bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline patients’ characteristics as predictors for therapeutic survival and response in patients with psoriasis on biological treatments
Authors: Xie Kenneth K , Braue Anna , Martyres Raymond , Varigos George
Published: January 2018

Background/Objectives

Biological agents provide a relatively safe and promising long‐term therapeutic option for patients with moderate to severe psoriasis in whom conventional treatment has failed. However, these agents are not effective in all patients. We aimed to examine the association of baseline patients’ characteristics with the short‐term efficacy and the long‐term survival of biological therapies in patients with moderate to severe psoriasis.

Methods

We performed a retrospective observational study of all patients who received biological treatment for psoriasis at the Royal Melbourne Hospital (N = 146). We extracted data on the patients’ characteristics and medical history. The outcomes we measured included a 75% reduction in psoriasis area and severity index (PASI) score at 12 and 24 weeks, the total duration of drug survival and dermatology life quality index (DLQI) scores. We used regression modelling to assess the association between each baseline patient‘s characteristic and outcome measures.

Results

An increase in baseline body mass index was associated with a reduced likelihood of achieving PASI75 at 12 and 24 weeks (P = 0.014) and also correlated with reduced long‐term therapeutic survival (P = 0.03). High rates of treatment termination were noted in patients with greater baseline DLQI (P = 0.038).

Conclusion

Greater body mass index at the initiation of biological treatment for psoriasis may contribute to its decreased short‐term efficacy. Similarly, a high body mass index or DLQI at baseline was associated with a relatively short duration of biological treatment retention.
The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update
Authors: Maurer M. , Magerl M. , Ansotegui I. , Aygören‐Pürsün E. , Betschel S. , Bork K. , Bowen T. , Balle Boysen H. , Farkas H. , Grumach A. S. , Hide M. , Katelaris C. , Lockey R. , Longhurst H. , Lumry W. R. , Martinez‐Saguer I. , Moldovan D. , Nast A. , Pawankar R. , Potter P. , Riedl M. , Ritchie B. , Rosenwasser L. , Sánchez‐Borges M. , Zhi Y. , Zuraw B. , Craig T.
Published: January 2018

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up‐to‐date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1‐inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE‐1/2 be defined and classified?, (2) How should HAE‐1/2 be diagnosed?, (3) Should HAE‐1/2 patients receive prophylactic and/or on‐demand treatment and what treatment options should be used?, (4) Should HAE‐1/2 management be different for special HAE‐1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE‐1/2 management incorporate self‐administration of therapies and patient support measures?
Food allergen‐sensitized CCR9+ lymphocytes enhance airways allergic inflammation in mice
Authors: Castan L. , Cheminant M.‐A. , Colas L. , Brouard S. , Magnan A. , Bouchaud G.
Published: January 2018

Background

The mechanisms of the atopic march, characterized by a natural progression from food and cutaneous allergies to rhinitis and asthma, are still unknown. However, as several organs can be involved, chemokines and their receptors might be implicated in this process and may be instrumental factors.

Objectives

We hypothesized that the T‐cell gut‐homing receptor CCR9 could be implicated in the evolution of allergic diseases.

Methods

We characterized the immune response and the role of CCR9 in a murine model combining food allergy to wheat gliadin and a model of acute airways inflammation in response to house dust mite.

Results

Compared with solely asthmatic‐like mice, we demonstrated that the aggravation of pulmonary symptoms in consecutive food and respiratory allergies, characterized by an increase in pulmonary resistance and a higher Th17/Treg ratio, was abrogated in CCR9 knockout mice. Moreover, transfer of food‐allergic CD4+ T cells from wild‐type but not from CCR9−/− aggravated airways inflammation demonstrating that CCR9 is involved in food allergy‐enhanced allergic airway inflammation to unrelated allergens.

