Patient-specific vascularized tumor model: Blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-ß (CSF1R/CCR2/TGF-ß Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.

Transcranial direct stimulation over left inferior frontal gyrus improves language production and comprehension in post-stroke aphasia: A double-blind randomized controlled study.

Transcranial direct current stimulation (tDCS) targeting Broca's area has shown promise for augmenting language production in post-stroke aphasia (PSA). However, previous research has been limited by small sample sizes and inconsistent outcomes. This study employed a double-blind, parallel, randomized, controlled design to evaluate the efficacy of anodal Broca's tDCS, paired with 20-minute speech and language therapy (SLT) focused primarily on expressive language, across 5 daily sessions in 45 chronic PSA patients. Utilizing the Western Aphasia Battery-Revised, which assesses a spectrum of linguistic abilities, we measured changes in both expressive and receptive language skills before and after intervention. The tDCS group demonstrated significant improvements over sham in aphasia quotient, auditory verbal comprehension, and spontaneous speech. Notably, tDCS improved both expressive and receptive domains, whereas sham only benefited expression. These results underscore the broader linguistic benefits of Broca's area stimulation and support the integration of tDCS with SLT to advance aphasia rehabilitation.

Reactivity to Peer Rejection Moderates the Effect of Victimization on Adolescent Girls' Depressive Symptoms: A Prospective Study.

Peer victimization and bullying behaviors are prevalent during adolescence and have been linked to depression. This study examined whether peer rejection reactivity, defined as physiological responses to peer exclusion, moderated the associations of victimization and bullying behaviors with depressive symptoms 12 months later in a sample of female youths (N = 79, Mage = 13.37 ± 2.31). Participants underwent the Yale Interpersonal Stressor-Child, during which systolic and diastolic blood pressure and heart rate were continuously measured. Parent and youth reports of the youth's depressive symptoms were utilized. Our results demonstrate that peer rejection reactivity moderates the relationship between victimization and subsequent depressive symptoms but does not moderate the relationship between bullying behaviors and subsequent depressive symptoms. Higher victimization was associated with increased youth-reported depressive symptoms among girls with high reactivity but decreased depressive symptoms among girls with low reactivity. Future research can explore whether reducing emotional and physiological reactivity to peer rejection, as well as increasing interpersonal effectiveness in peer relationships, can reduce depressive symptoms in adolescent girls experiencing victimization.

Enablers and Barriers of Research Engagement Among Clinician Researchers: Nursing, Allied Health and Medical Professionals.

Background: In response to the increasing involvement of nursing, allied health and medical professionals in research within clinical service roles, understanding the varying research capacities across public health institutions and professions is crucial. This study aims to explore the lived experiences of conducting research among nursing, allied health and medical health professionals within a tertiary public hospital setting in New South Wales (NSW). The focus is on identifying barriers and enablers to research engagement. Methods: Research active health professionals across nursing, allied health and medical professions were invited to participate in a semi-structured interview to discuss enablers and barriers experienced whilst conducting research. All interviews were transcribed verbatim, conceptual and thematic analysis of the interviews was conducted. Results: Nine allied health professionals, eight nurses/midwives and thirteen medical officers were interviewed. Key themes were categorised as barriers or enablers. The ethics regulatory process was identified as a strong barrier in all professions, other commonly identified barriers were lack of time to conduct research and lack of funding. Researchers reported difficulties knowing where to obtain assistance and support when required. Mentorship was the most common enabler identified by all three professions. In addition, a positive research culture and organisational support and assistance within the organisation were seen as strong enablers. Conclusion: This research provides insight into the barriers and enablers for active clinician researchers across three professional groups. We have identified priority areas to increase research capacity within our health care organisation and will focus on training in the ethics regulatory process and mentorship along with infrastructure support to strengthen the positive research culture across all professions.

Plain Language Summary: Research by healthcare professionals employed in publicly funded health services is encouraged across nursing/midwifery, allied health and medical professionals. This study sought to identify barriers and enablers to undertaking research for these healthcare professionals. Interviews were conducted with representatives from each of the professions. Barriers identified across all professional groups were inconsistencies and difficulties with the ethical regulatory process. Enablers such as a positive research culture within the institutions were found meaningful by the professional groups. This study will allow health organisations to tailor training and infrastructure support to all researchers.

Widespread haemorrhages in infants post-shunting (WHIPS): clinical features, risk factors and neuroimaging characteristics of a rare and under-recognised phenomenon.

