Tumor-associated genetic amplifications impact extracellular vesicle miRNA cargo and their recruitment of nerves in head and neck cancer.

Cancer neuroscience is an emerging field of cancer biology focused on defining the interactions and relationships between the nervous system, developing malignancies, and their environments. Our previous work demonstrates that small extracellular vesicles (sEVs) released by head and neck squamous cell carcinomas (HNSCCs) recruit loco-regional nerves to the tumor. sEVs contain a diverse collection of biological cargo, including microRNAs (miRNAs). Here, we asked whether two genes commonly amplified in HNSCC, CCND1, and PIK3CA, impact the sEV miRNA cargo and, subsequently, sEV-mediated tumor innervation. To test this, we individually overexpressed these genes in a syngeneic murine HNSCC cell line, purified their sEVs, and tested their neurite outgrowth activity on dorsal root ganglia (DRG) neurons in vitro. sEVs purified from Ccnd1-overexpressing cells significantly increased neurite outgrowth of DRG compared to sEVs from parental or Pik3ca over-expressing cells. When implanted into C57BL/6 mice, Ccnd1 over-expressing tumor cells promoted significantly more tumor innervation in vivo. qPCR analysis of sEVs shows that increased expression of Ccnd1 altered the packaging of miRNAs (miR-15-5p, miR-17-5p, and miR-21-5p), many of which target transcripts important in regulating axonogenesis. These data indicate that genetic amplifications harbored by malignancies impose changes in sEV miRNA cargo, which can influence tumorc innervation.

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer.

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a male mouse model for head and neck cancer, we utilized neuronal tracing techniques and show that tumor-infiltrating nerves indeed connect to distinct brain areas via the ipsilateral trigeminal ganglion. The activation of this neuronal circuitry led to behavioral alterations represented by decreased nest-building, increased latency to eat a cookie, and reduced wheel running. Tumor-infiltrating nociceptor neurons exhibited heightened activity, as indicated by increased calcium mobilization. Correspondingly, the specific brain regions receiving these neural projections showed elevated cFos and delta FosB expression in tumor-bearing mice, alongside markedly intensified calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons in tumor-bearing mice led to decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running. This discrepancy points towards an intricate relationship, where pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer. Significance Statement: Head and neck cancers are infiltrated by sensory nerves which connect to a pre-existing circuit that includes areas in the brain. Neurons within this circuit are altered and mediate modifications in behavior.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.

PURPOSE: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. METHODS: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. RESULTS: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. CONCLUSION: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.

Boldly going Introducing conflict management training to Starship Children's Hospital.

Conflict between health professionals and whanau (families) in paediatric hospitals is common and leads to significant distress for families and staff. The likelihood of challenges and conflict around communication and critical medical decision-making is increased where there are cultural and social complexities. Training staff to recognise and manage conflict as early as possible improves patient/whanau outcomes and staff well-being. This article describes an ongoing collaboration between Starship Children's Hospital in Auckland New Zealand (NZ) and the UK Medical Mediation Foundation (MMF) focused on educating staff in the early recognition and management of conflict using mediation skills. An evidence-based training programme and structured ongoing supervision of a small group of champions has enabled this training to be embedded into Starship clinical practice. The collaboration has included careful consideration of the New Zealand setting, ensuring that the content of the programme specifically addresses our unique cultural and social context. Mediation skills are an important step in ensuring that our patients and whanau feel heard, acknowledged, and respected, and contribute to the Starship Child Health's strategic priority of eliminating inequity and addressing institutional bias.

Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients.

Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass. Imaging commonly revealed involvement of some combination of mediastinal, pulmonary, pleural, and pericardial compartments and most often included spleen and skeleton. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. An activating lesional NRAS variant was documented in 9 of 10 patients. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%.

Transforming training into practice with the conflict management framework: a mixed methods study.

Objective: To implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services. Design: Mixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews. Setting: Eight inpatient or day care wards across four tertiary UK paediatric services. Interventions: The two-stage CMF was used in daily huddles to prompt the recognition and management of conflict. Results: Conflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p<0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p<0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management. Conclusions: The CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs.

Evaluation of APOE ɛ2/ɛ3/ɛ4 Alleles in a Cohort of Individuals Affected by Developmental Topographical Disorientation.

