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Background: Normative data for the effect of cardiopulmonary bypass (CPB) on coronary artery Doppler velocities by transesophageal echocardiography in paediatric patients with congenital heart disease (CHD) are lacking. The objective of the study was to prospectively examine the effects of CPB on coronary artery flow patterns by transesophageal echocardiography before and after CPB in children with CHD. Methods: All cases undergoing CHD surgery at the Hospital for Sick Children, Toronto, were eligible. The excluded cases included Norwood operation, heart transplantation, or weight

(1) Background: Dalbavancin is a long-acting lipoglycopeptide antibiotic approved for skin and soft-tissue infections. Post-marketing experience suggests dalbavancin is being used for off-label indications that normally require long-term intravenous (IV) antibiotics; however, data assessing this off-label usage are limited. The purpose of this study was to evaluate the real-world efficacy, safety, and financial impact of off-label dalbavancin use. (2) Methods: This is a retrospective, observational study conducted within a 4-hospital health system. Adult patients who received dalbavancin from January 2018 to January 2021 for an off-label indication were included. The primary outcome was clinical success at 90 days. Secondary outcomes included safety (nephrotoxicity and hepatotoxicity). A pharmacoeconomic analysis was performed by comparing the cost of dalbavancin to the anticipated cost of patient stay if standard IV therapy was given. (3) Results: Forty-eight patients met study criteria. Indications included osteomyelitis (54%), endocarditis (23%), bacteremia (15%), and prosthetic joint infection (8%). The predominant organism was S. aureus (60%), with 42% caused by methicillin-resistant S. aureus. Overall, 41 (85%) patients achieved clinical success at 90 days, including 85% with osteomyelitis, 82% with endocarditis, and 86% with bacteremia. There were no instances of nephrotoxicity or hepatotoxicity. Estimated cost avoidance per patient was USD 5313 and USD 1683 if traditional IV therapy would have been completed in the hospital and skilled nursing facility, respectively. (4) Conclusion: Dalbavancin was associated with a relatively high success rate for the treatment of off-label indications and may be a cost-effective alternative to traditional IV antibiotic therapy.

Abstract Background We aimed to create a questionnaire to assess the health-related quality of life including functioning, symptoms, and general health status of adult patients with current or previous COVID-19. Here, we report on Phase I and II of the development. Methods Internationally recognized methodology for questionnaire development was followed. In Phase I, a comprehensive literature review was performed to identify relevant COVID-19 issues. Decisions for inclusion, exclusion, and data extraction were completed independently in teams of two and then compared. The resulting issues were discussed with health care professionals (HCPs) and current and former COVID-19 patients. The input of HCPs and patients was carefully considered, and the list of issues updated. In Phase II, this updated list was operationalized into items/questions. Results The literature review yielded 3342 publications, 339 of which were selected for full-text review, and 75 issues were identified. Discussions with 44 HCPs from seven countries and 52 patients from six countries showed that psychological symptoms, worries, and reduced functioning lasted the longest for patients, and there were considerable discrepancies between HCPs and patients concerning the importance of some of the symptoms. The final list included 73 issues, which were operationalized into an 80-item questionnaire. Conclusion The resulting COVID-19 questionnaire covers health–related quality of life issues relevant to COVID-19 patients and is available in several languages. The next steps include testing of the applicability and patients’ acceptability of the questionnaire (Phase IIIA) and preliminary psychometric testing (Phase IIIB).

Patients surviving head and neck cancer (HNC) suffer from high physical, psychological, and socioeconomic burdens. Achieving cancer-free survival with an optimal quality of life (QoL) is the primary goal for HNC patient management. So, maintaining lifelong surveillance is critical. An ambitious goal would be to carry this out through the advanced analysis of environmental, emotional, and behavioral data unobtrusively collected from mobile devices. The aim of this clinical trial is to reduce, with non-invasive tools (i.e., patients’ mobile devices), the proportion of HNC survivors (i.e., having completed their curative treatment from 3 months to 10 years) experiencing a clinically relevant reduction in QoL during follow-up. The Big Data for Quality of Life (BD4QoL) study is an international, multicenter, randomized (2:1), open-label trial. The primary endpoint is a clinically relevant global health-related EORTC QLQ-C30 QoL deterioration (decrease ≥10 points) at any point during 24 months post-treatment follow-up. The target sample size is 420 patients. Patients will be randomized to be followed up using the BD4QoL platform or per standard clinical practice. The BD4QoL platform includes a set of services to allow patients monitoring and empowerment through two main tools: a mobile application installed on participants’ smartphones, that includes a chatbot for e-coaching, and the Point of Care dashboard, to let the investigators manage patients data. In both arms, participants will be asked to complete QoL questionnaires at study entry and once every 6 months, and will undergo post-treatment follow up as per clinical practice. Patients randomized to the intervention arm (n=280) will receive access to the BD4QoL platform, those in the control arm (n=140) will not. Eligibility criteria include completing curative treatments for non-metastatic HNC and the use of an Android-based smartphone. Patients undergoing active treatments or with synchronous cancers are excluded.Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05315570).

