Pulmonary vein thrombosis: Clinical presentation and outcomes.

BACKGROUND: Pulmonary vein thrombosis (PVT) is a rare thromboembolic disease with potential high-risk complications related to arterial embolization, but little is known regarding risk factors and outcomes. OBJECTIVE: To describe the etiology, management, and clinical course of PVT. METHODS: Institutional health records were queried (1/1/2001-12/30/2023) to identify patients ≥18 years of age diagnosed with PVT. Thrombosis, bleeding, respiratory failure, and all-cause mortality were analyzed. Suspected tumor thrombus cases were excluded. RESULTS: 72 patients with PVT were identified (median age 62 years, 50 % female), and PVT was overall rare at 3.1 diagnosed cases per year at our institution. PVT primarily affected a single vein (89 %), most commonly the left upper PV (40 %). Of these, 37 % occurred while on therapeutic anticoagulation. The most common risk factors included cancer (55 %) and related surgical lobectomy (21 %). Extrinsic vein compression (17 %) and recent surgery (19 %) were also common; 19 % were deemed idiopathic. Most patients (76 %) were treated with anticoagulation and frequently indefinite duration (80 %). During a median follow-up of 11.7 months (IQR 39.5 months), serial imaging (available for 68 %) revealed PVT resolution in 64 %. Four-year Kaplan-Meier probability of outcome included: left atrial thrombus (21 %), need for mechanical ventilation (14 %), pneumonia (9 %), and ischemic stroke (9 %). The mortality rate was 46 % with median survival 14 months after PVT diagnosis. CONCLUSION: PVT is often associated with active malignancy, lobectomy, recent surgery, and extrinsic vein compression; 1 in 5 cases were idiopathic. Notable complications include left atrial thrombus with arterial embolism including stroke. With anticoagulation, most thrombi resolve over time. Mortality rates are high, reflecting the high the prevalence of cancer.

Arrhythmic manifestations and outcomes of definite and probable cardiac sarcoidosis.

BACKGROUND: The 2014 Heart Rhythm Society consensus statement defines histological (definite) and clinical (probable) diagnostic categories of cardiac sarcoidosis (CS), but few studies have compared their arrhythmic phenotypes and outcomes. OBJECTIVE: The purpose of this study was to evaluate the electrophysiological/arrhythmic phenotype and outcomes of patients with definite and probable CS. METHODS: We analyzed the arrhythmic/electrophysiological phenotype in a single-center North American cohort of 388 patients (median age 56 years; 39% female, n = 151) diagnosed with definite (n = 58) or probable (n = 330) CS (2000-2022). The primary composite outcome was survival to first ventricular tachycardia/fibrillation (VT/VF) event or sudden cardiac death. Key secondary outcomes were also assessed. RESULTS: At index evaluation, in situ cardiac implantable electronic devices and antiarrhythmic drug use were more common in definite CS. At a median follow-up of 3.1 years, the primary outcome occurred in 22 patients with definite CS (38%) and 127 patients with probable CS (38%) (log-rank, P = .55). In multivariable analysis, only a higher ratio of the 18F-fluorodeoxyglucose maximum standardized uptake value of the myocardium to the maximum standardized uptake value of the blood pool (hazard ratio 1.09; 95% confidence interval 1.03-1.15; P = .003, per 1 unit increase) was associated with the primary outcome. During follow-up, patients with definite CS had a higher burden of device-treated VT/VF events (mean 2.86 events per patient-year vs 1.56 events per patient-year) and a higher rate of progression to heart transplant/left ventricular assist device implantation but no difference in all-cause mortality compared with patients with probable CS. CONCLUSION: Patients with definite and probable CS had similarly high risks of first sustained VT/VF/sudden cardiac death and all-cause mortality, though patients with definite CS had a higher overall arrhythmia burden. Both CS diagnostic groups as defined by the 2014 Heart Rhythm Society criteria require an aggressive approach to prevent arrhythmic complications.

Improving colorectal cancer screening disparities among Somali-speaking patients in an Internal Medicine Residency Clinic.

