AI-Dentify: deep learning for proximal caries detection on bitewing x-ray - HUNT4 Oral Health Study.

BACKGROUND: Dental caries diagnosis requires the manual inspection of diagnostic bitewing images of the patient, followed by a visual inspection and probing of the identified dental pieces with potential lesions. Yet the use of artificial intelligence, and in particular deep-learning, has the potential to aid in the diagnosis by providing a quick and informative analysis of the bitewing images. METHODS: A dataset of 13,887 bitewings from the HUNT4 Oral Health Study were annotated individually by six different experts, and used to train three different object detection deep-learning architectures: RetinaNet (ResNet50), YOLOv5 (M size), and EfficientDet (D0 and D1 sizes). A consensus dataset of 197 images, annotated jointly by the same six dental clinicians, was used for evaluation. A five-fold cross validation scheme was used to evaluate the performance of the AI models. RESULTS: The trained models show an increase in average precision and F1-score, and decrease of false negative rate, with respect to the dental clinicians. When compared against the dental clinicians, the YOLOv5 model shows the largest improvement, reporting 0.647 mean average precision, 0.548 mean F1-score, and 0.149 mean false negative rate. Whereas the best annotators on each of these metrics reported 0.299, 0.495, and 0.164 respectively. CONCLUSION: Deep-learning models have shown the potential to assist dental professionals in the diagnosis of caries. Yet, the task remains challenging due to the artifacts natural to the bitewing images.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence.

BACKGROUND: The endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)-an enzyme that regulates endocannabinoid signaling-to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. METHODS: This study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9-11 years at Baseline, 11-13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. RESULTS: A significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p's<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p's>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p's>0.05). CONCLUSIONS: Our findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

The association between work-related activities and leisure-time physical activity among Latinos.

OBJECTIVES: Latinos engage in high levels of occupational physical activity, yet low levels of leisure-time physical activity. Limited research has examined specific work-based activities that may contribute to leisure-time physical activity for meeting current physical activity recommendations among Latinos. The purpose of our study was to examine associations between frequency of work-related exertion and standing/walking with meeting the aerobic and muscle-strengthening physical activity guidelines among Latinos and whether associations varied by nativity. DESIGN: We used cross-sectional 2015 National Health Interview Survey data on Latinos ≥18 years of age (n = 3162). Logistic regression models were used to estimate associations between the frequency of work-related activities with meeting the aerobic and muscle-strengthening physical activity guidelines. Models were adjusted for age, sex, education, Latino subpopulation, shift work, and nativity. We also examined whether associations varied by nativity. RESULTS: In adjusted models, compared with those never engaging in exertion at work, participants always exerting themselves were significantly less likely to meet the aerobic activity guideline (Odds Ratio [OR]: 0.66, 95% Confidence Interval [CI]: 0.51-0.87). Compared with those never standing/walking at work, participants seldom standing/walking were also less likely to meet the aerobic activity guideline (OR: 0.57, 95% CI: 0.34, 0.95). Models were adjusted for age, sex, education, Latino subpopulation, shift work, and nativity. When stratified by nativity, the patterns in the strength of the associations were similar, while differences were observed in the associations of work-related activities with meeting guidelines. CONCLUSION: Our findings suggest that engaging in higher frequency of exertion and standing/walking at work are associated with being less likely to meet the aerobic physical activity guideline during leisure time among Latinos, with variation observed in meeting guidelines by nativity. Insight into physical activities performed at work could inform efforts aimed at promoting recommended levels of physical activity among Latinos.

The First "Hit" to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children.

Background: Cannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). Methods: This study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). Results: PCE was associated with lower fractional anisotropy of the right (ß = -0.005, p < .001) and left (ß = -0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. Conclusions: In sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Effects of Different Anticoagulation Doses on Moderate-to-Severe COVID-19 Pneumonia With Hypoxemia.

