Real-world reported adverse events related to systemic immunomodulating therapy in patients with atopic dermatitis: Results from the TREAT NL (TREatment of ATopic eczema, the Netherlands) registry.

BACKGROUND: Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse. OBJECTIVES: To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs). METHODS: We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs. RESULTS: We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction. CONCLUSIONS: Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

Local administration of gentamicin collagen sponge in surgical excision of sacrococcygeal pilonidal sinus disease: a systematic review and meta-analysis of the literature.

Surgical site infections occur in up to 24 % of patients after surgical excision of sacrococcygeal pilonidal sinus disease with primary wound closure. Local administration of antibiotics by a gentamicin collagen sponge could reduce this infection rate. The objective of this systematic review and meta-analysis was to evaluate the effect of a gentamicin collagen sponge on outcome after surgical excision in patients with sacrococcygeal pilonidal sinus disease. A structured literature search was performed in the PubMed, Embase, The Cochrane Library, and Scopus databases. Studies comparing surgical excision of sacrococcygeal pilonidal sinus disease with versus without a gentamicin collagen sponge were included. Outcome measures were surgical site infection, wound healing, and recurrence. The search strategy yielded six studies with a total of 669 patients. Three randomized controlled trials, comparing excision of pilonidal sinus disease and primary wound closure with versus without gentamicin collagen sponge, were eligible for inclusion in the meta-analysis (319 patients), demonstrating a trend towards reduced surgical site infections after administration of gentamicin collagen sponge [absolute risk reduction 20 %, 95 %-confidence interval (CI) 1-41 %, p = 0.06]. The wound healing (absolute risk reduction 22 %, 95 % CI 32-77 %, p = 0.42) and recurrence rate (absolute risk reduction 8 %, 95 % CI 7-22 %, p = 0.30) were not significantly different between both groups. Administration of a gentamicin collagen sponge after surgical excision of sacrococcygeal pilonidal sinus disease showed no significant influence on wound healing and recurrence rate, but a trend towards a reduced incidence of surgical site infections. Therefore, additional larger well-designed randomized controlled trials are required.

Sudden cardiac death after repair of anomalous origin of left coronary artery from right sinus of Valsalva with an interarterial course : Case report and review of the literature.

Anomalous aortic origin of the coronary artery from the opposite sinus with interarterial course (AAOCA) is a rare condition with a high risk of sudden cardiac death (SCD) during or after strenuous exertion. SCD after repair of this anomaly is extremely rare. Here we present a 15-year-old athlete who collapsed on the basketball court in whom an anomalous origin of the left coronary artery from the right sinus of Valsalva with interarterial course (ALCA) was diagnosed. In spite of extensive pre-sport participation testing, SCD occurred shortly after surgical correction. We reviewed the literature to establish an evidence-based recommendation to aid physicians in conducting the optimal pre-sport participation management for the prevention of SCD in patients with a surgically corrected AAOCA/ALCA, especially for those who participate in strenuous exercise. Review of the literature (60 articles with 325 patients) reveals that post-surgical, pre-sport participation testing varies greatly but that mortality after surgical repair is extremely low (1.5 %). In conclusion, SCD can still rarely occur after repair of AAOCA despite extensive pre-sport participation testing. This should raise awareness among physicians treating these patients and raises the question whether or not return-to-play guidelines need to be revised.

Human oral mucosa and gingiva: a unique reservoir for mesenchymal stem cells.

Mesenchymal stem cells (MSCs) represent a heterogeneous population of progenitor cells with self-renewal and multipotent differentiation potential. Aside from their regenerative role, extensive in vitro and in vivo studies have demonstrated that MSCs are capable of potent immunomodulatory effects on a variety of innate and adaptive immune cells. In this article, we will review recent experimental studies on the characterization of a unique population of MSCs derived from human oral mucosa and gingiva, especially their immunomodulatory and anti-inflammatory functions and their application in the treatment of several in vivo models of inflammatory diseases. The ease of isolation, accessible tissue source, and rapid ex vivo expansion, with maintenance of stable stem-cell-like phenotypes, render oral mucosa- and gingiva-derived MSCs a promising alternative cell source for MSC-based therapies.

Non-exposed bisphosphonate-related osteonecrosis of the jaw: a critical assessment of current definition, staging, and treatment guidelines.