PURPOSE: Infants undergoing CSF shunting procedures face a rare complication which we propose to rename "Widespread Haemorrhages in Infants Post-Shunting" (WHIPS) to better capture this unique phenomenon specific to infants undergoing CSF diversion. Our objective is to analyse the risk factors for WHIPS development and provide a detailed neuroradiological description of these haemorrhages. MATERIALS AND METHODS: A radiology information system (RIS) was searched using the search terms "shunt" and/or "catheter" and/or "drain" and/or "ventriculoperitoneal" and/or "VP" between September 2008 to January 2021 for patients < 12 months of age. Clinical data was compiled for each patient meeting the inclusion criteria. Included cases were reviewed by three radiologists for the presence of WHIPS with calculation of the bifrontal ratio and documenting haemorrhage number, morphology, location and lobar distribution. RESULTS: 51 patients met inclusion criteria, 8 WHIPS patients and 43 controls. There was a statistically significant correlation between a larger post-op head circumference and WHIPS (p = 0.04). WHIPS was associated with post-haemorrhagic hydrocephalus and post-infectious hydrocephalus (p = 0.009). WHIPS were identified in the cortico-subcortical regions, periventricular white matter, and deep white matter. Haemorrhages were either punctate, ovoid or confluent. Haemorrhages ranged from single to innumerable. CONCLUSIONS: WHIPS represent a rare and under-recognised complication of CSF shunting unique to the infantile population. We postulate deep and superficial medullary venous haemorrhage as an underlying mechanism related to disordered intracranial hydrodynamics which are exacerbated in the infantile population due to underdeveloped arachnoid granulations and a compliant skull.

Dietary linoleic acid supplementation fails to rescue established cardiomyopathy in Barth syndrome.

Barth syndrome (BTHS) is a mitochondrial lipid disorder caused by mutations in TAFAZZIN (TAZ), required for cardiolipin (CL) remodeling. Cardiomyopathy is a major clinical feature, with no curative therapy. Linoleic acid (LA) supplementation is proposed to ameliorate BTHS cardiomyopathy by enhancing linoleoyl group incorporation into CL. While the beneficial effect of dietary LA supplementation in delaying the development of BTHS cardiomyopathy has been recently tested, its potential to reverse established BTHS cardiomyopathy remains unclear. Our study revealed that LA supplementation cannot rescue established BTHS cardiomyopathy in mice, highlighting the importance of early initiation of LA supplementation for maximum benefits.

Addressing Burnout and Enhancing Well-Being Among Academic Physicians: A Call for Future Research and Organizational Support.

Description Burnout among academic physicians, who navigate multiple roles beyond the clinical environment, is a pressing issue. However, the factors driving burnout among academic physicians are not fully understood. Prior research has revealed differences in burnout dimensions between clinical and basic science faculty, but the impact of balancing research, education, and clinical demands on academic physicians is still unclear. This knowledge gap negatively affects the clinical, translational science, research, and medical education workforces and has particular implications for minoritized and marginalized groups working in academic medical centers. Creating a culture of well-being has been vital in addressing burnout. Further research is needed to explore the unique experiences and demands of academic physicians- particularly those from minoritized and marginalized backgrounds-and to develop effective strategies to promote well-being as they balance diverse roles and contexts. This commentary highlights gaps in understanding burnout among academic physicians and proposes guidelines for future research as well as strategies to improve well-being at academic medical centers.

Pediatric Monitoring Technologies and Congenital Heart Disease: A Systematic Review.

Outpatient monitoring of infants with congenital heart disease has been shown to significantly reduce rates of mortality in the single ventricle population. Despite the accelerating development of miniaturized biosensors and electronics, and a growing market demand for at-home monitoring devices, the application of these technologies to infants and children is significantly delayed compared with the development of devices for adults. This article aims to review the current landscape of available monitoring technologies and devices for pediatric patients to describe the gap between technologies and clinical needs with the goal of progressing development of clinically and scientifically validated pediatric monitoring devices.

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (-T); (2) Trauma, No Symptoms (T - S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the -T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T - S group. There were no differences between the T - S group and - T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Topical Diclofenac Versus Oral Ibuprofen Versus Diclofenac + Ibuprofen for Emergency Department Patients With Acute Low Back Pain: A Randomized Study.

