Telehealth use during the early COVID-19 public health emergency and subsequent health care costs and utilization.

Telehealth utilization increased during the COVID-19 pandemic, yet few studies have documented associations of telehealth use with subsequent medical costs and health care utilization. We examined associations of telehealth use during the early COVID-19 public health emergency (March-June 2020) with subsequent total medical costs and health care utilization among people with heart disease (HD). We created a longitudinal cohort of individuals with HD using MarketScan Commercial Claims data (2018-2022). We used difference-in-differences methodology adjusting for patients' characteristics, comorbidities, COVID-19 infection status, and number of in-person visits. We found that using telehealth during the stay-at-home order period was associated with a reduction in total medical costs (by -$1814 per person), number of emergency department visits (by -88.6 per 1000 persons), and number of inpatient admissions (by -32.4 per 1000 persons). Telehealth use increased per-person per-year pharmacy prescription claims (by 0.514) and average number of days' drug supply (by 0.773 days). These associated benefits of telehealth use can inform decision makers, insurance companies, and health care professionals, especially in the context of disrupted health care access.

Association of Economic Policies With Hypertension Management and Control: A Systematic Review.

Importance: Economic policies have the potential to impact management and control of hypertension. Objectives: To review the evidence on the association between economic policies and hypertension management and control among adults with hypertension in the US. Evidence Review: A search was carried out of PubMed/MEDLINE, Cochrane Library, Embase, PsycINFO, CINAHL, EconLit, Sociological Abstracts, and Scopus from January 1, 2000, through November 1, 2023. Included were randomized clinical trials, difference-in-differences, and interrupted time series studies that evaluated the association of economic policies with hypertension management. Economic policies were grouped into 3 categories: insurance coverage expansion such as Medicaid expansion, cost sharing in health care such as increased drug copayments, and financial incentives for quality such as pay-for-performance. Antihypertensive treatment was measured as taking antihypertensive medications or medication adherence among those who have a hypertension diagnosis; and hypertension control, measured as blood pressure (BP) lower than  140/90 mm Hg or a reduction in BP. Evidence was extracted and synthesized through dual review of titles, abstracts, full-text articles, study quality, and policy effects. Findings: In total, 31 articles were included. None of the studies examined economic policies outside of the health care system. Of these, 16 (52%) assessed policies for insurance coverage expansion, 8 (26%) evaluated policies related to patient cost sharing for prescription drugs, and 7 (22%) evaluated financial incentive programs for improving health care quality. Of the 16 studies that evaluated coverage expansion policies, all but 1 found that policies such as Medicare Part D and Medicaid expansion were associated with significant improvement in antihypertensive treatment and BP control. Among the 8 studies that examined patient cost sharing, 4 found that measures such as prior authorization and increased copayments were associated with decreased adherence to antihypertensive medication. Finally, all 7 studies evaluating financial incentives aimed at improving quality found that they were associated with improved antihypertensive treatment and BP control. Overall, most studies had a moderate or low risk of bias in their policy evaluation. Conclusions and Relevance: The findings of this systematic review suggest that economic policies aimed at expanding insurance coverage or improving health care quality successfully improved medication use and BP control among US adults with hypertension. Future research is needed to investigate the potential effects of non-health care economic policies on hypertension control.

Racial and Ethnic Differences in Hypertension-Related Telehealth and In-Person Outpatient Visits Before and During the COVID-19 Pandemic Among Medicaid Beneficiaries.