Non-exposed bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a newly reported complication arising from bisphosphonate therapy that presents with atypical symptoms and no apparent mucosal fenestration or exposure of necrotic bone. The clinical observation of the presence of necrotic bone underneath normal epithelial coverage was not conclusive for the diagnosis of BRONJ based on current guidelines established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the American Society for Bone and Mineral Research (ASBMR), which specify the presence of clinically exposed necrotic bone for more than 8 weeks. Hence, the purpose of this review is to critically assess the current guidelines for diagnosis and management of BRONJ and propose a modified staging system and treatment guidelines to properly address the non-exposed variant of BRONJ lesions.

Determination of explosives in soil and ground water by liquid chromatography-amperometric detection.

Electrochemical reduction of trinitrotoluene (TNT) and several nitroaromatics has been exploited toward the development of an amperometric detector for liquid chromatography (LC). Up to a ten-fold increase in sensitivity was accomplished for the explosives using amperometric detection instead of conventional UV measurement. A working glassy carbon electrode (poised at -0.80 V vs. Ag/AgCl) offered a detection limit of 9, 44 and 550 nM for trinitrobenzene, TNT and 1,4-dinitrobenzene, respectively. Separation of eleven TNT-related compounds in a mixture was achieved within 15 min using a C18 column and a mobile phase consisting of acetonitrile-50 mM phosphate buffer pH 5 (1:2, v/v) and 18 mM sodium dodecylsulfate. The LC-amperometric detection system was applicable for analyzing soil extracts and ground water and the results obtained agreed well with that of the US Environmental Protection Agency recommended procedure. Extension to analysis of HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine) and RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) was accomplished with a silver working electrode instead of a glassy carbon electrode installed in a thin channel cell.

Nonaqueous capillary electrophoresis equipped with amperometric detection for analysis of chlorinated phenolic compounds.

Nonaqueous capillary electrophoresis (NACE) equipped with amperometric detection has been developed for separation and detection of an 11-member model mixture of chlorinated phenolic compounds. With triacetyl-beta-cyclodextrin (TACD) as a novel selectivity selector, acetonitrile proved to be an excellent solvent for this water-insoluble cyclodextrin derivative. Resolution of the analytes was achieved by using an optimized acetonitrile medium consisting of 500 mM acetic acid, 10 mM sodium acetate, 12 mM TACD and 50 mM tetrabutylammonium perchlorate. Separation of analytes was attributed to differential electrostatic and/or inductive interactions of the analytes with the TACD/TBA+ complex and charged tetrabutylammonium phases. A simple end-column amperometric detector (Pt vs. Ag/AgCl, poised at +1.6 V) in conjunction with NACE was used to analyze chlorophenols. Amperometric detection of such target compounds in acetonitrile-based media offers high sensitivity and alleviates electrode fouling compared to aqueous buffers. The detection limits obtained, ranging from 30 nM to 500 nM, are 3-8-fold lower than those obtained with aqueous buffers.

Noise levels and hearing ability of female workers in a textile factory in Vietnam.

Noise and hearing ability profiles were determined in a textile factory in Vietnam. Noise mapping done in the weaving section showed that the noise levels exceeded the Vietnamese standard of 90 dBA by as much as 9 dBA in some areas. Audiometric tests performed on 69 female workers from the weaving section revealed that workers with more than 10 years of noise exposure had the worst hearing threshold levels at 1,000 and 4,000 Hz. Similar findings were observed for workers greater than 35 years old. The 4,000 Hz notch, suggestive of exposure to intense noise, was noted in the audiograms of 26 subjects.

Pneumoconiosis problem among the Vietnamese coal mine workers.

In this report, the authors present the pneumoconiosis problem among Vietnamese coal mine workers. As coal is one of the most important products for export, its production has been intensified recently. With the strong incentive for rapid economic development, health problems of miners tend to take second place. As shown in the present report, miners' working conditions are very bad, and health protection measures are not sufficiently implemented. It is apparent that official statistics underestimate the actual situation because of the inadequacy of the reporting system. Because the financial barrier to establishing a sufficient reporting system for pneumoconiosis is enormous, an epidemiologic study is the most effective way to assess the actual situation. It is also useful to conduct epidemiologic studies as part of an international collaborative project, in order to transfer necessary knowledge and epidemiologic skills from the developed countries to Vietnam.

Occupational exposure and chronic respiratory symptoms--a population based study in Vietnam.

