Smad4 controls proliferation of interstitial cells in the neonatal kidney.

Expansion of interstitial cells in the adult kidney is a hallmark of chronic disease, whereas their proliferation during fetal development is necessary for organ formation. An intriguing difference between adult and neonatal kidneys is that the neonatal kidney has the capacity to control interstitial cell proliferation when the target number has been reached. In this study, we define the consequences of inactivating the TGFß/Smad response in the mouse interstitial cell lineage. We find that pathway inactivation through loss of Smad4 leads to overproliferation of interstitial cells regionally in the kidney medulla. Analysis of markers for BMP and TGFß pathway activation reveals that loss of Smad4 primarily reduces TGFß signaling in the interstitium. Whereas TGFß signaling is reduced in these cells, marker analysis shows that Wnt/ß-catenin signaling is increased. Our analysis supports a model in which Wnt/ß-catenin-mediated proliferation is attenuated by TGFß/Smad to ensure that proliferation ceases when the target number of interstitial cells has been reached in the neonatal medulla.

Family characteristics and childcare patterns associated with early social functioning in cancer-bereaved parents.

BACKGROUND: Bereaved parents experience life-long grief after the death of their child from cancer. Parents who can integrate their grief and maintain their social functioning early in bereavement, even in the setting of concurrent psychosocial distress, have improved outcomes. Identifying the factors associated with bereaved parents' early social functioning can guide future supportive interventions. METHODS: The authors surveyed parents of children who died from cancer at two large centers 6-24 months after death, assessing bereavement experiences using validated and pilot tested tools. Univariable and multivariable logistical regression models were used to examine which family and child demographic, treatment, and end-of-life (EOL) factors were associated with maintained parental social functioning (T scores ≥40 on the Patient-Reported Outcomes Measurement Information System Ability to Participate in Social Roles and Activities-Short Form questionnaire). RESULTS: One hundred twenty-eight parents of 88 children participated (38% household response rate); most parents identified as female (63%) and White (88%). Parents' median age was 47 years (interquartile range, 10 years); and the median time from the child's death to survey completion was 13 months (interquartile range, 10 months). In multivariate modeling, parents without household material hardship and those who felt prepared for EOL circumstances had increased odds of maintained social functioning (odds ratio, 4.7 [95% confidence interval, 1.6-13.7; p < .004] and 5.5 [95% confidence interval, 1.9-15.9; p < .002], respectively). CONCLUSIONS: Parents who felt prepared for their child's EOL and those without household material hardship were more likely to have maintained social functioning in the first 2 years after their child's death. Interventions targeting EOL preparedness and alleviating household material hardship may improve bereavement outcomes.

Consultation patterns before and after embedding pediatric palliative care into a pediatric hematology/oncology clinic.

INTRODUCTION: Palliative care is a critical component of pediatric oncology care. Embedded pediatric palliative care (PPC) is relatively new in pediatric hematology/oncology (PHO) and may improve access, utilization, and quality of PPC. In June 2020, the Mayo Clinic PPC service transitioned from an afternoon, physically independent clinic to an all-day clinic embedded within PHO. METHODS: Retrospective chart review was used to quantify consultation rates from PHO to PPC in 12-month study periods before and after establishment of an embedded clinic. Changes in descriptive statistics and consult patterns were calculated. Study periods were compared using either chi-square or Fisher's exact tests for categorical variables and Wilcox rank sum tests for continuous variables. RESULTS: There was an 89% increase in consultations from PHO to PPC after initiation of an embedded clinic (n = 20 vs. n = 38 per 12 months). The absolute number of completed outpatient consults increased from three (15% of visits) pre-embedment to fourteen (37%) post-embedment (p = .082). The median number of days from first oncology visit to PPC assessment was unchanged after embedment (36 vs. 47 days, p = .98). Consults for solid tumors increased from 22% (n = 4) pre-embedment to 60% (n = 18) post-embedment (p < .05). Consults for symptom management increased from 60% (n = 12) to 87% (n = 33) (p < .05). CONCLUSIONS: Embedment of PPC into a PHO workspace was associated with an increased number of total consults, outpatient consults, solid tumor consults, and consults for symptom management. Our "partial-PPO" model allowed for provision of PPC in the outpatient oncology setting in a clinic where there is not enough volume to support a full-time oncology-focused clinician team.

Competencies for Psychology Practice in Pediatric Palliative Care.

