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PurposeThis randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC).MethodsAt 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety.ResultsOf 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5–10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3–11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74–1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3–17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7–5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%).ConclusionAS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.

To properly adjudicate a case characterized by technical details, a judge needs to spend considerable effort and resources to understand the relevant knowledge and evidence. Incorporating this element into a litigation model, private incentives in evidence collection are shown to be increasing in a judge's effort to process information. Diverting limited judicial resources to collect information, then, may generate multiple equilibria with different resource allocations. An equilibrium with more judicial resources devoted to information collection is accompanied with fewer resources for understanding, and thus lower private search effort. Unless the search capacity of the court is sufficiently high, public search will reduce the overall quality of judicial decision making. The model is also extended to consider whether a judge should disclose his ＂inner conviction＂ (心證), captured as the interim belief, before litigants present their evidence to the court. Disclosure is socially optimal under a general sufficient condition, namely, the first-order effect of the belief on private search dominates the second-order effect.

Objectives To understand prevalence of occupation-related disease and promote the recognition of occupation hazard exposure for hairdresser and cosmetologist. Methods Anonymous questionaires were surveilled in 467 female and 46 male workers of aged 15 to 64 (33.9±10.4 y)in Kaohsiung City. Results Overwork daily hours in 86%, burnout in 30%, and work satisfaction in 57% could be noted. More frequent in fatigue and low satisfaction was in younger workers. There were work-related asthma (n=6), rhinitis (n=19), hand eczema (7.2%), hand injury (3.7%), carpal tunnel syndrome (CTS) (3.5%), neck-shoulder pain (22.2%), low back pain (9.7%). Skin disorder occurred more in hair-washing (p=0.013), injury (p=0.004) and CTS (p=0.013) in hair cutting and design, neck-shoulder pain (p=0.006) and low back pain (p=0.04) also in hair-designers. Near 15% to 20% of workers did not know about irritant/allergic components in products for hair-washing, colour agents, nail agents, and did not wear protective masks or gloves. More than 30% knew nothing about chemical exposure in their workplace and health-hazard effect. Eighty percent of workers knew the risk of trasmission of turberculosis, but less than 60% had protective practice. Most (90%) knew the viral-trasmission hazards of blood-contaminated instruments and sterile procedures, but no protective measures during chemical sterilisation. Less knowledge about chemical hazards and opposition against mask-wearing could be noted in older workers, trainees, and employees than bosses or managers. About 60% thought their pain came from work-related condition, but their work-station was not ergonomically suitable. Conclusions Highly prevalent overwork and occupation-related disorders were noted. Education program to promote recognition of chemical hazards and protective measures should be reinforced.

ContextCushing disease (CD) due to adrenocorticotropic hormone–secreting pituitary tumors can be a management challenge.ObjectiveTo better understand the outcomes of stereotactic radiosurgery (SRS) for CD and define its role in management.DesignInternational, multicenter, retrospective cohort analysis.SettingTen medical centers participating in the International Gamma Knife Research Foundation.PatientsPatients with CD with >6 months endocrine follow-up.InterventionSRS using Gamma Knife radiosurgery.Main Outcome MeasuresThe primary outcome was control of hypercortisolism (defined as normalization of free urinary cortisol). Radiologic response and adverse radiation effects (AREs) were recorded.ResultsIn total, 278 patients met inclusion criteria, with a mean follow-up of 5.6 years (0.5 to 20.5 years). Twenty-two patients received SRS as a primary treatment of CD. Mean margin dose was 23.7 Gy. Cumulative initial control of hypercortisolism was 80% at 10 years. Mean time to cortisol normalization was 14.5 months. Recurrences occurred in 18% with initial cortisol normalization. Overall, the rate of durable control of hypercortisolism was 64% at 10 years and 68% among patients who received SRS as a primary treatment. AREs included hypopituitarism (25%) and cranial neuropathy (3%). Visual deficits were related to treatment of tumor within the suprasellar cistern (P = 0.01), whereas both visual (P < 0.0001) and nonvisual cranial neuropathy (P = 0.02) were related to prior pituitary irradiation.ConclusionsSRS for CD is well tolerated and frequently results in control of hypercortisolism. However, recurrences can occur. SRS should be considered for patients with persistent hypercortisolism after pituitary surgery and as a primary treatment in those unfit for surgery. Long-term endocrine follow-up is essential after SRS.We studied the outcomes of stereotactic radiosurgery for Cushing disease in 278 patients and found that this treatment can result in durable endocrine remission in appropriately selected patients.