Conclusion

Taken together, our results demonstrated a crucial role of the T‐cell homing receptor CCR9 in this model and validated its potential for use in the development of therapeutic strategies for allergic diseases.
Depressed mood is associated with loss of productivity in allergic rhinitis
Authors: Campbell A. P. , Hoehle L. P. , Phillips K. M. , Caradonna D. S. , Gray S. T. , Sedaghat A. R.
Published: January 2018

Allergic rhinitis (AR) is associated with significant decreases in quality of life and productivity losses. We hypothesized that symptoms of AR may differentially associate with lost productivity due to AR. We performed a cross‐sectional cohort study of 105 prospectively recruited patients with persistent AR. AR control, severity of depressed mood, and sinonasal symptoms were assessed with the Rhinitis Control Assessment Test (RCAT), Patient Health Questionnaire (PHQ‐2), and the 22‐item Sinonasal Outcome Test (SNOT‐22), respectively. Lost productivity was assessed by asking the number of days of work/school missed due to AR in the last 3 months. Patients missed a mean of 1.5 days (SD:2.9) of work or school. Lost productivity was associated with PHQ‐2 (adjusted linear regression coefficient [β] = .68, 95% CI: 0.20‐1.15, P = .007) analysis but not SNOT‐22 or RCAT scores. Productivity losses due to AR are associated with severity of depressed mood rather than classic nasal or extra‐nasal symptoms of AR.
Tumor necrosis factor family member LIGHT acts with IL‐1β and TGF‐β to promote airway remodeling during rhinovirus infection
Authors: Mehta A. K. , Doherty T. , Broide D. , Croft M.
Published: January 2018

Background

Rhinovirus (RV) can exacerbate allergen‐driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma‐like features in childhood without prior allergen exposure.

Aim

We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling.

Methods

We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL‐1β and TGF‐β, each previously shown to contribute to lung remodeling driven by allergen.

Results

Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT‐deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT‐deficient mice. Furthermore, neutralizing IL‐1β or TGF‐β also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV.

Conclusion

Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen‐associated airway remodeling.
Isolation of a high‐affinity Bet v 1‐specific IgG‐derived ScFv from a subject vaccinated with hypoallergenic Bet v 1 fragments
Authors: Gadermaier E. , Marth K. , Lupinek C. , Campana R. , Hofer G. , Blatt K. , Smiljkovic D. , Roder U. , Focke‐Tejkl M. , Vrtala S. , Keller W. , Valent P. , Valenta R. , Flicker S.
Published: January 2018

Background

Recombinant hypoallergenic allergen derivatives have been used in clinical immunotherapy studies, and clinical efficacy seems to be related to the induction of blocking IgG antibodies recognizing the wild‐type allergens. However, so far no treatment‐induced IgG antibodies have been characterized.

Objective

To clone, express, and characterize IgG antibodies induced by vaccination with two hypoallergenic recombinant fragments of the major birch pollen allergen, Bet v 1 in a nonallergic subject.

Methods

A phage‐displayed combinatorial single‐chain fragment (ScFv) library was constructed from blood of the immunized subject and screened for Bet v 1‐reactive antibody fragments. ScFvs were tested for specificity and cross‐reactivity to native Bet v 1 and related pollen and food allergens, and epitope mapping was performed. Germline ancestor genes of the antibody were analyzed with the ImMunoGeneTics (IMGT) database. The affinity to Bet v 1 and cross‐reactive allergens was determined by surface plasmon resonance measurements. The ability to inhibit patients’ IgE binding to ELISA plate‐bound allergens and allergen‐induced basophil activation was assessed.

Results

A combinatorial ScFv library was obtained from the vaccinated donor after three injections with the Bet v 1 fragments. Despite being almost in germline configuration, ScFv (clone H3‐1) reacted with high affinity to native Bet v 1 and homologous allergens, inhibited allergic patients’ polyclonal IgE binding to Bet v 1, and partially suppressed allergen‐induced basophil activation.

Conclusion

Immunization with unfolded hypoallergenic allergen derivatives induces high‐affinity antibodies even in nonallergic subjects which recognize the folded wild‐type allergens and inhibit polyclonal IgE binding of allergic patients.
Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice
Authors: Soria I. , López‐Relaño J. , Viñuela M. , Tudela J.‐I. , Angelina A. , Benito‐Villalvilla C. , Díez‐Rivero C. M. , Cases B. , Manzano A. I. , Fernández‐Caldas E. , Casanovas M. , Palomares O. , Subiza J. L.
Published: January 2018

Background

Polymerized allergoids coupled to nonoxidized mannan (PM‐allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM‐allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM‐allergoids administered sublingually in comparison with native allergens.

Methods

Three immunization protocols (4‐8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells.

