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Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans-activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.

Advances made in pediatric cardiology, cardiac surgery and critical care have significantly improved the survival rate of patients with congenital heart disease (CHD) leading to an increase in children with CHD presenting for noncardiac surgical procedures. This study aims (1) to describe the trend and perioperative mortality rates in patients with CHD undergoing noncardiac surgical procedures at children’s hospitals over the past 5 years and (2) to describe the patient characteristics and the most common type of surgical procedures. The Pediatric Health Information System (PHIS) is an administrative database that contains inpatient, observation, and outpatient surgical data from 52 freestanding children’s hospitals. Thirty-nine of the 52 hospitals submitted data on all types of patient encounters for the duration of the study from 2015 to 2019. The total numbers of non-cardiac surgical encounters among patients with history of a CHD diagnosis significantly increased each year from 38,272 in 2015 to 45,993 in 2019 (P < 0.001). Despite the increase in case numbers, there has been a significant decline in mortality rates to the most recent incidence of 1.06% in 2019. Careful patient selection and medical optimization of patients aligned with specific expertise at dedicated children’s hospitals may lead to improvement in mortality rate. Future studies comparing the outcomes of patients with cardiac disease based on hospital type and volume as well as type of providers may help determine the future of care including potential need for regionalization of noncardiac care for this vulnerable patient population.

Purpose Large Language Models (LLMs) are widely used and accessible. We investigate whether publicly available LLMs provide useful, safe, helpful and accurate information to the non-expert general community seeking answers about moyamoya. Methods ChatGPT-4o and Gemini 1.5 Flash were directly single-shot prompted with ten frequently asked questions about moyamoya. A survey of these responses was posted on the Moyamoya Foundation website for ten weeks. Respondents were randomly assigned to read either ChatGPT or Gemini generated responses. Clinicians treating cerebrovascular disease evaluated the safety and accuracy of all responses. Results Community respondents evaluated 27 sets of ChatGPT output and 20 sets of Gemini output. Output length was significantly different ( p  < 0.001). 1.2% and 20.8% of ChatGPT and Gemini answers were reported as “short,” respectively. The LLMs failed to address potential risks for procedures and medications it mentioned (ChatGPT 38%, Gemini 28.6%). Responses omitted when these self-care strategies become insufficient and a medical professional should be consulted (ChatGPT 27.2%, Gemini 40.8%). However, community respondents felt LLM answers were of similar quality (ChatGPT 47.8%, Gemini 49%) or somewhat better (ChatGPT 24.4%, Gemini 22.4%) than one received from their physicians. Physicians evaluating the same LLM outputs reported the answers failed to address recent advances and research within the field (ChatGPT 57.5%, Gemini 62.5%) and failed to address urgent symptoms warranting referral to higher levels of care (ChatGPT 70.0%, Gemini 70.0%). Conclusion LLM responses are perceived as being of similar quality to a physician, but limitations remain for safety, omission of data and their impact on patient-physician relationships.

Background Building health research capacity in low- and middle-income countries is essential to achieving universal access to safe, high-quality healthcare. It can enable healthcare workers to conduct locally relevant research and apply findings to strengthen their health delivery systems. However, lack of funding, experience, know-how, and weak research infrastructures hinders their ability. Understanding research capacity, engagement, and contextual factors that either promote or obstruct research efforts by healthcare workers can inform national strategies aimed at building research capacity. Methods We used a convergent mixed-methods study design to understand research capacity and research engagement of healthcare workers in Tanzania’s public health system, including the barriers, motivators, and facilitators to conducting research. Our sample included 462 randomly selected healthcare workers from 45 facilities. We conducted surveys and interviews to capture data in five categories: (1) healthcare workers research capacity; (2) research engagement; (3) barriers, motivators, and facilitators; (4) interest in conducting research; and (5) institutional research capacity. We assessed quantitative and qualitative data using frequency and thematic analysis, respectively; we merged the data to identify recurring and unifying concepts. Results Respondents reported low experience and confidence in quantitative (34% and 28.7%, respectively) and qualitative research methods (34.5% and 19.6%, respectively). Less than half (44%) of healthcare workers engaged in research. Engagement in research was positively associated with: working at a District Hospital or above ( p  =  0.006 ), having a university degree or more ( p  =  0.007 ), and previous research experience ( p  =  0.001 ); it was negatively associated with female sex ( p  =  0.033 ) . Barriers to conducting research included lack of research funding, time, skills, opportunities to practice, and research infrastructure. Motivators and facilitators included a desire to address health problems, professional development, and local and international collaborations. Almost all healthcare workers (92%) indicated interest in building their research capacity. Conclusion Individual and institutional research capacity and engagement among healthcare workers in Tanzania is low, despite high interest for capacity building. We propose a fourfold pathway for building research capacity in Tanzania through (1) high-quality research training and mentorship; (2) strengthening research infrastructure, funding, and coordination; (3) implementing policies and strategies that stimulate engagement; and (4) strengthening local and international collaborations.

