Evidence of steady-state fibroblast subtypes in the normal human breast as cells-of-origin for perturbed-state fibroblasts in breast cancer.

BACKGROUND: Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes-the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship-if any-with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. METHODS: Primary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells' gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database. RESULTS: We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival. CONCLUSIONS: We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.

Gender dynamics and academic rank in emergency medicine collaboration networks: A social network and gender propensity analysis.

BACKGROUND: Academic productivity is bolstered by collaboration, which is in turn related to connectivity between individuals. Gender disparities have been identified in academics in terms of both academic promotion and output. Using gender propensity and network analysis, we aimed to describe patterns of collaboration on publications in emergency medicine (EM), focusing on two Midwest academic departments. METHODS: We identified faculty at two EM departments, their academic rank, and their publications from 2020 to 2022 and gathered information on their co-authors. Using network analysis, gender propensity and standard statistical analyses we assessed the collaboration network for differences between men and women. RESULTS: Social network analysis of collaboration in academic emergency medicine showed no difference in the ways that men and women publish together. However, individuals with higher academic rank, regardless of gender, had more importance to the network. Men had a propensity to collaborate with men, and women with women. The rates of gender propensity for men and women fell between the gender ratios of emergency medicine (65%/35%) and the general population (50%/50%), 59.6% and 44%, respectively, suggesting a tendency toward homophily among men. CONCLUSION: Our study aims to use network analysis and gender propensity to identify patterns of collaboration. We found that further work in the area of network analysis application to academic productivity may be of value, with a particular focus on the role of academic rank. Our methodology may aid department leaders by using the information from local analyses to identify opportunities to support faculty members to broaden and diversify their networks.

Associations between illness perceptions, word recognition, and perceived sound quality in cochlear implant users.

OBJECTIVE: Illness perceptions refer to thoughts and ideas an individual has about an illness. The aim was to understand how cochlear implant (CI) users' illness perceptions, in addition to their monosyllabic word recognition abilities, are associated with their self-perceived sound quality. DESIGN: Data were collected during routine CI check-up appointments. Participants completed the Brief Illness Perception Questionnaire (assessing their illness perceptions) and the Hearing Implant Sound Quality Index (assessing their subjective sound quality). Additionally, monosyllabic word recognition abilities were measured with the Freiburg Monosyllable Word Test. Hierarchical regression analysis were utilised to model users' sound quality ratings. Participants' age was entered first as a control variable. In the next step, monosyllabic word recognition was entered. Finally, participants' illness perceptions were entered. STUDY SAMPLE: Fifty-five participants with unilateral CI provision. RESULTS: Monosyllabic word recognition was significant in the second step. When illness perceptions and monosyllabic word recognition were both included in the third step, illness perceptions, but not monosyllabic word recognition, were significant. The model explained 22% of the variance of subjective sound quality. CONCLUSIONS: Monosyllabic word recognition abilities and illness perceptions of CI users are important for their self-reported sound quality, but illness perceptions appear to be potentially more relevant.

Does the implementation of a trauma system affect injury-related morbidity and economic outcomes? A systematic review.

BACKGROUND: Trauma accounts for a huge burden of disease worldwide. Trauma systems have been implemented in multiple countries across the globe, aiming to link and optimise multiple aspects of the trauma care pathway, and while they have been shown to reduce overall mortality, much less is known about their cost-effectiveness and impact on morbidity. METHODS: We performed a systematic review to explore the impact the implementation of a trauma system has on morbidity, quality of life and economic outcomes, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All comparator study types published since 2000 were included, both retrospective and prospective in nature, and no limits were placed on language. Data were reported as a narrative review. RESULTS: Seven articles were identified that met the inclusion criteria, all of which reported a pre-trauma and post-trauma system implementation comparison in high-income settings. The overall study quality was poor, with all studies demonstrating a severe risk of bias. Five studies reported across multiple types of trauma patients, the majority describing a positive impact across a variety of morbidity and health economic outcomes following trauma system implementation. Two studies focused specifically on traumatic brain injury and did not demonstrate any impact on morbidity outcomes. DISCUSSION: There is currently limited and poor quality evidence that assesses the impact that trauma systems have on morbidity, quality of life and economic outcomes. While trauma systems have a fundamental role to play in high-quality trauma care, morbidity and disability data can have large economic and cultural consequences, even if mortality rates have improved. The sociocultural and political context of the surrounding healthcare infrastructure must be better understood before implementing any trauma system, particularly in resource-poor and fragile settings. PROSPERO REGISTRATION NUMBER: CRD42022348529 LEVEL OF EVIDENCE: Level III.

