Safety of the JAK and TNF inhibitors in rheumatoid arthritis: real world data from the Hong Kong Biologics Registry.

OBJECTIVES: To compare the incidence of major adverse cardiovascular events (MACEs), cancer and infective complications in RA patients using Janus kinase (JAKis) and TNF (TNFis) inhibitors. METHOD: A retrospective analysis of data from the Hong Kong Biologics Registry 2008-2021 was performed. RA patients who had ever used JAKis or TNFis were included. The incidence of MACEs, cancer and infections were compared between the two groups, with adjustment for confounding factors. RESULTS: A total of 2471 courses of JAKis (n = 551) and TNFis (n = 1920) were used in 1732 RA patients (83.7% women, age 53.8 [12.5] years; follow-up 6431 patient-years). JAKi users had significantly older age, more atherosclerotic risk factors and higher frequency of past malignancies. A total of 15 and 40 MACEs developed in the JAKi and TNFi users, respectively (incidence 1.34 vs 0.75 per 100 patient-years; P = 0.22). There was no significant difference in the incidence of cancers between the two groups (0.81 [JAKi] vs 0.85 [TNFi] per 100 patient-years; P = 0.25). The adjusted hazard ratios of MACE and cancer in the JAKi users were 1.36 (95% CI: 0.62, 2.96) (P = 0.44) and 0.87 (95% CI: 0.39, 1.95) (P = 0.74), respectively. Rates of infections were significantly higher in the JAKi than TNFi users (16.3 vs 9.9 per 100 patient-years; P = 0.02), particularly herpes zoster (3.49 vs 0.94 per 100 patient-years; P < 0.001). CONCLUSIONS: In a real-life setting, there is no increase in MACEs or cancers in users of JAKis compared with TNFis. However, the incidence of non-serious infections, including herpes zoster, was increased in users of JAKis.

Predicting Gambling Propensity and Behavior: The Role of Social Axioms and Distortive Beliefs.

Theory and research have revealed the impact of cognitive factors on propensity for gambling, but the role of generalized beliefs and their underlying mechanisms receive little attention. In the present research, we operationalized generalized beliefs as social axioms (Leung et al. in J Cross Cult Psychol 33:286-302, 2002) and tested how the axiom factors of fate control and social cynicism affected the likelihood to gamble in hypothetical scenarios (Study 1) and the actual behaviour of gambling (Study 2). In Study 1, we found that both fate control and social cynicism positively predicted the propensity to participate in horse betting and casino gambling among university students (n = 184). The effect of fate control was mediated by perceived benefit of gambling, whereas social cynicism affected gambling propensity directly. In Study 2, we showed the same effects of fate control and social cynicism on gambling frequency among at-risk adolescents (n = 547), and identified two types of gambling-related cognition (i.e., distortive gambling cognitions and attitudes towards money) as mediators. Overall, this research provided evidence for the importance of social beliefs in formulating specific gambling cognitions and gambling behaviours, shedding light on intervention strategies for helping frequent gamblers through altering their worldviews in general and risk-taking beliefs in particular.

Clinical presentation, treatment and outcome of Takayasu's arteritis in southern Chinese: a multicenter retrospective study.

To study the clinical presentation, treatment and outcome of southern Chinese patients with Takayasu's arteritis (TA). This is a retrospective chart review study of 78 patients managed in 14 public hospitals in Hong Kong between the years 2000 and 2010. Patients were identified from the hospital registry using the ICD-10 diagnostic code of the disease. The classification of TA was based on the American College of Rheumatology (ACR) or modified Ichikawa's criteria. Demographic data, clinical presentation, angiographic findings, pattern of vascular involvement (Numano's classification), treatment and outcome of these patients were presented. 78 patients were studied (82% women, age at presentation 34.2 ± 14 years). The estimated point prevalence of TA was 11/million population. The commonest initial manifestations were hypertension (62%) and vascular ischemic symptoms (38%). Systemic symptoms occurred in nine (12%) patients only. The proportion of patients fulfilling the angiographic subtypes of the Numano's classification was: types I (13%), IIa (4%), IIb (12%), III (12%), IV (20%) and V (39%), respectively. Thirty-two patients (41%) were treated with high-dose glucocorticoids (GCs) and 22 patients (28%) received additional non-GC immunosuppressive drugs. Vascular complications occurred in 26 (33%) patients and revascularization surgery was performed in 23(29%) patients. Three (4%) patients died of vascular complication at a median of 8 years after disease onset. TA is rare in southern Chinese patients of Hong Kong. Most patients present with ischemic symptoms during the stenotic phase of the disease. Although mortality is low, a significant proportion of patients developed vascular stenosis that required surgical interventions. More awareness of TA as a differential diagnosis of non-specific systemic symptoms with elevated inflammatory markers in younger patients is needed for earlier diagnosis.

