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Background: The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation. Methods: This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc. Results: Within the cirrhosis group, admission lactate levels of 2–4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03–2.81, aOR: 4.02, CI: 2.53–6.52]. Median 24-hour MAP 60–65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64–4.92 and aOR: 7.34, CI: 3.17–18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2–4 and >4 mmol/L (aOR: 1.32, CI: 0.77–2.27 and aOR: 2.25, CI: 1.40–3.67) and median 24-hour MAP 60–65 and <60 mm Hg (aOR: 1.70, CI: 0.65–4.14 and aOR: 4.41, CI: 0.79–29.38). Conclusions: These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.

While congenital heart disease historically was a pathology primarily restricted to specialized pediatric centers, advances in technology have dramatically increased the number of people living into adulthood, the number of complications faced by these patients, and the number of patients visiting non-specialized emergency departments for these concerns. Clinicians need to be aware of the issues specific to patients’ individual congenital defects but also have an understanding of how typical cardiac pathology may manifest in this special group of patients. This manuscript attempts to provide an overview of this diverse but increasingly common group of adult patients with congenital heart diseases, including a review of their anatomical variants, the complications they face at the highest rates, and ways that emergency physicians may need to manage these patients differently to avoid causing harm.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

AbstractBackgroundTriplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology.MethodCross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired.ResultSignificant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres.ConclusionCT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment.1. Dincer (2020). NeuroImage: Clinical, 28, 102491.2. Su (2019). Alzheimer’s Dement, 11, 180‐190.

AbstractBackgroundAdults with Down Syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second hallmark of AD and may be measured using tau positron emission tomography (PET) imaging. The pattern of tau accumulation remains unknown in DS.MethodIn a cross‐sectional analysis we evaluated amyloid and tau positron emission tomography (PET) in 124 participants with DS (109 cognitively stable, 8 symptomatic, 7 no consensus), 29 ADAD mutation carriers (26 asymptomatic, 3 symptomatic), and 201 cognitively normal non‐mutation carriers (CN). Regional cortical standard uptake value ratios (SUVR) for tau imaging were obtained and compared by cognitive status. Similarly, regional cortical amyloid SUVR were obtained and converted to centiloids. We then compared the magnitude of tau burden as well as spatial spread of tau across groups relative to amyloid burden.ResultCompared to CN, tau PET binding was elevated in participants with (µDS = 2.12 ± 0.22 SUVR, µADAD = 2.52 ± 0.37 SUVR) and without (µDS = 1.24 ± 0.15 SUVR, µADAD = 1.16 ± 0.19 SUVR) cognitive changes. For both groups, tau increased with increasing amyloid (centiloids). In some regions, DS had greater tau burden for a given amyloid level (centiloids) (Figure 1). There was increased spatial distribution of tau throughout the brain for participants with DS compared to CN. In contrast, tau burden was more focal in participants with ADAD with tau primarily elevated in posterior regions (Figure 2).ConclusionWhile tau burden was higher with symptomatic disease for both groups, significant differences existed in the overall amount and spatial spread. Tau spread was greatest in participants with DS and more diffuse compared to ADAD. These results indicate a substantial tau burden is present in DS, and suggest not only anti‐amyloid but also tau‐reducing agents should be considered for treating cognitive decline in adults with DS.