Results

A quick antibody response and higher IgG2a/IgE ratio were observed with PM‐allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL‐4 ratio with a quick IL‐10 production by submandibular LN cells. An increase in CD4+CD25highFOXP3+ Treg cells was detected in LNs and spleen of mice treated with PM‐allergoids. These allergoids were better captured than native allergens by antigen‐presenting (CD45+MHC‐II+) cells obtained from the sublingual mucosa, including DCs (CD11b+) and macrophages (CD64+). Importantly, all the differential effects induced by PM‐allergoids were abolished when using oxidized instead of nonoxidized PM‐allergoids.

Conclusion

Our results demonstrate for the first time that PM‐allergoids administered through the sublingual route promote the generation of Th1 and FOXP3+ Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen‐presenting cells.
Immunoprofile of α‐Gal‐ and B‐antigen‐specific responses differentiates red meat‐allergic patients from healthy individuals
Authors: Apostolovic D. , Rodrigues R. , Thomas P. , Starkhammar M. , Hamsten C. , van Hage M.
Published: January 2018

Background

The galactose‐α‐1,3‐galactose (α‐Gal) epitope is involved in red meat allergy. As α‐Gal is structurally similar to the blood group B‐antigen, we explored the relationship between the immune responses to α‐Gal‐ and the B‐antigen in red meat‐allergic patients compared to healthy A/O or B blood donors.

Methods

Sera from 51 red meat‐allergic patients IgE‐positive to α‐Gal and 102 healthy blood donors (51 blood group A/O; 51 blood group B) were included. α‐Gal‐ and B‐antigen‐specific IgE (ImmunoCAP) and IgG/IgG1‐4 (ELISA) responses were determined. Basophil activation tests were performed.

Results

Fifteen healthy donors were IgE positive to α‐Gal, of which 3 had blood group B. The allergic patients had significantly higher α‐Gal IgE levels compared to the healthy donors. The majority of the allergic patients, but none of the healthy donors, had IgE against the B‐antigen. Inhibition studies revealed cross‐reactivity between α‐Gal and the B‐antigen. The biological activity of the B‐antigen was confirmed by basophil activation tests. Anti‐α‐Gal IgG1 and IgG4 levels were significantly higher in the patients compared to the healthy donors. Moreover, the IgG response to the B‐antigen was comparable between the allergic patients and healthy A/O donors.

Conclusion

Red meat‐allergic patients showed significantly higher α‐Gal IgE, IgG1, and IgG4 levels, reflecting a Th2 response, compared to healthy blood donors. Blood group B donors had significantly reduced antibody responses to α‐Gal, due to similarities with the B‐antigen, resulting in a lower risk of sensitization to α‐Gal and development of red meat allergy.
Skin inflammation exacerbates food allergy symptoms in epicutaneously sensitized mice
Authors: Kawasaki A. , Ito N. , Murai H. , Yasutomi M. , Naiki H. , Ohshima Y.
Published: January 2018

Background

Cutaneous exposure to food antigen through impaired skin barrier has been shown to induce epicutaneous sensitization, thereby causing IgE‐mediated food allergies.

Objective

We examined whether skin barrier impairment following epicutaneous sensitization exacerbates food allergies.

Methods

BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to MC903‐pretreated ear skin for 48 hours weekly and then intragastrically challenged with OVA. After the first oral challenge, the skin barrier was disrupted with topical application of MC903 or by tape‐stripping. Mice were monitored for changes in body temperature and the occurrence of diarrhea after undergoing the second oral challenge. Serum levels of mouse mast cell protease‐1 (mmcp1) and OVA‐specific IgE, IgG1, IgG2a antibodies and OVA‐specific IgA levels in intestinal lavage fluid were measured by ELISA. Tissue accumulation of eosinophils was determined histologically.

Results

Epicutaneously sensitized mice developed anaphylaxis after intragastric challenge, as evidenced by diarrhea, decreased body temperature, and increased serum mmcp1 levels. Skin barrier disruption by MC903 treatment or tape‐stripping exacerbated allergic reactions induced by oral challenge. MC903 treatment increased serum baseline and postchallenge mmcp1 levels. Topical pretreatment with dexamethasone alleviated allergic reactions that were exacerbated by MC903 treatment.