OBJECTIVE: Pediatric psychologists have unique expertise to contribute to the care of youth with serious illnesses yet are not routinely integrated into pediatric palliative care (PPC) teams. To better define the role and unique skillset of psychologists practicing in PPC, support their systematic inclusion as part of PPC teams, and advance trainee knowledge of PPC principles and skills, the PPC Psychology Working Group sought to develop core competencies for psychologists in this subspecialty. METHODS: A Working Group of pediatric psychologists with expertise in PPC met monthly to review literature and existing competencies in pediatrics, pediatric and subspecialty psychology, adult palliative care, and PPC subspecialties. Using the modified competency cube framework, the Working Group drafted core competencies for PPC psychologists. Interdisciplinary review was conducted by a diverse group of PPC professionals and parent advocates, and competencies were revised accordingly. RESULTS: The six competency clusters include Science, Application, Education, Interpersonal, Professionalism, and Systems. Each cluster includes essential competencies (i.e., knowledge, skills, attitudes, roles) and behavioral anchors (i.e., examples of concrete application). Reviewer feedback highlighted clarity and thoroughness of competencies and suggested additional consideration of siblings and caregivers, spirituality, and psychologists' own positionality. CONCLUSIONS: Newly developed competencies for PPC psychologists highlight unique contributions to PPC patient care and research and provide a framework for highlighting psychology's value in this emerging subspecialty. Competencies help to advocate for inclusion of psychologists as routine members of PPC teams, standardize best practices among the PPC workforce, and provide optimal care for youth with serious illness and their families.

Disaster Preparedness and Housing Tenure: How Do Subsidized Renters Fare?

Homeowners are significantly more prepared for disasters than renters. However, disaster preparedness among subsidized renters is an understudied topic despite their increased vulnerability to negative disaster outcomes. Previous research shows that one in three subsidized units is at risk for exposure to disasters, relative to one in four unsubsidized rental units, and one in seven owner-occupied units. Subsidized housing residents often fall into many vulnerable statuses that would make them less prepared than renters and owners. Using 2017 American Housing Survey data, we examine differences in household disaster preparedness by housing tenure, with and without controls for such factors. Logistic regression analyses indicate that subsidized renters are significantly less prepared than unsubsidized renters, and both renter types are significantly less prepared than homeowners, controlling for demographic and neighborhood characteristics. The policy implications of this research are considered as they relate to the location and management of subsidized housing in an era of climate change.

Feasibility and acceptability of the "Day 100 Talk": An interdisciplinary communication intervention during the first six months of childhood cancer treatment.

BACKGROUND: Communication gaps arise early in the childhood cancer trajectory and may persist. The authors conducted a pilot study of the feasibility and acceptability of a communication intervention, the Day 100 Talk (D100). D100 involves an interprofessional family conference during initial months of treatment between oncologists, psychosocial clinicians, and parents, facilitated by a 3-part conversation tool. METHODS: The authors enrolled English-speaking parents of children with nonrelapsed, nonprogressive cancer who were receiving continuity care from enrolled pediatric oncologists and psychosocial clinicians at a single site. The a priori feasibility threshold was 60% parent completion of the D100 intervention. Surveys from parents and professionals and debrief interviews with professionals assessed D100 acceptability. RESULTS: Thirty-seven parents (77%) and 38 oncology professionals (67%) enrolled. Twenty of 33 evaluable parents (61%) participated in a D100 family conference. Most commonly, parents did not complete the D100 intervention because of scheduling difficulties related to clinical team constraints. All 17 parents who completed a post-D100 survey agreed or strongly agreed that D100 participation was helpful. In debrief interviews, professionals identified D100 benefits, namely, stepping back to the big picture and getting on the same page, and barriers related to logistical challenges and professionals' anticipatory dread. CONCLUSIONS: The D100 intervention pilot demonstrates high acceptability among parents of children with cancer. Despite meeting the prespecified feasibility threshold, findings highlight important barriers to D100 dissemination, namely, perceived burdens on professionals. Potential strategies to reduce burden may include using virtual visit platforms, incorporating D100 elements across multiple visits, or prioritizing intervention delivery to parents with the greatest need for enhanced communication.

"What Matters to Me": What pediatric stem cell transplant patients want their providers to know.