Caution with interpreting laboratory results after lipid rescue therapy.

Intravenous lipid rescue therapy (LRT) may be implemented to attenuate drug toxicity. Little is known about LRT interference with laboratory tests in overdose settings. A 54-year-old man with a history of depression consumed unknown amounts of diphenhydramine, amitriptyline, and acetaminophen (APAP). Initial workup showed aspartate aminotransferase (AST) of 138 U/L, APAP of 177 µg/mL, and a QRS interval of 136 milliseconds. N-acetylcysteine, sodium bicarbonate, and 20% intravenous LRT were initiated. Laboratory test results drawn less than 6 hours later showed an APAP level of 44 µg/mL and an undetectable AST (Siemens Vista 1500 analyzer, lower limit of detection: alanine aminotransferase, 6 U/L; AST, 3 U/L). N-acetylcysteine and LRT infusions were stopped. Eight hours later, serum AST was measured at 488 U/L and increased over the next 2 days to a peak of 1600 U/L before recovery. Given a gradually rising course of AST following APAP ingestion, a single undetectable measurement is highly unlikely and probably erroneous. For this Siemens analyzer, serum lipid concentrations greater than 400 mg/dL cause interference with the AST measurement. Because lipid levels greater than 400 mg/dL with other similar analyzers are known to falsely decrease the AST, it is possible that extreme lipemia caused this laboratory result; a triglyceride level of 3648 mg/dL has been reported after LRT infusion. This conclusion is limited by the lack of repeat measurement of liver enzymes or measurement of serum lipid levels. Lipid rescue therapy may cause lipemia that interferes with the assay for liver enzymes. Suspected abnormal laboratory values should be repeated, or other techniques can be used to remove lipemic interference.

Validation of the Chinese version of the Gamblers' Belief Questionnaire (GBQ-C).

A growing body of evidence is documenting the significant role of cognitive factors in influencing gambling behaviors. Although measures of cognitive biases have been developed, further validation of these scales is needed among non-Western samples. The 21-item Gamblers' Belief Questionnaire was originally developed and validated by Steenbergh et al. (in Psychol. Addict. Behav., 16: 143-149, 2002). The scale then has been widely used in the gambling research of the West. The present study was designed to examine and validate the Chinese version of Gamblers' Belief Questionnaire (GBQ-C) using 258 Chinese participants. Confirmatory factor analyses indicated the 2-factor model provided a good fit to the data as evidenced by various model fit indices (CFI = .91, RMSEA = .08 and SRMR = .05). Additional evidence for the validity of the GBQ-C was provided by significant correlations with other relevant measures (range .40-.75). In sum, the present study provides support for the GBQ-C as a valuable tool for assessing gambling cognitions among Chinese samples.

Toxicities of nano zinc oxide to five marine organisms: influences of aggregate size and ion solubility.

Nano zinc oxide (nZnO) is increasingly used in sunscreen products, with high potential of being released directly into marine environments. This study primarily aimed to characterize the aggregate size and solubility of nZnO and bulk ZnO, and to assess their toxicities towards five selected marine organisms. Chemical characterization showed that nZnO formed larger aggregates in seawater than ZnO, while nZnO had a higher solubility in seawater (3.7 mg L(-1)) than that of ZnO (1.6 mg L(-1)). Acute tests were conducted using the marine diatoms Skeletonema costatum and Thalassiosia pseudonana, the crustaceans Tigriopus japonicus and Elasmopus rapax, and the medaka fish Oryzias melastigma. In general, nZnO was more toxic towards algae than ZnO, but relatively less toxic towards crustaceans and fish. The toxicity of nZnO could be mainly attributed to dissolved Zn(2+) ions. Furthermore, molecular biomarkers including superoxide dismutase (SOD), metallothionein (MT) and heat shock protein 70 (HSP70) were employed to assess the sublethal toxicities of the test chemicals to O. melastigma. Although SOD and MT expressions were not significantly increased in nZnO-treated medaka compared to the controls, exposure to ZnO caused a significant up-regulation of SOD and MT. HSP70 was increased two to fourfold in all treatments indicating that there were probably other forms of stress in additional to oxidative stress such as cellular injury.