Background: Little is known about the trends and costs of hypertension management through telehealth among individuals enrolled in Medicaid. Methods: Using MarketScan® Medicaid database, we examined outpatient visits among people with hypertension aged 18-64 years. We presented the numbers of hypertension-related telehealth and in-person outpatient visits per 100 individuals and the proportion of hypertension-related telehealth outpatient visits to total outpatient visits by month, overall, and by race and ethnicity. For the cost analysis, we presented total and patient out-of-pocket (OOP) costs per visit for telehealth and in-person visits in 2021. Results: Of the 229,562 individuals, 114,445 (49.9%) were non-Hispanic White, 80,692 (35.2%) were non-Hispanic Black, 3,924 (1.71%) were Hispanic. From February to April 2020, the number of hypertension-related telehealth outpatient visits per 100 persons increased from 0.01 to 6.13, the number of hypertension-related in-person visits decreased from 61.88 to 52.63, and the proportion of hypertension-related telehealth outpatient visits increased from 0.01% to 10.44%. During that same time, the proportion increased from 0.02% to 13.9% for non-Hispanic White adults, from 0.00% to 7.58% for non-Hispanic Black adults, and from 0.12% to 19.82% for Hispanic adults. The average total and patient OOP costs per visit in 2021 were $83.82 (95% confidence interval [CI], 82.66-85.05) and $0.55 (95% CI, 0.42-0.68) for telehealth and $264.48 (95% CI, 258.87-269.51) and $0.72 (95% CI, 0.65-0.79) for in-person visits, respectively. Conclusions: Hypertension management via telehealth increased among Medicaid recipients regardless of race and ethnicity, during the COVID-19 pandemic. These findings may inform telehealth policymakers and health care practitioners.

Rural and Urban Differences in Hypertension Management Through Telehealth Before and During the COVID-19 Pandemic Among Commercially Insured Patients.

BACKGROUND: The COVID-19 pandemic prompted a rapid increase in telehealth use. However, limited evidence exists on how rural and urban residents used telehealth and in-person outpatient services to manage hypertension during the pandemic. METHODS: This longitudinal study analyzed 701,410 US adults (18-64 years) in the MarketScan Commercial Claims Database, who were continuously enrolled from January 2017 through March 2022. We documented monthly numbers of hypertension-related telehealth and in-person outpatient visits (per 100 individuals), and the proportion of telehealth visits among all hypertension-related outpatient visits, from January 2019 through March 2022. We used Welch's two-tail t-test to differentiate monthly estimates by rural-urban status and month-to-month changes. RESULTS: From February through April 2020, the monthly number of hypertension-related telehealth visits per 100 individuals increased from 0.01 to 6.05 (P < 0.001) for urban residents and from 0.01 to 4.56 (P < 0.001) for rural residents. Hypertension-related in-person visits decreased from 20.12 to 8.30 (P < 0.001) for urban residents and from 20.48 to 10.15 (P < 0.001) for rural residents. The proportion of hypertension-related telehealth visits increased from 0.04% to 42.15% (P < 0.001) for urban residents and from 0.06% to 30.98% (P < 0.001) for rural residents. From March 2020 to March 2022, the monthly average of the proportions of hypertension-related telehealth visits was higher for urban residents than for rural residents (10.19% vs. 6.96%; P < 0.001). CONCLUSIONS: Data show that rural residents were less likely to use telehealth for hypertension management. Understanding trends in hypertension-related telehealth utilization can highlight disparities in the sustained use of telehealth to advance accessible health care.

Trends in Drug Spending of Oral Anticoagulants for Atrial Fibrillation, 2014-2021.

INTRODUCTION: This study documents cost trends in oral anticoagulants (OAC) in patients with newly diagnosed atrial fibrillation. METHODS: Using MarketScan databases, the mean annual patients' out-of-pocket costs, insurance payments, and the proportion of patients initiating OAC within 90 days from atrial fibrillation diagnosis were calculated from July 2014 to June 2021. Costs of OACs (apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) and the payments by three insurance types (commercial payers, Medicare, and Medicaid) were calculated. Patients' out-of-pocket costs and insurance payments were adjusted to 2021 prices. Joinpoint regression models were used to test trends of outcomes and average annual percent changes (AAPC) were reported. Data analyses were performed in 2022-2023. RESULTS: From July 2014 to June 2021, the mean annual out-of-pocket costs of any OAC increased for commercial insurance (AAPC 3.0%) and Medicare (AAPC 5.1%) but decreased for Medicaid (AAPC -3.3%). The mean annual insurance payments for any OAC significantly increased for all insurance groups (AAPC 13.1% [95% CI 11.3-15.0] for Medicare; AAPC 11.8% [95% CI 8.0-15.6] for commercial insurance; and AAPC 16.3% [95% CI 11.3-21.4] for Medicaid). The initiation of any OAC increased (AAPC 7.3% for commercial insurance; AAPC 10.2% for Medicare; AAPC 5.3% for Medicaid). CONCLUSIONS: There was a substantial increase in the overall cost burden of OACs and OAC initiation rates in patients with newly diagnosed atrial fibrillation in 2014-2021; these findings provide insights into the current and anticipated impact of rising drug prices on patients' and payers' financial burden.