Pregnant women are a highly vaccine-resistant population and face unique circumstances that complicate vaccine decision-making. Pregnant women are also at increased risk of adverse maternal and neonatal outcomes to many vaccine-preventable diseases. Several models have been proposed to describe factors informing vaccine hesitancy and acceptance. However, none of these existing models are applicable to the complex decision-making involved with vaccine acceptance during pregnancy. We propose a model for vaccine decision-making in pregnancy that incorporates the following key factors: (1) perceived information sufficiency regarding vaccination risks during pregnancy, (2) harm avoidance to protect the fetus, (3) relationship with a healthcare provider, (4) perceived benefits of vaccination, and (5) perceived disease susceptibility and severity during pregnancy. In addition to these factors, the availability of research on vaccine safety during pregnancy, social determinants of health, structural barriers to vaccine access, prior vaccine acceptance, and trust in the healthcare system play roles in decision-making. As a final step, the pregnant individual must balance the risks and benefits of vaccination for themselves and their fetus, which adds greater complexity to the decision. Our model represents a first step in synthesizing factors informing vaccine decision-making by pregnant women, who represent a highly vaccine-resistant population and who are also at high risk for adverse outcomes for many infectious diseases.

Abstract Physical instabilities of proteins in the form of protein aggregation continue to be a major challenge in the development of protein drug candidates. Aggregation can occur during different stages of product lifecycle such as freeze–thaw, manufacturing, shipping, and storage, and can potentially delay commercialization of candidates. A lack of clear understanding of the underlying mechanism(s) behind protein aggregation and the potential immunogenic reactions renders the presence of aggregates in biotherapeutic products undesirable. Understanding and minimizing aggregation can potentially reduce immunogenic responses and make protein therapeutics safer. Therefore, it is imperative to identify, understand, and control aggregation during early formulation development and develop reliable and orthogonal analytical methodologies to detect and monitor levels of aggregation. Freezing and thawing are typical steps involved in the manufacturing of drug product and could result in complex physical and chemical changes, which in turn could potentially cause protein aggregation. This study provides a systematic approach in understanding and selecting the ideal freeze–thaw conditions for manufacturing of protein-based therapeutics. It identifies the importance of balancing different excipients with an overall goal of sufficiently reducing or eliminating aggregation and developing a stable and scalable formulation. The results demonstrated that the freeze–thaw damage of mAb-1 in aqueous solutions was significantly reduced by identification of optimal freeze–thaw conditions using first a small-scale model with subsequent at-scale verifications. The work provides a framework for successful transfer of drug product manufacturing process from small-scale to the manufacturing scale production environment especially for molecules that are susceptible to freeze–thaw induced degradations.

This mixed-method study investigated vaccine hesitancy among pregnant women living in rural western United States and their response to social media ads promoting COVID-19 vaccine uptake. Thirty pregnant or recently pregnant participants who live in rural zip codes in Washington, Oregon, California, and Idaho were interviewed between November 2022 and March 2023. Interviews were transcribed and coded, while the ad ratings were analyzed using linear mixed models. The study identified five main themes related to vaccine uptake, including perceived risk of COVID, sources of health information, vaccine hesitancy, and relationships with care providers. Participants rated ads most highly that used peer-based messengers and negative outcome-based content. Ads with faith-based and elder messengers were rated significantly lower than peer messengers (p = 0.04 and 0.001, respectively). An activation message was also rated significantly less favorably than negative outcome-based content (p = 0.001). Participants preferred evidence-based information and the ability to conduct their own research on vaccine safety and efficacy rather than being told to get vaccinated. Primary concerns of vaccine-hesitant respondents included the short amount of time the vaccine had been available and perceived lack of research on its safety during pregnancy. Our findings suggests that tailored messaging using peer-based messengers and negative outcome-based content can positively impact vaccine uptake among pregnant women living in rural areas of the Western United States.

Abstract Direct delivery of therapeutic enzymes to the Central Nervous System requires stringent formulation design. Not only should the formulation design consider the delicate balance of existing ions, proteins, and osmolality in the cerebrospinal fluid, it must also provide long term efficacy and stability for the enzyme. One fundamental approach to this predicament is designing formulations with no buffering species. In this study, we report a high concentration, saline-based formulation for a human sulfatase for its delivery into the intrathecal space. A high concentration formulation (≤ 40 mg/mL) was developed through a series of systematic studies that demonstrated the feasibility of a self-buffered formulation for this molecule. The self-buffering capacity phenomenon was found to be a product of both the protein itself and potentially the residual phosphates associated with the protein. To date, the self-buffered formulation for this molecule has been stable for up to 4 years when stored at 5 ± 3 °C, with no changes either in the pH values or other quality attributes of the molecule. The high concentration self-buffered protein formulation was also observed to be stable when exposed to multiple freeze–thaw cycles and was robust during in-use and agitation studies.