Background COVID-19 is a prothrombotic disease that can cause thromboembolism and microthrombi, which could lead to multiorgan failure and death. Since COVID-19 is a relatively new disease, there are guidelines for anticoagulation dosing for COVID-19 patients without consensus on the dosing. We studied the effects of different doses of anticoagulation in hospitalized patients with COVID-19 pneumonia and hypoxemia on any differences in need for high-flow oxygen, mechanical ventilation, and mortality. We also analyzed the patient population who benefited most from anticoagulation. Methodology We performed a retrospective chart review of all patients who were admitted with the diagnosis of COVID-19 infection with positive polymerase chain reaction, pneumonia (confirmed either by chest X-ray or CT chest), and hypoxemia (oxygen saturation of <94%, while on room air). These patients were studied for outcomes (the need for high-flow oxygen, the requirement for mechanical ventilation, and overall mortality) for different doses of anticoagulation (prophylactic, escalated, and therapeutic). Results The sample consists of 132 subjects, predominantly males (116, 87%), with a mean age of 59 years and a standard deviation of 15. About one-third of the participants had diabetes, and more than 50% had hypertension. Additionally, 27 (20.3%) had a history of heart disease, and 70 (53%) of the subjects were admitted to the intensive care unit (ICU) at some point during the study. Among those admitted to the ICU, about 11 (8%) subjects required mechanical ventilation and 16 (12%) passed away during the study. Those who died had higher use of high-flow oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation and had a longer stay on mechanical ventilation. There was no significant difference in mortality or need for mechanical ventilation for any strategy of anticoagulation. Conclusions Different doses of anticoagulation did not show any statistically significant relationship between the need for mechanical ventilation and mortality. More patients on high-flow oxygen had received escalated doses of anticoagulation as compared to those who were not on high-flow oxygen. Anticoagulation levels did not have any statistically significant effect on overall survival of patients.

The role of neighborhood social cohesion in the association between seeing people walk and leisure-time walking among Latino adults.

Few studies have investigated the association between seeing people walk and leisure-time walking, and the role of neighborhood social cohesion among Latinos/Latinx. We examined the association between frequency of seeing people walk within sight of home and leisure-time walking, and whether neighborhood social cohesion explained this association. We utilized cross-sectional data from the 2015 National Health Interview Survey from Latinos aged 18+ years (n=4,669). A structural equation model was used to estimate the association between seeing people walk and leisure-time walking, and to test the extent to which neighborhood social cohesion accounted for the association. Findings indicate that there is a strong association between seeing people walk and leisure-time walking, and neighborhood social cohesion partially explains this association among Latinos/Latinx. Neighborhood social cohesion may strengthen efforts focused on neighborhood-level behavioral norms that promote walking.

Carcinoembryonic Antigen, Carbohydrate Antigen 19-9, Cancer Antigen 125, Prostate-Specific Antigen and Other Cancer Markers: A Primer on Commonly Used Cancer Markers.

Cancer markers are molecules produced by cancer cells which may serve to identify the presence of cancer. Cancer markers can be differentiated as serum-based, radiology-based and tissue-based, and are one of the most important tools in diagnosing, staging and monitoring of treatment of many cancers. The most used cancer markers are serum cancer markers due to its relative ease and lower cost of testing. However, serum cancer markers have poor mass screening utilization due to poor positive predictive value. Several markers such as prostate-specific antigen (PSA), beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are used to aid in diagnosis of cancer in cases of high suspicion. Serum markers such as carcinoembryonic antigen (CEA), AFP, carbohydrate antigen 19-9 (CA 19-9), and 5-hydroxyindoleacetic acid (5-HIAA) play a significant role in assessing disease prognosis as well as response to treatment. This work reviews the role of some of the biomarkers in the diagnosis and treatment of cancer.

A case report of haemophilia: a review of haemophilia and oral health implications.

Haemophilia is an inherited haematological disorder that can result in prolonged bleeding in patients. Dental procedures such as extractions and periodontal surgery can be associated with post-operative bleeding; therefore, patients with the diagnosis of haemophilia must have proper medical management. In this article, we aim to illustrate the importance of: having the appropriate knowledge to manage a patient with haemophilia suspected by the dental team; the need for proper medical management; and referral of patients with symptoms of a bleeding disorder.