Social Determinants of Health-Related Z Codes and Health Care Among Patients With Hypertension.

Introduction: Tracking social needs can provide information on barriers to controlling hypertension and the need for wraparound services. No recent studies have examined ICD-10-CM social determinants of health-related Z codes (Z55-Z65) to indicate social needs with a focus on patients with hypertension. Methods: Three cohorts were identified with a diagnosis of hypertension during 2016-2017 and continuously enrolled in fee-for-service insurance through June 2021: (1) commercial, age 18-64 years (n=1,024,012); (2) private insurance to supplement Medicare (Medicare Supplement), age ≥65 years (n=296,340); and (3) Medicaid, age ≥18 years (n=146,484). Both the proportion of patients and healthcare encounters or visits with social determinants of health-related Z code were summarized annually. Patient and visit characteristics were summarized for 2019. Results: In 2020, the highest annual documentation of social determinants of health-related Z codes was among Medicaid beneficiaries (3.02%, 0.46% commercial, 0.42% Medicare Supplement); documentation was higher among inpatient than among outpatient visits for all insurance types. Z63 (related to primary support group) was more common among commercial and Medicare Supplement beneficiaries, and Z59 (housing and economic circumstances) was more common among Medicaid beneficiaries. The 2019 total unadjusted medical expenditures were 1.85, 1.78, and 1.61 times higher for those with social determinants of health-related Z code than for those without commercial, Medicare Supplement, and Medicaid, respectively. Patients with social determinants of health-related Z code also had higher proportions of diagnosed chronic conditions. Among Medicaid beneficiaries, differences in the presence of social determinants of health-related Z code by race or ethnicity were observed. Conclusions: Although currently underreported, social determinants of health-related Z codes provide an opportunity to integrate social and medical data and may help decision makers understand the need for additional services among individuals with hypertension.

Timing of outpatient postpartum care utilization among women with chronic hypertension and hypertensive disorders of pregnancy.