Local, collaborative, stepped, and personalized care management for older people with chronic diseases - results from the randomized controlled LoChro-trial.

BACKGROUND: In the aging population of Western societies, an increasing number of older adults have multiple chronic diseases. As multifaceted health problems imply the involvement of several healthcare professionals, multimorbid older people frequently face a fragmentation of health care. Addressing these challenges, we developed a local, collaborative, stepped, and personalized care management approach (LoChro-Care) and evaluated its effectiveness. METHODS: A two-group, parallel randomized controlled trial was conducted comparing LoChro-Care recipients (IG) to participants with usual care (CG). Patients aged 65 + with chronic conditions were recruited at inpatient and outpatient departments of the Medical Center, University of Freiburg. Participants were allocated using block randomization (nIG = 261, nCG = 263). LoChro-Care comprised individualized care provided by chronic care managers with 7 to 13 contacts over 12 months. Questionnaires were given at 3 time points (T0: baseline, T1: after 12 months, T2: after 18 months). The primary outcome was the physical, psychological, and social health status represented by a composite score of functional health and depressive symptoms. Secondary outcomes were the participants' evaluation of their health care situation, health-related quality of life (HRQL), and life-satisfaction (LS). The data were analyzed using linear mixed modelling. RESULTS: We analyzed N = 491 participants (nIG = 244, nCG = 247), aged M = 76.78 years (SD = 6.35). For the composite endpoint, neither a significant difference between IG and CG (p = .88) nor a group-time interaction (p = .52; p = .88) could be observed. Participants in both groups showed a significant decline on the primary outcome between T0 and T2 (p < .001). Post hoc analyses revealed a decline in both functional health (p < .001) and depressive symptoms (p = .02). Both groups did not differ in their evaluation of their health care situation (p = .93), HRQL (p = .44) or LS (p = .32). Relevant confounding variables were female gender and multimorbidity. CONCLUSION: Supporting patients' self-management in coordinating their individual care network through LoChro-Care did not result in any significant effect on the primary and secondary outcomes. A decline of functional health and depressive symptoms was observed among all participants. Potential future intervention adaptations are discussed, such as a more active case management through direct referral to (in-)formal support, an earlier treatment initiation, and the consideration of specific sociodemographic factors in care management planning. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00013904 (02.02.2018), https://drks.de/search/de/trial/DRKS00013904.

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set.

BACKGROUND: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. METHODS: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method. RESULTS: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. CONCLUSIONS: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021).

Depressive symptoms affect short- and long-term speech recognition outcome in cochlear implant users.

PURPOSE: To investigate the impact of the amount of depressive symptoms in cochlear implant (CI) recipients on the development of speech recognition after CI-activation up to 2 years. DESIGN: Retrospective data analysis of a German short form of the Beck Depression Inventory given at initial activation of the implant in relation to monosyllabic word recognition score at conversational level at initial activation and at 3 months, 1 and 2-year follow-up measurements. STUDY SAMPLE: Thirty-one CI-patients (11 female, 20 male) aged between 41 and 83 (M = 64.77, SD = 10.43) who were German native speakers, postlingually deafened, with severe hearing loss in both sides but unilaterally implanted (19 right-sided, 12 left-sided). RESULTS: The amount of depressive symptoms at initial activation was negatively correlated with the monosyllabic recognition score after 3 months and after 1 year of implant use. CONCLUSION: The psychological status in terms of depressive symptoms is an important parameter regarding the rehabilitative outcome of CI-patients. Care staff and CI-users should be sensitized to the link between depressive symptoms and the development of speech recognition with CI.