Impact of Childhood Trauma Exposure, Genetic Variation in Endocannabinoid Signaling, and Anxiety on Frontolimbic Pathways in Children.

Introduction: The endocannabinoid (eCB) system plays a key role in modulating brain development, including myelination processes. Recent studies link a common variant (C385A, rs324420) in the fatty acid amide hydrolase (FAAH) gene to higher circulating eCB levels, lower anxiety, and altered frontolimbic development. Frontolimbic pathways, which demonstrate a protracted maturational course across childhood and adolescence, are associated with anxiety, and are vulnerable to environmental stressors such as trauma exposure. Here, we examined the impact of trauma exposure, FAAH genotype, and anxiety on frontolimbic white matter microstructure in children. Materials and Methods: We leveraged baseline data from the Adolescent Brain Cognitive Development (ABCD) study (n=9969; mean±standard deviation age=9.92±0.62 years; 47.1% female). Saliva samples were used for genotyping, and caregivers reported on their child's anxiety symptoms and trauma exposure. Fractional anisotropy (FA), a nonspecific measure of white matter integrity, was estimated for frontolimbic tracts. Results: Thirty-six percent of youth experienced one or more potentially traumatic events according to DSM-5 Criterion A (64% controls), and 45% were FAAH A-allele carriers (55% noncarriers). Relative to controls, trauma-exposed youth demonstrated higher anxiety and higher FA of the left uncinate. The FAAH A-allele (vs. CC) was associated with lower FA in the left fornix and left parahippocampal cingulum, and there was an indirect effect of FAAH genotype on anxiety through FA of the left fornix. Moreover, genotype moderated the association between FA of the left cingulum and anxiety. Conclusions: Our findings demonstrate distinct effects of trauma exposure and the FAAH C385A variant on frontolimbic pathways and subsequent anxiety risk in preadolescent children. This line of work may provide important insights into neurodevelopmental mechanisms leading to anxiety risk, and potential targets for intervention.

Salt-tolerant bacteria enhance the growth of mung bean (Vigna radiata L.) and uptake of nutrients, and mobilize sodium ions under salt stress condition.

Salinity is one of the significant abiotic stresses that exert harmful effects on plant growth and crop production. It has been reported that the harmfulness of salinity can be mitigated by the use of salt-tolerant plant growth-promoting (PGP) bacteria. In this study, four bacteria were selected from a total of 30 cultures, based on salt-tolerant and PGP properties. The isolates were found to produce indole acetic acid (8.49-19.42 µg/ml), siderophore (36.04-61.77%), and solubilize potassium and inorganic phosphate. Identification based on 16S rRNA gene sequencing revealed that the isolates belonged to Cronobacter (two isolates) and Enterobacter (two isolates). Inoculation of PGP bacteria under 2 and 10% salinity stress showed enhanced plant growth parameters in Vigna radiata compared to both salinity and non-salinity control plants. The rate of germination (113.32-206.64%), root length (128.79-525.31%), shoot length (34.09-50.32%), fresh weight, and dry weight were 3-fold higher in bacteria-treated seeds than control plants. The estimation of chlorophyll (1-5-fold), carotenoids (1-4-fold), and proline content (3.65-14.45%) was also higher compared to control plants. Further, the bacterized seeds showed enhanced nitrogen and phosphorous uptake and mobilized sodium ions from roots to leaves. Overall the strains SS4 and SS5 performed well in both 2 and 10% salt-amended soils. These strains could be formulated as a bioinoculant to mitigate the salinity stress in salinized soils.