BackgroundAlthough the COVID-19 pandemic has not led to a uniform increase of mental health concerns among older adults, there is evidence to suggest that some older veterans did experience an exacerbation of preexisting mental health conditions, and that mental health difficulties were associated with a lack of social support and increasing numbers of pandemic-related stressors. Mobile mental health apps are scalable, may be a helpful resource for managing stress during the pandemic and beyond, and could potentially provide services that are not accessible due to the pandemic. However, overall comfort with mobile devices and factors influencing the uptake and usage of mobile apps during the pandemic among older veterans are not well known. COVID Coach is a free, evidence-informed mobile app designed for pandemic-related stress. Public usage data have been evaluated; however, the uptake and usage of the app among older veterans have not been explored. ObjectiveThe purpose of this study was to characterize smartphone ownership rates among US veterans, identify veteran characteristics associated with downloading and use of COVID Coach, and characterize key content usage within the app. MethodsData were analyzed from the 2019-2020 National Health and Resilience in Veterans Study (NHRVS), which surveyed a nationally representative, prospective cohort of 3078 US military veterans before and 1 year into the pandemic. The NHRVS sample was drawn from KnowledgePanel, a research panel of more than 50,000 households maintained by Ipsos, Inc. The median time to complete the survey was nearly 32 minutes. The research version of COVID Coach was offered to all veterans who completed the peripandemic follow-up assessment on a mobile device (n=814; weighted 34.2% of total sample). App usage data from all respondents who downloaded the app (n=34; weighted 3.3% of the mobile completers sample) were collected between November 14, 2020, and November 7, 2021. ResultsWe found that most US veterans (81.5%) own smartphones, and that veterans with higher education, greater number of adverse childhood experiences, higher extraversion, and greater severity of pandemic-related posttraumatic stress disorder symptoms were more likely to download COVID Coach. Although uptake and usage of COVID Coach were relatively low (3.3% of eligible participants, n=34), 50% of the participants returned to the app for more than 1 day of use. The interactive tools for managing stress were used most frequently. ConclusionsThe COVID-19 pandemic has increased the need for and creation of digital mental health tools. However, these resources may require tailoring for older veteran populations. Future research is needed to better understand how to optimize digital mental health tools such as apps to ensure uptake and usage among older adults, particularly those who have experienced traumas across the lifespan.

Abstract Background Patients with multiple myeloma report more problems with quality of life (QoL) than other haematological malignancies over the course of their incurable illness. The patient-centred Myeloma Patient Outcome Scale (MyPOS) was developed to assess and monitor symptoms and supportive care factors in routine care. Our aim was to translate and culturally adapt the outcome measure to the German context, and to explore its face and content validity. Methods Translation and cultural adaptation following established guidelines used an exploratory, sequential mixed method study design. Steps included: (1) forward translation to German; (2) backward translation to English; (3) expert review; (4) focus groups with the target population (patients, family members, healthcare professionals) to achieve conceptual equivalence; (5) cognitive interviews using Tourangeau’s model with think-aloud technique to evaluate comprehension and acceptability; (6) final review. Results were analysed using thematic analysis. Results Cultural and linguistic differences were noted between the German and English original version. The focus groups (n = 11) and cognitive interviews (n = 9) both highlighted the need for adapting individual items and their answer options to the German healthcare context. Greater individuality regarding need for information with the right to not be informed was elaborated by patients. While the comprehensive nature of the tool was appreciated, item wording regarding satisfaction with healthcare was deemed not appropriate in the German context. Before implementation into routine care, patients’ concerns about keeping their MyPOS data confidential need to be addressed as a barrier, whereas the MyPOS itself was perceived as a facilitator/prompt for a patient-centred discussion of QoL issues. Conclusion With adaptations to answer options and certain items, the German version of the MyPOS can help monitor symptoms and problems afflicting myeloma patients over the course of the disease trajectory. It can help promote a model of comprehensive supportive and patient-centred care for these patients.

