Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of ...patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.
Summary
Anaphylaxis in pregnancy is a rare but severe complication for both mother and infant. Population‐based data on anaphylaxis in pregnancy are lacking from mainland European countries. This ...multinational study presents the incidence, causative agents, management and maternal and infant outcomes of anaphylaxis in pregnancy. This descriptive multinational study used a combination of retrospective (Finnish medical registries) and prospective population‐based studies (UK, France, Belgium and the Netherlands) to identify cases of anaphylaxis. Sixty‐five cases were identified among 4,446,120 maternities (1.5 per 100,000 maternities; 95%CI 1.1–1.9). The incidence did not vary between countries. Approximately three‐quarters of reactions occurred at the time of delivery. The most common causes were antibiotics in 27 women (43%), and anaesthetic agents in 11 women (17%; including neuromuscular blocking drugs, 7), which varied between countries. Anaphylaxis had very poor outcomes for one in seven mothers and one in seven babies; the maternal case fatality rate was 3.2% (95%CI 0.4–11.0) and the neonatal encephalopathy rate was 14.3% (95%CI 4.8–30.3). Across Europe, anaphylaxis related to pregnancy is rare despite having a multitude of causative agents and different antibiotic prophylaxis protocols.
Objective
The aim of this study was to estimate the incidence of anaphylaxis in pregnancy and describe the management and outcomes in the UK.
Design
A population‐based descriptive study using the UK ...Obstetric Surveillance System (UKOSS).
Setting
All consultant‐led maternity units in the UK.
Population
All pregnant women who had anaphylaxis between 1 October 2012 and 30 September 2015. Anaphylaxis was defined as a severe, life‐threatening generalised or systemic hypersensitivity reaction.
Methods
Prospective case notification using UKOSS.
Main outcome measures
Maternal mortality, severe maternal morbidity, neonatal mortality and severe neonatal morbidity.
Results
There were 37 confirmed cases of anaphylaxis in pregnancy, giving an estimated incidence of 1.6 (95% CI: 1.1–2.2) per 100 000 maternities. Four cases of anaphylaxis were in women with known penicillin allergies: two received co‐amoxiclav and two cephalosporins. Twelve women had anaphylaxis following prophylactic use of antibiotics at the time of a caesarean delivery. Prophylactic use of antibiotics for Group B streptococcal infection accounted for anaphylaxis in one woman. Two women died (5%), 14 (38%) women were admitted to intensive care and seven women (19%) had one or more additional severe maternal morbidities, which included three haemorrhagic events, two cardiac arrests, one thrombotic event and one pneumonia. No infants died; however, in those infants whose mother had anaphylaxis before delivery (n = 18) there were seven (41%) neonatal intensive care unit admissions, three preterm births and one baby was cooled for neonatal encephalopathy.
Conclusions
Anaphylaxis is a rare severe complication of pregnancy and frequently the result of a reaction to antibiotic administration. This study highlights the seriousness of the outcomes of this condition for the mother. The low incidence is reassuring given the large proportion of the pregnant population that receive prophylactic antibiotics during delivery.
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Anaphylaxis is a rare severe complication of pregnancy and frequently the result of a reaction to antibiotic administration.
Tweetable
Anaphylaxis is a rare severe complication of pregnancy and frequently the result of a reaction to antibiotic administration.
A 2DH numerical, model which is capable of computing nearshore circulation and morphodynamics, including dune erosion, breaching and overwash, is used to simulate overwash caused by Hurricane Ivan ...(2004) on a barrier island. The model is forced using parametric wave and surge time series based on field data and large-scale numerical model results. The model predicted beach face and dune erosion reasonably well as well as the development of washover fans. Furthermore, the model demonstrated considerable quantitative skill (upwards of 66% of variance explained, maximum bias −
0.21
m) in hindcasting the post-storm shape and elevation of the subaerial barrier island when a sheet flow sediment transport limiter was applied. The prediction skill ranged between 0.66 and 0.77 in a series of sensitivity tests in which several hydraulic forcing parameters were varied. The sensitivity studies showed that the variations in the incident wave height and wave period affected the entire simulated island morphology while variations in the surge level gradient between the ocean and back barrier bay affected the amount of deposition on the back barrier and in the back barrier bay. The model sensitivity to the sheet flow sediment transport limiter, which served as a proxy for unknown factors controlling the resistance to erosion, was significantly greater than the sensitivity to the hydraulic forcing parameters. If no limiter was applied the simulated morphological response of the barrier island was an order of magnitude greater than the measured morphological response.