Management of glucocorticoid-related osteoporotic vertebral fracture.

The vertebral column is the most common site of osteoporotic fractures in long-term users of glucocorticoids. Vertebral fracture leads to significant morbidities such as unrelenting pain, spinal deformities and reduced mobility, leading to diminished quality of life. Epidemiological data on the prevalence of glucocorticoid-induced vertebral fractures are limited. As vertebral fracture is a strong risk factor for further fragility fractures and mortality, it should be treated appropriately. This article reviews recent data on the prevalence of vertebral fractures in glucocorticoid users, fracture risk stratification, and evidence-based treatment options. The risk of osteoporotic fractures estimated by FRAX should be adjusted for glucocorticoid users. The first-line treatment of glucocorticoid-induced osteoporosis remains the bisphosphonates. Teriparatide and denosumab are alternative options. Percutaneous vertebroplasty and kyphoplasty may be considered for symptomatic control of acute vertebral fracture-related pain when conservative measures fail.

Sunscreens containing zinc oxide nanoparticles can trigger oxidative stress and toxicity to the marine copepod Tigriopus japonicus.

The study, for the first time, evaluated the leaching rate of zinc oxide nanoparticles (nZnO) from human skins which were applied with three commercial sunscreens containing nZnO as an active ingredient. The leaching rate of nZnO varied greatly among the sunscreens, with a range of 8-72% (mean ± SD: 45% ± 33%). We further investigated their toxicities to the marine copepod Tigriopus japonicus. We found that 96-h median lethal concentrations of the three sunscreens to T. japonicus were > 5000, 230.6, and 43.0 mg chemical L-1, respectively, equivalent to Zn2+ concentrations at >82.5, 3.2, and 1.2 mg Zn L-1, respectively. Exposure to the individual sunscreens at environmentally realistic concentrations for 96 h led to up-regulation of antioxidant genes in T. japonicus, while they triggered the release of reactive oxygen species based on the results of in vivo assays. Evidently, these nZnO-included sunscreens can cause oxidative stress and hence pose risk to marine organisms.

In vivo toxicities of nine engineered nano metal oxides to the marine diatom Skeletonema costatum and rotifer Brachionus koreanus.

This study compared in vivo acute toxicities of nine engineered nano metal oxides to the marine diatom Skeletonema costatum and rotifer Brachionus koreanus. The sequence of their toxicities to S. costatum, based on growth inhibition, was: nano zinc oxide (nZnO) > nTiO2 (rutile) > nMgO > Annealed nMgO > nTiO2 (anatase) > Î³-nAl2O3 > nIn2O3 > α-nAl2O3 > nSnO2. Similarly, nZnO was also the most toxic to B. koreanus, but the other nano metal oxides were non-lethal. nMgO and nZnO were confirmed to trigger reactive oxygen species (ROS) mediated toxicity to the two marine organisms, while nTiO2 (both anatase and rutile forms) likely induced oxidative stress as shown by their acellular ROS production. nZnO may also cause damage in the endocrine system of B. koreanus, as indicated by the increased transcription of retinoid X receptor. Annealed nMgO reduces its toxicity via removal of O2- and impurities from its surface.

Antibacterial activities of naturally occurring compounds against Mycobacterium avium subsp. paratuberculosis.