The three common alleles of the APOE gene, ɛ2/ɛ3/ɛ4, have been linked to human spatial orientation. We investigated the genetic role of APOE in developmental topographical disorientation (DTD), a lifelong condition that results in topographical disorientation. We genotyped the APOE ɛ2/ɛ3/ɛ4 alleles in a cohort of 20 unrelated DTD probands, and found allele frequencies not statistically different from the those seen in the population as a whole. Therefore, we found no evidence that DTD occurs preferentially on a genetic background containing any particular APOE allele, making it unlikely that these APOE alleles are contributing to the development of DTD.

The Healthcare Conflict Scale: development, validation and reliability testing of a tool for use across clinical settings.

Despite the widespread incidence of conflict and its detrimental impact across a range of health-care settings, there is no validated tool with which to measure it. This paper describes the international innovation of a tool to measure staff-family conflict in pediatrics, intensive care, emergency, palliative care, and nursing homes. Sixty-two health-care workers contributed to focus group discussions to refine a draft tool developed from the literature. Subsequently, 101 health-care workers applied the tool to fictionalized vignettes. The psychometric properties (construct validity, internal consistency, repeatability, and reliability) were explored using principal component analysis, Cronbach's alpha, and intra-class correlation (ICC) tests. The initial 17-item tool was reduced to seven items within three factors that explained 70.2% of the total variance in overarching construct. The internal consistency of the final overall scale was good (Cronbach's alpha: 0.750); test-retest reliability of each item was excellent with ICCs ≥0.9. This new tool can be used to identify and score conflict, making it a key reference point in healthcare conflict work across clinical specialties. It's development and testing across specialities and across countries means it can be used in a variety of contexts. The tool provides health-care professionals with a new way to identify and measure conflict, and consequently has the potential to transform health-care relationships across disciplines and settings.

Reducing healthcare conflict: outcomes from using the conflict management framework.

OBJECTIVE: To test a new conflict management framework (CMF) to help staff identify and de-escalate conflict between staff and patients/families. DESIGN: Before/after study that reports staff quality of life, frequency/severity of conflicts and qualitative interviews on using the framework. Data were collected from May 2017 to September 2017. SETTING: A paediatric oncology department day-patient and 23-bed inpatient ward. INTERVENTION: A two-stage CMF used by staff during daily handovers to identify and then manage conflict cases with families. RESULTS: Staff found the CMFto be helpful in identifying and de-escalating conflicts. The number of conflicts reported decreased by 64% from baseline to follow-up. Communication regarding conflict identification improved. Reports of staff burn-out decreased between the two time-points (n=55 at baseline, n=31 at follow-up; p=0.001). Scores on compassion and secondary traumatic stress did not change. CONCLUSIONS: The CMF substantially reduces the incidence of conflicts and is an acceptable approach for staff. Continued use of the framework would require it to be fully integrated into the working of the ward, which would need to include senior medical buy-in. Further refinements to the framework have been made and will be tested in four UK sites in 2018/2019.

A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

PURPOSE: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. METHODS: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. RESULTS: We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues. CONCLUSION: The activating NRAS p.Q61R variant is a known "hotspot" variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.

ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison.

BACKGROUND: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands. RESULTS: Detailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands. CONCLUSIONS: ROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.

Erratum: Author Correction: The effectiveness of public health advertisements to promote health: a randomized-controlled trial on 794,000 participants.

[This corrects the article DOI: 10.1038/s41746-018-0031-7.].

The effectiveness of public health advertisements to promote health: a randomized-controlled trial on 794,000 participants.

As public health advertisements move online, it becomes possible to run inexpensive randomized-controlled trials (RCTs) thereof. Here we report the results of an online RCT to improve food choices and integrate exercise into daily activities of internet users. People searching for pre-specified terms were randomized to receive one of several professionally developed campaign advertisements or the "status quo" (ads that would otherwise have been served). For 1-month pre-intervention and post-intervention, their searches for health-promoting goods or services were recorded. Our results show that 48% of people who were exposed to the ads made future searches for weight loss information, compared with 32% of those in the control group-a 50% increase. The advertisements varied in efficacy. However, the effectiveness of the advertisements may be greatly improved by targeting individuals based on their lifestyle preferences and/or sociodemographic characteristics, which together explain 49% of the variation in response to the ads. These results demonstrate that online advertisements hold promise as a mechanism for changing population health behaviors. They also provide researchers powerful ways to measure and improve the effectiveness of online public health interventions. Finally, we show that corporations that use these sophisticated tools to promote unhealthy products can potentially be outbid and outmaneuvered.

