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1.
Clin Toxicol (Phila) ; : 1-11, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31389254

RESUMO

Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment. Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured. Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics. Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

2.
Clin Toxicol (Phila) ; 57(11): 1053-1063, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31130018

RESUMO

Introduction: Liquid laundry detergent capsules (also called single-use detergent sacs; laundry pods; laundry packets) have become an increasingly popular household product worldwide. Objectives: To review the composition and mechanisms of toxicity of liquid laundry detergent, capsules, and the circumstances, routes, clinical features (and impact of packaging changes) and management of exposure. Methods: The databases PubMed and EMBASE were searched using the terms: "detergent" and "capsule", "pod", "pac" or "sac" combined with "poison", "ingest", "expos" but not "animal" or "in vitro" or "bacteria". The searches yielded 289 articles, of which 186 were excluded: 38 duplicates, 133 not relevant, 10 abstracts which had been published as a paper and 5 non-English language articles. The bibliographies of relevant articles were hand-searched which yielded 14 additional citations. Searching of abstracts from scientific meetings produced five additional citations. A total of 122 publications were relevant to the objectives of the review. Capsules and composition: Capsules typically contain anionic surfactants (20-35%), non-ionic surfactants (10-20%), propylene glycol (8-20%) and ethanol (2-5%) within a water-soluble polyvinyl alcohol membrane. Mechanisms of toxicity: Non-ionic surfactants are the primary mechanism, though anionic surfactants, ethanol and propylene glycol may also contribute. Circumstances of exposure: The majority (60%) of children are exposed when the capsule is removed from its original container. Routes of exposure: Ingestion is the most common (>85%); ocular (<15%) and dermal (<8%) exposure account for the remainder. Features following ingestion: Features develop in around half of all exposures, though >90% are minor. In those with features, vomiting occurs in some 50%; coughing and drowsiness are reported in <5%. Respiratory depression (<0.5%), central nervous system depression (<0.1%) esophageal or gastric injury (<0.5%), metabolic acidosis and hyperlactatemia (<0.05%) have been reported rarely. Of 17 deaths reported, 13 were adults and nine were suffering from cognitive impairment. Features following ocular exposure: Conjunctivitis, eye irritation and/or eye pain are commonly experienced; corneal injury is less common but complete recovery typically occurs within one week. Features following dermal exposure: Clinically important dermal toxicity seldom occurs, though skin burns can develop in <5% of cases when skin contact is prolonged. Impact of packaging changes on features: The implementation of packaging changes resulted in a fall in the number of exposures and their severity in the United States and in the number in Italy. Management-ingestion: Gut decontamination is not recommended, though small amounts of fluid can be administered orally to rinse out the mouth. Symptomatic and supportive care should be offered to all patients that develop features of toxicity. Supplemental oxygen should be administered for hypoxemia, and bronchodilators for laryngospasm/bronchospasm. Intubation and assisted ventilation may be required if CNS and respiratory depression develop. A chest radiograph should be performed if respiratory features develop. In patients with swallowing difficulties, drooling or oropharyngeal burns, endoscopy should be performed; if substantial mucosal damage is present MRI should be considered. In addition, intravenous fluids will be required if prolonged vomiting or diarrhea occur and acid-base disturbances should be corrected. Management-eye exposure: Thorough irrigation of the eye with sodium chloride 0.9% is required. Instillation of a local anesthetic will reduce discomfort and help more thorough decontamination. Due to the potential for corneal injury, fluorescein should be instilled. If ocular injury is present, the patient should be referred to an ophthalmologist. Management-skin exposure: Skin should be irrigated thoroughly with soap and water, and burns should be treated as a thermal burn. Conclusions: Accidental ingestion usually produces no or only minor features. Very rarely respiratory depression, central nervous system depression, esophageal or gastric injury, hyperlactatemia and metabolic acidosis occur. Ocular exposure results in corneal injury infrequently and skin burns can develop uncommonly following prolonged dermal contact. Of 17 deaths reported, 13 were adults and nine were suffering from cognitive impairment.

