Role and prevalence of impaired awareness of hypoglycaemia in ambulance service attendances to people who have had a severe hypoglycaemic emergency: a mixed-methods study

Objectives (1) To compare the experiences of people who are affected by diabetes-related hypoglycaemia and either do or do not require an emergency attendance and (2) to measure the prevalence of impaired awareness of hypoglycaemia in patients who are attended by an ambulance service due to a severe hypoglycaemic event.  Design A sequential mixed-methods study.  Setting A qualitative interview study was undertaken with 31 people with diabetes (types 1 and 2) resident in the central belt of Scotland. A national prevalence survey of 590 Scottish Ambulance Service patients who had recently experienced a severe hypoglycaemic emergency requiring ambulance clinicians attendance. Impaired awareness of hypoglycaemia was measured using two standardised measures.  Results Considerable differences in impaired awareness of hypoglycaemia were found in the experiences of participants who did or did not require the ambulance service to treat their severe hypoglycaemic events. Those who required an ambulance reported fewer warning signs and symptoms. The prevalence of impaired awareness of hypoglycaemia in ambulance service call-outs as assessed by two standardised measures was 53% and 60%, respectively.  Conclusions The prevalence of impaired awareness of hypoglycaemia among those who require an ambulance following a hypoglycaemic event is more than twice that found in the general population of people with diabetes. This may be because the experiences of impaired awareness in people who require an ambulance following a severe hypoglycaemic event differ to those who do not. This study provides important information to guide future prehospital clinical practice, and to develop and evaluate theoretically informed interventions. Improvements in prehospital care for this patient population could lead to global improvements in health outcomes and decreased service costs

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site

Recent trends in breast cancer incidence in US white women by county-level urban/rural and poverty status

<p>Abstract</p> <p>Background</p> <p>Unprecedented declines in invasive breast cancer rates occurred in the United States between 2001 and 2004, particularly for estrogen receptor-positive tumors among non-Hispanic white women over 50 years. To understand the broader public health import of these reductions among previously unstudied populations, we utilized the largest available US cancer registry resource to describe age-adjusted invasive and <it>in situ </it>breast cancer incidence trends for non-Hispanic white women aged 50 to 74 years overall and by county-level rural/urban and poverty status.</p> <p>Methods</p> <p>We obtained invasive and <it>in situ </it>breast cancer incidence data for the years 1997 to 2004 from 29 population-based cancer registries participating in the North American Association of Central Cancer Registries resource. Annual age-adjusted rates were examined overall and by rural/urban and poverty of patients' counties of residence at diagnosis. Joinpoint regression was used to assess trends by annual quarter of diagnosis.</p> <p>Results</p> <p>Between 2001 and 2004, overall invasive breast cancer incidence fell 13.2%, with greater reductions among women living in urban (-13.8%) versus rural (-7.5%) and low- (-13.0%) or middle- (-13.8%) versus high- (-9.6%) poverty counties. Most incidence rates peaked around 1999 then declined after second quarter 2002, although in rural counties, rates decreased monotonically after 1999. Similar but more attenuated patterns were seen for <it>in situ </it>cancers.</p> <p>Conclusion</p> <p>Breast cancer rates fell more substantially in urban and low-poverty, affluent counties than in rural or high-poverty counties. These patterns likely reflect a major influence of reductions in hormone therapy use after July 2002 but cannot exclude possible effects due to screening patterns, particularly among rural populations where hormone therapy use was probably less prevalent.</p

Recent breast cancer trends among Asian/Pacific Islander, Hispanic, and African-American women in the US: changes by tumor subtype

Abstract available at publisher's website

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype

How to specify healthcare process improvements collaboratively using rapid, remote consensus-building: a framework and a case study of its application