BackgroundWith widespread smartphone ownership, mobile health apps (mHealth) can expand access to evidence-based interventions for mental health conditions, including posttraumatic stress disorder (PTSD). Research to evaluate new features and capabilities in these apps is critical but lags behind app development. The initial release of PTSD Coach, a free self-management app developed by the US Departments of Veterans Affairs and Defense, was found to have a positive public health impact. However, major stakeholder-driven updates to the app have yet to be evaluated. ObjectiveWe aimed to characterize the reach, use, and potential impact of PTSD Coach Version 3.1 in the general public. As part of characterizing use, we investigated the use of specific app features, which extended previous work on PTSD Coach. MethodsWe examined the naturalistic use of PTSD Coach during a 1-year observation period between April 20, 2020, and April 19, 2021, using anonymous in-app event data to generate summary metrics for users. ResultsDuring the observation period, PTSD Coach was broadly disseminated to the public, reaching approximately 150,000 total users and 20,000 users per month. On average, users used the app 3 times across 3 separate days for 18 minutes in total, with steep drop-offs in use over time; a subset of users, however, demonstrated high or sustained engagement. More than half of users (79,099/128,691, 61.46%) accessed one or more main content areas of the app (ie, Manage Symptoms, Track Progress, Learn, or Get Support). Among content areas, features under Manage Symptoms (including coping tools) were accessed most frequently, by over 40% of users (53,314/128,691, 41.43% to 56,971/128,691, 44.27%, depending on the feature). Users who provided initial distress ratings (56,971/128,691, 44.27%) reported relatively high momentary distress (mean 6.03, SD 2.52, on a scale of 0-10), and the use of a coping tool modestly improved momentary distress (mean −1.38, SD 1.70). Among users who completed at least one PTSD Checklist for DSM-5 (PCL-5) assessment (17,589/128,691, 13.67%), PTSD symptoms were largely above the clinical threshold (mean 49.80, SD 16.36). Among users who completed at least two PCL-5 assessments (4989/128,691, 3.88%), PTSD symptoms decreased from the first to last assessment (mean −4.35, SD 15.29), with approximately one-third (1585/4989, 31.77%) of these users experiencing clinically significant improvements. ConclusionsPTSD Coach continues to fulfill its mission as a public health resource. Version 3.1 compares favorably with version 1 on most metrics related to reach, use, and potential impact. Although benefits appear modest on an individual basis, the app provides these benefits to a large population. For mHealth apps to reach their full potential in supporting trauma recovery, future research should aim to understand the utility of individual app features and identify strategies to maximize overall effectiveness and engagement.

Children vary in how sensitive they are to experiences, with consequences for their developmental outcomes. In the current study, we investigated how behavioral sensitivity at age 3 years predicts mental health in middle childhood. Using a novel repeated measures design, we calculated child sensitivity to multiple psychological and social influences: parent praise, parent stress, child mood, and child sleep. We conceptualized sensitivity as the strength and direction of the relationship between psychosocial influences and child behavior, operationalized as toothbrushing time, at age 3 years. When children were 5-7 years old (n = 60), parents reported on children's internalizing and externalizing problems. Children who were more sensitive to their parents' praise at age 3 had fewer internalizing (r = -0.37, p = 0.016, p[subscript FDR] = 0.042) and externalizing (r = -0.35, p = 0.021, p[subscript FDR] = 0.042) problems in middle childhood. Higher average parent praise also marginally predicted fewer externalizing problems (r = -0.33, p = 0.006, p[subscript FDR] = 0.057). Child sensitivity to mood predicted fewer internalizing (r = -0.32, p = 0.013, p[subscript FDR] = 0.042) and externalizing (r = -0.38, p = 0.003, p[subscript FDR] = 0.026) problems. By capturing variability in how children respond to daily fluctuations in their environment, we can contribute to the early prediction of mental health problems and improve access to early intervention services for children and families who need them most.

Abstract Background Falls among older adults are both a common reason for presentation to the emergency department, and a major source of morbidity and mortality. It is critical to identify fall patients quickly and reliably during, and immediately after, emergency department encounters in order to deliver appropriate care and referrals. Unfortunately, falls are difficult to identify without manual chart review, a time intensive process infeasible for many applications including surveillance and quality reporting. Here we describe a pragmatic NLP approach to automating fall identification. Methods In this single center retrospective review, 500 emergency department provider notes from older adult patients (age 65 and older) were randomly selected for analysis. A simple, rules-based NLP algorithm for fall identification was developed and evaluated on a development set of 1084 notes, then compared with identification by consensus of trained abstractors blinded to NLP results. Results The NLP pipeline demonstrated a recall (sensitivity) of 95.8%, specificity of 97.4%, precision of 92.0%, and F1 score of 0.939 for identifying fall events within emergency physician visit notes, as compared to gold standard manual abstraction by human coders. Conclusions Our pragmatic NLP algorithm was able to identify falls in ED notes with excellent precision and recall, comparable to that of more labor-intensive manual abstraction. This finding offers promise not just for improving research methods, but as a potential for identifying patients for targeted interventions, quality measure development and epidemiologic surveillance.