3.
Radiother Oncol ; 137: 110-116, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31085390

RESUMO

BACKGROUND AND PURPOSE: Stereotactic ablative body radiotherapy for lung plans requires 4DCT. Most radiotherapy centres use this to determine an internal target volume (ITV), despite studies suggesting that planning on a mid-ventilation (Mid-V) phase can reduce target volumes. The purpose of this study is two-fold: to determine whether the Mid-V approach provides adequate coverage and to discuss methods to enable the Mid-V approach to be applied more widely. METHOD: 4D scans of 79 patients were outlined on every phase. The mid-V phase was identified. Margins were determined from the range of motion, and plans generated with a 55 Gy prescription. A grid-based method was used to get the probability of tumour coverage in the presence of systematic and random uncertainties, with and without blurring for breathing motion. RESULTS: For the Mid-V plans with the margins calculated from the van-Herk formula, after blurring doses for breathing, the coverage (dose covering 95% of the CTV 95% of the time) was greater than for plans with isotropic 5 mm margins uncorrected for breathing (58.2 Gy v 57.3 Gy). Similar results were obtained for a linear margin chosen as 0.15 of the breathing range. Deformable contour propagation in a commercial outlining system (ProSoma) identified the same mid-V phase in the majority of cases. CONCLUSION: Our results confirm that a mid-V approach can be used to reduce the PTV size, with no loss of tumour coverage. We propose the use of a simplified margin formula equal to the margin ignoring breathing plus 0.15 of the range of motion.

4.
Shock ; 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-30998650

RESUMO

BACKGROUND: Major trauma leads to complex immune reactions, known to result in a transient immunodeficiency. The long-term consequences of severe trauma on immune function and regulation as well as its clinical impact remain unclear. METHODS: Six months (ranging from -12 to +5 days) after a major trauma event, 12 former trauma patients (ISS ≥ 16) and 12 healthy volunteers were enrolled. The current clinical status and infection history since discharge were assessed by a standardized questionnaire. Immune cell subsets (CD4, CD8, CD14), cell surface receptor expression (PD-1, BTLA, CTLA-4, TLR-2, -4, and -5, Dectin-1, PD-1L) and HLA-DR-expression were quantified by flow cytometry. Cytokine secretion (IL-2, -4, -6, -10, and 17A, TNF-α, and IFN-γ) was assessed after stimulation of whole blood with LPS-, α-CD3/28, or zymosan. RESULTS: Analysis of surface receptors on T cells revealed a significant elevation of PD-1 expression on CD4 T cells, whereas BTLA expression on CD4 and CD8 T cells was significantly suppressed in the trauma cohort. Monocytes showed a significantly reduced expression of TLR-2 and -4 as well as a reduced proportion of TLR-4 monocytes. HLA-DR receptor density revealed no significant changes between both cohorts. LPS-induced IL-6 and TNF-α secretion showed non-significant trends towards reduced values. No differences regarding clinical apparent infections could be detected. CONCLUSIONS: Six months following major trauma, changes of cell surface receptors on CD4 and CD8 T cells as well as on CD14 monocytes were present, hinting towards an immunosuppressive phenotype. Following major trauma, although IL-6 and TNF-α release after stimulation were reduced, they did not reach statistical significance. Overall, further studies are necessary to evaluate the clinical implications of these findings. TRIAL REGISTRATION: DRKS00009876, Internet Portal of the German Clinical Trials Register (DRKS), registration date 11.08.2016, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00009876.