STUDY OBJECTIVE: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for a variety of musculoskeletal injuries. It is not known whether topical NSAIDs should be used for patients presenting with acute nonradicular musculoskeletal low back pain. METHODS: We conducted a randomized, placebo-controlled double-blind study in which patients 18 to 69 years of age visiting the emergency department (ED) with acute, nontraumatic, nonradicular, musculoskeletal low back pain were randomized at the time of discharge to treatment with 400 mg oral ibuprofen + placebo topical gel, 1% diclofenac topical gel + oral placebo, or 400 mg ibuprofen + 1% diclofenac topical gel. We measured outcomes using the Roland Morris Disability Questionnaire (RMDQ), a 24-item yes/no instrument about the effect of back pain on a respondent's daily activities. The primary outcome was change in RMDQ score between ED discharge and 2 days later. Medication-related adverse events were elicited by asking whether the study medications caused any new symptoms. RESULTS: In total, 3,281 patients were screened for participation, and 198 were randomized. Overall, 36% of the population were women, the mean age was 40 years (standard deviation, 13), and the median RMDQ score at baseline was 18 (25th to 75th percentile: 13 to 22), indicating substantial low back-related functional impairment. In total, 183 (92%) participants provided primary outcome data. Two days after the ED visit, the ibuprofen + placebo group had improved by 10.1 (95% confidence interval [CI] 7.5 to 12.7), the diclofenac gel + placebo group by 6.4 (95% CI 4.0 to 8.8), and the ibuprofen + diclofenac gel by 8.7 (95% CI 6.3 to 11.1). The between-group differences were as follows: ibuprofen versus diclofenac, 3.7 (95% CI 0.2 to 7.2); ibuprofen versus both medications 1.4 (95% CI -2.1 to 4.9); and diclofenac versus both medications, 2.3 (95% CI -5.7 to 1.0). Medication-related adverse events were reported by 3/60 (5%) ibuprofen patients, 1/63 (2%) diclofenac patients, and 4/64 (6%) patients who received both. CONCLUSION: Among patients with nontraumatic, nonradicular acute musculoskeletal low back pain discharged from an ED, topical diclofenac was probably less efficacious than oral ibuprofen. It demonstrated no additive benefit when coadministered with oral ibuprofen.

Female adolescents' early life stress and body mass index: Differential effects of anger and anxiety in response to rejection.

INTRODUCTION: Early life stress is linked to childhood obesity. As children enter adolescence, early life stress may be associated with increased rejection sensitivity, resulting in activation of behavioral and physiological changes that contribute to higher body mass index (BMI). Understanding the potential influence of rejection sensitivity on the association between early life stress and BMI is important to examine in female adolescents. For this secondary data analysis, we hypothesized that female adolescents with greater early life stress and greater rejection sensitivity would exhibit higher BMI-for-age 12 months later. METHODS: Seventy-eight adolescents (Mage = 13.1 years; 100% female sex; MBMI = 23.2 kg/m2) in the United States completed study procedures from 2012 to 2016. Among these procedures, the Psychosocial Schedule was used to assess cumulative early life stress and the Children's Rejection Sensitivity Questionnaire was used to assess anger and anxiety in response to rejection. Twelve months later, height and weight were measured to derive BMI-for-age. RESULTS: Higher early life stress was associated with higher BMI-for-age among female adolescents with low rejection-provoked anger (1 SD below the mean). However, this association was not observed among female adolescents with high rejection-provoked anger (1 SD above the mean). Finally, there was no significant interaction between early life stress and rejection-provoked anxiety in predicting BMI-for-age. CONCLUSIONS: Experiencing early life stress may interact with rejection-provoked anger, but not anxiety, to predict BMI-for-age. Findings inform a developmental perspective of how rejection sensitivity may influence the association between early life stress and early cardiometabolic risk.

Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.

While pancreatic ß and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from ß cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that ß cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the ß cell glucose threshold and consequently lowers the glycaemic set point in vivo.

Patient-Specific Vascularized Tumor Model: Blocking TAM Recruitment with Multispecific Antibodies Targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, with the infiltration of monocyte-derived tumor-associated macrophages (TAMs) associated with poor prognosis in diverse cancers. Targeting TAMs holds potential against solid tumors, but effective immunotherapies require testing on immunocompetent human models prior to clinical trials. Here, we develop an in vitro model of microvascular networks that incorporates tumor spheroids or patient tissues. By perfusing the vasculature with human monocytes, we investigate monocyte trafficking into the tumor and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via TAM-produced CCL7 and CCL2, mediated by CSF-1R. Additionally, we assess a novel multispecific antibody targeting CCR2, CSF-1R, and neutralizing TGF-ß, referred to as CSF1R/CCR2/TGF-ß Ab, on monocytes and macrophages using our 3D models. This antibody repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and effectively blocks monocyte migration. Finally, we show that the CSF1R/CCR2/TGF-ß Ab inhibits monocyte recruitment in patient-specific vascularized tumor models. Overall, this vascularized tumor model offers valuable insights into monocyte recruitment and enables functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment (TME).

Does use of health behaviours to cope with stress predict sleep impairment in trauma-exposed community adults?

Individuals who have been exposed to trauma experience high levels of sleep impairment. Given the well-established negative effects of stress on sleep, the ways in which trauma-exposed individuals cope with stress is likely to be associated with their sleep. This study examined how the use of health behaviours (i.e., exercise, comfort eating, and maintaining a self-care routine) to cope relate to sleep impairment in a community sample of trauma-exposed adults (N = 84, mean age = 35.1, 83% female). We also tested whether use of health behaviours to cope moderates the relationship between psychological distress and sleep impairment. Results demonstrate that exercise and maintaining a self-care routine to cope are associated with less sleep impairment, while comfort eating to cope is associated with greater sleep impairment. Further, comfort eating to cope moderated the relationship between distress and sleep impairment. Findings suggest that the use of health behaviours to cope is differentially associated with sleep impairment, which has important clinical and research implications for the health of trauma-exposed adults.