The antibacterial activities of 18 naturally occurring compounds (including essential oils and some of their isolated constituents, apple and green tea polyphenols, and other plant extracts) against three strains of Mycobacterium avium subsp. paratuberculosis (a bovine isolate [NCTC 8578], a raw-milk isolate [806R], and a human isolate [ATCC 43015]) were evaluated using a macrobroth susceptibility testing method. M. avium subsp. paratuberculosis was grown in 4 ml Middlebrook 7H9 broth containing 10% oleic acid-albumin-dextrose-catalase, 0.05% Tween 80 (or 0.2% glycerol), and 2 microg/ml mycobactin J supplemented with five concentrations of each test compound. The changes in the optical densities of the cultures at 600 nm as a measure of CFU were recorded at intervals over an incubation period of 42 days at 37 degrees C. Six of the compounds were found to inhibit the growth of M. avium subsp. paratuberculosis. The most effective compound was trans-cinnamaldehyde, with a MIC of 25.9 microg/ml, followed by cinnamon oil (26.2 microg/ml), oregano oil (68.2 microg/ml), carvacrol (72.2 microg/ml), 2,5-dihydroxybenzaldehyde (74 microg/ml), and 2-hydroxy-5-methoxybenzaldehyde (90.4 microg/ml). With the exception of carvacrol, a phenolic compound, three of the four most active compounds are aldehydes, suggesting that the structure of the phenolic group or the aldehyde group may be important to the antibacterial activity. No difference in compound activity was observed between the three M. avium subsp. paratuberculosis strains studied. Possible mechanisms of the antimicrobial effects are discussed.

Serotonin syndrome triggered by a single dose of suboxone.

Suboxone (buprenorphine/naloxone) is an oral medication used for the treatment of opiate dependence. Because of its mixed properties at the opiate receptors, buprenorphine has a ceiling on its euphoric effects. We report the first case of serotonin syndrome caused by buprenorphine and review other medications implicated in serotonin syndrome. A 54-year-old man on tricyclic antidepressants took an unprescribed dose of buprenorphine/naloxone. He presented to the emergency department with signs and symptoms of severe serotonin syndrome including clonus, agitation, and altered mental status. His agitation was not controlled with benzodiazepines and was electively intubated. At the recommendation of the toxicology service, cyproheptadine, a serotonin receptor antagonist, was administered with improvement in the patient's symptoms. Emergency physicians should be aware of the potential of buprenorphine/naloxone to trigger serotonin syndrome.

Detection of clenbuterol in heroin users in twelve postmortem cases at the Philadelphia medical examiner's office.

The presence of clenbuterol, a beta2-adrenergic agonist banned for human use in the United States because of its serious side effects, is reported in a series of 12 postmortem cases in which the cause of death was attributed to illicit drug use. During the first three months of 2007, postmortem specimens from cases previously screening positive for opiates or fentanyl were screened specifically for clenbuterol using enzyme-linked immunosorbent assay. Confirmation of clenbuterol was performed using solid-phase extraction, derivatization with trimethylboroxine, and analysis utilizing a gas chromatograph-mass spectrometer (GC-MS) operated in the full-scan mode. The limits of detection and quantitation in blood were 2.5 and 5 ng/mL, respectively. Linearity was from 5 to 100 ng/mL. Clenbuterol was positive in 12/106 (11%) drug-related cases and in 12/575 (2.1%) of the total cases tested. In each of the 12 cases positive for clenbuterol, heroin use was either confirmed by the presence of 6-acetylmorphine or strongly suspected by the presence of morphine with a history of heroin abuse. Because the use of clenbuterol in the United States is restricted to veterinary medicine, its detection is an unexpected finding. Its presence in these cases serves as a caution to emergency room physicians and toxicologists to consider and test for clenbuterol when treating a suspected heroin user who presents atypically. This is the first known series of clenbuterol-positive cases of illicit drug users to be reported from a medical examiner's toxicology laboratory.

Concurrent detection of heroin, fentanyl, and xylazine in seven drug-related deaths reported from the Philadelphia Medical Examiner's Office.

Recreational drugs, such as cocaine and heroin, are often adulterated with other pharmacological agents to either enhance or diminish the drug effects. Between April 21, 2006 and August 8, 2006, the Philadelphia Medical Examiner's Office detected xylazine (a veterinary sedative) and fentanyl (a synthetic opioid) in specimens taken from seven cases. Initial immunoassay screening was performed on urine and blood for fentanyl, opiate, cocaine, phencyclidine (PCP), and benzodiazepines. All tests reported positive were confirmed by gas chromatography-mass spectrometry. All seven xylazine positive cases tested positive for fentanyl and six cases tested positive for 6-acetylmorphine (a metabolite and definitive marker for heroin). The seventh case was positive for morphine and had a history of heroin abuse. Xylazine was present in urine in all seven cases and blood levels were detected in three cases. The blood concentrations ranged from trace to 130 ng/mL. Fentanyl was present in the blood and urine in each case and blood concentrations ranged from 4.7 to 47 ng/mL. Adulteration of illicit drugs has become an epidemic health concern for drug users. Healthcare professionals need to be aware of this issue, so the patients can be treated in an effective, timely manner.