BACKGROUND: The postpartum period represents an opportunity to assess the cardiovascular health of women who experience chronic hypertension or hypertensive disorders of pregnancy. OBJECTIVE: This study aimed to determine whether women with chronic hypertension or hypertensive disorders of pregnancy access outpatient postpartum care more quickly compared to women with no hypertension. STUDY DESIGN: We used data from the Merative MarketScan Commercial Claims and Encounters Database. We included 275,937 commercially insured women aged 12 to 55 years who had a live birth or stillbirth delivery hospitalization between 2017 and 2018 and continuous insurance enrollment from 3 months before the estimated start of pregnancy to 6 months after delivery discharge. Using the International Classification of Diseases Tenth Revision Clinical Modification codes, we identified hypertensive disorders of pregnancy from inpatient or outpatient claims from 20 weeks gestation through delivery hospitalization and identified chronic hypertension from inpatient or outpatient claims from the beginning of the continuous enrollment period through delivery hospitalization. Distributions of time-to-event survival curves (time-to-first outpatient postpartum visit with a women's health provider, primary care provider, or cardiology provider) were compared between the hypertension types using Kaplan-Meier estimators and log rank tests. We used Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals. Time points of interest (3, 6, and 12 weeks) were evaluated per clinical postpartum care guidelines. RESULTS: Among commercially insured women, the prevalences of hypertensive disorders of pregnancy, chronic hypertension, and no documented hypertension were 11.7%, 3.4%, and 84.8%, respectively. The proportions of women with a visit within 3 weeks of delivery discharge were 28.5%, 26.4%, and 16.0% for hypertensive disorders of pregnancy, chronic, and no documented hypertension, respectively; by 12 weeks, the proportions increased to 62.4%, 64.5%, and 54.2%, respectively. Kaplan-Meier analyses indicated significant differences in utilization by hypertension type and interaction between hypertension type, and time before and after 6 weeks. In adjusted Cox proportional hazards models, the utilization rate before 6 weeks among women with hypertensive disorders of pregnancy was 1.42 times the rate for women with no documented hypertension (adjusted hazard ratio, 1.42; 95% confidence interval, 1.39-1.45). Women with chronic hypertension also had higher utilization rates compared to women with no documented hypertension before 6 weeks (adjusted hazard ratio, 1.28; 95% confidence interval, 1.24-1.33). Only chronic hypertension was significantly associated with utilization compared to the no documented hypertension group after 6 weeks (adjusted hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). CONCLUSION: In the 6 weeks following delivery discharge, women with hypertensive disorders of pregnancy and chronic hypertension attended outpatient postpartum care visits sooner than women with no documented hypertension. However, after 6 weeks this difference extended only to women with chronic hypertension. Overall, postpartum care utilization remained around 50% to 60% by 12 weeks in all groups. Addressing barriers to postpartum care attendance can ensure timely care for women at high risk for cardiovascular disease.

Screening of adolescent idiopathic scoliosis using generative adversarial network (GAN) inversion method in chest radiographs.

OBJECTIVE: Conventional computer-aided diagnosis using convolutional neural networks (CNN) has limitations in detecting sensitive changes and determining accurate decision boundaries in spectral and structural diseases such as scoliosis. We devised a new method to detect and diagnose adolescent idiopathic scoliosis in chest X-rays (CXRs) employing the latent space's discriminative ability in the generative adversarial network (GAN) and a simple multi-layer perceptron (MLP) to screen adolescent idiopathic scoliosis CXRs. MATERIALS AND METHODS: Our model was trained and validated in a two-step manner. First, we trained a GAN using CXRs with various scoliosis severities and utilized the trained network as a feature extractor using the GAN inversion method. Second, we classified each vector from the latent space using a simple MLP. RESULTS: The 2-layer MLP exhibited the best classification in the ablation study. With this model, the area under the receiver operating characteristic (AUROC) curves were 0.850 in the internal and 0.847 in the external datasets. Furthermore, when the sensitivity was fixed at 0.9, the model's specificity was 0.697 in the internal and 0.646 in the external datasets. CONCLUSION: We developed a classifier for Adolescent idiopathic scoliosis (AIS) through generative representation learning. Our model shows good AUROC under screening chest radiographs in both the internal and external datasets. Our model has learned the spectral severity of AIS, enabling it to generate normal images even when trained solely on scoliosis radiographs.

Quality Characteristics of Sweet Potato Jelly Prepared Using the Enzymatic Saccharification Method.

In this study, jelly was prepared using saccharified sweet potatoes without sugar, and its quality characteristics were compared according to the sweet potato cultivar. Three sweet potato varieties, namely Juwhangmi (orange color), Sinjami (purple color), and Daeyumi (yellow flesh color), were used. The total free sugar and glucose contents of the hydrolysate were found to increase during the enzyme treatment. However, no differences in the moisture, total soluble solids, or textural properties were found among the sweet potato cultivars. Sinjami had high total polyphenol and flavonoid contents of 446.14 mg GAE/100 g and 243.59 mg CE/100 g, respectively, and it had the highest antioxidant activity among the cultivars. Based on the sensory evaluation, an overall preference appeared in the order of Daeyumi, Sinjami, and Juwhangmi cultivars. This result shows that jelly can be manufactured by saccharifying sweet potatoes, and it was confirmed that the characteristics of raw sweet potatoes had a great influence on the quality characteristics of the jelly. Further, the characteristics of raw sweet potatoes had a remarkable influence on the quality characteristics of the jelly.