Clinical comparisons do not usually take laterality into account and thus may report erroneous or misleading data. The concept of laterality, well evaluated in brain and motor systems, may also apply at the level of peripheral nerves. Therefore, we sought to evaluate the extent to which we could observe an effect of laterality in MRI-collected white matter indices of the sciatic nerve and its two branches (tibial and fibular). We enrolled 17 healthy persons and performed peripheral nerve diffusion weighted imaging (DWI) and magnetization transfer imaging (MTI) of the sciatic, tibial and fibular nerve. Participants were scanned bilaterally, and findings were divided into ipsilateral and contralateral nerve fibers relative to self-reporting of hand dominance. Generalized estimating equation modeling was used to evaluate nerve fiber differences between ipsilateral and contralateral legs while controlling for confounding variables. All findings controlled for age, sex and number of scans performed. A main effect of laterality was found in radial, axial, and mean diffusivity for the tibial nerve. Axial diffusivity was found to be lateralized in the sciatic nerve. When evaluating mean MTR, a main effect of laterality was found for each nerve division. A main effect of sex was found in the tibial and fibular nerve fiber bundles. For the evaluation of nerve measures using DWI and MTI, in either healthy or disease states, consideration of underlying biological metrics of laterality in peripheral nerve fiber characteristics need to considered for data analysis. Integrating knowledge regarding biological laterality of peripheral nerve microstructure may be applied to improve how we diagnosis pain disorders, how we track patients' recovery and how we forecast pain chronification.

Background Breast cancer (BC) is a complex heterogenous disease that is a leading cause of death in women. For patients with early stage disease following primary BC therapy, approximately 30% will develop metastatic BC (MBC). The median survival of MBC patients is ~ 2–3 yr. While the early detection and monitoring of BC progression have improved prognosis and reduced BC-related mortality, there is a lack of long-term surveillance strategies for monitoring patients for recurrence of MBC. The aim of our study was to identify non-invasive urinary biomarkers for detection and monitoring of MBC. Methods We have conducted a comparative label-free LC–MS/MS analysis of the urinary proteome of patients with MBC and healthy age-matched, sex-matched controls (HC). A hybrid quadrupole time of flight (Q-Tof™) mass spectrometer was used for urine analysis via liquid chromatography (LC) with tandem mass spectrometry (MS/MS). Retrospective analysis of urine samples from MBC and locally invasive breast cancer (IBC) patients as well as HC was conducted. Diagnostic accuracies of candidate markers were validated using independent training and validation sets according to the REMARK criteria. Results Using this approach, we have identified 212 urinary proteins of which 83 and 25 were unique to the MBC and HC groups, respectively. Upregulated proteins in the MBC cohort were associated with angiogenesis, Ca 2+ homeostasis, apoptosis, proteolysis, extracellular matrix regulation, cell adhesion and protein synthesis pathways. A specific non-invasive metastasis signature comprised of candidate biomarkers (urinary CALB1, S100A8, ZAG, VTN and TN) were validated and analyzed via monospecific ELISA assays. Urinary vitronectin (uVTN) levels correlated with disease status and were significantly higher in samples from MBC compared to those from IBC patients and HC. uVTN alone (cutoff > 500 ng/ml) could discriminate between HC and MBC groups ( AUC  = 0.782, P  < 0.001). Longitudinal analysis of samples from MBC patients indicated a strong correlation between uVTN levels and disease status. Conclusions Our findings suggest that uVTN is a promising and non-invasive biomarker for the diagnosis and monitoring of MBC. While future validation in larger cohorts should be done, these results identify a novel urinary protein that represents the first non-invasive diagnostic test for monitoring BC progression and recurrence.

Quality of cardiopulmonary resuscitation (CPR) contributes significantly to outcomes. Key determinants of CPR quality pertaining to chest compressions are compression rate, compression depth, duration of interruptions, and chest recoil. Several studies have demonstrated that real-time audiovisual feedback improves CPR quality. We hypothesize that a mobile application using sensor data from built-in accelerometers in smartphones can provide accurate chest compression quality feedback in real time. This study aims to develop and validate an application for smartphone which can provide real-time audiovisual and haptic feedback on determinants of CPR quality. A mobile application was developed to detect the compression depth and compression rate in real time using data captured from a smartphone's intrinsic accelerometer. The mobile device was placed on an adult manikin's chest at the point of compressions. In a simulated environment, data obtained using the application was compared directly to data obtained from a validated standard CPR quality tool. CPR quality parameters were obtained from the application and industry standard for 60, 30s-long sessions. Bland-Altman plot analysis for compression depth showed agreement between the app measurements and standard within ±4 mm (<10% error). The interclass correlation for agreement in the measurement of compression count was 0.92 (95% CI: 0.88–0.95), indicative of very strong agreement. Smart device applications using acceleration sensor data derived from smart phones can accurately provide real-time CPR quality feedback. With further development and validation, they can provide a ubiquitously available CPR feedback tool valuable for out-of-hospital arrests and in-hospital arrests in under-privileged areas.