Conclusion

Even after eliminating exposure to the antigen, inflammation from skin barrier disruption can exacerbate the severity of food allergy symptoms. Serum baseline mmcp1 levels might be an effective marker for predicting the severity of antigen‐induced allergic symptoms.
Transrectal prostate biopsy sepsis rate following reduced quinolone antibiotic prophylaxis from six doses to single dose
Authors: Bangash Haider K. , Hawks Cynthia , McCombie Steve P. , Brown Matthew , Hayne Dickon
Published: January 2018

Background

This study aimed to evaluate the rates of infective complication related to transrectal prostate biopsy (TRPB) as our centre changed its protocol from six doses over 3 days to a single pre‐procedure prophylactic dose.

Methods

This prospective cohort study identified infective complication in patients who attended and subsequently underwent TRPB at the time of their one‐stop prostate clinic at our public tertiary hospital between August 2011 and April 2017. Patients who underwent TRPB between August 2011 and November 2014 received six doses of 500 mg of ciprofloxacin, taken twice daily over 3 days. This protocol was changed to a single dose of 500 mg of ciprofloxacin prior to biopsy from February 2015 to April 2017. Patients who had travelled to South East Asia in the 6 months prior to TRPB received a single dose of 1 g intravenous ertapenem prior to biopsy, and this remained unchanged throughout the study period. The rates of infective complication were recorded and compared between the groups of patients who had undergone six doses versus a single dose of prophylactic ciprofloxacin.

Results

A total of 766 patients underwent TRPB from August 2011 to April 2017. Of these, 357 patients received the 3‐day course of prophylaxis (Group 1) and 409 patients received the single dose prophylaxis (Group 2). Fifty‐five patients were excluded from analysis. There was no significant difference in infective complications between the two groups (3.4% (11/326) Group 1 versus 4.9% (19/385) Group 2, P = 0.40).

Conclusion

Our study supports the use of a single dose of ciprofloxacin as sufficient antibiotic prophylaxis prior to TRPB.
Robotic‐assisted radical cystectomy with intracorporeal urinary diversion versus open: early Australian experience
Authors: Chow Ken , Zargar Homayoun , Corcoran Niall M. , Costello Anthony J. , Peters Justin S. , Dundee Philip
Published: January 2018

Background

The aim of this study was to describe our initial Australian single surgeon experience with robotic‐assisted radical cystectomy (RARC) and intracorporeal urinary diversion (ICUD) and to compare the outcomes with open radical cystectomy (ORC).

Methods

Between January 2014 and June 2016, consecutive patients diagnosed with muscle invasive and high‐risk non‐muscle invasive bladder cancer undergoing radical cystectomy were included. Treatment modalities included either RARC with ICUD or ORC. ICUD consisted of either intracorporeal ileal conduit or orthotopic neobladder formation. Prospectively collected perioperative and oncological outcomes were analysed.

Results

Twenty‐six RARC and 13 ORC were performed. Median operating times were 362 and 240 min for RARC and ORC, respectively (P < 0.001). Estimated blood loss for RARC was 300 mL compared with 500 mL for ORC (P = 0.01). Post‐operative haemoglobin drop was less in the RARC cohort (20% versus 24%, P = 0.03). There was no statistical difference in overall 90‐day complication rates (81% versus 62%, P = 0.25) and 90‐day major complication rates (19% versus 23%, P = 0.67) between the RARC and ORC groups, respectively. Positive surgical margins for RARC were 4% and 8% for ORC (P = 1.0).

Conclusion

Early results demonstrate that the safe introduction of RARC with ICUD in Australia is potentially feasible without compromising perioperative and oncological outcomes. Future randomized trial with larger numbers will be required for further analysis in the Australian setting.
Five‐country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration
Authors: Fabbri Laura , Klebermass‐Schrehof Katrin , Aguar Marta , Harrison Catherine , Gulczyńska Ewa , Santoro Debora , Di Castri Marco , Rigo Vincent
Published: January 2018

Aim

Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting.

Methods

This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well‐recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10‐item questionnaire.

Results

The responses to nine of 10 questions showed that 67‐95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two‐thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath.