Non-typhoid Salmonella mycotic aneurysm of the aortic arch.

Salmonella mycotic aneurysm is a rare but potentially fatal condition. Mortality is high without timely intervention. The clinical presentation is protean and early diagnosis requires a high degree of clinical alertness. Prompt surgical intervention and prolonged antimicrobial therapy are keys to successful treatment. We report an 81-year-old man with an atypical presentation of Salmonella mycotic aneurysm in the aortic arch. The case highlights the need to evaluate all patients over 50 years with non-typhoid Salmonella bacteraemia for possible endovascular infections. Contrast-enhanced computed tomography is useful for making an early diagnosis of this disease.

Salinity-dependent toxicities of zinc oxide nanoparticles to the marine diatom Thalassiosira pseudonana.

This study comprehensively investigated the influences of salinity, exposure concentration and time on the aggregate size, surface charge and dissolution of zinc oxide nanoparticles (ZnO-NPs; 20nm) in seawater, and examined the interacting effect of salinity and waterborne exposure of ZnO-NPs on the marine diatom Thalassiosira pseudonana for 96h. We found that aggregate sizes of ZnO-NPs significantly increased with increasing salinity, but generally decreased with increasing exposure concentration. Ion release decreased with increasing salinity, whereas the surface charge of the particles was not affected by salinity. The increased aggregate size and decreased ion release with increasing salinity, and consequently lower concentration of bioavailable zinc ions, resulted in decreased toxicity of ZnO-NPs at higher salinity in general in terms of growth inhibition (IC50) and chlorophyll fluorescence (EC50 - ФPo and EC50 - Ф2). However, IC50s and EC50s of ZnO-NPs were smaller than those of Zn(2+) (from ZnO-NPs ultrafiltrate and ZnCl2), indicating that dissolved Zn(2+) can only partially explain the toxicity of ZnO-NPs. SEM images showed that ZnO-NPs attached on the diatom frustule surface, suggesting that the interaction between the nanoparticles and the cell surface may acerbate the toxicity of ZnO-NPs. Our results linked the physicochemical characteristics of ZnO-NPs in seawater with their toxicities to the marine diatom and highlighted the importance of salinity as an influential environmental factor governing the aggregation, dissolution and the toxicity of ZnO-NPs.

Metal oxide nanoparticles with low toxicity.

A number of different nanomaterials produced and incorporated into various products are rising. However, their environmental hazards are frequently unknown. Here we consider three different metal oxide compounds (SnO2, In2O3, and Al2O3), which have not been extensively studied and are expected to have low toxicity. This study aimed to comprehensively characterize the physicochemical properties of these nanomaterials and investigate their toxicity on bacteria (Escherichia coli) under UV illumination and in the dark, as well as on a marine diatom (Skeletonema costatum) under ambient illumination/dark (16-8h) cycles. The material properties responsible for their low toxicity have been identified based on comprehensive experimental characterizations and comparison to a metal oxide exhibiting significant toxicity under illumination (anatase TiO2). The metal oxide materials investigated exhibited significant difference in surface properties and interaction with the living organisms. In order for a material to exhibit significant toxicity, it needs to be able to both form a stable suspension in the culture medium and to interact with the cell walls of the test organism. Our results indicated that the observed low toxicities of the three nanomaterials could be attributed to the limited interaction between the nanoparticles and cell walls of the test organisms. This could occur either due to the lack of significant attachment between nanoparticles and cell walls, or due to their tendency to aggregate in solution.

Toxicity of CeO2 nanoparticles - the effect of nanoparticle properties.