AbstractBackgroundLoss of function mutations in PINK1 and PRKN are the most common causes of early‐onset Parkinson disease (PD). The encoded ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN together regulate the autophagic degradation of dysfunctional mitochondria, termed mitophagy. During this cytoprotective process, PINK1 and PRKN identify and jointly decorate damaged mitochondria with phosphorylated Ub (pS65‐Ub) that serves as the mitophagy tag. Accumulating evidence suggest a pathogenic role for impaired mitophagy in PD and related neurodegenerative conditions. This is in line with our previous finding of increased levels of the mitophagy marker pS65‐Ub in the hippocampus of postmortem Lewy body disease (LBD) brain.MethodWe performed a genome‐wide association study (GWAS) of hippocampal pS65‐Ub level to identify novel regulators of the PINK1‐PRKN‐directed mitophagy in LBD. In our two‐stage GWAS, we obtained 1,012 autopsy confirmed LBD samples (754 discovery stage, 258, replication stage) from Caucasian participants of European ancestry. Using an established, mostly automated workflow, hippocampal sections were immunostained for pS65‐Ub, scanned, and quantified with unbiased algorithms.ResultOur findings identified that APOE rs429358 (β: 0.50, 95% CI: 0.41 to 0.69, p = 8.67×10−25) was very strongly associated with pS65‐Ub levels in LBD brain. The APOE4 genotype is known to exacerbate Aβ and tau deposition. We did observe strong correlations of pS65‐Ub levels with both tau tangle and senile plaque density in the entire LBD cohort. Nevertheless, the increased pS65‐Ub levels in APOE4‐carrying LBD brains were also independent of Aβ and tau deposition in a subgroup (N = 175) with medium levels of these pathologies. To further explore APOE4 effects on mitophagy outside disease context, this observation was also confirmed in APOE‐targeted replacement mice and in induced pluripotent stem cell‐derived astrocytes.ConclusionOur findings nominate a novel mitophagy regulator in LBD brain and highlight a strong association of APOE4 with mitophagy alteration. Our results suggested that APOE4 may mediate mitophagy defects through two mechanisms, by aggravating Alzheimer’s‐type pathologies and also independent of them. With APOE4 being the strongest known risk factor for Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

BACKGROUND AND OBJECTIVES: Lesions located in the retrosellar region, interpeduncular cistern, and petroclival region are among the most difficult to access in neurosurgery. Transcranial approaches are useful; however, the large distance between the surgeon and the lesion as well as the presence of major neurovascular structures surrounding the lesion may limit surgical exposure. A midline transsphenoidal route avoids transgression of the neurovascular plane and provides direct access to the interpeduncular cistern. To safely access the interpeduncular fossa, it requires mobilization of the pituitary gland. The pituitary hemitransposition technique permits mobilization of the gland, while preserving its venous drainage and arterial supply to the gland on one of its sides, preserving gland function. The authors aim to describe the intradural pituitary hemitransposition technique and to demonstrate its safe application for resection of skull base tumors in the retrosellar space. METHODS: The authors describe the surgical technique and illustrate its application in 5 cases of different types of skull base tumors, including a video demonstrating all the steps to perform this approach. In addition, the authors discuss the advantages and limitations of this technique compared with other approaches to the retrosellar space. RESULTS: The intradural pituitary hemitransposition technique was used to safely resect a chondrosarcoma, chordoma, craniopharyngioma, teratoma, and meningioma involving the parasellar and retrosellar spaces, while minimizing endocrine morbidity. We had one patient with mild, albeit permanent hyperprolactinemia and hypothyroidism after surgery. No other patients had permanent dysfunction related to surgery. CONCLUSION: The endonasal endoscopic intradural pituitary hemitransposition approach is an effective technique for resection of lesions located within the retrosellar and petroclival regions, allowing adequate exposure while potentially optimizing the preservation of the pituitary function.

Abstract Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an estrogen-secreting, 4.3-cm right adrenal mass discovered during work-up for bilateral gynecomastia. Gynecomastia and hyperestrogenism resolved after laparoscopic adrenalectomy, and pathology was reported as adrenocortical adenoma. However, 5 years later, he again developed bilateral gynecomastia because of recurrent hyperestrogenism. Imaging revealed multiple metastases in the abdomen. Urine steroid profiling demonstrated increased androgen precursors, androgen metabolites, and glucocorticoid precursors. Ultrasound-guided biopsy of one of the metastases confirmed ACC. Initial therapy included debulking surgery with removal of metastatic lesions. Mitotane therapy was initiated 4 weeks later along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. Histopathology from the adrenalectomy specimen 5 years earlier was rereviewed and confirmed ACC. Estrogen-secreting adrenal tumors are exceedingly rare, and the majority are malignant. This case underlines the importance of making an initial accurate diagnosis of adrenal malignancy that allows better surgical planning and appropriate monitoring. Indeterminate imaging characteristics of the adrenal mass, as well as the presentation with estrogen excess, suggested an elevated risk for ACC. Initial pathology-based misdiagnosis illustrates the need for an expert adrenal pathologist to review these rare tumors.