Non-canonical C-terminal variant of MeCP2 R344W exhibits enhanced degradation rate.

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants in the MECP2 gene. While the majority of RTT-causing variants are clustered in the methyl-CpG binding domain and NCoR/SMRT interaction domain, we report a female patient with a functionally uncharacterized MECP2 variant in the C-terminal domain, c.1030C>T (R344W). We functionally characterized MECP2-R344W in terms of protein stability, NCoR/SMRT complex interaction, and protein nuclear localization in vitro. MECP2-R344W cells showed an increased protein degradation rate without significant change in NCoR/SMRT complex interaction and nuclear localization pattern, suggesting that enhanced MECP2 degradation is sufficient to cause a Rett Syndrome-like phenotype. This study highlights the pathogenicity of the C-terminal domain in Rett Syndrome, and demonstrates the potential of targeting MECP2 protein stability as a therapeutic approach.

Long-term outcomes of symptomatic optic pathway glioma: 32-year experience at a single Western Australian tertiary pediatric oncology center.

Introduction: Optic pathway gliomas (OPGs) are associated with significant risk of visual and endocrine morbidity, but data on long-term outcomes in symptomatic patients is sparse. This study reviews the clinical course, disease progression, survival outcomes and long-term sequelae in pediatric patients with symptomatic OPGs in our institution over three decades. Methods: Retrospective review of patients with symptomatic OPG treated in a single tertiary pediatric oncology center from 1984 to 2016. Results: A total of 37 patients were diagnosed with symptomatic OPG. Decreased visual acuity was the commonest presenting symptom (75.7%). Surgical intervention was performed in 62.2%; 56.5% underwent biopsy, 26.1% surgical debulking and 17.4% had orbital decompression with cystic fenestration and cosmetic optic nerve excision at different treatment intervals. CSF diversion was performed in 47.8% patients. Histopathologic examination confirmed 86% to be pilocytic astrocytoma and 1 ganglioglioma. 46% received chemotherapy and 48% had radiotherapy, at different intervals. Median follow-up was 13.74 years. In NF1 patients, overall survival (OS) was 100% at 5 years and 55.6 ± 24.8% at 25 years while progression-free-survival (PFS) was 50 ± 15.8% at 5 and 20 years. In non-NF1 patients, OS was 96.2 ± 3.8% at 5 years and 87.4 ± 9% at 25-years. 5-year PFS was 53.8 ± 9.8% and 25-year PFS was 49.0 ± 10%. Cumulative PFS was 53 ± 8.3% at 5 years and 49.7 ± 8.4% at 20 years while cumulative OS was 97.2 ± 2.7% at 5 years and 77.5 ± 10.8% at 25 years. 59.5% patients developed post-operative endocrinopathy. Long-term vision was normal in 8.1%, improved in 13.5%, stabilized in 40.5% but worsened in 37.8% patients. Three patients treated with radiotherapy developed second brain tumors. Conclusion: 25-year OS in this cohort was 77.5% but survivorship carried significant long-term morbidities including radiation-induced second malignant brain tumors.

Clinical trial simulations in pulmonary fibrosis: patient-focused insights and adaptations.

Background: Patient recruitment and retention are a challenge when conducting clinical trials in patients with pulmonary fibrosis, including idiopathic pulmonary fibrosis and other interstitial lung diseases. This study aimed to understand and address the barriers associated with trial participation for these populations. Methods: Nine patients, nine caregivers and three healthcare professionals participated in virtual simulations of planned phase III trials. During the simulations, participants received information about the trials and either tested a home spirometry device or watched a home spirometry demonstration, before providing their insights in debriefs. The findings were interpreted in advisory boards with representatives from patient organisations and expert investigators. Results: Regarding barriers to participation, patient fatigue and breathlessness were emphasised as posing challenges for travel, visit length and completion of onsite assessments. Lack of information, support and appreciation were also identified as factors that may exacerbate anxiety and negatively affect participant retention rates. Feedback on the home spirometry was mixed, with participants appreciating being able to complete the test at home but worrying about device handling. Based on the insights gained, patient-friendly adaptations were made to the trial protocol and conduct, including remote assessment of patient-reported outcomes, increased visit flexibility, travel support services, patient and caregiver information campaigns, and training of investigators on patients' needs. Conclusions: Participants identified important barriers to participation, which led to patient-friendly changes being made to the planned trials. As a result, participation in the planned trials should be less burdensome, with improved recruitment and retention rates, and ultimately, improved data quality.