Since May 2020, several COVID-19 outbreaks have occurred in the German meat industry despite various protective measures, and temperature and ventilation conditions were considered as possible high-risk factors. This cross-sectional study examined meat and poultry plants to assess possible risk factors. Companies completed a self-administered questionnaire on the work environment and protective measures taken to prevent SARS-CoV-2 infection. Multivariable logistic regression analysis adjusted for the possibility to distance at least 1.5 meters, break rules, and employment status was performed to identify risk factors associated with COVID-19 cases. Twenty-two meat and poultry plants with 19,072 employees participated. The prevalence of COVID-19 in the seven plants with more than 10 cases was 12.1% and was highest in the deboning and meat cutting area with 16.1%. A subsample analysis where information on maximal ventilation rate per employee was available revealed an association with the ventilation rate (adjusted odds ratio (AOR) 0.996, 95% CI 0.993–0.999). When including temperature as an interaction term in the working area, the association with the ventilation rate did not change. When room temperatures increased, the chance of testing positive for COVID-19 (AOR 0.90 95% CI 0.82–0.99) decreased, and the chance for testing positive for COVID-19for the interaction term (AOR 1.001, 95% CI 1.000–1.003) increased. Employees who work where a minimum distance of less than 1.5 m between workers was the norm had a higher chance of testing positive (AOR 3.61; 95% CI 2.83–4.6). Our results further indicate that climate conditions and low outdoor air flow are factors that can promote the spread of SARS-CoV-2 aerosols. A possible requirement for pandemic mitigation strategies in industrial workplace settings is to increase the ventilation rate.

Parental presence in the neonatal intensive care unit (NICU) positively impacts infant development. Few studies have examined the impact of presence on parental distress. Alienation, or lack of trust in the healthcare team, may occur independently from other forms of distress. Increased parental presence was hypothesized to reduce alienation by allowing for more positive in-person interaction with hospital staff. Parents of infants born < 28 weeks or < 1000 grams were prospectively enrolled and completed several surveys measuring distress prior to discharge, including a novel hospital alienation questionnaire. Spearman correlation was used to compare distress measures and visitation rates of 68 mothers and 6 fathers. Alienation was rarely reported and was uncorrelated with other distress measures. Maternal presence was most strongly correlated with anxiety, though this was not statistically significant. Fathers who were more alienated were present in the NICU less and correlation between maternal and paternal alienation was strong. These results were not statistically significant, however. Though statistically significant results were not produced in this research, hospital alienation does appear to be a distinct concept that has been unstudied previously. Experience Framework This article is associated with the Patient, Family & Community Engagement lens of The Beryl Institute Experience Framework. (http://bit.ly/ExperienceFramework) Access other PXJ articles related to this lens. Access other resources related to this lens.

La resistencia a los antibióticos sigue siendo uno de los más importantes problemas de salud global a la fecha. La resistencia a los antibióticos en América Latina, representa uno de los grandes retos de la medicina actual debido a los diversos mecanismos de resistencia bacteriana y el incremento de los mismos a nivel mundial. Analizamos las tasas de resistencia a los antibióticos en aislamientos bacterianos de pacientes que asistieron a dos hospitales de la región rural de Ecuador desde el año 2017 hasta el año 2018. Un total de 907 cultivos bacterianos fueron analizados, los cuales se obtuvieron desde el 1 de enero 2017 al 31 de diciembre 2018 y se evaluaron frente a 33 tipos de antibióticos diferentes. Más de la mitad de los aislamientos donde se identificaron enterobacterias, fueron resistentes a ampicilina (79.8%), ampicilina/sulbactam (57.5%), amoxicilina/ácido clavulánico (62.6%). El Staphylococcus aureus presentó (55.4%) de resistencia a la oxacilina. Se concluye que existen altas tasas de resistencia a los antibióticos en zonas rurales del Ecuador, que siguen los patrones mundiales de resistencia ya publicados, y que tanto los médicos como los sistemas de salud deberían tomar en cuenta al crear normativas y políticas para el uso racional de antibióticos.

Cancer remains one of the leading causes of death worldwide despite extensive efforts at developing curative treatments. Chemotherapy, one of the most common forms of treatment, lacks specificity and can induce collateral damages to healthy surrounding tissues/cells and elicit off-target toxic side effects. The carbon-based nanomaterial graphene, can load aromatic drugs with high efficiency, has good biocompatibility, and can be easily functionalised with targeting ligands, antibodies, and biomolecules to increase the accuracy of targeting specific areas; graphene has therefore been explored as a nanocarrier for classical chemotherapy drugs. In this work, seventeen publications that report the release of doxorubicin (DOX) from 2D graphene-based nanohybrids (graphene oxide and reduced graphene oxide) for the treatment of breast and ovarian cancers have been identified based on a range of inclusion and exclusion criteria. To aid in the clinical translation of proof-of-concept studies, this work identifies the pre-clinical experimental protocols and analyses the release kinetics of these publications. Fifteen of the papers utilised a change in pH as the stimulus for drug release, and two utilised either near infrared (NIR) or ultrasound as the stimulus. The extracted drug release data from these publications were fit to four known kinetic models. It was found that the majority of these data best fit the Weibull kinetic model. The agreement between the kinetic data in previously published literature provides a predictable estimation of DOX release from graphene-based nanocarriers. This study demonstrates the potential conjugation of graphene and DOX in drug delivery applications, and this knowledge can help improve to the design and formulation of future graphene-based nanocarriers. In addition, the use of further experimental testing and the standardisation of experimental protocols will be beneficial for future work. The incorporation of computational modelling prior to pre-clinical testing will also aid in the development of controlled and sustained DOX release systems that offer efficient and efficacious results.

