Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel disease. But the epithelial-specific contribution to mucosal healing in vivo is poorly understood. We evaluated mucosal healing in an acute dextran sulfate sodium mouse model that shows an alleviated colitis response after epithelial-specific loss of Smad4. We find that enhanced epithelial wound healing alleviates the fibrotic response. Dextran sulfate sodium caused increased mesenchymal collagen deposition-indicative of fibrosis-within a week in the WT but not in the Smad4 KO colon. The fibrotic response correlated with decreased epithelial proliferation in the WT, whereas uninterrupted proliferation and an expanded zone of proliferation were observed in the Smad4 KO colon epithelium. Furthermore, the Smad4 KO colon showed epithelial extracellular matrix alterations that promote epithelial regeneration. Our data suggest that epithelium is a key determinant of the mucosal healing response in vivo, implicating mucosal healing as a strategy against fibrosis in inflammatory bowel disease patients.

Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon.

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis. NEW AND NOTEWORTHY: We show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo .

The role of patients' stories in medicine: a systematic scoping review.

BACKGROUND: Patients' stories provide Palliative Care physicians with a glimpse into the former's lives and their psycho-emotional, sociocultural, and contextual considerations. Yet, few physicians are trained to interpret and apply patients' stories in their practice. Inherent variability in how stories are transmitted and interpreted raises questions over their potential effects on care. Amidst a dearth of accounts in Palliative Care, we map current use of patient stories to guide the training, assessment, and oversight of this 'care influencing' practice in medicine. METHODS: This systematic scoping review was guided by the Systematic Evidence-Based Approach (SEBA) to ensure a reproducible and structured approach. The themes and categories identified through the Split Approach's concurrent and independent thematic and directed content analyses provided a comprehensive sketch of the included articles. The Jigsaw Perspective combined the themes and categories identified. The last stage of SEBA compared these results with two recent reviews of storytelling to ensure consistency of the domains created that guided the discussion. RESULTS: Ten thousand two hundred seven articles were reviewed, 963 full text articles were evaluated, and 199 articles were included. The four domains identified were study characteristics, benefits, approaches, and positive effects and concerns. CONCLUSION: Stories support patient-centered, personalized, and holistic clinical care. However, variability in the stories, their interpretations and use in care decisions underscore the need for further study on the structuring, teaching, assessing, and delivery of this 'care influencing' practice.

Physician-patient boundaries in palliative care.

BACKGROUND: Nurturing effective physician-patient relationships is essential to the provision of patient-centred care. Palliative care physicians may apply boundary-crossings or breaches in professional standards to nurture effective physician-patient relationships. Being highly individualized and shaped by the physician's narratives, clinical experience, and contextual considerations, boundary-crossings are susceptible to ethical and professional violations. To better appreciate this concept, we employ the Ring Theory of Personhood (RToP) to map the effects of boundary-crossings on the physician's belief systems. METHODS: As part of the Tool Design SEBA methodology, a Systematic Evidence-Based Approach (SEBA) guided systematic scoping review was employed to guide the design of a semi-structured interview questionnaire with palliative care physicians. The transcripts were simultaneously content and thematically analysed. The themes and categories identified were combined using the Jigsaw Perspective and the resulting domains formed the basis for the discussion. RESULTS: The domains identified from the 12 semi-structured interviews were catalysts and boundary-crossings. Boundary-crossings attempt to address threats to a physician's belief systems (catalysts) and are highly individualized. Employ of boundary-crossings depend on the physician's sensitivity to these 'catalysts', their judgement and willingness to act, and their ability to balance various considerations and reflect on their actions and their ramifications. These experiences reshape belief systems, understandings of boundary-crossings and may influence decision-making and practice, underscoring the potential for greater professional breaches when unchecked. CONCLUSION: Underlining its longitudinal effects, the Krishna Model underscores the importance of longitudinal support, assessment and oversight of palliative care physicians, and lays the foundation for a RToP-based tool to be employed within portfolios.

Monte Carlo evaluation of high-gradient magnetically focused planar proton minibeams in a passive nozzle.

Objective. To investigate the potential of using a single quadrupole magnet with a high magnetic field gradient to create planar minibeams suitable for clinical applications of proton minibeam radiation therapy.Approach. We performed Monte Carlo simulations involving single quadrupole Halbach cylinders in a passively scattered nozzle in clinical use for proton therapy. Pencil beams produced by the nozzle of 10-15 mm initial diameters and particle range of âˆ¼10-20 cm in water were focused by magnets with field gradients of 225-350 T m-1and cylinder lengths of 80-110 mm to produce very narrow elongated (planar) beamlets. The corresponding dose distributions were scored in a water phantom. Composite minibeam dose distributions composed from three beamlets were created by laterally shifting copies of the single beamlet distribution to either side of a central beamlet. Modulated beamlets (with 18-30 mm nominal central SOBP) and corresponding composite dose distributions were created in a similar manner. Collimated minibeams were also compared with beams focused using one magnet/particle range combination.Main results. The focusing magnets produced planar beamlets with minimum lateral FWHM of ∼1.1-1.6 mm. Dose distributions composed from three unmodulated beamlets showed a high degree of proximal spatial fractionation and a homogeneous target dose. Maximal peak-to-valley dose ratios (PVDR) for the unmodulated beams ranged from 32 to 324, and composite modulated beam showed maximal PVDR ranging from 32 to 102 and SOBPs with good target dose coverage.Significance.Advantages of the high-gradient magnets include the ability to focus beams with phase space parameters that reflect beams in operation today, and post-waist particle divergence allowing larger beamlet separations and thus larger PVDR. Our results suggest that high gradient quadrupole magnets could be useful to focus beams of moderate emittance in clinical proton therapy.