In order to investigate the relationship between occupational exposure to dust/chemicals (toxic gases/fumes) and chronic respiratory symptoms in Vietnam, the questionnaire standardized by the American Thoracic Society was applied to 368 subjects living in Ha Thai district of Vietnam. According to the results of multiple logistic regression analyses, the odds ratios of chronic respiratory symptoms by occupational exposure are over unity, except for the relationship between chronic cough and occupational exposure to chemicals. Especially for chronic breathlessness, significantly higher odds ratios are observed among people with a history of occupational exposure to dust or chemicals: 2.925 (95% CI: 1.130-7.574) for dust, and 3.721 (95% CI: 1.412-9.803) for chemicals. As for the interaction between occupational exposure to dust and cigarette smoking, it is considered that occupational exposure leads to an increase in chronic respiratory symptoms independent of the effects of cigarette smoking.

The effect of cyclodextrin modifiers on electrophoretic separation of aromatic hydrocarbons.

Cyclodextrin-modified capillary electrophoresis has been developed for separation and analysis of benzene and its derivatives. The procedure used a mixture of negatively charged sulfobutyl ether-beta-cyclodextrin (SB beta CD) and neutral hydroxypropyl-beta-cyclodextrin (HP beta CD) to effect differential distribution (partitioning) of the aromatic hydrocarbons between the buffer and CD phases. In 80 mM phosphate buffer, containing 15 mM SB beta CD and 5 mM HP beta CD, benzene, toluene, ethyl benzene and three xylene isomers (BTEXs) were well resolved with a number of theoretical plates well above 100,000, for 50 cm of effective length. Some halogenated benzenes were also observed to separate well from the BTEX components to indicate their suitability as an internal standard for BTEX analyses. Equilibrium complexation models were used for investigating the effect of the cyclodextrin(s) at different concentrations and temperature on the electrophoretic mobility.

Separation and determination of polycyclic aromatic hydrocarbons by solid phase microextraction/cyclodextrin-modified capillary electrophoresis.

A sensitive method for the determination of polycyclic aromatic hydrocarbons (PAHs) by solid phase microextraction coupled with cyclodextrin (CD)-modified capillary electrophoresis (CE) using UV detection has been developed. A glass fiber was prepared and used for absorbing 16 EPA priority PAHs from diluted samples until equilibrium was reached. After the glass fiber was connected to a separation capillary via an adapter, the absorbed analytes were directly released into the CE buffer stream, and electrophoretic separation was effected using a 50 mM borate, pH 9.2, buffer containing 35 mM sulfobutyloxy-ß-CD, 10 mM methyl-ß-CD, and 4 mM α-CD. Separation was effected since neutral PAHs differentially partitioned between the neutral and charged CD phases. Under 30 kV applied potential, separation was achieved in less than 15 min with high resolution and number of theoretical plates. Pyrene as low as 8 ppb was detected, while the highest limit of detection was 75 ppb for acenaphthene. Very satisfactory reproducibility with respect to migration time and peak area was obtained for repetitions using the same separation capillary and adapter, where only the extraction fiber was discarded after each analysis.

Achiral selectivity in cyclodextrin-modified capillary electrophoresis.

Torus-shaped, circular, and hydrophilic cyclodextrins (CD) have been frequently used in capillary electrophoresis (CE) as buffer modifiers to effect chiral separation of enantiomers of drugs and specialty chemicals. Although less common, both neutral and charged cyclodextrins have also been exploited in CE to optimize the achiral separations of peptides, proteins, small molecules and a variety of positional isomers. Nonionic CDs are only useful for separations of net charged analytes through judicious partitioning of such guest molecules into their hydrophobic cavity of the former. However, they can be used with a surfactant for an effective resolution of neutral solutes as a result of a differential partitioning of such solutes in the micellar and the cyclodextrin-modified buffer phase. Ionic cyclodextrins, particularly, negatively charged derivatives with their own electrophoretic mobilities, increase the separation window and enable better resolution of analytes which weakly complex with or are poorly differentiated by neutral cyclodextrins.

Effects of earplugs on catecholamine and cortisol excretion in noise-exposed textile workers.

To investigate physiological and psychological effects of industrial noise, a survey was performed on 50 female workers exposed to machinery noise [93-100 dB(A)] (noise group) and 25 female workers in less-noisy environments [71-75 dB(A)] (control group) in a textile factory in Vietnam. Urine was collected for analysis of catecholamines and cortisol. The subjects were also asked to fill out a questionnaire. Each subject was examined over 2 working days. The workers in the noise group were asked to put earplugs in their ears during the working hours of the 2nd day. On the 1st day without earplugs, urinary excretion of catecholamines in the noise group were greater than those in the control group. Cortisol in urine showed a similar tendency. Differences in catecholamine excretion between the noise group and the control group decreased on the 2nd day when the earplugs were used for attenuation of noise level in the noise group. Frequency of subjective fatigue symptoms was lower on the 2nd day than that on the 1st day in noise group, while the control group showed almost no day-difference. The results indicate that the catecholamine response to noise in workers was reduced through the use of earplugs.

