Capacity to Consent to Research Among Adolescent-Parent Dyads in Rakai, Uganda.

OBJECTIVES: To assess the cognitive capacity of early, middle, and late adolescents and their parents or guardians to provide informed consent to a population-based cohort study. STUDY DESIGN: Adolescent-parent/guardian dyads including 40 early (n = 80; 10-14 years), 20 middle (15-17 years), and 20 late (18-19 years) adolescents were recruited from the Rakai Community Cohort Study, an open demographic cohort in Uganda. Participants were administered the MacArthur Competence Assessment Tool for Clinical Research, a structured open-ended assessment; interviews were recorded and transcribed. Twenty transcripts were scored independently by two coders; the intraclass correlation coefficient was 0.89. The remaining interviews were scored individually. We compared mean scores for early and middle/late adolescents using a one-sided t test and score differences between parent/guardian and adolescent dyads using two-sided paired t tests. RESULTS: Early adolescents (mean score, 28.8; 95% CI, 27.1-30.5) scored significantly lower (P < .01) than middle/late adolescents (32.4; 31.6-33.1). In paired dyad comparisons, we observed no statistically significant difference in scores between parents/guardians and middle/late adolescents (difference, -0.2; 95% CI, -1.0-0.6). We found a statistically significant difference in scores between parents/guardians and early adolescents (difference, 3.0; 95% CI, 1.2-4.8). CONCLUSIONS: The capacity of adolescents-of different ages and in diverse settings-to comprehend risks, benefits, and other elements of informed consent is a critical but understudied area in research ethics. Our findings support the practice of having middle and late adolescents provide independent informed consent for sexual and reproductive health studies. Early adolescents may benefit from supported decision-making approaches.

Identification of ancestral sex chromosomes in the frog Glandirana rugosa bearing XX-XY and ZZ-ZW sex-determining systems.

Sex chromosomes constantly exist in a dynamic state of evolution: rapid turnover and change of heterogametic sex during homomorphic state, and often stepping out to a heteromorphic state followed by chromosomal decaying. However, the forces driving these different trajectories of sex chromosome evolution are still unclear. The Japanese frog Glandirana rugosa is one taxon well suited to the study on these driving forces. The species has two different heteromorphic sex chromosome systems, XX-XY and ZZ-ZW, which are separated in different geographic populations. Both XX-XY and ZZ-ZW sex chromosomes are represented by chromosome 7 (2n = 26). Phylogenetically, these two systems arose via hybridization between two ancestral lineages of West Japan and East Japan populations, of which sex chromosomes are homomorphic in both sexes and to date have not yet been identified. Identification of the sex chromosomes will give us important insight into the mechanisms of sex chromosome evolution in this species. Here, we used a high-throughput genomic approach to identify the homomorphic XX-XY sex chromosomes in both ancestral populations. Sex-linked DNA markers of West Japan were aligned to chromosome 1, whereas those of East Japan were aligned to chromosome 3. These results reveal that at least two turnovers across three different sex chromosomes 1, 3 and 7 occurred during evolution of this species. This finding raises the possibility that cohabitation of the two different sex chromosomes from ancestral lineages induced turnover to another new one in their hybrids, involving transition of heterogametic sex and evolution from homomorphy to heteromorphy.

Novel genetic sex markers reveal high frequency of sex reversal in wild populations of the agile frog (Rana dalmatina) associated with anthropogenic land use.