Abstract Background Tumors commonly are infiltrated by leukocytes, or tumor infiltrating leukocytes (TILs). It remains unclear, however, if the density and type of individual TILs has a direct or simply correlative role in promoting poor prognosis in breast cancer patients. Breast cancer in Kenyan women is aggressive with presentation at a young age, with advanced grade (grade III), large tumor size (>2.0 cm), and poor prognosis. We previously observed that the tumors were predominantly estrogen receptor positive (ER+) but also included both a high percentage of triple negative tumors and also increased immune cell infiltration within the tumors. We used breast tumor tissues from each patient to make tissue microarrays that were then stained for leukocyte and myeloid markers including CD4, CD8, CD20, CD25, CD68, and CD163 using immunohistochemical techniques. The immune cell infiltration into the cancer tissue included increased numbers of macrophages (CD68+), helper T cells (CD4+), and CD25+ lymphocytes compared to benign tissue. Results This study characterized the grade, molecular subtypes, and proliferation index of these tumors and determined if TIL density was enriched across any of these factors. We analyzed 49 malignant patient tissue samples for this study. The patient population had a mean age of 51.9 years. The tumors analyzed were heterogeneous by grade: grade I (6%), grade II (47%), and grade III (39%). Most patients presented with large tumors (>2.0 cm) (69%). We classified the tumors into molecular subtypes based on clinical marker expression. Based on this analysis, the molecular subtype distribution was heterogeneous with luminal B (41%), basal/triple negative (TN) (37%), luminal A (14%) and HER2 (8%) breast cancer subtypes. While the basal/TN subtype had a much higher proliferative index (Ki-67+) than did the other molecular subtypes, we did not see a significant correlation between TIL density and either subtype or tumor grade. Therefore, TIL density is independent of molecular subtype and grade. Conclusion This study identified a Kenyan patient cohort that develops large, high-grade tumors primarily of the luminal B and basal molecular subtypes. After analyzing the TILs within these tumors, we found that immune cell infiltration of these tumors correlated with increased proliferation but not grade or molecular subtype. Future research is required to determine if the aberrant recruitment of TILs to tumors contributes to cancer progression and response to cancer treatments.

Since the conception of the Education for All Handicapped Children Act in 1975, there has been substantial progress regarding the education of learners with disabilities. Nevertheless, significant challenges remain for addressing the diverse needs of these learners and improving in- and out-of-school outcomes. This special topic focuses on an approach that holds promise for the delivery of interventions that are aligned to learners’ social, emotional, behavioral, and learning needs—multitiered systems of support (MTSS). The four articles that comprise the special topic highlight the need for actionable information for schools implementing MTSS, early intervention for children with or at risk for disabilities, and an enhanced focus on intensive interventions. This introduction to the special topic provides information on the meeting that motivated the special topic, a summary of each of the four articles, and paths forward for early and sustained intervention for learners with or at risk for disabilities.

Krabbe disease, also known as globoid cell leukodystrophy, is a rare genetic neurodegenerative disease caused by a deficiency of the galactocerebrosidase enzyme. To understand the association status of human beta-galactocerebrosidase (hGALC) in solution, we employed analytical ultracentrifugation (AUC). Our AUC results show that hGALC has a tendency for reversible self-association. Self-association decreases as the concentration of sodium chloride increases from 50 to 500 mM. This indicates that ionic interactions are involved in the association. The association is also dependent on pH, and high order oligomerization decreases as the pH increases from 4.5 to 7.5. Taken together, our results indicate that hGALC has the highest tendency for oligomerization at physiological ionic strength and pH (lysosomal lumen). This is the first report describing the self-associating property of hGALC in solution.