Colorectal cancer (CRC) is the third-most lethal cancer in the USA, and early detection through screening is crucial for improving outcomes. However, significant disparities in access and utilisation of CRC screening exist among patients with limited English proficiency. Our Quality Improvement (QI) team developed and implemented a video, featuring a Somali-speaking physician, created with input from internal medicine (IM) residents, patient education experts and community leaders to increase the rate of CRC screening uptake within a Somali-speaking population receiving primary care within an IM Residency Clinic. The baseline proportion of average-risk Somali-speaking patients who had successfully been screened for CRC was 46.3% (63/134). The proportion of patients agreeable to undergo CRC screening was assessed monthly from the beginning of video implementation (June 2022 to December 2022). We found that this intervention corresponded with a significant increase in willingness to undergo CRC screening from 36.4% to 100% during the early stages of intervention. At the end of our measurement timeframe, the proportion of the original population fully screened for CRC was 50.7% (68/134). Implementation of the video intervention was also assessed and determined to be minimally disruptive to the clinic flow.

Clinical Response to Tumor Necrosis Factor-α Inhibitor Therapy in the Management of Cardiac Sarcoidosis.

Evidence that tumor necrosis factor-α (TNF-α) inhibitors may benefit patients with cardiac sarcoidosis (CS) is limited to small case series and both imaging and clinical outcomes in this population are not well known. This study aimed to evaluate the disease course of patients with CS treated with either infliximab or adalimumab therapy based on serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and clinical outcomes. An institutional CS research database was queried for patients treated with TNF-α inhibitors between 2016 and 2021. Outcomes included (1) change in mean prednisone dose, (2) FDG-PET improvement, and (3) unplanned hospitalizations, advanced heart failure therapies, or death. Our query yielded 31 patients with CS. A total of 13 patients were on infliximab, 15 patients were on adalimumab, and 3 patients were on adalimumab before transitioning to infliximab. Mean prednisone dose decreased between FDG-PET immediately preceding TNF-α and second after TNF-α FDG-PET (18.6 ± 15.7 mg to 7.7 ± 12.4 mg, p = 0.018). A significant decrease was seen in the mean number of segments demonstrating FDG uptake between most recent pre-TNF-α and first after TNF-α inhibitor FDG-PET (mean segments = 4.2 vs 3.1, p = 0.048). Between earliest pre-TNF-α and first after TNF-α FDG-PET there was a numerical decrease in average myocardial maximum standard uptake values (SUVmax) (4.4 vs 3.1, p = 0.18), and the ratio of SUVmax myocardium:SUVmax blood pool (1.9 vs 1.5, p = 0.26). Within 36 months of initiating TNF-α inhibitor, 4 patients (13%) experienced unplanned cardiovascular hospitalization (median time to hospitalization = 12.1 months). In conclusion, in patients with CS, TNF-α inhibitor therapy is associated with decreased glucocorticoid use, numerical decrease in cardiac FDG uptake, and minimal cardiac morbidity.

Limb and cardiovascular event risk in type 1 and 2 diabetic patients with peripheral artery disease.

Background: Peripheral artery disease (PAD) is a risk factor for adverse limb events (LE) and cardiovascular events (CVE) that coexists with type 1 (T1) and 2 (T2) diabetes mellitus (DM). Little is known about comparative risk of LE and CVE in T1/T2 DM patients with PAD. Patients and methods: We queried our database of 40,144 patients ≥18 years old who underwent ankle brachial index (ABI) measurement from 01/1996-02/2020. We isolated T1/T2 DM patients with PAD diagnosed by ankle brachial index (ABI; low [<1.0] or elevated [>1.4]) and retrieved demographics including glycated hemoglobin (HbA1c). Primary outcomes were LE (critical limb ischemia/vascular amputation) and CVE (myocardial infarction/ischemic stroke). All-cause mortality was a secondary outcome. Multivariable Cox proportional regression yielded hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for pertinent risk factors including age, hypertension, hyperlipidemia, smoking, and HbA1c. Results: Our study found 10,156 patients with PAD and DM (34% T1DM, 66% T2DM) with median follow-up time 34 mo (IQR 85 mo). T1DM patients were younger than T2DM (mean age 67 vs. 70 years), with higher median HbA1c (7.7 [IQR 1.9] vs. 6.7% [IQR 1.6]), and more prevalent hypertension, hyperlipidemia, CAD, and CKD. Antiplatelet and statin use was equivocal. Elevated ABI was more common in T1DM (47 vs. 28%). LE occurred in 23% and CVE in 12% patients. LE risk was higher in T1 than T2 DM patients (HR 1.58 [95% CI 1.44, 1.73], p<0.0001), but CVE and all-cause mortality were equivocal. These observations were preserved across ABI and HbA1c subgroup analyses. Conclusions: PAD patients with T1DM had a higher LE risk than those with T2DM, even after adjustment for glycemic control and pertinent risk factors, but CVE risk and all-cause mortality were equivocal. These data suggest a potential role for more intensive LE risk modification in PAD patients with T1DM, but further investigation is needed.