Salinity severely affects the growth and productivity of Vigna radiate (mung bean) worldwide. Approximately 50 mM concentration of NaCl can cause >60% yield loss of mung bean. In this study, inoculation of salt-tolerant root nodule-associated plant growth-promoting bacteria showed 2­3-fold enhancements in mung bean plant growth, biomass, and physiology even at 2 and 10% salinity stress. Further, the inoculated mung bean plants showed an increment in the uptake of nitrogen and phosphorous in the salinized conditions and mobilized the Na⁺ ions from root to shoot to reduce the toxicity posed by Na⁺ ions. Therefore the strains identified in this study could be formulated to mitigate the salinity stress and improve the mung bean growth in salinized soils.

Shared cis-regulatory modules control expression of the tandem paralogs midline and H15 in the follicular epithelium.

The posterior end of the follicular epithelium is patterned by midline (MID) and its paralog H15, the Drosophila homologs of the mammalian Tbx20 transcription factor. We have previously identified two cis-regulatory modules (CRMs) that recapitulate the endogenous pattern of mid in the follicular epithelium. Here, using CRISPR/Cas9 genome editing, we demonstrate redundant activity of these mid CRMs. Although the deletion of either CRM alone generated marginal change in mid expression, the deletion of both CRMs reduced expression by 60%. Unexpectedly, the deletion of the 5' proximal CRM of mid eliminated H15 expression. Interestingly, expression of these paralogs in other tissues remained unaffected in the CRM deletion backgrounds. These results suggest that the paralogs are regulated by a shared CRM that coordinates gene expression during posterior fate determination. The consistent overlapping expression of mid and H15 in various tissues may indicate that the paralogs could also be under shared regulation by other CRMs in these tissues.

Cervical cancer prevention: Human papillomavirus testing as primary screening.

Low- and middle-income countries carry a high burden of preventable cervical cancer cases and deaths. Because human papillomavirus DNA-based testing is increasingly becoming the preferred method of screening for cervical cancer prevention, this commentary discusses next steps and key considerations for its expansion.

A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System.

Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.

Bimodal Age Distribution in Cancer Incidence.

Cancer is caused by accumulation of genetic changes which include activation of protooncogenes and loss of tumor suppressor genes. The age-specific incidence of cancer in general increases with advancing age. However, some cancers exhibit a bimodal distribution. Commonly recognized cancers with bimodal age distribution include acute lymphoblastic leukemia, osteosarcoma, Hodgkin's lymphoma, germ cell tumors and breast cancer. Delayed infection hypothesis has been used to provide explanation for the early childhood peak in leukemias and lymphomas, whereas the peak at an older age is associated with accumulation of protooncogenes and weakened immune system. Further genetic analysis and histopathological variations point to distinctly different cancers, varying genetically and histologically, which are often combined under a single category of cancers. Tumor characteristics and age distribution of these cancers varies also by population groups and has further implications on cancer screening methods. Although significant advances have been made to explain the bimodal nature of such cancers, the specific genetic mechanisms for each age distribution remain to be elucidated. Further distinction among the different cancer subtypes may lead to improvements in individual risk assessments, prevention and enhancement of treatment strategies.

A Comparison of the Pulmonary Valve, Main Pulmonary Artery, and Branch Pulmonary Artery Measurements by Echocardiography and Computed Tomography Scan.

INTRODUCTION: Congenital heart diseases (CHD) are one of the most commonly occurring congenital anomalies. Echocardiography is usually the initial investigation for suspected CHD. However, it is operator-dependent and limited by available chest windows. Multidetector computed tomography (MDCT) scan provides superior temporal and spatial resolution producing excellent cross-sectional anatomical images. MDCT is specifically helpful for pulmonary artery anomalies if not clearly visible on an echocardiogram. OBJECTIVE AND METHODS: The study aims to compare measurements of branch pulmonary arteries, pulmonary valve, and main pulmonary artery obtained from trans-thoracic echocardiography measurements and MDCT. Forty-nine patients younger than 17 years of age underwent MDCT, and an echocardiogram was included in the study. The measurements of the pulmonary valve, main pulmonary artery, and branch pulmonary arteries were measured on MDCT and echocardiogram. RESULTS: Bland-Altman analysis revealed the mean difference (95% confidence limits) in measurements of diameter between echocardiogram and MDCT for the right pulmonary artery, left pulmonary artery, pulmonary valve, and main pulmonary artery, which were -0.5 (-3.1, 2.2) mm, -0.6 (-3.3, 2.1) mm, 0.7 (-2.5, 3.9) mm, and 1.2 (-6.9, 4.5) mm, respectively. CONCLUSION:  The analysis revealed acceptable agreement in measurements of the pulmonary valve, main pulmonary artery, and branch pulmonary arteries obtained from MDCT and echocardiogram. The difference was marginally more for the main pulmonary artery compared to the pulmonary valve and branch pulmonary arteries.