The aim of this pilot study was to assess: (1) the feasibility and acceptability of a Mindfulness-Based Virtual Reality (MBVR) intervention among children and young adults with Inflammatory Bowel Disease (IBD), and (2) the preliminary efficacy of MBVR on key psychological (anxiety) and physical (pain) outcomes. Participants were 62 children to young adults with IBD (M = 15.6 years; 69.4% Crohn’s disease; 58% male) recruited from an outpatient pediatric IBD clinic. Participants completed a baseline assessment, underwent the 6-min MBVR intervention, completed a post-intervention assessment and study satisfaction survey, and provided qualitative feedback. Results suggest strong feasibility and acceptability. Participants reported high levels of satisfaction with MBVR including high levels of enjoyment (M = 4.38; range 1–5) and relaxation (M = 4.35; range 1–5). Qualitative data revealed several key themes including participants interest in using MBVR in IBD medical settings (e.g., hospitalizations, IBD procedures, IBD treatments), as well as in their daily lives to support stress and symptom management. Preliminary analyses demonstrated improvements in anxiety (t = 4.79, p = 0.001) and pain (t = 3.72, p < 0.001) following MBVR. These findings provide initial support for the feasibility and acceptability of MBVR among children and young adults with IBD. Results also suggest MBVR may improve key IBD outcomes (e.g., anxiety, pain) and highlight the importance of conducting a randomized controlled trial and more rigorous research to determine intervention efficacy.

Background: Migration of African-trained health workers to countries with higher health care worker densities adds to the severe shortage of health personnel in many African countries. Policy initiatives to reduce migration levels are informed by many studies exploring the reasons for the original decision to migrate. In contrast, there is little evidence to inform policies designed to facilitate health workers returning home or providing other forms of support to the health system of their home country. Objective: This study explores the links that South African-trained health workers who now live and work in the United Kingdom maintain with their country of training and what their future migration plans may be. Design: Semi-structured interviews were conducted with South African trained health workers who are now living in the United Kingdom. Data extracts from the interviews relating to current links with South Africa and future migration plans were studied. Results: All 16 participants reported strong ongoing ties with South Africa, particularly through active communication with family and friends, both face-to-face and remotely. Being South African was a significant part of their personal identity, and many made frequent visits to South Africa. These visits sometimes incorporated professional activities such as medical work, teaching, and charitable or business ventures in South Africa. The presence and location of family and spouse were of principal importance in helping South African-trained health care workers decide whether to return permanently to work in South Africa. Professional aspirations and sense of duty were also important motivators to both returning and to being involved in initiatives remotely from the United Kingdom. Conclusions: The main barrier to returning home was usually the development of stronger family ties in the United Kingdom than in South Africa. The issues that prompted the original migration decision, such as security and education, also remained important reasons to remain in the United Kingdom as long as they were perceived as unresolved at home. However, the strong residual feeling of identity and regular ongoing communication meant that most participants expressed a sense of duty to their home country, even if they were unlikely to return to live there full-time. This is a resource for training and short-term support that could be utilised to the benefit of African health care systems.

This article extends existing research on school effectiveness by focusing on identifying the combination of programs, practices, processes, and policies that explain why some high schools in a large urban district are effective at serving low-income students, minority students, and English language learners. Using a mixed methods study of high schools selected on the basis of value-added indicators, we conducted a comparative case study to understand what differentiated schools that “beat the odds” from those that struggled to improve student achievement. We found that the higher-value-added schools enacted practices that integrated academic press and support in ways that fostered student efficacy and engagement. These findings contribute to the larger literature on school effectiveness by highlighting the importance of the student culture of learning and noncognitive student characteristics. They do so by identifying student ownership and responsibility as a critical area for research on school effectiveness and improvement.

Space travel presents unlimited opportunities for exploration and discovery, but requires better understanding of the biological consequences of long-term exposure to spaceflight. Immune function in particular is relevant for space travel. Human immune responses are weakened in space, with increased vulnerability to opportunistic infections and immune-related conditions. In addition, microorganisms can become more virulent in space, causing further challenges to health. To understand these issues better and to contribute to design of effective countermeasures, we used the Drosophila model of innate immunity to study immune responses in both hypergravity and spaceflight. Focusing on infections mediated through the conserved Toll and Imd signaling pathways, we found that hypergravity improves resistance to Toll-mediated fungal infections except in a known gravitaxis mutant of the yuri gagarin gene. These results led to the first spaceflight project on Drosophila immunity, in which flies that developed to adulthood in microgravity were assessed for immune responses by transcription profiling on return to Earth. Spaceflight alone altered transcription, producing activation of the heat shock stress system. Space flies subsequently infected by fungus failed to activate the Toll pathway. In contrast, bacterial infection produced normal activation of the Imd pathway. We speculate on possible linkage between functional Toll signaling and the heat shock chaperone system. Our major findings are that hypergravity and spaceflight have opposing effects, and that spaceflight produces stress-related transcriptional responses and results in a specific inability to mount a Toll-mediated infection response.