Incidentally Discovered Right Atrial Mass: A Rare and Unexpected Etiology.

Primary cardiac sarcoma is a rare type of intracardiac mass. This report describes a patient with atrial flutter who had a new right atrial mass incidentally discovered on transesophageal echocardiography. A thrombus was suspected based on radiographic appearance, but there was minimal change with anticoagulation. The mass was resected and found to be an undifferentiated pleomorphic cardiac sarcoma, an uncommon sub-type within the already rare category of primary cardiac neoplasms. This report highlights the importance of considering primary malignancy and thoroughly correlating radiographic and clinical evidence during the diagnostic workup of patients with intracardiac masses.

The Mechanism and Natural History of Mitral Regurgitation in Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is an infl/ammatory cardiomyopathy that can present with mitral regurgitation (MR), but few studies describe the mechanisms and natural history of MR in CS. We queried an institutional registry of 512 patients with CS for moderate or greater MR at diagnosis. Baseline demographic and echocardiography (TTE) data were collected. MR was classified by Carpentier type. Positron emission tomography was analyzed for 2-deoxy-2-[fluorine-18] fluoro-d-glucose (FDG) avidity of anterolateral and posteromedial papillary muscles. Follow-up TTE and positron emission tomography imaging of patients treated with immunosuppression was analyzed for MR severity and FDG avidity changes. Fifty-four patients were identified. Mean left ventricular ejection fraction was 39.3%, effective regurgitant orifice 0.34 cm2, and MR regurgitant volume 46.3 ml. Carpentier type I was the most common MR mechanism (46.3%). Forty-one patients had follow-up TTE (median follow-up 1.7 years, interquartile range 2.6 years). Evaluating preprocedural follow-up TTE only, MR severity was significantly reduced, with 37% of patients showing reduction by at least 1 severity grade (p = 0.04). With postprocedural TTE included, 61% of patients showed alleviation of MR severity with mean decrease in grade - 0.98 (p <0.001). Sixty-eight percent of patients had anterolateral/posteromedial FDG avidity. Papillary muscle FDG avidity resolved in 80% of patients (n = 20, median follow-up 1.6 years, interquartile range 2.5 years). In conclusion, Carpentier type I functional MR is the most common MR mechanism in CS. MR severity and papillary muscle FDG avidity decrease after treatment, and MR resolution is further strengthened by procedural intervention in a minority of patients, suggesting an overall favorable natural history of MR in CS.

Peripheral artery disease and the risk of venous thromboembolism.

Background: Peripheral artery disease (PAD) impacts 3-12% of patients worldwide and is characterized by endothelial dysfunction and inflammatory pathways which are also common to venous thromboembolism (VTE), but there is a paucity of evidence regarding VTE risk in PAD patients. We investigated whether PAD is an independent risk factor for VTE. Patients and methods: We reviewed medical records of patients undergoing ABI studies at Mayo Clinic from 01/1996-02/2020. We classified patients by ABI (low [<1.0], normal [1.0-1.4], or elevated [>1.4]), as well as by specific low ABI subgroup: severely reduced (ABI: 0.00-0.39), moderately reduced (0.40-0.69), mildly reduced (0.70-0.90), and borderline reduced (0.91-0.99). The primary outcome was incident VTE event (acute lower extremity deep vein thrombosis or pulmonary embolism) after ABI measurement. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, active smoking, cancer, previous VTE, thrombophilia, anticoagulation, and revascularization. Results: 39,834 unique patients (mean age 66.3±14.3 years, median follow-up 34 months) were identified. 2,305 VTE events occurred in patients without PAD (13.0%), 2,218 in low ABI patients (13.0%), and 751 in elevated ABI patients (14.8%). After risk factor adjustment, VTE risk was modestly increased for PAD overall (HR: 1.12, 95% CI [1.06, 1.18]), including low ABI (HR: 1.11, 95% CI [1.04, 1.18]) and elevated ABI groups (HR: 1.15, 95% CI [1.04, 1.26]), compared to patients without PAD. The greatest VTE risk was in severely low ABI patients (HR: 1.46, 95% CI [1.31, 1.64]). Conclusions: In a large longitudinal cohort, we present strong clinical evidence of PAD, with low and elevated ABI, as an independent VTE risk factor, with the highest risk seen in patients with severely low ABI. Continued research is required to further investigate this relationship and its intersection with functional performance status to optimize VTE risk reduction or anticoagulation strategies in the PAD population.