Strobilanthes cusia (Nees) Kuntze is a Chinese herbal medicine used in the treatment of respiratory virus infections. The methanol extract of S. cusia leaf contains chemical components such as β-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B that have diverse biological activities. However, the antiviral action of S. cusia leaf and its components against human coronavirus remains to be elucidated. Human coronavirus NL63 infection is frequent among immunocompromised individuals, young children, and in the elderly. This study investigated the anti-Human coronavirus NL63 (HCoV-NL63) activity of the methanol extract of S. cusia leaf and its major components. The methanol extract of S. cusia leaf effectively inhibited the cytopathic effect (CPE) and virus yield (IC50 = 0.64 μg/mL) in HCoV-NL63-infected cells. Moreover, this extract potently inhibited the HCoV-NL63 infection in a concentration-dependent manner. Among the six components identified in the methanol extract of S. cusia leaf, tryptanthrin and indigodole B (5aR-ethyltryptanthrin) exhibited potent antiviral activity in reducing the CPE and progeny virus production. The IC50 values against virus yield were 1.52 μM and 2.60 μM for tryptanthrin and indigodole B, respectively. Different modes of time-of-addition/removal assay indicated that tryptanthrin prevented the early and late stages of HCoV-NL63 replication, particularly by blocking viral RNA genome synthesis and papain-like protease 2 activity. Notably, tryptanthrin (IC50 = 0.06 μM) and indigodole B (IC50 = 2.09 μM) exhibited strong virucidal activity as well. This study identified tryptanthrin as the key active component of S. cusia leaf methanol extract that acted against HCoV-NL63 in a cell-type independent manner. The results specify that tryptanthrin possesses antiviral potential against HCoV-NL63 infection.

While corticosteroids have been hypothesized to exert protective benefits in patients infected with SARS-CoV-2, data remain mixed. This study sought to investigate the outcomes of methylprednisone administration in an Italian cohort of hospitalized patients with confirmed SARS-CoV-2 infection. Among 311 patients enrolled, 71 patients received steroids and 240 did not receive steroids. The mean age was 63.1 years, 35.4% were female, and hypertension, diabetes, heart disease, and chronic pulmonary disease were present in 3.5%, 1.3%, 14.8% and 12.2% respectively. Crude analysis revealed no statistically significant reduction in the incidence of 30-day mortality (36,6% vs 21,7%; OR, 2.09; 95% CI, 1.18-3.70; p = 0.011), shock (2.8% vs 4.6%; OR, 0.60; 95% CI = 0.13-2.79; p = 0.514) or ARF (12.7% vs 15%; OR, 0.82; 95% CI = 0.38-1.80; p = 0.625) between the steroid and non-steroid groups. After IPTW analysis, the steroid-group had lower incidence of shock (0.9% vs 4.1%; OR, 0.21; 95% CI,0.06-0.77; p = 0.010), ARF (6.6% vs 16.0%; OR, 0.37; 95% CI, 0.22-0.64; p<0.001) and 30-day mortality (20.3% vs 22.8%; OR 0.86; 95% CI, 0.59-1.26 p = 0.436); even though, for the latter no statistical significance was reached. Steroid use was also associated with increased length of hospital stay both in crude and IPTW analyses. Subgroup analysis revealed that patients with cardiovascular comorbidities or chronic lung diseases were more likely to be steroid responsive. No significant survival benefit was seen after steroid treatment. Physicians should avoid routine methylprednisolone use in SARS-CoV-2 patients, since it does not reduce 30-day mortality. However, they must consider its use for severe patients with cardiovascular or respiratory comorbidities in order to reduce the incidence of either shock or acute respiratory failure.

Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common cardiac conditions with high mortality risks, which can be improved through early intervention. Telehealth services, which allow for remote monitoring of patient conditions, have been proven to improve the health management of chronic diseases, but the effects on MR and TR progression are unknown. This study aimed to explore whether patients receiving telehealth services have less MR and TR progression compared with a control group. We also aimed to identify the determinants of MR and TR progression. This single-center retrospective study conducted at the National Taiwan University Hospital compared MR and TR progression (defined as either progression to moderate or greater MR and TR or MR and TR progression by ≥2 grades during the study period) between the telehealth and control groups. Patients had a minimum of 2 transthoracic echocardiograms at least 6 months apart; baseline mild-moderate MR and TR or lower; and no prior surgeries on the mitral or tricuspid valve. Telehealth patients were defined as those who received telehealth services for at least 28 days within 3 months of baseline. Basic demographics, baseline blood pressure measurements, prescribed medication, and Charlson Comorbidity Index components were obtained for all patients. A total of 1081 patients (n=226 in the telehealth group and n=855 in the control group) were included in the study analyses. The telehealth group showed significantly lower baseline systolic blood pressure (P<.001), higher Charlson Comorbidity Index (P=.02), higher prevalence of prior myocardial infarction (P=.01) and heart failure (P<.001), higher beta-blocker (P=.03) and diuretic (P=.04) use, and lower nitrate use (P=.04). Both groups showed similar cardiac remodeling conditions at baseline. Telehealth was found to be neutral for both MR (hazard ratio 1.10, 95% CI 0.80-1.52; P=.52) and TR (hazard ratio 1.27, 95% CI 0.92-1.74; P=.14) progression. Determinants for moderate or greater MR progression included older age, female sex, diuretic use, larger left atrial dimension, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction. Determinants of moderate or greater TR progression included older age, female sex, diuretic use, presence of atrial fibrillation, LA dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction; statin use was found to be protective. This is the first study to assess the association between telehealth services and the progression of MR and TR. Telehealth patients, who had more comorbidities, displayed similar MR and TR progression versus control patients, indicating that telehealth may slow MR and TR progression. Determinants of MR and TR progression included easy-to-measure traditional echo parameters of cardiac function, older age, female sex, and atrial fibrillation, which can be incorporated into a telehealth platform and advanced alert system, improving patient outcomes through personalized care.