Monitoring the activity of glucose oxidase during the cultivation of Aspergillus niger using novel amperometric sensor with 1, 1'-dimethylferricinium as a mediator.

1, 1'-dimethylferricinium (DMF+), a deep blue, and stable mediator, was prepared from a water-soluble 1, 1'-dimethylferrocene(DMF):2-hydroxypropyl- beta-cyclodextrin complex via enzymatic oxidation using immobilised bilirubin oxidase. This mediator was superior to other soluble ferrocenes, notably carboxyferrocene, in terms of both solubility (110 mM vs 0.5 mM) and oxidation potential (150 mV vs 300 mV against Ag/AgCl). Although the cyclic voltammogram of DMF+ was electrochemically equivalent to DMF, the use of the former resulted in a significantly lower background current (< 10 nA vs 30 nA). Because of its higher solubility, concentrated stock solutions of DMF+ can be prepared and supplied to the electrode. This is of particular importance when the signal is severely limited by the rate at which the working electrode can oxidase DMF to DMF+. A linear response of current versus units of glucose oxidase (GOD) was obtained up to 0.5 unit/ml. The detection limit was estimated to be 0.03 unit/ml and the response time was 2.5 min or less. The amperometric system was used successfully to follow the GOD activity during the growth of Aspergillus niger a well-known GOD producer. The results obtained correlated well with a standard absorbance-based assay using dichlorophenol-indophenol (DCPIP). The KM of GOD for the glucose in the lysate was measured as 38 mM. A reduced response and higher KM (48 mM) of the cell homogenate, compared to the lysate, illustrated the requirement for the DMF+ and glucose to diffuse across the cell membrane to interact with GOD in whole cells.

Retention of enzyme by electropolymerized film: a new approach in developing a hypoxanthine biosensor.

An amperometric biosensor for hypoxanthine was constructed by forming a layer of crosslinked xanthine oxidase on a platinum electrode, followed by electropolymerization of a submonolayer film of resorcinol and para-diaminobenzene. The fabricated electrodes were evaluated for speed of response, sensitivity, and reusability. Optimal performance was obtained with enzyme-based electrodes sparsely covered with film which was formed by electropolymerization in less than 6 min. The resulting electrodes exhibited linear response to hypoxanthine in the. range 5-300 microM with a response time of 2 min. Application of the biosensor in monitoring hypoxanthine content of fish extracts yielded results which agreed well with spectrophotometric assays using soluble xanthine oxidase. The biosensor was stable for 60 days when stored at 4 degrees C in phosphate buffer and it could be used continuously for 6 h with over 50 assays.

Determination of nucleotides in fish tissues using capillary electrophoresis.

Capillary electrophoresis has been applied to quantitate nucleotide degradation in fish tissues, to provide a basis for determining the K value, an indicator of fish freshness. The three major compounds, inosine monophosphate (IMP), inosine (HxR), and hypoxanthine (Hx) were distinctively separated at 416 V/cm applied potential, 100 mM CAPS buffer, pH 11. There was a good correlation between the peak area and the nucleotide concentration. By using a short distance (22 cm) from the sample entrance to the detector, the identification and determination of these compounds in each sample were completed within 15 min. The results obtained correlated very well with those obtained by enzymatic assays. The capillary was completely regenerated with 1 N NaOH, to dissociate all bound materials from the capillary wall, mainly cations in the fish extract. This provided the same silica surface for repeated runs, resulting in reproducible electropherograms.

The development and application of a new affinity partitioning system for enzyme isolation and purification.

A reactive water-soluble polymer was synthesized by copolymerizing N-isopropylacrylamide and glycidyl acrylate. The reactive polymer could react with the amino groups of enzymes/proteins or other ligands to form an affinity polymer. As a model, the reactive polymer was allowed to react with paraaminobenzamidine, a strong trypsin inhibitor. The affinity polymer could easily form an aqueous two-phase system with either dextran or pullulan, and the phase diagram was compared favorably to that of the well-known polyethylene glycol-dextran system. Once trypsin was attracted to the affinity polymer dominant phase, the enzyme could be dissociated from the polymer at low pH. Owing to the N-isopropylacrylamide units, the affinity polymer could be isolated from the solution by precipitation at a low level of ammonium sulfate. The enzyme recovery was always greater than 50%, and the affinity polymer could be reused in several cycles of affinity partitioning and recovery.