Patient Age at Diagnosis of Peripheral Artery Disease and Its Impact on Cardiovascular and Limb Outcomes.

Peripheral artery disease (PAD) prevalence increases with age, but the relation between age at PAD diagnosis and outcomes is unclear. We investigated the cardiovascular and limb outcomes of patients diagnosed with PAD at different ages. We studied patients with PAD aged ≥18 years who were diagnosed between 1996 and 2020 at Mayo Clinic. Patients were grouped by diagnosis age (<50, 50 to 59, 60 to 69, ≥70 years) and ankle brachial index (ABI): low ABI (<1.0) or elevated ABI (>1.4). Primary outcomes were cardiovascular events (CVEs; myocardial infarction or ischemic stroke) and limb events (LEs; critical limb ischemia or amputation). Competing risk analysis was performed to calculate adjusted hazard ratios. The cohort included 22,073 patients with PAD (low ABI: 77.1%; elevated ABI: 22.9%). CVEs were observed in 8.2% of patients and LEs in 15.6%. The highest CVE risk was observed in patients diagnosed with PAD before age 50 (compared with patients diagnosed after age 70; hazard ratio 2.33 [95% confidence interval 1.95 to 2.78]). CVE risk decreased with older age at diagnosis. Although younger groups demonstrated higher LE risk, there was no clear association with diagnosis age. These patterns of risk were seen both in low and elevated ABI subgroups but in greater magnitude with elevated ABI. Younger patients diagnosed with PAD face increased risk of myocardial infarction and ischemic stroke compared with patients diagnosed at an older age. CVE risk notably exceeds LE risk. In conclusion, younger age at PAD diagnosis may be an important risk factor, which warrants more aggressive interventions focused on CVE prevention.

An Agitated Patient With COVID-19 Infection and Early-onset Alzheimer Disease.

Encephalopathy, delirium, and agitation are documented symptoms of coronavirus disease (COVID-19) infection, but research into the management of agitation in the setting of COVID-19 and pre-existing neuropsychiatric disease is ongoing. We present a 55-year-old male patient with early-onset Alzheimer disease and deteriorating mental and functional status who presented to our institution with agitation and persistent COVID-19 positivity on polymerase chain reaction testing. His agitation was improved through pharmacologic optimization including the avoidance of benzodiazepines and initiation of clonidine and prazosin, which temporally coincided with the resolution of his nearly 2-month long COVID-19 positivity.

Morphological features of single cells enable accurate automated classification of cancer from non-cancer cell lines.

Accurate cancer detection and diagnosis is of utmost importance for reliable drug-response prediction. Successful cancer characterization relies on both genetic analysis and histological scans from tumor biopsies. It is known that the cytoskeleton is significantly altered in cancer, as cellular structure dynamically remodels to promote proliferation, migration, and metastasis. We exploited these structural differences with supervised feature extraction methods to introduce an algorithm that could distinguish cancer from non-cancer cells presented in high-resolution, single cell images. In this paper, we successfully identified the features with the most discriminatory power to successfully predict cell type with as few as 100 cells per cell line. This trait overcomes a key barrier of machine learning methodologies: insufficient data. Furthermore, normalizing cell shape via microcontact printing on self-assembled monolayers enabled better discrimination of cell lines with difficult-to-distinguish phenotypes. Classification accuracy remained robust as we tested dissimilar cell lines across various tissue origins, which supports the generalizability of our algorithm.

Abnormal vascular physiology in the lower extremities as a risk factor for ischemic stroke and mortality.

CONTEXT: Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. OBJECTIVES: To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. METHODS: We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. RESULTS: A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10-1.35]) and severe (HR, 1.19 [95% CI, 1.02-1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15-1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88-3.27]). CONCLUSIONS: This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

3D mesenchymal cell migration is driven by anterior cellular contraction that generates an extracellular matrix prestrain.