Populations of ectothermic vertebrates are vulnerable to environmental pollution and climate change because certain chemicals and extreme temperatures can cause sex reversal during early ontogeny (i.e. genetically female individuals develop male phenotype or vice versa), which may distort population sex ratios. However, we have troublingly little information on sex reversals in natural populations, due to unavailability of genetic sex markers. Here, we developed a genetic sexing method based on sex-linked single nucleotide polymorphism loci to study the prevalence and fitness consequences of sex reversal in agile frogs (Rana dalmatina). Out of 125 juveniles raised in laboratory without exposure to sex-reversing stimuli, 6 showed male phenotype but female genotype according to our markers. These individuals exhibited several signs of poor physiological condition, suggesting stress-induced sex reversal and inferior fitness prospects. Among 162 adults from 11 wild populations in North-Central Hungary, 20% of phenotypic males had female genotype according to our markers. These individuals occurred more frequently in areas of anthropogenic land use; this association was attributable to agriculture and less strongly to urban land use. Female-to-male sex-reversed adults had similar body mass as normal males. We recorded no events of male-to-female sex reversal either in the laboratory or in the wild. These results support recent suspicions that sex reversal is widespread in nature, and suggest that human-induced environmental changes may contribute to its pervasiveness. Furthermore, our findings indicate that sex reversal is associated with stress and poor health in early life, but sex-reversed individuals surviving to adulthood may participate in breeding.

White spot syndrome virus (WSSV) disturbs the intestinal microbiota of shrimp (Penaeus vannamei) reared in biofloc and clear seawater.

White spot syndrome virus (WSSV) is one of the most virulent pathogens afflicting shrimp farming. Understanding its influence on shrimp intestinal microbiota is paramount for the advancement of aquaculture, since gut dysbiosis can negatively impact shrimp development, physiology, and immunological response. Thereupon, the data presented herein assesses the influence of WSSV infection and different rearing systems on the intestinal microbiota of Penaeus vannamei. Our study aimed to describe and correlate the composition of shrimp (Penaeus vannamei) gut microbiota, when reared in biofloc and clear seawater, before and (48 h) after WSSV experimental infection. Shrimp were kept in two different systems (biofloc and clear seawater) and experimentally infected with WSSV. Intestine and water samples were characterized by 16S rRNA gene sequencing, before and after viral infection. We observed (i) WSSV induced higher mortality among shrimp reared in biofloc; (ii) WSSV led to a loss of intestinal microbiota heterogeneity, at the genus level, in shrimp kept in clear seawater; (iii) there was a prevalence of Cetobacterium and Bacillus in the intestine of shrimp from both systems; (iv) WSSV did not cause significant changes in intestinal microbiota diversity or richness; (v) regardless of the type of system and time of infection, intestinal microbiota was dissimilar to that of the surrounding water, despite being influenced by the type of system. Therefore, WSSV infection leads to punctual dysbiotic changes in shrimp microbiota, although the virus is sufficiently virulent to cause high mortalities even in well-managed systems, such as a balanced experimental biofloc system. KEY POINTS: • WSSV infection leads to a perturbed gut microbiota in shrimp. • WSSV infection greater impacts microbiota of shrimp reared in CSW than those in BFT. • WSSV infection caused higher mortality levels in shrimp reared in BFT than in CSW. • Rearing system influences shrimp gut microbiota composition. Graphical abstract.

Supporting people with an intellectual disability and dementia: A constructivist grounded theory study exploring care providers' views and experiences in the UK.

BACKGROUND: There is a need to better understand the experiences and support needs of paid and family carers of people with an intellectual disability and dementia, and the role of Intellectual Disability Dementia Care Pathways (IDDCPs). This study explored the experiences of carers, and IDDCPs and other support structures within those experiences. METHODS: A constructivist grounded theory methodology was implemented. Data were obtained through 23 semi-structured interviews with two family carers, eight paid carers and eight healthcare professionals. FINDINGS: The study's theory produced five interrelated categories: Impact of Dementia, Challenging the Diagnosis Process, Continuum of Support, Continuity and Continuum of Understanding. CONCLUSIONS: Findings have demonstrated the importance of planning and supporting carers' holistic needs; the role of an IDDCP in the post-diagnostic support (or lack of it) for carers; and the importance of a timely diagnosis of dementia. Recommendations for practice are offered.

Collaboration Matters: Honey Bee Health as a Transdisciplinary Model for Understanding Real-World Complexity.