Testicular Pain and Mesenteric Adenitis as an Atypical Presentation of COVID-19.

A 21-year-old Caucasian male with no past medical history presented to the emergency department with right lower quadrant pain radiating to the right testicle for two days. He reported an occasional dry cough that day but denied any fever or other infectious symptoms. The patient was afebrile with a normal physical examination. CT of the abdomen and pelvis showed prominent right lower quadrant lymphadenopathy. Viral panel for common respiratory pathogens returned negative. A nasopharyngeal swab for SARS-CoV-2 by Xpert® Xpress SARS-CoV-2 reverse transcriptase-polymerase chain reaction (Cepheid Inc., Sunnyvale, CA) was positive. The patient remained in quarantine for 14 days. He was reevaluated seven weeks later with spontaneous resolution of his abdominal pain and the continued absence of upper respiratory symptoms. A repeat CT scan seven weeks later showed persistent mesenteric lymphadenopathy. Repeat COVID-19 testing was not performed at this time. While the frequency of atypical presentation of COVID-19 remains unknown, healthcare providers must continue to remain vigilant and consider COVID-19 as a differential diagnosis in any patient presenting to the emergency department despite the lack of respiratory and gastrointestinal symptoms. Further research is warranted to examine the possibility of asymptomatic spread in asymptomatic patients with persistent radiologic findings and to assess whether repeat COVID-19 testing is warranted in such patients.

Thrombocytopenia in Chronic Liver Disease: Challenges and Treatment Strategies.

Thrombocytopenia is a common hematologic complication seen in patients with chronic liver disease (CLD). The pathophysiology of thrombocytopenia in CLD is multifactorial, primarily stemming from platelet sequestration and decreased platelet production. This review focuses on the pathophysiology and current treatment options in the treatment of thrombocytopenia in chronic liver disease. While platelet transfusions are the gold standard of treatment, considerations ought to be given to CLD patients who can benefit from transjugular intrahepatic portosystemic shunt and splenic artery embolization. Finally, the recent approval of thrombopoietin receptor agonists for use in CLD patients paves a way for a safe and effective alternative method of improving platelet levels and reducing the need for recurrent platelet transfusions.

Prolonged Self-Resolving Neutropenia Following Asymptomatic COVID-19 Infection.

Multiple hematologic complications have been reported as a result of the novel coronavirus disease 2019 (COVID-19) infection. These include leukopenia, lymphopenia, thrombocytopenia as well as increased risk of venous thromboembolism. Neutropenia is a relatively uncommon finding, especially in asymptomatic patients with no other evidence of systemic infection. A young, healthy male undergoing training for the Navy was admitted with rhabdomyolysis following intense physical activity. He was incidentally noted to have severe neutropenia with the white blood cell (WBC) count of 2.1 × 109/L and an absolute neutrophil count (ANC) of 355 cells/µL one month following prior asymptomatic COVID-19 infection. Further evaluation was negative for other infectious processes, nutritional deficiency, or underlying malignancy. Given young age without comorbidities and lack of febrile illness, watchful waiting was recommended in lieu of bone marrow biopsy which resulted in spontaneous resolution of neutropenia and normalization of WBC. The authors argue that although most hematologic complications of COVID-19 are reported in symptomatic patients, asymptomatic patients also appear to have a risk of developing hematologic complications including bone marrow suppression. Watchful waiting may be an appropriate diagnostic approach in such young, healthy individuals.