OBJECTIVES: Engagement of pediatric patients in conversations about their healthcare can lead to better psychological and physical outcomes. We used a communication tool called "What Matters to Me" (WMTM) to provide insight into what seriously ill children want to tell their healthcare providers about what is important to them. RESEARCH APPROACH: Content analysis of completed tools. PARTICIPANTS: 21 pediatric patients hospitalized on a stem cell transplant unit. METHODOLOGICAL APPLICATION: Direct content analysis. FINDINGS: Three themes were identified: importance of personal identity, preferences for communication, and preferences for care delivery. INTERPRETATIONS: Children and adolescents with serious medical illnesses are willing to share what matters to them with members of their care team. WMTM provides an opportunity for pediatric units to systematically offer this opportunity to pediatric patients. FINDINGS FOR PSYCHOSOCIAL PROVIDERS: Children and adolescents are able to identify and share what matters to them with their healthcare providers, providing an opportunity for engagement in medical care.

Inclusion of children in the initial conversation about their cancer diagnosis: impact on parent experiences of the communication process.

INTRODUCTION: Including children in medical conversations is considered the standard of care for children with cancer. However, previous qualitative research has raised concerns about how the child's presence impacts the parent's communication experience. The current study examines the frequency and impact of child presence during a serious medical conversation on the parent's communication experience in pediatric oncology. METHODS: Three hundred sixty parents of children newly diagnosed with cancer completed questionnaires assessing the child's presence during the initial conversation with the oncologist about diagnosis and treatment and parental communication experiences. Primary oncologists completed a survey question about the child's prognosis. RESULTS: Sixty-one percent of children were present during the initial conversation, with lowest rates among children aged 3-6 (44%) and 7-12 (44%). Child presence was not associated with parents' reports that they received prognostic information (p = 0.20), high-quality information (p = 0.19), or high-quality communication about the child's cancer (p = 1.0). DISCUSSION: The parent's communication experience is not diminished by the choice to include the child. Given the bioethical imperative to include children in conversations about serious illness whenever possible, this concern should not be used to exclude children, but rather to give parents additional time of their own when needed to fully process decisions.

Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain.

Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the µ-opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of heat-shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an in vivo model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain but only slightly blocked anti-nociception in a naive tail-flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned pain models and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.

IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-ß1-induced fibrotic responses.

TGF-ß1 is a prototypic profibrotic cytokine and major driver of fibrosis in the kidney and other organs. Induced in high glucose-1 (IHG-1) is a mitochondrial protein which we have recently reported to be associated with renal disease. IHG-1 amplifies responses to TGF-ß1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localisation of IHG-1 is pivotal in the amplification of TGF-ß1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-ß1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Δmts-IHG-1) repressed TGF-ß1 fibrotic signalling in renal epithelial cells. In cells expressing Δmts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-ß1. Δmts-IHG-1 modulation of TGF-ß1 signalling was associated with increased Smad7 protein expression. Δmts-IHG-1 modulated TGF-ß1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-ß1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-ß1 signal transduction and that IHG-1 is a key player in this modulation.

Genomic variability of monkeypox virus among humans, Democratic Republic of the Congo.

Monkeypox virus is a zoonotic virus endemic to Central Africa. Although active disease surveillance has assessed monkeypox disease prevalence and geographic range, information about virus diversity is lacking. We therefore assessed genome diversity of viruses in 60 samples obtained from humans with primary and secondary cases of infection from 2005 through 2007. We detected 4 distinct lineages and a deletion that resulted in gene loss in 10 (16.7%) samples and that seemed to correlate with human-to-human transmission (p = 0.0544). The data suggest a high frequency of spillover events from the pool of viruses in nonhuman animals, active selection through genomic destabilization and gene loss, and increased disease transmissibility and severity. The potential for accelerated adaptation to humans should be monitored through improved surveillance.

Acute Streptococcus pneumoniae Meningitis: A Case Report.

A 69-year-old woman without significant medical history presented to an emergency department for evaluation and management of altered mental status and a 10-day history of worsening symptoms of upper respiratory infection. Two days previously, she had been evaluated at an urgent care center, where she reported productive cough and neck pain. Evaluation in the emergency department aroused suspicions of sepsis and meningitis, and computed tomography of the head revealed nontraumatic pneumocephalus with evidence of bony erosion of the sinus into the brain. Culture results revealed disseminated Streptococcus pneumoniae. Cerebral vasculopathy secondary to the meningitis caused bilateral acute ischemic strokes in areas of the brain, with the potential to lead to significant disability.

Psychologists as Pivotal Members of the Pediatric Palliative Care Team.