5.
Clin Toxicol (Phila) ; : 1-8, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30892959

RESUMO

INTRODUCTION: Liquid laundry detergent capsules contain concentrated liquid laundry detergent in a water-soluble polyvinyl alcohol membrane. OBJECTIVE: To review 4652 exposures reported to the United Kingdom National Poisons Information Service (NPIS) and to assess the impact of regulatory changes on potential toxicity. METHODS: Telephone enquiries to the NPIS and returned questionnaires for these products were analyzed for the period January 2008 to December 2018. RESULTS: Data on 4652 exposures were reported by telephone or questionnaire, of which 95.4% involved children aged ≤5 years. Overall, 1738 of 4594 patients remained asymptomatic (Poisoning Severity Score [PSS] 0), 2729 developed minor (PSS 1) features, 107 suffered moderate features (PSS 2), 19 were graded as severe (PSS 3) and one died. Ingestion was involved in most exposures (n = 4175): vomiting occurred in 46.5%, coughing occurred in 4.3% and central nervous system depression in 3.2%. Nine (0.2%) children were intubated and ventilated. The eye was exposed in 646 cases: 371 (59.8%) suffered conjunctivitis or eye irritation and 21 (3.4%) had keratitis/corneal damage, which persisted in one patient for 9 d. The skin was involved in 364 cases; in 127 (35.5%) minor dermal features developed including erythema, irritation and rash. The most commonly reported features in the 127 cases with PSS ≥2 were vomiting (n = 75), stridor (n = 34), CNS depression (n = 22), keratitis/corneal damage (n = 21), coughing (n = 18), conjunctivitis (n = 13), hypersalivation (n = 12), foaming from the mouth (n = 11) and hypoxemia (n = 11). However, respiratory features (stridor, hypoxemia, bronchospasm, respiratory distress, dyspnea, pulmonary aspiration and tachypnea) were the reason for grading 56 of 127 cases as PSS ≥2. CONCLUSIONS: This large data set of 4652 exposures is reassuring in that 97.2% of exposures resulted in no or only minor features, only 107 patients suffered moderate features (PSS 2) and 19 severe (PSS 3) features; one patient died.

6.
Clin Toxicol (Phila) ; 57(7): 663-667, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30676081

RESUMO

Objective: Use of the New Psychoactive Substance (NPS) methiopropamine was first reported in 2011, but there are limited data on its acute toxicity. We report 11 patients presenting with analytically confirmed methiopropamine use. Methods: Adults presenting to 26 hospitals in the UK with severe acute toxicity after suspected NPS use were recruited from March 2015 to April 2018. Clinical features were recorded and biological samples analysed using tandem mass spectrometry. Results: Methiopropamine was detected in 11 of 414 patients, with the last detection in August 2016. It was the only substance detected in one patient; other substances detected included other NPS in nine and conventional drugs of misuse in five. Common features included tachycardia (10/11), agitation (7/11), confusion (7/11), reduced level of consciousness (5/11), hallucinations (5/11) and a raised creatine kinase (7/11). The median length of hospital stay was 17 hours; ten were discharged without sequelae and one was transferred for in-patient psychiatric treatment. Conclusions: Methiopropamine was only detected during 2015 and 2016; most patients had other drugs detected, particularly other NPS. Raised CK was common but it is not possible to determine the degree to which this and other features could be contributed to by co-use of other substances.

7.
Technol Cult ; 59(4): 850-874, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581180

RESUMO

In 1969 Miles Davis started to use the credit "Directions in Music by Miles Davis" on his record sleeves as a statement asserting his creative control of the recording process. This article develops the idea of using the ecological approach to perception and embodied cognition to provide a psychological/cognitive basis for an Actor Network Theory (and to a lesser extent Social Construction of Technology) analysis for the collaborative creative and technological network which came together for the making of Miles Davis' 1969 album, Bitches Brew. Using the notions of invariant properties and affordances from Gibson's work on the ecological approach to perception and of schemata from Lakoff's work in embodied cognition, the article seeks to provide a more nuanced approach to the process of translation in terms of the influence that agents exert upon each other.

8.
Thorax ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166424

RESUMO

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype-phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.

10.
Radiother Oncol ; 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30049455

RESUMO

BACKGROUND AND PURPOSE: The impact of weight loss and anatomical change during head and neck (H&N) radiotherapy on spinal cord dosimetry is poorly understood, limiting evidence-based adaptive management strategies. MATERIALS AND METHODS: 133 H&N patients treated with daily mega-voltage CT image-guidance (MVCT-IG) on TomoTherapy, were selected. Elastix software was used to deform planning scan SC contours to MVCT-IG scans, and accumulate dose. Planned (DP) and delivered (DA) spinal cord D2% (SCD2%) were compared. Univariate relationships between neck irradiation strategy (unilateral vs bilateral), T-stage, N-stage, weight loss, and changes in lateral separation (LND) and CT slice surface area (SSA) at C1 and the superior thyroid notch (TN), and ΔSCD2% [(DA - DP) D2%] were examined. RESULTS: The mean value for (DA - DP) D2% was -0.07 Gy (95%CI -0.28 to 0.14, range -5.7 Gy to 3.8 Gy), and the mean absolute difference between DP and DA (independent of difference direction) was 0.9 Gy (95%CI 0.76-1.04 Gy). Neck treatment strategy (p = 0.39) and T-stage (p = 0.56) did not affect ΔSCD2%. Borderline significance (p = 0.09) was seen for higher N-stage (N2-3) and higher ΔSCD2%. Mean reductions in anatomical metrics were substantial: weight loss 6.8 kg; C1LND 12.9 mm; C1SSA 12.1 cm2; TNLND 5.3 mm; TNSSA 11.2 cm2, but no relationship between weight loss or anatomical change and ΔSCD2% was observed (all r2 < 0.1). CONCLUSIONS: Differences between delivered and planned spinal cord D2% are small in patients treated with daily IG. Even patients experiencing substantial weight loss or anatomical change during treatment do not require adaptive replanning for spinal cord safety.

