OBJECTIVE: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. METHODS: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. RESULTS: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. CONCLUSIONS: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Genome-Wide Association Study to Identify Possible Candidate Genes of Snap Bean Leaf and Pod Color.

Color can be an indicator of plant health, quality, and productivity, and is useful to researchers to understand plant nutritional content in their studies. Color may be related to chlorophyll content and photosynthetic activity and provides information for those studying diseases and mineral nutrition because every nutrient deficiency and many diseases produce symptoms that affect color. In order to identify significant loci related to both leaf and pod color in a snap bean (Phaseolus vulgaris L.) diversity panel, a genome-wide association study (GWAS) was carried out. Leaf color in one and pod traits in multiple environments were characterized using a colorimeter. L*a*b* color data were recorded and used to calculate chroma (C*) and hue angle (H°). Leaves were evaluated at three positions (lower, middle, and upper) in the canopy and both pod exterior and interior colors were obtained. GWAS was conducted using two reference genomes that represent the Andean (G19833) and Middle American (5-593) domestication centers. Narrow sense heritabilities were calculated using the mixed linear model (MLM) method in genome association and prediction integrated tool (GAPIT), and significant single nucleotide polymorphisms (SNPs) for each color parameter were obtained using the Bayesian-information and linkage-disequilibrium iteratively nested keyway (BLINK) GWAS model with two principal components (PCAs). In comparison to pod color traits, narrow sense heritabilities of leaf traits were low and similar for both reference genomes. Generally, narrow sense heritability for all traits was highest in the lower, followed by middle, and then upper leaf positions. Heritability for both pod interior and exterior color traits was higher using the G19833 reference genome compared to 5-593 when evaluated by year and means across years. Forty-five significant SNPs associated with leaf traits and 872 associated with pods, totaling 917 significant SNPs were identified. Only one SNP was found in common for both leaf and pod traits on Pv03 in the 5-593 reference genome. One-hundred thirteen significant SNPs, 30 in leaves and 83 in pods had phenotypic variation explained (PVE) of 10% or greater. Fourteen SNPs (four from G19833 and ten from 5-593) with ≥10 PVE%, large SNP effect, and largest p-value for L* and H° pod exterior was identified on Pv01, Pv02, Pv03, and Pv08. More SNPs were associated with pod traits than with leaf traits. The pod interior did not exhibit colors produced by anthocyanins or flavonols which allowed the differentiation of potential candidate genes associated with chloroplast and photosynthetic activity compared to the pod exterior where candidate genes related to both flavonoids and photosynthesis affected color. Several SNPs were associated with known qualitative genes including the wax pod locus (y), persistent color (pc), purple pods (V), and two genes expressed in seeds but not previously reported to affect other plant tissues (B and J). An evaluation of significant SNPs within annotated genes found a number, within a 200 kb window, involved in both flavonoid and photosynthetic biosynthetic pathways.

Crohn's Disease Features in Anastomotic Biopsies from Patients With and Without Crohn's Disease: Diagnostic and Prognostic Value.

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn's disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Inter-Examiner Agreement of the National Upper Cervical Chiropractic Association Analysis of the Atlas Subluxation Complex in a 3-View Upper Cervical Radiographic Series.

Objective: The purpose of this study was to measure the inter-examiner agreement between radiograph markings of 2 National Upper Cervical Chiropractic Association board-certified chiropractors. Methods: Two chiropractic examiners who had standardized training marked and analyzed 254 conventional orthogonal radiographic film sets. The level of agreement and potential biases in their measurements were assessed using intraclass correlation coefficients for absolute agreement and Bland-Altman plot analyses. Results: There was 96.1% agreement between the examiners in the measurements of the side of atlas laterality and 94.5% for atlas rotation. The intraclass correlation coefficient was 0.95 (95% CI, 0.93-0.96) for atlas laterality and 0.92 (95% CI, 0.89-0.94) for atlas rotation. The mean difference in the measurement between the 2 examiners was -0.11, P = .12 for atlas laterality and 0.05, P = .55 for atlas rotation. Neither atlas laterality nor atlas rotation measurements were significantly different from zero. Bland-Altman plots were not suggestive of any proportional biases in the 2 measurements. Conclusion: Results of this study show almost perfect agreement between 2 trained chiropractic examiners, with no apparent proportional bias in the analysis of conventional orthogonal radiographic film sets.