CONTEXT: Pediatric psychologists possess unique expertise to positively impact the care provided to children with serious illness and their families. Despite increasing recognition regarding the value of psychology in palliative care, psychologists are not yet routinely integrated into pediatric palliative care (PPC) teams. OBJECTIVES: This special paper seeks to demonstrate distinctive contributions psychologists can offer to PPC teams, patients, and families, as well as highlight how psychologists enhance the work of their interdisciplinary PPC colleagues. METHODS: Existing literature, consensus and policy statements, and recently developed competencies inform and provide evidence for the value of incorporating psychologists into PPC. RESULTS: As children with serious illness are at risk for mental and physical health symptoms, psychologists' specialized training in evidence-based assessment and intervention allows them to assess areas of concern, create treatment plans, and implement nonpharmacological therapies targeting symptom management and promotion of quality of life. By improving patient and family outcomes, psychology involvement saves money. In addition to clinical care, psychologists are skilled researchers, which can help to advance PPC interdisciplinary research. Lastly, psychologists can play a valuable role in contributing to PPC team education, dynamics, and well-being. CONCLUSIONS: With strong skills in research, clinical care, education, and advocacy, pediatric psychologists are exceptionally equipped to provide care to children with serious illness and their families. Given their unique contributions, it is critical future efforts are directed towards advocating for the inclusion of psychologists into PPC, with the ultimate goal of improving care for children with serious illness and their families.

One-year Results of Minimally Invasive Sutured Fixation of the Slipped Ribs in the Pediatric Population.

PURPOSE: Costal cartilage resection with or without rib resection is the gold standard surgery for slipping rib syndrome. Minimally invasive restoration of normal anatomy via nonabsorbable sutures has been described in the adult population with encouraging results. We sought to assess the efficacy of minimally invasive sutured fixation of the hypermobile rib in the pediatric population. METHODS: A retrospective review was performed at Mayo Clinic involving 31 pediatric patients diagnosed with slipped rib syndrome. Minimally invasive sutured open reduction internal fixation was performed between 2020 and 2022. The standardized Örebro Musculoskeletal Pain Screening Questionnaire was given at dedicated time points pre- and post-operatively to assess efficacy. Significance was determined via the Wilcoxon rank sum test. RESULTS: SRS was diagnosed clinically in 31 patients (24 females, 7 males, 1220 years-old). Symptoms were present for an average of 18.9 months and patients had seen an average of 4.7 specialists. Traumatic causes were identified in three patients and eight patients had hypermobility. At one month follow up, there were no surgical complications and patients reported significantly less pain (p < 0.001). Preoperative analgesics reduced by 80%. Ultimately, seven patients underwent a second operation; three patients underwent a third operation; one patient underwent five total operations. Recurrent pain was reported in six patients. Only nine patients followed-up at 1-year post-operation. CONCLUSION: Pediatric patients with SRS demonstrated an early positive response to suture fixation without costal cartilage excision. Reoperation and recurrent pain, however, remain significant in this population. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Case series with no comparison group.

The Birth and Beyond (BABY) study: protocol for a birth cohort study investigating the social and environmental determinants of pregnancy-related outcomes in Black American families.

INTRODUCTION: In the USA, Black birthing people and infants experience disproportionately worse pregnancy-related health outcomes. The causes for these disparities are unknown, but evidence suggests that they are likely socially and environmentally based. Efforts to identify the determinants of these racial disparities are urgently needed to elucidate the highest priority targets for intervention. The Birth and Beyond (BABY) study evaluates how micro-level (eg, interpersonal and family) and macro-level (eg, neighbourhood and environmental) risk and resiliency factors transact to shape birth person-infant health, and underlying psychobiological mechanisms. METHODS AND ANALYSIS: The BABY study will follow 350 Black families (birthing parents, non-birthing parents and infants) from pregnancy through the first postpartum year, with research visits during pregnancy and at infant ages 6 and 12 months. Research visits comprise a combination of interview about a range of recent and life course stress and resiliency exposures and supports, psychophysiological (sympathetic, parasympathetic and adrenocortical) assessment and behavioural observations of parent-infant coregulatory behaviours. Spatial analyses are completed by mapping parent current and past residential addresses onto archival public data (eg, about neighbourhood quality and racial segregation). Finally, EMRs are abstracted for information about birthing parent relevant medical history, pregnancy conditions and infant birth outcomes. Analyses will evaluate the risk and resiliency mechanisms that contribute to pregnancy and birth-related outcomes for Black birthing people and their infants, and the protective role of individual, familial, cultural, and community supports. ETHICS AND DISSEMINATION: The BABY study has been approved by the Institutional Review Board at Albany Medical Centre. The study team consulted with local organisations and groups comprised of stakeholders and community leaders and continues to do so throughout the study. Research results will be disseminated with the scientific and local community as appropriate.