We develop a transdisciplinary deliberative model that moves beyond traditional scientific collaborations to include nonscientists in designing complexity-oriented research. We use the case of declining honey bee health as an exemplar of complex real-world problems requiring cross-disciplinary intervention. Honey bees are important pollinators of the fruits and vegetables we eat. In recent years, these insects have been dying at alarming rates. To prompt the reorientation of research toward the complex reality in which bees face multiple challenges, we came together as a group, including beekeepers, farmers, and scientists. Over a 2-year period, we deliberated about how to study the problem of honey bee deaths and conducted field experiments with bee colonies. We show trust and authority to be crucial factors shaping such collaborative research, and we offer a model for structuring collaboration that brings scientists and nonscientists together with the key objects and places of their shared concerns across time.

Analysis of hospital community benefit expenditures' alignment with community health needs: evidence from a national investigation of tax-exempt hospitals.

OBJECTIVES: We investigated whether federally tax-exempt hospitals consider community health needs when deciding how much and what types of community benefits to provide. METHODS: Using 2009 data from hospital tax filings to the Internal Revenue Service and the 2010 County Health Rankings, we employed both univariate and multivariate analyses to examine the relationship between community health needs and the types and levels of hospitals' community benefit expenditures. The study sample included 1522 private, tax-exempt hospitals throughout the United States. RESULTS: We found some patterns between community health needs and hospitals' expenditures on community benefits. Hospitals located in communities with greater health needs spent more as a percentage of their operating budgets on benefits directly related to patient care. By contrast, spending on community health improvement initiatives was unrelated to community health needs. CONCLUSIONS: Important opportunities exist for tax-exempt hospitals to improve the alignment between their community benefit activities and the health needs of the community they serve. The Affordable Care Act requirement that hospitals conduct periodic community health needs assessments may be a first step in this direction.

Equity in practice: Assigning competence to shape STEM student participation.

Improving equity in undergraduate STEM is a national imperative. Although there is a rapidly growing body of research in this area, there is still a need to generate empirical evidence for equitable teaching techniques. We ground our work in Complex Instruction, an extensively researched pedagogical approach based on sociological theories and the malleability of status. This approach has been applied primarily in K-12 classrooms. In this manuscript, we explore the application of one strategy from Complex Instruction-assigning competence-to undergraduate STEM classrooms. We provide an analysis of three instructors' implementation of assigning competence and track the impact on student participation. This work makes a unique contribution to the field, as the first study that directly documents changes in student participation resulting from assigning competence in undergraduate STEM.

Multi-scale statistical deformation based co-registration of prostate MRI and post-surgical whole mount histopathology.