Background A well-qualified workforce is critical to effective functioning of health systems and populations; however, skill gaps present a challenge in low-resource settings. While an emerging body of evidence suggests that mentorship can improve quality, access, and systems in African health settings by building the capacity of health providers, less is known about its implementation in surgery. We studied a novel surgical mentorship intervention as part of a safe surgery intervention (Safe Surgery 2020) in five rural Ethiopian facilities to understand factors affecting implementation of surgical mentorship in resource–constrained settings. Methods We designed a convergent mixed-methods study to understand the experiences of mentees, mentors, hospital leaders, and external stakeholders with the mentorship intervention. Quantitative data was collected through a survey ( n  = 25) and qualitative data through in-depth interviews ( n  = 26) in 2018 to gather information on (1) intervention characteristics including areas of mentorship, mentee-mentor relationships, and mentor characteristics, (2) organizational context including facilitators and barriers to implementation, (3) perceived impact, and (4) respondent characteristics. We analyzed the quantitative and qualitative data using frequency analysis and the constant comparison method, respectively; we integrated findings to identify themes. Results All mentees (100%) experienced the intervention as positive. Participants perceived impact as: safer and more frequent surgical procedures, collegial bonds between mentees and mentors, empowerment among mentees, and a culture of continuous learning. Over 70% of all mentees reported their confidence and job satisfaction increased. Supportive intervention characteristics included a systems focus, psychologically safe mentee-mentor relationships, and mentor characteristics including generosity with time and knowledge, understanding of local context, and interpersonal skills. Supportive organizational context included a receptive implementation climate. Intervention challenges included insufficient clinical training, inadequate mentor support, and inadequate dose. Organizational context challenges included resource constraints and a lack of common understanding of the intervention. Conclusion We offer lessons for intervention designers, policy makers, and practitioners about optimizing surgical mentorship interventions in resource-constrained settings. We attribute the intervention’s success to its holistic approach, a receptive climate, and effective mentee-mentor relationships. These qualities, along with policy support and adapting the intervention through user feedback are important for successful implementation.

Management of difficult tracheal intubation during induction of anesthesia in children with congenital heart disease is challenging. The aim of this study is to evaluate the incidence of difficult tracheal intubation in patients with congenital heart disease and compare the incidence of perioperative complications and outcomes in patients with and without difficult tracheal intubation. Retrospective cohort study. Tertiary Children's Hospital. 6858 patient-encounters including cardiac diagnostic, interventional or surgical procedures from 2012 to 2018 were reviewed. Exclusion criteria: age > 18 years, endotracheal tube or tracheostomy in-situ. Patients' demographics, number and methods of intubation, peri-intubation hemodynamics, intensive care unit and postoperative hospital length of stay were recorded. Multivariable mixed-effects median, logistic, ordinal, and multinomial regression modeling were implemented to analyze outcomes in the matched sets. Of the 6014 encounters examined in the study, the incidence of DTI was 0.96% and all 58 difficult tracheal intubations (DTI) were matched using 1:2 propensity score matching to 116 non-DTI encounters. Number of intubation attempts was significantly higher among patients with difficult tracheal intubation (ordinal logistic regression odds ratio = 2; 95% CI; 1.3, 2.7; P < 0.001). No significant differences in peri-intubation hemodynamic stability were noted. Patients with difficult tracheal intubation had longer postoperative hospital length of stay (median = 12.1 vs 7.9 days, coef. = 4; 95% CI: 1.3, 6.8; P = 0.004) than patients without. Despite a higher number of intubation attempts, our study shows no major differences in the peri-intubation hemodynamics in patients with and without difficult tracheal intubation. This risk can be mitigated by a good understanding of cardiac physiology, management of hemodynamics, and early use of an indirect intubation technique to maximize first attempt success. •There are no major differences in the peri-intubation hemodynamics in cardiac patients with and without difficult intubation.•The risk of peri-intubation hemodynamic instability can be mitigated by a good understanding of cardiac physiology.•Early use of an indirect intubation technique maximizes first attempt success and might mitigate risks.