We describe a cellular contractile mechanism employed by fibroblasts and mesenchymal cancer cells to migrate in 3D collagen gels. During 3D spreading, fibroblasts strongly deform the matrix. They protrude, polarize, and initiate migration in the direction of highest extracellular matrix (ECM) deformation (prestrain). This prestrain is maintained through anterior cellular contractions behind the leading edge prior to protrusion, coordinating a distinct 3D migration cycle that varies between cell types. Myosin IIA is required for strain polarization, generating anterior contractions, and maintaining prestrain for efficient directional cell migration. Local matrix severing disrupts the matrix prestrain, suppressing directional protrusion. We show that epithelial cancer and endothelial cells rarely demonstrate the sustained prestrain or anterior contractions. We propose that mesenchymal cells sense ECM stiffness in 3D and generate their own matrix prestrain. This requires myosin IIA to generate polarized periodic anterior contractions for maintaining a 3D migration cycle.

Synthetic Tuning of Domain Stoichiometry in Nanobody-Enzyme Megamolecules.

This paper presents a method to synthetically tune atomically precise megamolecule nanobody-enzyme conjugates for prodrug cancer therapy. Previous efforts to create heterobifunctional protein conjugates suffered from heterogeneity in domain stoichiometry, which in part led to the failure of antibody-enzyme conjugates in clinical trials. We used the megamolecule approach to synthesize anti-HER2 nanobody-cytosine deaminase conjugates with tunable numbers of nanobody and enzyme domains in a single, covalent molecule. Linking two nanobody domains to one enzyme domain improved avidity to a human cancer cell line by 4-fold but did not increase cytotoxicity significantly due to lowered enzyme activity. In contrast, a megamolecule composed of one nanobody and two enzyme domains resulted in an 8-fold improvement in the catalytic efficiency and increased the cytotoxic effect by over 5-fold in spheroid culture, indicating that the multimeric structure allowed for an increase in local drug activation. Our work demonstrates that the megamolecule strategy can be used to study structure-function relationships of protein conjugate therapeutics with synthetic control of protein domain stoichiometry.

Increased Inpatient Length of Stay After Early Unplanned Transfer to Higher Levels of Care.

Patients admitted to a medical-surgical unit infrequently require early transfer to higher level care, although how their inpatient length of stay compares to untransferred patients, or those directly admitted to intermediate care, is unknown. We sought to compare the inpatient length of stay of these groups. DESIGN: Single-site retrospective analysis. SETTING: An academic hospital specializing in complex care. PATIENTS: We evaluated 23,694 patients admitted to the Hospital Internal Medicine service over a 4-year period (January 1, 2013, to December 31, 2016). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using 6- and 24-hour definitions of early transfer, we categorized patients as admitted to medical-surgical unit without early transfer (medical-surgical unit), transferred (TX) early to higher level care, or initially admitted to an intermediate care unit. We report patient characteristics and inpatient length of stay adjusted for patient demographics (age and sex) and initial acuity (measured by Emergency Severity Index). There were significant increases in both unadjusted inpatient length of stay (6 hr: medical-surgical unit = 73.4 hr, TX = 137.9 hr, intermediate care unit = 101.1 hr; 24 hr: medical-surgical unit = 72.4 hr, TX = 141.9 hr, intermediate care unit = 98.2 hr; p < 0.01 for all groups) and adjusted inpatient length of stay (6-hr definition: medical-surgical unit = 50.9 hr [95% CI, 50.3-51.6 hr], TX = 100.4 hr [90.4-112.0 hr], intermediate care unit = 72.3 hr [70.6-74.0 hr]; 24-hr definition: medical-surgical unit = 50.3 hr [49.7-50.9 hr], TX = 108.3 hr [101.5-116.0 hr], intermediate care unit = 70.7 hr [69.0-72.3 hr]; p < 0.0001 for comparison of TX to medical-surgical unit and intermediate care unit in both groups). The increases in inpatient length of stay for the TX groups were not explained by differences in demographics or acuity. CONCLUSIONS: In a single facility study, patients admitted to a medical/surgical unit who require early transfer to intermediate care unit have a significant and unexplained increase in inpatient length of stay. This unexplained increased inpatient length of stay suggests that triage to the appropriate inpatient unit significantly affects inpatient length of stay.

Using Peptide Arrays to Profile Phosphatase Activity in Cell Lysates.

Phosphorylation is an important post-translational modification on proteins involved in many cellular processes; however, understanding of the regulation and mechanisms of global phosphorylation remains limited. Herein, we utilize self-assembled monolayers on gold for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) with three phosphorylated peptide arrays to profile global phosphatase activity in cell lysates derived from five mammalian cell lines. Our results reveal significant differences in the activities of protein phosphatases on phospho- serine, threonine, and tyrosine substrates and suggest that phosphatases play a much larger role in the regulation of global phosphorylation on proteins than previously understood.