BACKGROUND: Accurate delineations of regions of interest (ROIs) on multi-parametric magnetic resonance imaging (mpMRI) are crucial for development of automated, machine learning-based prostate cancer (PCa) detection and segmentation models. However, manual ROI delineations are labor-intensive and susceptible to inter-reader variability. Histopathology images from radical prostatectomy (RP) represent the "gold standard" in terms of the delineation of disease extents, for example, PCa, prostatitis, and benign prostatic hyperplasia (BPH). Co-registering digitized histopathology images onto pre-operative mpMRI enables automated mapping of the ground truth disease extents onto mpMRI, thus enabling the development of machine learning tools for PCa detection and risk stratification. Still, MRI-histopathology co-registration is challenging due to various artifacts and large deformation between in vivo MRI and ex vivo whole-mount histopathology images (WMHs). Furthermore, the artifacts on WMHs, such as tissue loss, may introduce unrealistic deformation during co-registration. PURPOSE: This study presents a new registration pipeline, MSERgSDM, a multi-scale feature-based registration (MSERg) with a statistical deformation (SDM) constraint, which aims to improve accuracy of MRI-histopathology co-registration. METHODS: In this study, we collected 85 pairs of MRI and WMHs from 48 patients across three cohorts. Cohort 1 (D1), comprised of a unique set of 3D printed mold data from six patients, facilitated the generation of ground truth deformations between ex vivo WMHs and in vivo MRI. The other two clinically acquired cohorts (D2 and D3) included 42 patients. Affine and nonrigid registrations were employed to minimize the deformation between ex vivo WMH and ex vivo T2-weighted MRI (T2WI) in D1. Subsequently, ground truth deformation between in vivo T2WI and ex vivo WMH was approximated as the deformation between in vivo T2WI and ex vivo T2WI. In D2 and D3, the prostate anatomical annotations, for example, tumor and urethra, were made by a pathologist and a radiologist in collaboration. These annotations included ROI boundary contours and landmark points. Before applying the registration, manual corrections were made for flipping and rotation of WMHs. MSERgSDM comprises two main components: (1) multi-scale representation construction, and (2) SDM construction. For the SDM construction, we collected N = 200 reasonable deformation fields generated using MSERg, verified through visual inspection. Three additional methods, including intensity-based registration, ProsRegNet, and MSERg, were also employed for comparison against MSERgSDM. RESULTS: Our results suggest that MSERgSDM performed comparably to the ground truth (p > 0.05). Additionally, MSERgSDM (ROI Dice ratio = 0.61, landmark distance = 3.26 mm) exhibited significant improvement over MSERg (ROI Dice ratio = 0.59, landmark distance = 3.69 mm) and ProsRegNet (ROI Dice ratio = 0.56, landmark distance = 4.00 mm) in local alignment. CONCLUSIONS: This study presents a novel registration method, MSERgSDM, for mapping ex vivo WMH onto in vivo prostate MRI. Our preliminary results demonstrate that MSERgSDM can serve as a valuable tool to map ground truth disease annotations from histopathology images onto MRI, thereby assisting in the development of machine learning models for PCa detection on MRI.

Information beyond the forum: Motivations, strategies, and impacts of citizen participants seeking information during a consensus conference.

During traditional consensus conferences, organizers control the formal information available to participants-by compiling structured background materials and recruiting expert panelists. Less formally, however, participants are encouraged to bring their own experiences into the deliberations, and in doing so, they often seek outside information. We explore this heretofore understudied phenomenon of information seeking during a deliberative event: the U.S. National Citizens' Technology Forum (2008), which addressed the convergence of nanotechnology, biotechnology, information technology, and cognitive science on the potential development of human-enhancement technologies. Through interviews with participants and observation of in-person and online deliberations, we identify outside information-seeking strategies and motivations. Our study demonstrates that conceptualizing models of deliberation as standalone settings of communication exchange ignores the reality of the complex information environment from which deliberative participants draw when making sense of technical issues. Future citizen deliberations must incorporate outside information seeking in the design of the exercises.

The negative health spillover effects of universal primary education policy: Ethnographic evidence from Uganda.

Scholars of global health have embraced universal education as a structural intervention to prevent HIV. Yet the costs of school, including fees and other ancillary costs, create an economic burden for students and their families, indicating both the challenge of realising the potential of education for preventing HIV and the ways in which the desire for education may produce vulnerabilities to HIV for those struggling to afford it. To explore this paradox, this article draws from collaborative, team-based ethnographic research conducted from June to August 2019 in the Rakai district of Uganda. Respondents reported that education is the most significant cost burden faced by Ugandan families, sometimes amounting to as much as 66% of yearly household budgets per student. Respondents further understood paying for children's schooling as both a legal requirement and a valued social goal, and they pointed to men's labour migrations to high HIV-prevalence communities and women's participation in sex work as strategies to achieve that. Building from regional evidence showing young East African women participate in transactional, intergenerational sex to secure school fees for themselves, our findings point to the negative health spillover effects of Uganda's universal schooling policies for the whole family.

Association of Brain Natriuretic Peptide Levels at Time of Injury with Morbidity and Mortality in Patients with Surgically Treated Hip Fractures.