Iatrogenic Kaposi Sarcoma Precipitated by Anti-Tumor Necrosis Factor-Alpha (Anti-TNF-α) Therapy.

Kaposi sarcoma (KS) is a vascular neoplasm caused by human gammaherpesvirus 8 (HHV-8). Four subtypes of KS are described: classic (Mediterranean), epidemic (acquired immunodeficiency syndrome (AIDS)-associated), endemic (sub-Saharan Africa), and iatrogenic. Iatrogenic KS due to tumor necrosis factor-alpha (TNF-α) inhibitor therapy is particularly rare. A 66-year-old female with a history of seropositive rheumatoid arthritis (RA) presented with a skin lesion on her right second toe. Diagnosed with RA four years prior, she failed to respond to methotrexate, hydroxychloroquine, and etanercept. As a result, she was started on adalimumab. Approximately two months into therapy, she presented to the emergency room with a dark brown skin lesion on her right second toe. She underwent excisional biopsy of the mass, which demonstrated a tumor composed of spindle cells forming slit-like spaces with extravasated red blood cells. The tumor was positive for cluster of differentiation 31 (CD31), CD34, and HHV-8 immunostains and negative for smooth muscle antibody (SMA) and desmin immunostains, consistent with Kaposi sarcoma. Human immunodeficiency virus (HIV) serology was negative. The patient was diagnosed with iatrogenic KS. Adalimumab was discontinued. The patient was started on alitretinoin and underwent adjuvant radiation therapy to minimize recurrence. TNF-α is a pro-inflammatory cytokine that has been implicated in many inflammatory diseases and in cell apoptosis. While anti-TNF-α agents have improved outcomes in many immune-mediated diseases, higher rates of infections and malignancy have also been reported. The incidence of KS with anti-TNF-α therapy remains a rare entity. Therefore, it is extremely important for patients receiving biologic agents, including TNF-α inhibitors, to have a close follow-up and receive routine skin evaluation for malignancy. Clinicians should have a high index of suspicion for KS in such non-HIV patients started on immunosuppressive agents.

A Study of Proton Pump Inhibitors and Other Risk Factors in Warfarin-Associated Gastrointestinal Bleeding.

Background Warfarin users are at increased risk for gastrointestinal bleeding (GIB). History of GIB, stroke, cardiovascular or chronic kidney disease, age greater than 65 years, and drug interaction with proton pump inhibitors (PPI) have previously been identified as risk factors for GIB in warfarin users. We hypothesized that concomitant use of warfarin and PPI would increase the incidence of GIB relative to warfarin use alone. Methods We did a retrospective review of medical records of 626 patients taking warfarin for at least two weeks. Parameters including age, concomitant medication use (non-steroidal anti-inflammatory drugs (NSAID), aspirin, selective serotonin reuptake inhibitors (SSRIs), PPI, and anti-platelet drug), history of GIB, chronic renal failure (CRF), and peptic ulcer disease (PUD) prior to warfarin use were analyzed. Results Variables that increase the likelihood of bleeding in warfarin users included aspirin, PPI, history of PUD, history of previous GIB, CRF, and elevated prothrombin time (PT)/international normalized ratio (INR) values. Concomitant antiplatelet use showed a slight increase in GIB but this was not statistically significant (p=0.082). NSAID use and SSRI use were not associated with a higher risk of GIB among warfarin users. Patients who are on PPI and warfarin simultaneously are more likely to be on acetylsalicylic acid (ASA) or have a history of PUD, GIB, or CRF, all of which are associated with increased incidences of GIB. Conclusions Although concomitant use of warfarin and PPI appears to be associated with an increased incidence of GIB, these patients are more likely to have other risk factors that also increase the risk of a GIB outcome. Therefore, the interaction between PPI and warfarin is clinically insignificant.