Development of a novel nonhuman primate model for Rift Valley fever.

Rift Valley fever (RVF) virus (RVFV) can cause severe human disease characterized by either acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. The existing nonhuman primate (NHP) model for RVF utilizes an intravenous (i.v.) exposure route in rhesus macaques (Macaca mulatta). Severe disease in these animals is infrequent, and large cohorts are needed to observe significant morbidity and mortality. To overcome these drawbacks, we evaluated the infectivity and pathogenicity of RVFV in the common marmoset (Callithrix jacchus) by i.v., subcutaneous (s.c.), and intranasal exposure routes to more closely mimic natural exposure. Marmosets were more susceptible to RVFV than rhesus macaques and experienced higher rates of morbidity, mortality, and viremia and marked aberrations in hematological and chemistry values. An overwhelming infection of hepatocytes was a major consequence of infection of marmosets by the i.v. and s.c. exposure routes. Additionally, these animals displayed signs of hemorrhagic manifestations and neurological impairment. Based on our results, the common marmoset model more closely resembles severe human RVF disease and is therefore an ideal model for the evaluation of potential vaccines and therapeutics.

Love in the PICU: The Hidden Language of Nurses.

A letter to my five-year-old daughter.

The Implications of Health Disparities: A COVID-19 Risk Assessment of the Hispanic Community in El Paso.

Since the outbreak of the COVID-19 pandemic in the United States, Latinos have suffered from disproportionately high rates of hospitalization and death related to the virus. Health disparities based on race and ethnicity are directly associated with heightened mortality and burden of illness and act as underlying causes for the staggering impacts of COVID-19 in Latin communities in the United States. This is especially true in the city of El Paso, Texas, where over 82% of the population is Hispanic. To ascertain the level of danger that COVID-19 poses in El Paso, we constructed a point-in-time risk assessment of its Latin population and assessed a Latin individual's likelihood of hospitalization or death related to COVID-19 by comparing relevant health profiles with high-risk co-morbidities that the Centers for Disease Control (CDC) identified in 2020. Data for this risk assessment come from 1152 surveys conducted in El Paso. The assessment included comprehensive demographic, socioeconomic, and health data to analyze disparities across Hispanic sub-populations in the city. Results revealed that around 49.3% of Hispanics in the study had been previously diagnosed with a high-risk co-morbidity and therefore have an increased likelihood of hospitalization or death related to COVID-19. Additional factors that led to increased risk included low income, homelessness, lack of U.S. citizenship, and being insured. The findings from this study additionally demonstrate that structural inequality in the U.S. must be addressed, and preventive measures must be taken at local and state levels to decrease the mortality of pandemics. Baseline population health data can help with both of these goals.

PKCzeta regulates cell polarisation and proliferation restriction during mammary acinus formation.

Mammary epithelial cells organize in three dimensions and generate acini when supported on laminin-rich extracellular matrix. Acinus formation begins with the apicobasal polarisation of the outer cells of the assembly and the withdrawal of these cells from the cell cycle. Internal cells then clear out to form a hollow lumen. Here, we show that PKCζ is phosphorylated (at T410) and activated in the early stages of acinus formation in both primary cells and MCF10A cells, and during mammary tree maturation in vivo. Phospho-PKCζ colocalised with tight junction components and bound to the Par polarising complex in developing acini. To further investigate the importance of PKCζ phosphorylation in this context, acinus formation was studied in MCF10A cells overexpressing non-phosphorylatable (T410A) or 'constitutively phosphorylated' (T410E) PKCζ. In both cell types, acinus-associated cell polarisation and lumen clearance were compromised, emphasising the importance of regulated phosphorylation of PKCζ at T410 for successful acinus formation. PKCζ can be activated in a phosphorylation (at T410)-dependent and a phosphorylation-independent manner. Cells overexpressing a complete kinase-deficient PKCζ (K281W) displayed a cell polarising deficit, but also generated large 'multi-acinar' structures with associated early lumenal cell hyperproliferation. Therefore our data shows, for the first time, that two separable PKCζ activities (one phosphorylation-dependent, the other not) are required to support the cell polarisation and proliferation restriction that underpins successful acinus formation. Paralleling these contributions, we found that low levels of PKCζ mRNA expression are associated with more 'poorly differentiated' tumours and a poor outcome in a cohort of 295 breast cancer patients.