Objective
This study aimed to examine the factors associated with maternal mortality among women aged ≥35 years.
Design
Unmatched population based case–control study.
Setting
United Kingdom.
...Population
Between 2009 and 2012, 105 cases of maternal deaths aged ≥35 years were extracted from the surveillance database of the MBRRACE‐UK confidential enquiries into maternal deaths in the UK. In addition, 766 controls aged ≥35 years were identified from the UK Obstetric Surveillance System (2005–2012).
Methods
Risk factors known to be associated with maternal mortality and morbidity and for which data were available were examined for their association with maternal mortality among women ≥35 years using logistic regression analysis.
Main outcome measures
Odds ratios and 95% confidence intervals associated with maternal death.
Results
Five factors were found to be significantly associated with increased odds of death among women aged ≥35 years: smoking during pregnancy (adjusted odds ratio (aOR) 2.06, 95% CI 1.13–3.75), inadequate use of antenatal care (aOR 23.62, 95% CI 8.79–63.45), medical co‐morbidities (aOR 5.92, 95% CI 3.56–9.86) and previous pregnancy problems (aOR 2.06, 95% CI 1.23–3.45). The odds associated with death increased by 12% per year increase in age (aOR 1.12, 95% CI 1.02–1.22).
Conclusion
Age was associated with maternal mortality even after adjusting for other known risk factors. Importantly, this study showed an association between maternal mortality and smoking among women aged 35 years or older. It emphasises the importance of public health action to reduce smoking levels and address trends in rising maternal age.
Tweetable
Smoking is a risk factor for maternal death for those aged over 35 years.
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Smoking is a risk factor for maternal death for those aged over 35 years.
Children exposed to institutional care often suffer from "structural neglect" which may include minimum physical resources, unfavorable and unstable staffing patterns, and socially emotionally ...inadequate caregiver-child interactions. This chapter is devoted to the analysis of the ill effects of early institutional experiences on resident children's development. Delays in the important areas of physical, hormonal, cognitive, and emotional development are discussed. The evidence for and against the existence of a distinctive set of co-occurring developmental problems in institutionalized children is weighed and found to not yet convincingly demonstrate a "postinstitutional syndrome." Finally, shared and nonshared features of the institutional environment and specific genetic, temperamental, and physical characteristics of the individual child are examined that might make a crucial difference in whether early institutional rearing leaves irreversible scars.
Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard ...of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT.
In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II).
In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy <partial remission by computed tomography (CT) as significant and non-redundant RFs for PFS. A risk score composed of these equally weighed RFs was significantly prognostic for PFS (HR = 1.67 for each additional RF; P < 0.0001). Validation in an independent sample of 389 patients treated in different clinical settings with evaluation of response to salvage therapy by functional imaging instead of CT confirmed the excellent discrimination of risk groups and significant prognostication of PFS and overall survival (OS) after ASCT (HR = 1.70 and HR = 1.63, respectively; P < 0.0001).
Based on this large study (n = 1045), precise and valid risk prognostication in HL patients undergoing ASCT can be achieved with five easily available clinical RFs. The proposed prognostic score hence allows reliable stratification of patients for innovative therapeutic approaches in clinical practice and future trials.
GHSG HD10 NCT00265018, HD11 NCT00264953, HD12 NCT00265031, HD13 ISRCTN63474366, HD14 ISRCTN04761296, HD15 ISRCTN32443041 and HDR2 NCT00025636.
The effects of ultrasound at 35–39
kHz on several wool dyeing and finishing processes have been investigated as a way of reducing environmental impact. Ultrasound improved the effectiveness of ...cleaning scoured wool in water and to a lesser extent in water-nonionic surfactant. Scanning electron microscopy did not indicate any surface damage. Fluorescence microscopy revealed increased levels of sulphydryl groups on the wool surface suggesting ultrasound caused the removal of thioester-bound lipids. Ultrasound pre-treatment increased the effectiveness of subsequent oxidative–reductive bleaching, but had no effect on the uptake of acid levelling and acid milling dyes. The pre-treatment retarded the uptake of reactive dye, possibly by increasing the crystallinity of the fibre or removing surface bound lipids. Ultrasound did not improve dyeing under conditions that are currently used in industry, but did show potential to reduce the chemical and energy requirements of dyeing wool with reactive and acid milling dyes, but not acid levelling dyes.
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