[Integrated care management for older people with chronic diseases in domesticity: evidence from Cochrane reviews]. / Integriertes Versorgungsmanagement für chronisch erkrankte ältere Menschen in der eigenen Häuslichkeit: Evidenz aus Cochrane-Reviews.

BACKGROUND: The number of multiple chronically ill older people is increasing and multimorbidity is associated with high utilization of health services. Integrated care management is increasingly used to address this problem; however, there is a substantial lack of reliable data on its effectiveness in this target group. OBJECTIVE: To assess the effectiveness of components of integrated care management in adults of all ages and to estimate the transferability to older, multimorbid people in Germany. METHODS: A systematic search was carried out in the Cochrane Library for Cochrane reviews (CR) on (a) the 13 most frequent health problems in old age, which (b) evaluated components of integrated care management in (c) adults of all ages. Experts assessed the transferability of the included CR to multiple chronically ill older people in Germany. RESULTS: Out of 1412 hits 126 CR were included. Regarding independence and functional health outcomes, 25 CR showed clinically relevant results with at least a moderate level of evidence. The following intervention components were estimated to be transferable and could be adapted to be part of an effective integrated care management for multimorbid chronically ill older people, specified by indications and taking identified barriers into account: (1) physical activation, (2) multidisciplinary interventions (3) interventions that enhance self-management, (4) cognitive therapy modalities, (5) telemedical interventions and (6) disease management programs. CONCLUSION: The effectiveness of the identified components in frail older patients should be assessed in care-related and patient-related randomized controlled studies.

[The impact of urban architecture on health: the PAKARA model]. / Wie Stadtarchitektur die Gesundheit beeinflusst: das PAKARA-Modell.

Humankind is in constant interaction with the environment. If this interaction leads to individual internalization of the environment, which is also called "appropriation" in psychology, it has a positive effect on health and wellbeing. To promote appropriation, urban architecture must respond to human needs. The PAKARA model illustrates the dynamic interaction of these needs with urban architecture, distinguishing three sectors: preventive, curative, and rehabilitative architecture. The PAKARA model was developed in 2019 at the Technical University of Munich.In addition to the model, the article explains three central needs that, influenced by urban architecture, can lead to health-promoting saturation or health-damaging over- or undersaturation: stimulation, identification, and privacy. Conclusively, it is shown that the future challenge is to expand close interdisciplinary cooperation against the background of a drastic increase in the global urban population and an associated complexity of need-oriented design. The needs of the individual - even if they contradict each other and change over the course of a lifetime - are the driving motor behind the health of an entire community. Urban architecture has the potential to keep this motor running, or, destroy it.

Evaluation of CEDIA and DRI Drugs of Abuse Immunoassays for Urine Screening on a Thermo Indiko Plus Analyzer.

BACKGROUND: For analysis of urine samples during abstinence control for driving ability assessment (medical and psychological assessment, MPA), a reliable screening method for ethyl glucuronide and drugs of abuse (cannabinoids, opiates, cocaine, amphetamines, methadone, and benzodiazepines) is needed. METHODS: In this study CEDIA and DRI immunoassays were applied on a Thermo Fisher Scientific Indiko Plus analyzer. Precision and accuracy as well as sensitivity and specificity at the required cut-offs for the MPA were evaluated. RESULTS: The specificity was satisfactory and ranged from 91% for methamphetamine to 100% for opiates, cocaine metabolite, amphetamine, EDDP, and benzodiazepines. Moreover, sensitivity was 100% for all assays except for cannabinoids (91%). CONCLUSION: The presented method can therefore be recommended for abstinence control.

Use of computer simulation to identify effects on hospital census with reduction of transfers for non-procedural patients in community hospitals.