11.
Phys Rev Lett ; 120(18): 183001, 2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29775374

RESUMO

We present a new measurement of the 1S-3S two-photon transition frequency of hydrogen, realized with a continuous-wave excitation laser at 205 nm on a room-temperature atomic beam, with a relative uncertainty of 9×10^{-13}. The proton charge radius deduced from this measurement, r_{p}=0.877(13) fm, is in very good agreement with the current CODATA-recommended value. This result contributes to the ongoing search to solve the proton charge radius puzzle, which arose from a discrepancy between the CODATA value and a more precise determination of r_{p} from muonic hydrogen spectroscopy.

12.
Mol Ther ; 26(5): 1266-1276, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29661681

RESUMO

Engineered T cell therapies show considerable promise in the treatment of refractory malignancies. Given the ability of engineered T cells to engraft and persist for prolonged periods along with unpredicted toxicities, incorporation of a suicide gene to allow selective depletion after administration is desirable. Rapamycin is a safe and widely available immunosuppressive pharmaceutical that acts by heterodimerization of FKBP12 with the FRB fragment of mTOR. The apical caspase caspase 9 is activated by homodimerization through its CARD domain. We developed a rapamycin-induced caspase 9 suicide gene. First, we showed that caspase 9 could be activated by a two-protein format with replacement of the CARD domain with both FRB and FKBP12. We next identified an optimal compact single-protein rapamycin caspase 9 (rapaCasp9) by fusing both FRB and FKBP12 with the catalytic domain of caspase 9. Functionality of rapaCasp9 when co-expressed with a CD19 CAR was demonstrated in vitro and in vivo.

13.
Clin Toxicol (Phila) ; : 1-9, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29587543

RESUMO

BACKGROUND: Iron poisoning is potentially serious, but mortality has fallen worldwide since implementation of pack size and packaging restrictions, and changes in iron use during pregnancy. The management of individual cases of overdose remains problematic due to uncertainty about indications for antidote. We examine the epidemiology of iron overdose in hospital cases referred to the UK National Poisons Information Service (NPIS) and evaluate the toxicokinetics of iron in patients ingesting only iron preparations. METHODS: Anonymized hospital referral patient data from the NPIS database were collated for the period 1 January 2008 to 31 July 2017. Information was extracted, where recorded, on type of ingestion [iron alone (single), or combined with other agents (mixed)], reported dose, iron salt, timed iron concentrations and symptoms. In single-agent ingestions, the relationships between reported elemental iron dose, early concentrations (4-6 h), and symptoms were evaluated in teenagers and adults (≥13 years) and children (≤12 years) using standard statistical techniques (correlation and unpaired nonparametric comparisons). In those patients with sufficient sample points (three or more), a simple kinetic analysis was conducted. RESULTS: Of 2708 patients with iron overdoses referred by UK hospitals for advice during the 9.7 years study period, 1839 were single-agent ingestions. There were two peaks in age incidence in single-agent exposures; 539/1839 (28.4%) were <6 years (54.1% males) while 675/1839 (36.7%) were between 13 and 20 years (91% females), the latter a substantial excess over the proportion in the totality of hospital referrals to the NPIS in the same period (13-20 years: 23,776/144,268 16.5%; 67.5% female) (p < .0001 overall and for female %). In 475 teenagers and adults and 86 children, with at least one-timed iron concentration available, there was no correlation between stated dose and iron concentration measured 4-6 h post-ingestion. Observed peak iron concentrations were not related to reported symptoms in adults. Initial iron concentrations were significantly higher in 30 patients (25 adults, 5 children) who received desferrioxamine (DFO) compared to those that did not [no DFO: mean 63.8 µmol/L (95% CI 62.1-65.6), median 64; DFO: mean 78.5 µmol/L (95% CI 69.2-87.7), median 78.1; Mann-Whitney p < .0018). No significant differences in symptoms were observed pre-treatment between DFO-treated and untreated groups. No patients died in this cohort. CONCLUSION: Single-agent iron exposures reported from UK hospitals were most common in children <5 years and young people aged 13-20 years. Poisoning with organ failure was not identified and there were no fatalities. No correlations were observed between reported iron doses and early concentrations, or between iron concentrations and symptoms in this cohort of mild-to-moderate poisoning.