Altruistic behavior, in which one individual provides aid to another at some cost to itself, is well documented. However, some species engage in a form of altruism, called rescue, that places the altruist in immediate danger. Here we investigate one such example, namely rescuing victims captured by predators. In a field experiment with two North American ant species, Tetramorium sp. E and Prenolepis imparis, individuals were held in artificial snares simulating capture. T. sp. E, but not P. imparis, exhibited digging, pulling, and snare biting, the latter precisely targeted to the object binding the victim. These results are the first to document precision rescue in a North American ant species; moreover, unlike rescue in other ants, T. sp. E rescues conspecifics from different colonies, mirroring their atypical social behavior, namely the lack of aggression between non-nestmate (heterocolonial) conspecifics. In a second, observational study designed to demonstrate rescue from an actual predator, T. sp. E victims were dropped into an antlion's pit and the behavior of a single rescuer was observed. Results showed that T. sp. E not only attempted to release the victim, but also risked attacking the predator, suggesting that precision rescue may play an important role in this species' antipredator behavior.

The paper attempts to unpick the real meaning of the term ‘prairie gardening’ and to explore its popularity in a European context. Establishment and maintenance techniques are also considered. The term is, however, applied without discrimination to a wide range of styles, from large-scale traditional prairie restoration or re-creation projects through to highly stylised prairie interpretations. Research included a literature review to assess the main ecological features of, and threats to, native North American Prairie and an examination of the origins of contemporary ‘prairie gardening’ in both the USA and Europe. Primary data was gathered from eight UK gardens associated with this planting style. The evidence suggests that the spectrum of styles encompassed by this term is broad even within the UK, a clear indication that its usage is over-simplistic and potentially ambiguous. The author offers her own classification of the genre under the umbrella term ‘prairie-style gardening’ in the hope of further clarification. The paper is a summary of a project which was carried out as part of the second-year project of the HND in Horticulture with Plantsmanship at Royal Botanic Garden Edinburgh.

Prophylactic administration of CpG oligodeoxynucleotides (CpG ODNs) is known to confer protection against lethal sepsis caused by Burkholderia pseudomallei in the mouse model. The mechanisms whereby CpG regulates the innate immune response to provide protection against B. pseudomallei, however, are poorly characterized. In the present study, we demonstrate that intranasal treatment of mice with Class C CpG, results in recruitment of inflammatory monocytes and neutrophils to the lung at 48 h post-treatment. Mice infected with B. pseudomallei 48 h post-CpG treatment had reduced organ bacterial load and significantly altered cytokine and chemokine profiles concomitant with protection as compared to control animals. CpG administration reduced the robust production of chemokines and pro-inflammatory cytokines in blood, lung and spleen, observed following infection of non-treated animals. Death of control animals coincided with the time of peak cytokine production (day 1-3), while a moderate; sustained cytokine production in CpG-treated animals was associated with survival. In general, CpG treatment resulted in diminished expression of cytokines and chemokines post-infection, though IL-12p40 was released in larger quantities in CpG treated animals. In contrast to CpG-treated animals, the lungs of infected control animals were infiltrated with leukocytes, especially neutrophils, and large numbers of necrotic lesions were observed in lung sections. Therapeutic treatment of B. pseudomallei-infected animals with CpG at 24 h post-infection did not impact survival compared to control animals. In summary, protection of CpG-treated animals was associated with recruitment of inflammatory monocytes and neutrophils into the lungs prior to infection. These responses correspond with early control of bacterial growth, a dampened inflammatory cytokine/chemokine response, reduced lung pathology, and greatly increased survival. In contrast, a delay in recruitment of inflammatory cell populations, despite a robust production of pro-inflammatory cytokines, was associated with poorly controlled bacterial growth, severe lung pathology, and death of control animals.

Purpose: A relatively new approach to principal evaluation is the use of multisource feedback, which typically entails a leader's self-evaluation as well as parallel evaluations from subordinates, peers, and/or superiors. However, there is little research on how principals interact with evaluation data from multisource feedback systems. This article explores how principals orient and react to multisource feedback on their effectiveness as instructional leaders and how they interpret gaps between their self-assessments of their leadership effectiveness and their teachers' ratings of their leadership effectiveness. Research Methods: Using interview data collected from 14 principals in an urban school district in the southeast United States at two points in time, this study conducts a qualitative analysis to examine principals' orientations and reactions to their feedback. Findings: Our study finds that principals often experience cognitive dissonance when feedback from different data sources (e.g., their self-ratings to those of their teachers) contrasts. This can result in a motivation to reduce dissonance either by providing explanations and excuses, or making actual changes that result in improvement. Implications for Research and Practice: As performance feedback continues to become more commonplace in school settings, it will become increasingly necessary to build capacity around the processes of giving and receiving feedback. Results from this study have implications for how principals can be supported to use their evaluation data.