An elevated brain natriuretic peptide (BNP) level has been shown to be associated with mortality and cardiac events in cardiac surgery, but its utility in the prediction of morbidity and mortality in hip fracture surgery is unknown. The primary aim of this study was to determine if there is a difference in BNP level at the time of injury between patients who do and do not develop complications after hip fracture surgery. The secondary aim was to determine if there is a predictive relationship between complications associated with the initial BNP level and mortality. Methods: A retrospective chart review of 455 hip fractures in patients ≥60 years old that were operatively treated between February 2014 and July 2018 was performed. Patients were included if they had a BNP level within 48 hours after injury (BNPi). Specific perioperative (≤7 days), 30-day, 1-year, and 2-year postoperative complications were recorded. Wilcoxon rank-sum tests were used to determine if higher BNPi values were associated with greater morbidity. The complications associated with higher BNPi values were further analyzed to assess if they were predictive of mortality, using univariate and multivariable analyses. Results: Higher BNPi was significantly associated with greater morbidity at all postoperative time points and with higher mortality at 1 and 2 years postoperatively. Furthermore, several complications including cardiac failure or exacerbation and altered mental status were associated with mortality at all time points in univariate analysis and at many time points in multivariable analysis. Conclusions: Patients with higher BNPi levels were more likely to develop complications up to 1 year postoperatively, and several of these complications were associated with increased mortality. Future studies to determine if delaying surgery until BNP levels are normalized or lowered may help guide management, and may be useful in determining the need for further medical optimization. Future studies aimed at defining a threshold BNP value at the time of injury may also help in better managing patients preoperatively. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia.

The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5-4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6-10 mmHg compared to 40-50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

Increasing the transmitted flow pulse in a rotary left ventricular assist device.

Long-term rotary left ventricular assist devices (LVADs) are increasingly employed to bridge patients with end-stage heart failure to transplant or as a destination therapy. Significant recent device development has increased patient support times, shifting further development focus toward physiologically sensitive control of the pump operation. Sensorless control of these devices would benefit from increased observability of the ventricular volume/preload to the pump, in order to regulate flow based on preload, imitating the native Frank-Starling flow control. Monitoring the transmitted flow pulse through the pump has been used as a surrogate for preload, although means of maximizing its transmission are not clear. However, it is known that a flat hydraulic performance curve of the rotary pump induces high changes in flow for a given change in pressure head. The aim of this study was to determine geometric pump parameters responsible for increasing this flow pulse transmission and to demonstrate this increase in vitro. The sensitivity of the performance gradient to blade angles, blade heights, blade clearance, and channel areas were studied. Resulting pressure head, flow, and hydraulic efficiency were analyzed with respect to textbook designed procedures. Then pumps with comparably "flat" and "steep" performance curves were used to simulate LVAD support in vitro over a range of pump flow rates to observe the transmitted flow pulsatility. It was found that an outlet blade angle of 90°, inlet blade angle between 25 and 45°, and large throat area generated a "flatter" performance curve. The transmitted flow pulsatility through a pump with a flat performance curve was 68% higher than that of a steep performance curve at a flow rate of 5 L/min. Substantial gains in the observability of LVAD preload/resident blood volume in the ventricle exist through the careful selection of specific pump geometries.

Comparison of preload-sensitive pressure and flow controller strategies for a dual device biventricular support system.

The use of rotary left ventricular assist devices (LVADs) has extended to destination and recovery therapy for end-stage heart failure. Incidence of right ventricular failure while on LVAD support requires a second device be implanted to support the failing right ventricle. Without a commercially available implantable rotary right ventricular assist device, rotary LVADs are cannulated into the right heart and operation modified to provide suitable support for the pulmonary system. While this approach can alleviate the demand for transplant through long-term biventricular support, it uncovers a new challenge with respect to controller strategies for these dual device support systems. This study compares the preload sensitivity of rotary, dual device biventricular assistance controllers in light of their ability to adjust the flow rate according to physiological demand. A Frank-Starling-like flow controller which requires both inlet pressure and flow sensors is compared to pressure controllers which maintain atrial or inlet cannula pressures through the use of a single pressure sensor. It was found that cannula selection and the location of a pressure controller's single pressure sensor can be tailored to adjust the preload sensitivity. When located within the atria, this sensitivity is effectively infinite. Moving the sensor to the base of a 450-mm cannula, however, decreased the sensitivity to 0.22 (L/min)/mm Hg. This indicates the potential for simple and reliable VAD controllers with increased preload sensitivity without the need for complex controllers requiring an array of hemodynamic sensors.