Conclusion

Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.
The effects of income transfers on poverty reduction in people with disabilities in South Korea
Authors: Lee Ji Sun , Choi Jeong‐Kyun
Published: January 2018

Using a nationally representative sample dataset from the 2016 Korean Welfare Panel Study, we examined the anti‐poverty effects of income transfers in people with disabilities. Our findings indicate that in households with a person with a disability, income transfers decreased by 55.9% and 84.8% of the pre‐transfer poverty rate and poverty gap, respectively. Before income transfers, households with a person with a disability were 1.94 times more likely to be poor compared to those without a person with a disability. When income transfers were offered, the chance of being poor in the disability group was only 1.11 times higher than that in the non‐disability group. Findings from the aggregated data suggest that means‐tested income transfers were more effective in reducing poverty levels than social insurance or private income transfers. At the individual level, the provision of means‐tested programs was also more likely to decrease the likelihood of experiencing poverty than social insurance and private income transfers.
Do final‐year medical students have sufficient prescribing competencies? A systematic literature review
Authors: Brinkman David J. , Tichelaar Jelle , Graaf Sanne , Otten René H. J. , Richir Milan C. , van Agtmael Michiel A.
Published: January 2018

Aims

Prescribing errors are an important cause of patient safety incidents and are frequently caused by junior doctors. This might be because the prescribing competence of final‐year medical students is poor as a result of inadequate clinical pharmacology and therapeutic (CPT) education. We reviewed the literature to investigate which prescribing competencies medical students should have acquired in order to prescribe safely and effectively, and whether these have been attained by the time they graduate.

Methods

PubMed, EMBASE and ERIC databases were searched from the earliest dates up to and including January 2017, using the terms ‘prescribing’, ‘competence’ and ‘medical students’ in combination. Articles describing or evaluating essential prescribing competencies of final‐year medical students were included.

Results

Twenty‐five articles describing, and 47 articles evaluating, the prescribing competencies of final‐year students were included. Although there seems to be some agreement, we found no clear consensus among CPT teachers on which prescribing competencies medical students should have when they graduate. Studies showed that students had a general lack of preparedness, self‐confidence, knowledge and skills, specifically regarding general and antimicrobial prescribing and pharmacovigilance. However, the results should be interpreted with caution, given the heterogeneity and methodological weaknesses of the included studies.

Conclusions

There is considerable evidence that final‐year students have insufficient competencies to prescribe safely and effectively, although there is a need for a greater consensus among CPT teachers on the required competencies. Changes in undergraduate CPT education are urgently required in order to improve the prescribing of future doctors.
Pharmacokinetic–pharmacodynamic modelling of neutrophil response to G‐CSF in healthy subjects and patients with chemotherapy‐induced neutropenia
Authors: Melhem Murad , Delor Isabelle , Pérez‐Ruixo Juan Jose , Harrold John , Chow Andrew , Wu Liviawati , Jacqmin Philippe
Published: January 2018

Aim

The objective of the present study was to use pharmacokinetic–pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy‐induced neutropenia treated with filgrastim and pegfilgrastim.

Methods

Data were extracted from 10 phase I–III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor–binding model that assumed quasi‐equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic–pharmacodynamic‐type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production.

Results

The systemic half‐lives of filgrastim (2.6 h) and pegfilgrastim (10.1 h) were as expected. The effective half‐life of chemotherapy was 9.6 h, with a 2‐day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model.

Conclusion

This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.
Teicoplanin anaphylaxis associated with surgical prophylaxis
Authors: Azamgarhi Tariq , Shah Ashik , Warren Simon
Published: January 2018

Aims

The aim of this paper is to determine the rate of true anaphylaxis to teicoplanin.

Methods

A case‐series including all suspected anaphylactic reactions attributed to teicoplanin anaphylaxis within a single institution over a 29‐month period were categorised according to the probability of true IgE‐mediated anaphylaxis using previously published criteria. The number of patients who received teicoplanin was determined and used to calculate the rate of IgE‐mediated anaphylaxis.

Results

Approximately 18 800–19 600 patients received teicoplanin during the study period, during which there were 14 cases of suspected anaphylaxis attributed to the administration of teicoplanin: five were categorised as definite IgE‐mediated anaphylaxis, four as probable, two as uncertain and three were excluded. Of the excluded cases, two were found to have positive intradermal skin testing to alternative agents (rocuronium and chlorhexidine), and one did not meet the published clinical criteria.

We therefore calculated the rate of IgE‐mediated anaphylaxis to be between 0.046% and 0.059% (equating to between 1:2088 and 1:1655).