OBJECTIVE: In-person healthcare delivery is rapidly changing with a shifting employment landscape and technological advances. Opportunities to care for patients in more efficient ways include leveraging technology and focusing on caring for patients in the right place at the right time. We aim to use computer modelling to understand the impact of interventions, such as virtual consultation, on hospital census for referring and referral centres if non-procedural patients are cared for locally rather than transferred. PATIENTS AND METHODS: We created computer modelling based on 25 138 hospital transfers between June 2019 and June 2022 with patients originating at one of 17 community-based hospitals and a regional or academic referral centre receiving them. We identified patients that likely could have been cared for at a community facility, with attention to hospital internal medicine and cardiology patients. The model was run for 33 500 days. RESULTS: Approximately 121 beds/day were occupied by transferred patients at the academic centre, and on average, approximately 17 beds/day were used for hospital internal medicine and nine beds/day for non-procedural cardiology patients. Typical census for all internal medicine beds is approximately 175 and for cardiology is approximately 70. CONCLUSION: Deferring transfers for patients in favour of local hospitalisation would increase the availability of beds for complex care at the referral centre. Potential downstream effects also include increased patient satisfaction due to proximity to home and viability of the local hospital system/economy, and decreased resource utilisation for transfer systems.

Artificial intelligence-enabled ophthalmoscopy for papilledema: a systematic review protocol.

Papilledema is a pathology delineated by the swelling of the optic disc secondary to raised intracranial pressure (ICP). Diagnosis by ophthalmoscopy can be useful in the timely stratification of further investigations, such as magnetic resonance imaging or computed tomography to rule out pathologies associated with raised ICP. In resource-limited settings, in particular, access to trained specialists or radiological imaging may not always be readily available, and accurate fundoscopy-based identification of papilledema could be a useful tool for triage and escalation to tertiary care centres. Artificial intelligence (AI) has seen a rise in neuro-ophthalmology research in recent years, but there are many barriers to the translation of AI to clinical practice. The objective of this systematic review is to garner and present a comprehensive overview of the existing evidence on the application of AI in ophthalmoscopy for papilledema, and to provide a valuable perspective on this emerging field that sits at the intersection of clinical medicine and computer science, highlighting possible avenues for future research in this domain.

Evaluating patient factors, operative management and postoperative outcomes in trauma laparotomy patients worldwide: a protocol for a global observational multicentre trauma study.

INTRODUCTION: Trauma contributes to the greatest loss of disability-adjusted life-years for adolescents and young adults worldwide. In the context of global abdominal trauma, the trauma laparotomy is the most commonly performed operation. Variation likely exists in how these patients are managed and their subsequent outcomes, yet very little global data on the topic currently exists. The objective of the GOAL-Trauma study is to evaluate both patient and injury factors for those undergoing trauma laparotomy, their clinical management and postoperative outcomes. METHODS: We describe a planned prospective multicentre observational cohort study of patients undergoing trauma laparotomy. We will include patients of all ages who present to hospital with a blunt or penetrating injury and undergo a trauma laparotomy within 5 days of presentation to the treating centre. The study will collect system, patient, process and outcome data, following patients up until 30 days postoperatively (or until discharge or death, whichever is first). Our sample size calculation suggests we will need to recruit 552 patients from approximately 150 recruiting centres. DISCUSSION: The GOAL-Trauma study will provide a global snapshot of the current management and outcomes for patients undergoing a trauma laparotomy. It will also provide insight into the variation seen in the time delays for receiving care, the disease and patient factors present, and patient outcomes. For current standards of trauma care to be improved worldwide, a greater understanding of the current state of trauma laparotomy care is paramount if appropriate interventions and targets are to be identified and implemented.

SSEA-1 Correlates With the Invasive Phenotype in Breast Cancer.