Early identification of impending in-hospital cardiac arrest (IHCA) improves clinical outcomes but remains elusive for practicing clinicians. We aimed to develop a multimodal machine learning algorithm based on ensemble techniques to predict the occurrence of IHCA. Our model was developed by the Multiparameter Intelligent Monitoring of Intensive Care (MIMIC)-IV database and validated in the Electronic Intensive Care Unit Collaborative Research Database (eICU-CRD). Baseline features consisting of patient demographics, presenting illness, and comorbidities were collected to train a random forest model. Next, vital signs were extracted to train a long short-term memory model. A support vector machine algorithm then stacked the results to form the final prediction model. Of 23,909 patients in the MIMIC-IV database and 10,049 patients in the eICU-CRD database, 452 and 85 patients, respectively, had IHCA. At 13 hours in advance of an IHCA event, our algorithm had already demonstrated an area under the receiver operating characteristic curve of 0.85 (95% CI 0.815-0.885) in the MIMIC-IV database. External validation with the eICU-CRD and National Taiwan University Hospital databases also presented satisfactory results, showing area under the receiver operating characteristic curve values of 0.81 (95% CI 0.763-0.851) and 0.945 (95% CI 0.934-0.956), respectively. Using only vital signs and information available in the electronic medical record, our model demonstrates it is possible to detect a trajectory of clinical deterioration up to 13 hours in advance. This predictive tool, which has undergone external validation, could forewarn and help clinicians identify patients in need of assessment to improve their overall prognosis.

Bone mineral density (BMD) is a crucial indicator of osteoporosis. Bioelectrical impedance analysis (BIA) introduces a new method for assessing body composition, specifically BMD measurement. Compared with existing ultrasound and dual-energy X-ray absorptiometry for BMD screening and diagnosis, BIA has the advantages of safety, convenience and speed. However, the accuracy of BIA for BMD measurement needs to be explored. This study aimed to evaluate the accuracy of the novel BIA technique in conducting whole-body BMD assessments in the general population of Taiwan. Overall, 318 healthy adults in Taiwan (37.67 ± 19.44 years of age; 145 male and 173 female patients) were included. Whole-body BMD was measured via foot-to-foot BIA-StarBIA-201 (StarBIA Meditek Co. LTD, Taichung, Taiwan) and the dual-energy X-ray absorptiometry (DXA) Lunar Prodigy technology (GE Medical Systems, Madison, WI, USA). Linear regression analysis, Pearson’s correlation coefficient, the Bland–Altman plot, and paired t tests were used. The whole-body BMDs measured by BIA and DXA were 1.139 ± 0.124 g/cm 2 and 1.202 ± 0.168 g/cm 2 , respectively. The regression equation was y = 1.057x + 0.063. The Pearson correlation coefficient, mean difference, and limits of agreement were r  = 0.737, − 0.053 g/cm 2 , and − 0.290–0.165 g/cm 2 , respectively. The regression equation was y = 1.057x + 0.063. The Pearson correlation coefficient, mean difference, and limits of agreement were r  = 0.737 ( p  < 0.001), − 0.053 g/cm 2 , and − 0.290–0.165 g/cm 2 , respectively. Standing BIA was correlated with the DXA gold standard for estimating whole-body BMD in adults; however, its interchangeability remains limited. The potential bias in the measurement results of this study represents a current challenge with BIA compared with that of DXA, and there is still room for improvement. The convenient BIA method for measuring whole-body BMD may be useful in the application of primary screening and future development of BMD assessment methods. BIA is widely used to measure body composition, but its application to the measurement of BMD represents a novel technological breakthrough.

Candida albicans (C. albicans) is an opportunistic human pathogen responsible for approximately a half of clinical candidemia. The emerging Candida spp. with resistance to azoles is a major challenge in clinic, suggesting an urgent demand for new drugs and therapeutic strategies. Alpha–enolase (Eno1) is a multifunctional protein and represents an important marker for invasive candidiasis. Thus, C. albicans Eno1 (CaEno1) is believed to be an important target for the development of therapeutic agents and antibody drugs. Recombinant CaEno1 (rCaEno1) was first used to immunize chickens. Subsequently, we used phage display technology to construct two single chain variable fragment (scFv) antibody libraries. A novel biopanning procedure was carried out to screen anti-rCaEno1 scFv antibodies, whose specificities were further characterized. The polyclonal IgY antibodies showed binding to rCaEno1 and native CaEno1. A dominant scFv (CaS1) and its properties were further characterized. CaS1 attenuated the growth of C. albicans and inhibited the binding of CaEno1 to plasminogen. Animal studies showed that CaS1 prolonged the survival rate of mice and zebrafish with candidiasis. The fungal burden in kidney and spleen, as well as level of inflammatory cytokines were significantly reduced in CaS1-treated mice. These results suggest CaS1 has potential of being immunotherapeutic drug against C. albicans infections.