14.
Br J Radiol ; 91(1084): 20170863, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29293373

RESUMO

Radiotherapy is a safe treatment; nevertheless, national reporting of serious incidents allows investigation of potential harm to individuals and failing safety culture. UK guidance has previously been limited to overexposures, but underexposures will be included in the new legislation, and positioning errors have also been explicitly included in recent guidance. This commentary reviews current guidance and suggests practical approaches to the additional categories, including the definition of a local error margin.


Assuntos
Diagnóstico por Imagem , Erros Médicos , Doses de Radiação , Monitoramento de Radiação/métodos , Radioterapia , Humanos , Segurança do Paciente , Guias de Prática Clínica como Assunto , Gestão de Riscos , Gestão da Segurança , Reino Unido
15.
Clin Chem ; 64(2): 346-354, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29038156

RESUMO

BACKGROUND: The emergence of novel psychoactive substances (NPS), particularly synthetic cannabinoid receptor agonists (SCRA), has involved hundreds of potentially harmful chemicals in a highly dynamic international market challenging users', clinicians', and regulators' understanding of what circulating substances are causing harm. We describe a toxicovigilance system for NPS that predicted the UK emergence and identified the clinical toxicity caused by novel indole and indazole carboxylate SCRA. METHODS: To assist early accurate identification, we synthesized 5 examples of commercially unavailable indole and indazole carboxylate SCRA (FUB-NPB-22, 5F-NPB-22, 5F-SDB-005, FUB-PB-22, NM-2201). We analyzed plasma and urine samples from 160 patients presenting to emergency departments with severe toxicity after suspected NPS use during 2015 to 2016 for these and other NPS using data-independent LC-MS/MS. RESULTS: We successfully synthesized 5 carboxylate SCRAs using established synthetic and analytical chemistry methodologies. We identified at least 1 SCRA in samples from 49 patients, including an indole or indazole carboxylate SCRA in 17 (35%), specifically 5F-PB-22 (14%), FUB PB-22 (6%), BB-22 (2%), 5F NPB-22 (20%), FUB NPB-22 (2%), and 5F-SDB-005 (4%). In these 17 patients, there was analytical evidence of other substances in 16. Clinical features included agitation and aggression (82%), reduced consciousness (76%), acidosis (47%), hallucinations and paranoid features (41%), tachycardia (35%), hypertension (29%), raised creatine kinase (24%), and seizures (12%). CONCLUSIONS: This toxicovigilance system predicted the emergence of misuse of indole and indazole carboxylate SCRA, documented associated clinical harms, and notified relevant agencies. Toxicity appears consistent with other SCRA, including mental state disturbances and reduced consciousness.