The nature of conflict in palliative care: A qualitative exploration of the experiences of staff and family members.

OBJECTIVES: Conflict is a significant and recurring problem in healthcare. This study aimed to understand staff and relatives' perspectives on the characteristics of conflict and serious disagreement in adult palliative care, including triggers, risk factors and the impact on themselves and clinical care. METHODS: Qualitative study of 25 staff and seven bereaved relatives using individual interviews, recruited from a multidisciplinary specialist palliative care setting in Australia. Data were analysed thematically. RESULTS: Communication was frequently cited as a cause of conflict. Further, different understandings regarding disease process, syringe drivers and providing nutrition/hydration caused conflict. Staff applied empathy to moderate their responses to conflict. Relatives' reactions to conflict followed a trend of anger/frustration followed by explanations or justifications of the conflict. Relatives identified systemic rather than interpersonal issues as triggering conflict. CONCLUSIONS: The data illustrate connections with conflict literature in other clinical areas, but also points of convergence such as the compassion shown by both families and staff, and the identification of systemic rather than always individual causes. PRACTICE IMPLICATIONS: Family meetings may fruitfully be applied to prevent and de-escalate conflict. Clinical audits may be useful to identify and provide support to families where there may be unresolved conflict impacting grief process.

Partnering for Evidence-Based Practice.

This column describes an academic service partnership to promote evidence-based practice.

Training paediatric healthcare staff in recognising, understanding and managing conflict with patients and families: findings from a survey on immediate and 6-month impact.

BACKGROUND: Conflict is a recognised component of healthcare. Disagreements about treatment protocols, treatment aims and poor communication are recognised warning signs. Conflict management strategies can be used to prevent escalation, but are not a routine component of clinical training. OBJECTIVE: To report the findings from a novel training intervention, aimed at enabling paediatric staff to identify and understand the warning signs of conflict, and to implement conflict resolution strategies. DESIGN AND SETTING: Self-report measures were taken at baseline, immediately after the training and at 6 months. Questionnaires recorded quantitative and qualitative feedback on the experience of training, and the ability to recognise and de-escalate conflict. The training was provided in a tertiary teaching paediatric hospital in England over 18 months, commencing in June 2013. INTERVENTION: A 4-h training course on identifying, understanding and managing conflict was provided to staff. RESULTS: Baseline data were collected from all 711 staff trained, and 6-month follow-up data were collected for 313 of those staff (44%). The training was successful in equipping staff to recognise and de-escalate conflict. Six months after the training, 57% of respondents had experienced conflict, of whom 91% reported that the training had enabled them to de-escalate the conflict. Learning was retained at 6 months with staff more able than at baseline recognising conflict triggers (Fischer's exact test, p=0.001) and managing conflict situations (Pearson's χ2 test, p=0.001). CONCLUSIONS: This training has the potential to reduce substantially the human and economic costs of conflicts for healthcare providers, healthcare staff, patients and relatives.

Familial aggregation in developmental topographical disorientation (DTD).

A variety of brain lesions may affect the ability to orient, resulting in what is termed "acquired topographical disorientation". In some individuals, however, topographical disorientation is present from childhood, with no apparent brain abnormalities and otherwise intact general cognitive abilities, a condition referred to as "developmental topographical disorientation" (DTD). Individuals affected by DTD often report relatives experiencing the same lifelong orientation difficulties. Here, we sought to assess the familial aggregation of DTD by investigating its occurrence in the families of DTD probands, and in the families of control probands who did not experience topographical disorientation. We found that DTD appears to cluster in the DTD families, with tested relatives displaying the trait, whereas in the control families we did not detect any individuals with DTD. These findings provide the very first evidence for the familial clustering of DTD and motivate further work investigating the genetic factors producing this clustering.