Abstract: Background: Practical methods for facilitating process improvement are needed to support high quality, safe care. How best to specify (identify and define) process improvements – the changes that need to be made in a healthcare process – remains a key question. Methods for doing so collaboratively, rapidly and remotely offer much potential, but are under-developed. We propose an approach for engaging diverse stakeholders remotely in a consensus-building exercise to help specify improvements in a healthcare process, and we illustrate the approach in a case study. Methods: Organised in a five-step framework, our proposed approach is informed by a participatory ethos, crowdsourcing and consensus-building methods: (1) define scope and objective of the process improvement; (2) produce a draft or prototype of the proposed process improvement specification; (3) identify participant recruitment strategy; (4) design and conduct a remote consensus-building exercise; (5) produce a final specification of the process improvement in light of learning from the exercise. We tested the approach in a case study that sought to specify process improvements for the management of obstetric emergencies during the COVID-19 pandemic. We used a brief video showing a process for managing a post-partum haemorrhage in women with COVID-19 to elicit recommendations on how the process could be improved. Two Delphi rounds were then conducted to reach consensus. Results: We gathered views from 105 participants, with a background in maternity care (n = 36), infection prevention and control (n = 17), or human factors (n = 52). The participants initially generated 818 recommendations for how to improve the process illustrated in the video, which we synthesised into a set of 22 recommendations. The consensus-building exercise yielded a final set of 16 recommendations. These were used to inform the specification of process improvements for managing the obstetric emergency and develop supporting resources, including an updated video. Conclusions: The proposed methodological approach enabled the expertise and ingenuity of diverse stakeholders to be captured and mobilised to specify process improvements in an area of pressing service need. This approach has the potential to address current challenges in process improvement, but will require further evaluation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Girls Who Had to Grow Up: Reflections on Motherhood and Dual Identity in Lewis Carroll\u27s Wonderland and J.M. Barrie\u27s Neverland

My thesis explores the world of the imaginary in Lewis Carroll\u27s Alice\u27s Adventures in Wonderland and J.M. Barrie\u27s Peter Pan and its connection to the world of the mundane experienced by the typical Victorian housewife and mother. Both are intimately connected within the texts, primarily in the characters\u27 dual roles as dictated by the gendered expectations of Victorian society. While in the imaginary world, both Alice and Wendy experience mini-versions of their future lives. They exist as girl and mother simultaneously. Carroll, by creating a hostile environment, grotesque motherimages, and a confused, argumentative Alice, shows a negative portrait of motherhood, since he never wanted little girls to become women. In contrast, Barrie depicts motherhood as sacred, something to be desired and protected at all costs. By necessity, maternal ideology is connected to female sexuality but is far superior in value. Both authors created an escape from the mundane realities of Victorian life wherein the audience could contemplate its societal roles. Barrie\u27s story elevates mothers and their connection to eternal childhood, and Carroll\u27s elevates girlhood, questioning the absurdities of grown-up reality. I also explore the dual nature of the secondary characters, analyzing the females against the Victorian Madonna/harlot dichotomy. For example, Tinker Bell, the working-class, profane fairy to Wendy\u27s middle-class angel, is allowed much more freedom of expression and power to control her life than Wendy, though this freedom comes with a price. Primarily, she seeks Peter\u27s company and attention, but she must settle for second place when Wendy is around. Mrs. Darling, the representation of angelic motherhood, is Barrie\u27s professed favorite character. Though she cannot go back to Neverland, she experiences it vicariously by tidying up her children\u27s minds. Through her we see what Wendy is destined to become, as well as Barrie\u27s expression of the pivotal, sacred role of the mother. The male characters also play dual roles - sons and husbands - though they mostly serve to further define the female heroines. Alice suffers an identity crisis throughout her time in Wonderland, particularly since her place in the hierarchy of power is constantly changing. Her relationships with the White Rabbit, the Caterpillar, the King of Hearts, and others are what she uses to understand herself within the dream. Conversely, in Peter Pan, Barrie\u27s male characters are defined by their relationship to the dominant females within the story. Mr. Darling and Captain Hook illustrate the dual nature of the Victorian male, though neither figure embodies the typical stereotype. The authors\u27 treatment of the male characters does show insight into, and even a forgiveness for, their multiple flaws, but they are most often depicted according to how their behavior affects the heroines. By creating these girl-characters in fantastic settings, both authors made an appeal to their audience to become (or avoid becoming) what seemed inevitable: adult females. By doing so, they also displayed how the institution of motherhood affected their own realities and, perhaps subconsciously, what they wanted to sustain or change about the gendered expectations of Victorian society