Conflicting reports on the toxicity of CeO2 nanomaterials have been published in recent years, with some studies finding CeO2 nanoparticles to be toxic, while others found it to have protective effects against oxidative stress. To investigate the possible reasons for this, we have performed a comprehensive study on the physical and chemical properties of nanosized CeO2 from three different suppliers as well as CeO2 synthesized by us, and tested their toxicity. For toxicity tests, we have studied the effects of CeO2 nanoparticles on a Gram-negative bacterium Escherichia coli in the dark, under ambient and UV illuminations. We have also performed toxicity tests on the marine diatom Skeletonema costatum under ambient and UV illuminations. We found that the CeO2 nanoparticle samples exhibited significantly different toxicity, which could likely be attributed to the differences in interactions with cells, and possibly to differences in nanoparticle compositions. Our results also suggest that toxicity tests on bacteria may not be suitable for predicting the ecotoxicity of nanomaterials. The relationship between the toxicity and physicochemical properties of the nanoparticles is explicitly discussed in the light of the current results.

Temperature-dependent toxicities of nano zinc oxide to marine diatom, amphipod and fish in relation to its aggregation size and ion dissolution.

This study, for the first time, concurrently investigated the influence of seawater temperature, exposure concentration and time on the aggregation size and ion dissolution of nano zinc oxides (nZnO) in seawater, and the interacting effect of temperature and waterborne exposure of nZnO to the marine diatom Skeletonema costatum, amphipod Melita longidactyla and fish Oryzias melastigma, respectively. Our results showed that aggregate size was jointly affected by seawater temperature, nZnO concentration and exposure time. Among the three factors, the concentration of nZnO was the most important and followed by exposure time, whereas temperature was less important as reflected by their F values in the three-way analysis of variance (concentration: F3, 300 = 247.305; time: F2, 300 = 20.923 and temperature: F4, 300 = 4.107; All p values <0.001). The aggregate size generally increased with increasing nZnO concentration and exposure time. The release of Zn ions from nZnO was significantly influenced by seawater temperature and exposure time; the ion dissolution rate generally increased with decreasing temperature and increasing exposure time. Growth inhibition of diatoms increased with increasing temperature, while temperature and nZnO had an interactional effect on their photosynthesis. For the amphipod, mortality was positively correlated with temperature. Fish larvae growth rate was only affected by temperature but not nZnO, while the two factors interactively modulated the expression of heat shock and metallothionein proteins. Evidently, temperature can influence aggregate size and ion dissolution and thus toxicity of nZnO to the marine organisms in a species-specific manner.

Development of freshwater sediment management standards for organic matters, nutrients, and metals in Korea.

Korean water quality managers are required to promptly develop national assessment standards for freshwater sediment quality due to the Four Major River Restoration Project in Korea in 2009. We conducted this study to develop sediment management standards (SMSs), determining obviously and severely polluted sediment, which could have adverse impacts on water quality and aquatic ecosystem. The SMSs values were derived from the 95th percentile of concentration distribution for organic matter and nutrients in sediment quality database. For the SMSs of metals, foreign sediment quality guidelines (SQGs) were adopted. As a result, 13% for loss on ignition (LOI), 1,600 mg/kg for total phosphorus (TP), and 5,600 mg/kg for total nitrogen (TN) were set as the SMSs for freshwater sediment in Korea. These values were higher than the range of heavily polluted sediment from USEPA Region 5 guideline derived by the similar approaches for the Great Lakes harbor sediments, and similar or lower than the severe effect level (SEL) from provincial sediment quality guideline (PSQG) of Ontario, Canada by screening level concentration (SLC) approach. However, SMSs in the present study are appropriate considering the concentration ranges and the Korean SMSs' definition for freshwater sediments in Korea. The Puget Sound marine sediment cleanup screening level (CSL) in Washington State, USA were adopted as the Korean SMSs for As (93 mg/kg), Cd (6.7 mg/kg), Cr (270 mg/kg), Cu (390 mg/kg), Pb (530 mg/kg), and Zn (960 mg/kg) in freshwater sediments. Hg concentration (0.59 mg/kg) of CSL was too low to determine the polluted freshwater sediments in Korea, and the SEL of Ontario, Canada for mercury concentration (2 mg/kg) was selected as the SMS for Hg. These values were found reasonable through the assessment of applicability with the datasets from locations directly affected by obvious point sources. These results indicate that SMSs for organic matter, nutrient, and metals derived within the present study can successfully determine obviously and severely polluted sediment in Korea. However, the SMSs have limits to specifically determine the effects of polluted sediment on water quality and aquatic ecosystem in Korea. Thus, we will revise and specify SMSs considering those effects and further sediment quality assessment framework in the near future.