16.
Clin Toxicol (Phila) ; 56(6): 427-432, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29156998

RESUMO

OBJECTIVE: To determine the toxicity of rinse aids which are used as drying aids to remove water from crockery. METHODS: Enquiries to the UK National Poisons Information Service (NPIS) were analysed retrospectively for the period January 2008 to December 2016. RESULTS: There were 855 enquiries relating to 828 patients; children aged 5 years or less accounted for 91.1%. Most exposures occurred from ingestion alone (n = 778, 94.0%), but 26 involved ingestion and other routes: 21 with skin contact, 3 with eye contact, and two with both skin and eye contact. There were a further 24 cases of eye contact alone (n = 20, 2.4%) or skin contact alone (n = 3, 0.4%) and a single case of inhalation alone. The World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists (WHO/IPCS/EC/EAPCCT) Poisoning severity score [PSS] was known in 824 of the 828 exposures: 425 of 824 (51.6%) patients did not develop clinical features, 381 (46.2%) had a PSS of 1 (minor toxicity), 15 (1.8%) developed moderate (PSS 2) and 3 (0.4%) severe (PSS 3) toxicity. Vomiting was the most common feature, occurring in over a third of all ingestions (n = 286, 35.8%), followed by coughing (n = 73, 9.1%). A higher proportion of adults than children developed clinical features (72.7% of 33 vs 46.0% of 767, p = .0026), although vomiting occurred significantly more frequently amongst children (p = .0315). Of the 25 eye contact cases, eye pain (n = 8) and/or eye irritation (n = 8) were reported, with or without abnormal vision (n = 7); there were two cases of corneal abrasion. Dermal contact rarely produced features; only 4 of 26 patients reported symptoms including skin rash or burning or numbness at the contact site. CONCLUSIONS: Severe clinical features were uncommon following rinse aid exposure; vomiting was the most frequently reported symptom following ingestion.

17.
Blood ; 131(7): 746-758, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29284597

RESUMO

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

18.
Lancet Gastroenterol Hepatol ; 3(2): 104-113, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29146439

RESUMO

BACKGROUND: Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation. METHODS: Using data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction. FINDINGS: Between June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC-area under the curve [AUC] 0·97 [95% CI 0·95-0·98]), HMGB1 (0·95 [0·93-0·98]), and full-length K18 (0·95 [0·92-0·97]). Results were similar in the validation cohort (miR-122 AUC 0·97 [95% CI 0·95-0·99], HMGB1 0·98 [0·96-0·99], and full-length K18 0·93 [0·86-0·99]). A combined model of miR-122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1·95 [95% CI 1·87-2·03], p<0·0001 in the MAPP cohort; 1·54 [1·08-2·00], p<0·0001 in the BIOPAR cohort). INTERPRETATION: Personalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines. FUNDING: Edinburgh and Lothians Health Foundation, UK Medical Research Council.


Assuntos
Acetaminofen/envenenamento , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Overdose de Drogas/diagnóstico , Medição de Risco/métodos , Acetaminofen/sangue , Acetilcisteína/uso terapêutico , Adulto , Antídotos/uso terapêutico , Overdose de Drogas/complicações , Overdose de Drogas/tratamento farmacológico , Feminino , Glutamato Desidrogenase/sangue , Proteína HMGB1/sangue , Humanos , Queratina-18/sangue , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
19.
Clin Toxicol (Phila) ; 56(5): 342-347, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29069928

RESUMO

BACKGROUND: Suspected poisoning is a common cause of hospital admission internationally. In the United Kingdom, the National Poisons Information Service (NPIS), a network of four poisons units, provides specialist advice to health professionals on the management of poisoning by telephone and via its online poisoning information and management database, TOXBASE®. OBJECTIVE: To demonstrate the impact of NPIS telephone advice and TOXBASE® guidance on poisoning-related referrals to emergency departments (ED) from primary healthcare settings. METHODS: A telephone survey of primary healthcare providers calling the NPIS and an online survey of TOXBASE® primary care users were conducted to evaluate the effect of these services on poisoning-related ED referrals. Enquirers were asked to indicate whether referral was needed before and after using these information sources. RESULTS: The number of cases considered by enquirers appropriate for ED referral was reduced from 1178 (58.1%) before to 819 (40.4%) after the provision of telephone advice for 2028 cases (absolute reduction 17.7%, 95% CI 14.6, 20.7%) and from 410 (48.2%) before to 341 (40.1%) after consideration of TOXBASE® guidance for 851 cases (absolute reduction 8.1%, 95% CI 3.3, 12.9%). By extrapolating these figures over a full year, it is estimated that these services prevent approximately 41,000 ED referrals annually. CONCLUSIONS: The use of NPIS services significantly reduced ED referrals from primary healthcare services with resulting avoided healthcare costs exceeding the current annual NPIS budget. Further studies are needed to evaluate other potential benefits of accessing NPIS services.

20.
Skeletal Radiol ; 47(3): 389-390, 433-4, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29101424
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