Presence of Specific Periodontal Pathogens in Prostate Gland Diagnosed With Chronic Inflammation and Adenocarcinoma.

Background Intraprostatic inflammation is frequently observed in the prostate and linked to prostatic diseases, including prostatitis, benign prostatic hyperplasia (BPH), and cancer. The etiology of prostate diseases is unclear. Periodontal diseases are associated with an increased risk of prostate diseases. In men, chronic prostatitis and moderate/severe periodontitis have significantly elevated serum prostate-specific antigen (PSA) levels. Treatment of periodontal disease reduced PSA levels in men. The presence of periodontal pathogens deoxyribonucleic acid (DNA) was identified in the prostate fluid of prostatitis patients. These pathogenic bacteria might have the potential to trigger prostatitis progressing to prostatic adenocarcinoma. The mechanism(s) explaining the etiology of association between periodontal disease and prostate cancer remains unclear. However, the presence of periodontal pathogens has not been analyzed in the prostate gland. Objective To identify and compare the presence of specific periodontal pathogens in the areas of BPH, inflammation, and cancer of the prostate glands diagnosed with malignancy. Materials and methods Whole-mount radical prostatectomy sections from men (n=30) were identified for BPH, inflammation, and cancer areas and marked for tissue procurement. The tissues were subjected to DNA isolation and analysis of microbial DNA and total bacterial load for the following pathogens, including Porphyromonas gingivalis strain ATCC 33277, Prevotella intermedia strain B422, Treponema denticola strain 35405, Fusobacterium nucleatum subsp. fusiform strain, Tannerella forsythia strain ATCC 43037, and Campylobacter​​​​​​​ rectus strain ATCC 33238performed real-time PCR. The universal bacterial primer pairs were used to detect genomic DNA (gDNA) from the total bacteria present in the samples. All species-specific primers were designed to target the variable regions of the 16S ribosomal RNA (rRNA). Data were analyzed using the 2-ΔΔCT method, statistically validated using unpaired t-test and ANOVA test. Results A total of 90 samples of prostate tissue specimens were analyzed for periodontal pathogens; only one pathogen (F. nucleatum subsp. fusiform strain ATCC 51190) showed a significant difference compared to the expression of S. epidermidis (internal control). In particular, F. nucleatum expression was 9, 11.9, and 10.3-fold higher in BPH, inflammation, and cancer, respectively, at p-value <0.05. Moreover, the bacterial load abundance/expression was almost similar in BPH (46.8-fold), inflammation (40.9 fold), and cancer (41.5 fold) higher. There was no significant difference in bacterial load (folder change) among the three areas of BPH, inflammation, and cancer (p-valve>0.05). Similarly, there was no significant difference between F. nucleatum (folder change) among the three areas (p-valve>0.05). Conclusion  Fusobacterium nucleatum is identified in the prostates that harbor cancer, chronic inflammation, and BPH.

Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype.

Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.

A single-cell and spatially resolved atlas of human breast cancers.

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.

A passively controlled biventricular support device.

Clinical studies have reported the balancing of pump outputs to be a serious control issue for rotary biventricular support (BiVS) systems. Poor reliability of long-term, blood immersed pressure sensors encouraged the development of a new control strategy to improve their viability. A rotary BiVS device was designed and constructed with a mechanical passive controller to autoregulate pump outputs to emulate the native baroreceptor response. In vitro testing in a dual circuit, hydraulic mock circulation loop showed that the prototype was able to maintain arterial pressures when subjected to sudden induced hemodynamic destabilization. However, inlet suction was observed when sudden simulated hypertension briefly reduced venous return to the cannulated ventricle. The results have encouraged further development of the device as a means to create an inherently stable, fully passive biventricular support device.