Abstract Objectives Recent work has demonstrated that automated fluorescence flow cytometry (FLC) is a potential alternative for the detection and quantification of Plasmodium parasites. The objective of this study was to apply this novel FLC method to detect and quantify Babesia parasites in venous blood and compare results to light microscopy and polymerase chain reaction methods. Methods An automated hematology/malaria analyzer (XN-31; Sysmex) was used to detect and quantify B microti–infected red blood cells from residual venous blood samples (n = 250: Babesia positive, n = 170; Babesia negative, n = 80). As no instrument software currently exists for Babesia, qualitative and quantitative machine learning (ML) algorithms were developed to facilitate analysis. Results Performance of the ML models was verified against the XN-31 software using P falciparum–infected samples. When applied to Babesia-infected samples, the qualitative ML model demonstrated an area under the curve (AUC) of 0.956 (sensitivity, 95.9%; specificity, 83.3%) relative to polymerase chain reaction. For valid scattergrams, the qualitive model achieved an AUC of 1.0 (sensitivity and specificity, 100%), while the quantitative model demonstrated an AUC of 0.986 (sensitivity, 94.4%; specificity, 100%). Conclusions This investigation demonstrates that Babesia parasites can be detected and quantified directly from venous blood using FLC. Although promising, opportunities remain to improve the general applicability of the method.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease associated with non-specific symptoms, which may lead to diagnosis delays and poor outcomes. Research Question: Which symptoms and diagnostic procedures occur prior to PAH diagnosis and do they vary based on diagnosis delay? Aim: To describe PAH symptoms and diagnostic procedures among patients newly diagnosed with PAH. Methods: Adults with PAH were identified from Optum’s de-identified Clinformatics ® Data Mart Database (2016-2021). Eligible patients had continuous health plan enrollment ≥12 months (mo) before the first recorded PAH-related symptoms (i.e., index date ) and from the index date until the first recorded PAH diagnosis on a medical claim (i.e., study period ). Patients also had ≥1 fill for a PAH treatment and ≥1 right heart catheterization at any time post-index. PAH symptoms and diagnostic procedures were described during the study period, overall, and stratified by time between the index date and first PAH diagnosis (i.e., diagnosis delay ; ≤12 mo, 12–24 mo, and >24 mo). Results: The sample included 538 patients (≤12 mo: N=327; 12–24 mo: N=126; >24 mo: N=85). Mean age was 66 years, 60.6% were female, and mean (range) diagnosis delay was 11.8 (0.0–50.2) mo. During the study period, most patients had ≥2 unique symptoms recorded, but those with longer delay had more fatigue (≤12 mo: 26.6%; 12–24 mo: 55.6%; >24 mo: 54.1%), edema (29.1%; 42.9%; 51.8%), and dizziness (10.1%; 23.0%; 18.8%), among others. Mean delay was shorter when the first symptoms were ascites (4.2 mo) and syncope (6.4 mo) and longer for fatigue (14.2 mo) and dizziness (14.0 mo). On average, patients with longer delay had more diagnostic procedures pre-diagnosis (≤12 mo: 4.3; 12–24 mo: 8.2; >24 mo: 8.7), driven by more electrocardiograms (ECG; 1.9; 4.2; 4.5). Overall, 85.5% of patients had an ECG and 83.5% had a transthoracic echocardiography pre-diagnosis. Conclusions: Symptoms such as fatigue, edema, and dizziness were more common in patients with longer time to diagnosis and these patients had more diagnostic procedures. Greater physician awareness and new screening tools (e.g., predictive algorithms using ECG data) could accelerate PAH diagnosis and treatment aiming at improving patient outcomes.