Trends and Costs of US Telehealth Use Among Patients With Cardiovascular Disease Before and During the COVID-19 Pandemic.

Background The COVID-19 pandemic affected outpatient care delivery and patients' access to health care. However, no prior studies have documented telehealth use among patients with cardiovascular disease. Methods and Results We documented the number of telehealth and in-person outpatient encounters per 100 patients with cardiovascular disease and the percentage of telehealth encounters from January 2019 to June 2021, and the average payments per telehealth and in-person encounters across a 12-month period (July 2020-June 2021) using the MarketScan commercial database. From February 2020 to April 2020, the number of in-person encounters per 100 patients with cardiovascular disease decreased from 304.2 to 147.7, whereas that of telehealth encounters increased from 0.29 to 25.3. The number of in-person outpatient encounters then increased to 280.7 in June 2020, fluctuated between 268.1 and 346.4 afterward, and ended at 268.1 in June 2021, lower than the prepandemic levels. The number of telehealth encounters dropped to 16.8 in June 2020, fluctuated between 8.8 and 16.6 afterward, and ended at 8.8 in June 2021, higher than the prepandemic levels. Patients who were aged 18 to 35 years, women, and living in urban areas had higher percentages of telehealth encounters than those who were aged 35 to 64 years, men, and living in rural areas, respectively. The mean (95% CI) telehealth and in-person outpatient encounter costs per visit were $112.8 (95% CI, $112.4-$113.2) and $161.4 (95% CI, $160.4- $162.4), respectively. Conclusions There were large fluctuations in telehealth and in-person outpatient encounters during the pandemic. Our results provide insight into increased telehealth use among patients with cardiovascular disease after telehealth policy changes were implemented during the pandemic.

CheSS: Chest X-Ray Pre-trained Model via Self-supervised Contrastive Learning.

Training deep learning models on medical images heavily depends on experts' expensive and laborious manual labels. In addition, these images, labels, and even models themselves are not widely publicly accessible and suffer from various kinds of bias and imbalances. In this paper, chest X-ray pre-trained model via self-supervised contrastive learning (CheSS) was proposed to learn models with various representations in chest radiographs (CXRs). Our contribution is a publicly accessible pretrained model trained with a 4.8-M CXR dataset using self-supervised learning with a contrastive learning and its validation with various kinds of downstream tasks including classification on the 6-class diseases in internal dataset, diseases classification in CheXpert, bone suppression, and nodule generation. When compared to a scratch model, on the 6-class classification test dataset, we achieved 28.5% increase in accuracy. On the CheXpert dataset, we achieved 1.3% increase in mean area under the receiver operating characteristic curve on the full dataset and 11.4% increase only using 1% data in stress test manner. On bone suppression with perceptual loss, we achieved improvement in peak signal to noise ratio from 34.99 to 37.77, structural similarity index measure from 0.976 to 0.977, and root-square-mean error from 4.410 to 3.301 when compared to ImageNet pretrained model. Finally, on nodule generation, we achieved improvement in Fréchet inception distance from 24.06 to 17.07. Our study showed the decent transferability of CheSS weights. CheSS weights can help researchers overcome data imbalance, data shortage, and inaccessibility of medical image datasets. CheSS weight is available at https://github.com/mi2rl/CheSS .

Effect of high-intensity circuit training on obesity indices, physical fitness, and browning factors in inactive female college students.