Conclusions

This is the first study to calculate a rate of IgE‐mediated anaphylaxis to teicoplanin in clinical practice. Our case series suggests that these life‐threatening reactions occur less commonly than reported by the manufacturers. Mast cell tryptase is unreliable when used to predict the likelihood of IgE‐mediated anaphylaxis to teicoplanin.
Improving the Safety Assessment of Chemicals and Drug Candidates by the Integration of Bioinformatics and Chemoinformatics Data
Authors: Steger‐Hartmann Thomas , Pognan Francois
Published: January 2018

The application of read‐across and in silico tools for regulatory decision‐making has been limited for pharmaceutical compounds to the assessment of genotoxic impurity. In contrast, the broad availability of toxicity data for industrial chemicals has triggered regulatory frameworks for read‐across (e.g. ECHA Read‐Across Assessment Framework), software tools and public databases for an automated process of gap filling in the context of safety assessment. This MiniReview provides an overview of the currently existing in silico and read‐across approaches for chemicals together with recent developments for pharmaceutical compounds in these areas. It also highlights the differences and commonalities in the in silico safety assessment of industrial chemicals and drug candidates. Whereas toxicity data collection and sharing is now common practice for chemicals falling under the European REACH regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals), the biggest hurdle for establishing preclinical safety databases for pharmaceutical compounds is the unwillingness to share proprietary data and lack of published data sets. In a recent consortium approach, thirteen pharmaceutical companies, eleven academic partners and six small to medium size enterprises (SMEs) of the bioinformatics sector joined forces over the last 7 years within the European Innovative Medicines Initiative project eTOX (‘electronic toxicity’) to design and implement a strategy for leveraging these preclinical data for small molecules and sharing them across project partners. The eTOX database has evolved as the largest preclinical toxicity database for drugs and drug candidates and currently contains more than 1900 different chemical structures and more than 8000 in vivo toxicity study data sets. It can be foreseen that the development and application of such databases for drugs or drug candidates will in the future also cross‐fertilize the read‐across and the in silico assessment of industrial or consumer chemicals particularly as soon as human safety data from clinical trials are integrated too.
Post‐partum haemorrhage and tranexamic acid: a global issue
Authors: Hibbs Stephen P. , Roberts Ian , Shakur‐Still Haleema , Hunt Beverley J.
Published: January 2018

Post‐partum haemorrhage (PPH) remains the major cause of maternal death worldwide, with the overwhelming majority of bleeding deaths occurring in low income countries. These bleeding deaths occur due to a complex network of biological and socioeconomic factors, including changes to haemostasis and fibrinolysis during pregnancy. Tranexamic acid (TxA) has been shown to reduce death in bleeding trauma patients safely and is effective in reducing bleeding in surgical patients, however its role in PPH has been less well established. We discuss the impact of the recently published World Maternal Antifibrinolytic (WOMAN) trial, which demonstrated a significant reduction in bleeding deaths (Risk ratio 0·81) in women with PPH who received intravenous TxA compared to those receiving placebo. There were no increases in post‐partum thrombotic rates in mothers or breast‐fed babies. This trial has shown that intravenous TxA can be used safely and effectively to treat PPH, and should be implemented widely to reduce death due to PPH. However, for the full benefit of TxA to be fully realised in resource‐constrained settings, the effectiveness of oral or topical administration and/or pre‐emptive dosing need to be investigated.
Treatment of relapsed/refractory acute myeloid leukaemia in adults
Authors: Rashidi Armin , Weisdorf Daniel J. , Bejanyan Nelli
Published: January 2018

The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo‐HCT), both transplant‐related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti‐leukaemia potential of the immune system. Several small‐molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre‐clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low‐toxicity maintenance strategies. While cure of relapsed/refractory AML without allo‐HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.
Comparing transfusion reaction risks for various plasma products – an analysis of 7 years of ISTARE haemovigilance data
Authors: Saadah Nicholas H. , van der Bom Johanna G. , Wiersum‐Osselton Johanna C. , Richardson Clive , Middelburg Rutger A. , Politis Constantina , Renaudier Philippe , Robillard Pierre , Schipperus Martin R.
Published: January 2018

Plasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion‐Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006–2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6–72·2 reactions/105 units transfused); febrile non‐haemolytic transfusion reactions (0–9·1); transfusion‐associated circulatory overload (0–1·9); transfusion related acute lung injury (TRALI) (0–1·2); and hypotensive reactions (0–0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19–1·40)] and hypotensive reactions [OR = 2·17 (1·38–3·41)] than whole blood‐derived plasma. Pathogen‐inactivated plasma was associated with fewer transfusion reactions than untreated plasma.
Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients
Authors: Jurczyszyn Artur , Radocha Jakub , Davila Julio , Fiala Mark A. , Gozzetti Alessandro , Grząśko Norbert , Robak Paweł , Hus Iwona , Waszczuk‐Gajda Anna , Guzicka‐Kazimierczak Renata , Atilla Erden , Mele Giuseppe , Sawicki Waldemar , Jayabalan David S. , Charliński Grzegorz , Szabo Agoston G. , Hajek Roman , Delforge Michel , Kopacz Agnieszka , Fantl Dorotea , Waage Anders , Avivi Irit , Rodzaj Marek , Leleu Xavier , Richez Valentine , Knopińska‐Posłuszny Wanda , Masternak Anna , Yee Andrew J. , Barchnicka Agnieszka , Druzd‐Sitek Agnieszka , Guerrero‐Garcia Thomas , Liu Jieqi , Vesole David H. , Castillo Jorge J.
Published: January 2018

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety‐eight patients were treated with novel agents, with an overall response rate of 78%. Fifty‐five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow‐up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109/l and peripheral blood plasma cell count ≥20 × 109/l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.
Profit‐Sharing and Wages: An Empirical Analysis Using French Data between 2000 and 2007
Authors: Delahaie Noélie , Duhautois Richard
Published: January 2018

Economic theory presents different arguments about how profit‐sharing may affect wages. First, profit‐sharing may substitute for the base wage. Second, profit‐sharing can be interpreted as an ‘efficiency wage’ that adds to the base wage and increases total compensation. The existing empirical literature has not determined which of these arguments is valid. This article attempts to address this issue for France between 2000 and 2007. Based on a difference‐in‐differences selection model, we show that bonuses in firms adopting profit‐sharing are too small to conclude whether it substitutes for or complements the base wage. While base wage levels are generally higher among profit‐sharing firms, changes in the base wage over this period are lower among firms that have had profit‐sharing for a number of years.
Nerve‐sparing radical cystectomy has a beneficial impact on urinary continence after orthotopic bladder substitution, which becomes even more apparent over time
Authors: Furrer Marc A. , Studer Urs E. , Gross Tobias , Burkhard Fiona C. , Thalmann George N. , Nguyen Daniel P.
Published: January 2018

Objective

To analyse urinary continence in long‐term survivors after radical cystectomy (RC) and orthotopic bladder substitution (OBS) according to attempted nerve‐sparing (NS) status.

Patients and Methods

We analysed 180 consecutive patients treated at our department between 1985 and 2007, who underwent RC with OBS, and survived ≥10 years after RC. We stratified patients by attempted NS status and evaluated continence outcomes using descriptive statistics and Cox proportional hazards regression models. A secondary analysis evaluated erectile function as a quality control for attempted NS.

Results

The median (interquartile range [IQR]) age at RC was 62 (57−71) years. Of 180 patients, attempted NS status was none in 24 (13%), unilateral in 100 (56%), and bilateral in 56 (31%). After a median (IQR) follow‐up of 169 (147−210) months, 160 (89%) patients were continent during daytime and 124 (69%) during night‐time. In multivariable analysis, any degree of attempted NS was significantly associated with daytime continence (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.05–4.11; P = 0.04). Correspondingly, any attempted NS was significantly associated with night‐time continence (OR 2.51, 95% CI 1.08–5.85; P = 0.03). Recovery of erectile function at 5 years was also significantly associated with attempted NS (P < 0.001).

Conclusion

Nerve‐sparing during RC and OBS was associated with better long‐term continence outcomes. This becomes more apparent as the patients age with their OBS. We advocate a NS RC whenever an OBS is considered.
Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO‐Conotoxin GeXIVA[1,2] and GeXIVA [1,4]
Authors: Yu Shurun , Wu Yong , Xu Pan , Wang Shuai , Zhangsun Dongting , Luo Sulan
Published: January 2018

αO‐conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC50s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation, and thiol, which would be the key factors to affect stabilities of the two isomers in vivo. Simultaneously, forced degradation was carried out to evaluate stabilities of the two isomers. GeXIVA[1,2] and GeXIVA[1,4] were unstable when they were incubated in serum and digestive enzymes at 37°C. Their disulfide bond frameworks were easy to be scrambled in GSH and HSA. For different stress conditions, their stabilities were impacted greatly by oxidation, temperature, and alkaline conditions. The results may provide a foundation for storage conditions, structural modification, and pharmaceutical preparation of GeXIVA[1,2] and GeXIVA[1,4].
Prevalence and longitudinal trends of food allergy during childhood and adolescence: Results of the Isle of Wight Birth Cohort study
Authors: Venkataraman D. , Erlewyn‐Lajeunesse M. , Kurukulaaratchy R. J. , Potter S. , Roberts G. , Matthews S. , Arshad S. H.
Published: January 2018

Background

The prevalence and time trends of food allergy change during childhood depending on the age of the child and the type of food.