The glycan moiety Lewis X (LeX) has been implicated in defining progenitor cells as well as playing a role in the progression of solid tumors, including breast cancer. Here, we used the original stage-specific embryonic antigen-1 (SSEA-1) antibody, MC-480, targeting the LeX motif to examine the expression pattern of this marker within the context of a differentiation hierarchy as well as functional properties of breast cancer cells. Immunohistochemical staining revealed the presence of SSEA-1 in a progenitor zone in the normal breast gland. In breast cancer, 81 of 220 carcinomas (37%) were positive for SSEA-1 and a distinct pattern could be correlated to major subtypes. Specifically, estrogen receptor alpha (ERα)-negative tumors showed a higher frequency of SSEA-1 expression compared to ERα-positive tumors, which are generally considered more differentiated (56% vs 29%, p<0.005). Functional assays performed on two representative breast cancer cell lines demonstrated that SSEA-1-expressing cells exhibited cancer stem cell properties as well as having more invasive potential, regardless of ERα status. A potential role of SSEA-1 in metastasis was confirmed by pairwise staining of primary- and corresponding lymph node tumors. Altogether, our data suggest that expression of SSEA-1 in breast cancer contributes to the malignant phenotype.

Directed acyclic graphs in perioperative observational research-A systematic review and critique against best practice recommendations.

The Directed Acyclic Graph (DAG) is a graph representing causal pathways for informing the conduct of an observational study. The use of DAGs allows transparent communication of a causal model between researchers and can prevent over-adjustment biases when conducting causal inference, permitting greater confidence and transparency in reported causal estimates. In the era of 'big data' and increasing number of observational studies, the role of the DAG is becoming more important. Recent best-practice guidance for constructing a DAG with reference to the literature has been published in the 'Evidence synthesis for constructing DAGs' (ESC-DAG) protocol. We aimed to assess adherence to these principles for DAGs constructed within perioperative literature. Following registration on the International Prospective Register of Systematic Reviews (PROSPERO) and with adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting framework for systematic reviews, we searched the Excerpta Medica dataBASE (Embase), the Medical Literature Analysis and Retrieval System Online (MEDLINE) and Cochrane databases for perioperative observational research incorporating a DAG. Nineteen studies were included in the final synthesis. No studies demonstrated any evidence of following the mapping stage of the protocol. Fifteen (79%) fulfilled over half of the translation and integration one stages of the protocol. Adherence with one stage did not guarantee fulfilment of the other. Two studies (11%) undertook the integration two stage. Unmeasured variables were handled inconsistently between studies. Only three (16%) studies included unmeasured variables within their DAG and acknowledged their implication within the main text. Overall, DAGs that were constructed for use in perioperative observational literature did not consistently adhere to best practice, potentially limiting the benefits of subsequent causal inference. Further work should focus on exploring reasons for this deviation and increasing methodological transparency around DAG construction.

Role of Defibrotide in the Prevention of Murine Model Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vascular endothelial cells are entirely exposed and damaged during the pathogenesis of acute GVHD (aGVHD). Defibrotide (DF) is a mixture of single-stranded oligonucleotides that has several pharmacologic effects that contribute to its endothelial protective properties. B10.BR mice were conditioned, followed by the infusion of donor C57BL/6J T cell-depleted bone marrow cells with or without splenocytes. The mice were either treated with DF or appropriate controls daily for the first week and then 3 times per week thereafter. Allogeneic DF-treated recipients demonstrated significantly better survival with reduced clinical GVHD. Significantly reduced organ pathology in the gut was associated with significantly decreased T cell infiltration in the ileum and colon on day +28. Serum cytokine analysis revealed significantly reduced levels of TNF and IL-6 at day +7 and of TNF at day +28 in allogeneic DF-treated recipients. Significantly reduced levels of ICAM-1 and angiopoietin-2 in serum and reduced VCAM-1 and HCAM levels in the ileum and colon of allogeneic DF-treated recipients were observed. Improved survival was seen in the graft-versus-leukemia (GVL) model (C3H.SW into C57BL/6J mice with C1498-luc). Through its anti-inflammatory and endothelial protective effects, DF treatment reduces the severity of aGVHD while not impairing GVL activity.