The recently discovered myokines, irisin and fibroblast growth factor-21, have emerged beneficial for metabolic health due to their role in regulating browning. This study examined the effects of high-intensity circuit training on obesity indices, physical fitness, and irisin and fibroblast growth factor-21 levels in inactive female college students. Ten female college students performed high-intensity circuit training (jogging, stretching, squat jumps, arm walking and push-ups, lunge jumps, burpee test, mountain climbers, side steps, and crunches and side crunches exercises). The exercise program consisted of 40 min of circuit training at 60%-80% hear rate reserve and was conducted 3 times per week for 4 weeks. The body composition, physical fitness, and concentration of plasma irisin and fibroblast growth factor-21 were analyzed before and after the exercise. The body weight (P=0.001), waist circumference (P=0.003), and body fat percentage (P=0.003) decreased, while the muscular strength (handgrip strength test, P=0.030; sit-ups test, P=0.024) and cardiorespiratory fitness (P=0.001) increased after the exercise program. However, there were no significant changes in the irisin and fibroblast growth factor-21 levels. These results suggest that high-intensity circuit training could be the ideal type of exercise in inactive female college students to induce a positive change in the obesity indices and physical fitness. Further studies are needed to determine the effects of exercise on the browning factors.

Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: The PILGRIM explorative cohort.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive chronic disease with poor outcomes. One reason for poor prognosis is the lack of understanding regarding individual variability in response to treatment. Idiopathic PAH (IPAH) patients with bone morphogenetic protein receptor type 2 (BMPR2) mutations have distinct phenotypes that are crucial for individualized therapy but evidence regarding their prevalence and clinical features in the Korean population is lacking. Therefore, the present study aimed to screen Korean IPAH patients for BMPR2 mutations and analyze their clinical phenotypes. METHODS: We enrolled 73 unrelated IPAH patients for BMPR2 mutation screening between March 2010 to November 2015 from 11 hospitals in Korea. Thirty-three lineal family members from 6 families of BMPR2 mutation carriers were also screened. RESULTS: Among 73 patients, 16 (22%) had BMPR2 mutations. Mutation carriers were younger (27 vs. 47 years; p = 0.02) and had a higher mean pulmonary arterial pressure (mPAP) than non-carriers (64 vs. 51 mmHg; p<0.05). Of the 16 individuals with mutations, 5 deletion, 2 splice-site, 6 nonsense, and 3 missense mutations were found, among which, 9 were newly identified mutation types. Patients less than 30 years old had more BMPR2 mutations (44 vs. 14%; p = 0.04) and a higher mPAP (64 vs. 50 mmHg; p = 0.04) compared with those equaled to or over 30 years old. There were no differences in hemodynamic profiles or the proportion of BMPR2 mutation carriers between groups according to sex. CONCLUSION: The prevalence of BMPR2 mutations in Korean IPAH patients was 22%. Mutation carriers were younger and had a poorer hemodynamic profile compared with the non-carriers. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01054105.

[The Efficacy of Rebamipide or Ecabet Sodium Supplementation for Helicobacter pylori Eradication Therapy Compared with Quadruple (Concomitant) Regimen].

Background/Aims: Although some previous studies reported that a treatment combined with mucoprotective agent could improve the eradication rate in dual or triple therapy, there are other reports that question the efficacy of combining these drugs in concomitant therapy (CoCTx). The aim of this study was to investigate the effects of rebamipide or ecabet on the Helicobacter pylori (H. pylori) eradication combined with CoCTx. Methods: We retrospectively reviewed the medical records of 277 patients with proven H. pylori infection. They were assigned to one of 3 regimens for 10 days, twice daily: (a) CoCTx (n=118): lansoprazole 30 mg, amoxicillin 1 g, metronidazole 500 mg, and clarithromycin 500 mg; (b) CoCTx+rebamipide (100 mg) (n=85); (c) CoCTx+ecabet (1 g) (n=74). Results: The baseline characteristics were not significantly different. H. pylori eradication rates were 82.2% (97/118) in CoCTx, 90.6% (77/85) in CoCTx+rebamipide, and 89.2% (66/74) in CoCTx+ecabet (p=0.17), which were statistically insignificant. Overall adverse events were more frequently reported in the CoCTx+rebamipide (50.6%. 43/85) and CoCTx+ecabet (44.6%, 33/74) groups than in the CoCTx (32.2%, 38/118) (p = 0.03) group. Drug compliances were not different between three groups (CoCTx: 95.8%, 113/118; CoCT+rebamipide: 92.9%, 79/85; CoCTx+ecabet 98.6%,73/74) (p=0.209). Multivariate analysis showed that the risk of eradication failure was significantly increased with decreased drug compliance (odds ratio 3.52, 95% confidence interval 1.00-12.32; p=0.05). Conclusions: Addition of these mucoprotective agent was not superior to CoCTx alone for eradicating H. pylori infection with frequent adverse events. Rather, drug compliance is the most related factor affecting the eradication rate. Our data suggest the importance of drug compliance over the drugs used.