Objective

To study prevalence and longitudinal trends in food allergy from birth to 18 years in an unselected birth cohort in the Isle of Wight.

Method

Information on food allergy was collected at ages 1, 2, 4, 10 and 18 years from the Isle of Wight Birth Cohort (n = 1456). Skin prick testing (SPT) was performed at the age of 1 and 2 years in symptomatic children. At 4, 10 and 18 years of age, participants were tested to a panel of food and aeroallergens. Food allergy was diagnosed based on the criteria: symptoms suggestive of a typical IgE‐mediated reaction and reaction <4 hours following exposure to a known food allergen. McNemar's test was used to determine significance of changes in prevalence over time.

Results

The prevalence of food allergy remained relatively constant in early childhood (5.3%, 4.4% and 5.0% at 1, 2 and 4 years, respectively), with significant decline at 10 years (2.3%, P < .001 vs 4 years) followed by significant rise at 18 years (4%, P = .02 vs 10 years). Cow's milk (1.6%‐3.5%) and egg (1.1%‐1.4%) were the most common allergens in the first 10 years with peanut (1%) and tree nuts (0.5%) becoming more prevalent beyond 10 years. Fruit and wheat allergy were less common at 10 years, and shellfish and kiwi emerged during adolescence. The prevalence of food allergy plus positive SPT was 1.3%, 0.8%, 0.8%, 0.9% and 2.2% at 1, 2, 4, 10 and 18 years, respectively.

Conclusion

Food allergy is highly prevalent in infancy with partial resolution during late childhood. However, a number of children acquire new food allergy during adolescence resulting in a relatively higher prevalence at 18 years.
Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection
Authors: de Leur K , Clahsen-van Groningen M C , van den Bosch T P P , de Graav G N , Hesselink D A , Samsom J N , Baan C C , Boer K
Published: January 2018

We hypothesize that T cells such as interleukin (IL)-21+B cell lymphoma 6 (BCL6)+ T follicular helper cells can regulate B cell-mediated immunity within the allograft during acute T cell-mediated rejection; this process may feed chronic allograft rejection in the long term. To investigate this mechanism, we determined the presence and activation status of organized T and B cells in so-called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection. Biopsies showing the following primary diagnosis were included: acute/active antibody-mediated rejection, C4d+ (a/aABMR), acute T cell-mediated rejection grade I (aTCMRI) and acute T cell-mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin (Ig)D, cell proliferation (Ki67) and double immunofluorescent stainings for IL-21 and BCL6 were performed. Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL-21 was present in all biopsies. However, co-localization with BCL6 was observed mainly in aTCMRI biopsies. In conclusion, ELSs with an activated phenotype are found predominantly in aTCMRI where T cells co-localize with B cells. These findings suggest a direct pathway of B cell alloactivation at the graft site during T cell mediated rejection.
First Nations parenting and child reunification: Identifying strengths, barriers, and community needs within the child welfare system
Authors: Toombs Elaine , Drawson Alexandra S. , Bobinski Tina , Dixon John , Mushquash Christopher J.
Published: January 2018

First Nations communities are seeking to improve current service delivery models and create alternative evidence‐based strategies. A First Nations child welfare organization has prioritized further understanding of reunification and parenting, including identification of successes and barriers to reunification, and service needs within communities. These priorities were addressed with a community‐based participatory research model and guided by a Research Advisory. Results were analysed using a blend of grounded theory and thematic analysis techniques. Participants indicated that placing children with extended family or within home communities facilitate best child outcomes. These reunifications could be increased by promoting parental and community capacity. Successes identified within communities included available supports, such as those that increased empowerment and community capacity. Identified barriers within communities were the lack of culturally appropriate services, hesitancy to obtain available support due to fears of child welfare intervention, and mental health difficulties of community member.