The Usefulness of Cap-assisted Endoscopic Retrograde Cholangiopancreatography for Cannulation Complicated by a Periampullary Diverticulum.

Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced therapeutic procedure to manage choledocholithiasis and pancreatobiliary malignancy. On occasion, ERCP failure is encountered due to difficulties in cannulation. We assessed the safety and feasibility of cap-assisted ERCP via analyzing cases in which cannulation was complicated by periampullary diverticulum. Between November 2013 and March 2014, ERCP procedures were performed in 346 patients in our tertiary medical center. Among the 73 patients who had a periampullary diverticulum, conventional ERCP failed in 5 patients due to hidden papilla (n=3) or use of tangential approach (n=2). As a rescue method, needle knife fistulotomy and selective biliary cannulation using cap-fitted forward-viewing endoscopy were successfully used in 4 patients without major complications. Based on our experience, cap-fitted forward-viewing endoscopy was relatively easy to measure the exact position of papilla and to perform biliary cannulation properly. Therefore, we recommend using cap-assisted ERCP by forward-viewing endoscopy as a useful and safe alternative to manage patients in whom cannulation is complicated by periampullary diverticulum.

Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity.

Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (αGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated αGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing αGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing αGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing αGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing αGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer=1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications.

MUC1 glycopeptide epitopes predicted by computational glycomics.

Bioinformatic tools and databases for glycobiology and glycomics research are playing increasingly important roles in functional studies. However, to verify hypotheses generated by computational glycomics with empirical functional assays is only an emerging field. In this study, we predicted glycan epitopes expressed by a cancer-derived mucin, MUC1, by computational glycomics. MUC1 is expressed by tumor cells with a deficiency in glycosylation. Although numerous diagnostic reagents and cancer vaccines have been designed based on abnormally glycosylated MUC1 sequences, the glycan and peptide sequences responsible for immune responses in vivo are poorly understood. The immunogenicity of synthetic MUC1 glycopeptides bearing Tn or sialyl-Tn antigens have been studied in mouse models, while authentic glyco-epitopes expressed by tumor cells remain unclear. To examine the immunogenicity of authentic cancer derived MUC1 glyco-epitopes, we expressed membrane bound forms of MUC1 tandem repeats in Jurkat, a mutant cancer cell line deficient of mucin-type core-1 ß1-3 galactosyltransferase activity, and immunized mice with cancer cells expressing authentic MUC1 glyco-epitopes. Antibody responses to individual glyco-epitopes were determined by chemically synthesized candidate MUC1 glycopeptides predicted through computational glycomics. Monoclonal antibodies can be generated toward chemically synthesized glycopeptide sequences. With RPAPGS(Tn)TAPPAHG as an example, a monoclonal antibody 16A, showed 25-fold higher binding to glycosylated peptide (EC50=9.278±1.059 ng/ml) compared to its non-glycosylated form (EC(50)=247.3±16.29 ng/ml) as measured by ELISA experiments with plate-bound peptides. A library of monoclonal antibodies toward authentic MUC1 glycopeptide epitopes may be a valuable tool for studying glycan and peptide sequences in cancer, as well as reagents for diagnosis and therapy.