Emotion-Focused Avoidance Coping Mediates the Association Between Pain and Health-Related Quality of Life in Children With Sickle Cell Disease.

Sickle cell disease (SCD) is associated with pain and decreased health-related quality of life (HRQOL). Coping strategies influence pain but have not been evaluated as mediating the relation between pain and HRQOL in pediatric SCD. The current study examined whether pain-related coping mediates the association between pain and HRQOL in children and adolescents with SCD. In total, 104 children and adolescents 8 to 18 years of age (Mage=12.93 y) with SCD attending outpatient clinics completed pain intensity, HRQOL, and pain-related coping measures. Multiple mediation analyses were used to examine whether pain-related coping mediated the pain and HRQOL relation and whether types of coping (ie, approach, emotion-focused avoidance, problem-focused avoidance) were independent mediators. Total indirect effects for models examining physical and psychosocial HRQOL were not significant. After controlling for covariates, emotion-focused avoidance significantly mediated the association between pain and physical HRQOL (effect: -0.023; bootstrapped SE: 0.018; 95% confidence interval: -0.0751, -0.0003) but not the pain and psychosocial HRQOL relation. Approach and problem-focused avoidance were not significant mediators. Coping with pain in pediatric SCD is an important avenue for clinical intervention and additional research. Among children with SCD reporting high pain intensity, interventions should emphasize negative impacts of emotion-focused avoidance coping and integrate other empirically supported coping strategies to improve HRQOL.

Unhealthy weight control behaviors mediate the association between weight status and weight-specific health-related quality of life in treatment-seeking youth who are obese.

PURPOSE: Examine whether unhealthy and extreme weight control behaviors (WCBs) mediate the relationship between youth weight status and disease-specific health-related quality of life (HRQOL) in treatment-seeking youth who are overweight and obese (OV/OB). METHOD: 82 youth 10-17 years of age who were OV/OB and attending an outpatient obesity-related medical appointment completed measures assessing unhealthy and extreme WCBs and disease-specific HRQOL. Parents completed a demographic questionnaire and medical staff measured youth height and weight. RESULTS: Regression analyses revealed that unhealthy WCBs mediated the associations between youth weight status and emotional and social avoidance disease-specific HRQOL, such that higher body mass index (BMI) predicted unhealthy WCBs, which were ultimately associated with poorer emotional and social HRQOL. Mediation analyses were not significant for total, physical, teasing/marginalization, and positive attributes disease-specific HRQOL. In addition, extreme WCBs did not mediate the association between youth weight status and any subscales of the disease-specific HRQOL measure. DISCUSSION: Weight status is an important predictor of disease-specific HRQOL in OV/OB youth; however, the association with emotional and social HRQOL is partially accounted for by youth engagement in unhealthy WCBs. Clinicians and researchers should assess WCBs and further research should explore and evaluate appropriate intervention strategies to address unhealthy WCBs in pediatric weight management prevention and treatment efforts.

An examination of comorbid asthma and obesity: assessing differences in physical activity, sleep duration, health-related quality of life and parental distress.

OBJECTIVE: Compare youth with comorbid asthma and obesity to youth with obesity only to determine if differences exist in body mass index, dietary intake, levels of physical activity, sleep duration and health-related quality of life. Levels of parent distress were also compared. METHODS: Participants included 248 children (n = 175 in Obesity group; n = 73 in Asthma + Obesity group) with a BMI ≥ 85th percentile for age and gender, and their participating parent(s) or legal guardian(s). Measures of child height and weight were obtained by study personnel and Z-scores for child body mass index were calculated using age- and gender-specific norms. Child physical activity and sleep duration were measured via accelerometers. Dietary intake, health-related quality of life and parent distress were assessed via self-report. RESULTS: The Asthma + Obesity group evidenced significantly higher body mass index scores, and had lower sleep duration. There was a non-statistically significant trend for lower levels of physical activity among children in the Asthma + Obesity group. Dietary intake, health-related quality of life and parent distress did not differ between groups. CONCLUSIONS: Youth with comorbid asthma and obesity are at increased risk for negative health and psychosocial difficulties compared to youth who are overweight or obese only. Professionals providing treatment for youth with asthma are encouraged to assess the implications of weight status on health behaviors and family psychosocial adjustment.

Changes in pediatric health-related quality of life in cystic fibrosis after IV antibiotic treatment for pulmonary exacerbations.

Intravenous (IV) antibiotic therapy for pulmonary exacerbations (PE) has been shown to improve pulmonary functioning for patients with cystic fibrosis (CF); however, little is known about its effects on pediatric health-related quality of life (HRQOL). This prospective study assessed the impact of IV treatment of a PE on generic and CF-specific HRQOL for children and adolescents with CF. Participants included 52 children and adolescents with CF experiencing a PE (M (age) = 13.6 years; 54% males; M(FEV(1%)) predicted = 58.8%). HRQOL, pulmonary functioning, and body mass index were assessed before and after IV antibiotic treatment. Results of this prospective, observational study indicated significant improvements on CFQ-R Respiratory (M (change score) = 11.7; 95% CI = 6.3-17.1; p < .0001) and Weight (M (change score) = 15.9; 95% CI = 7.9-23.8; p < .0001) scales. The CF-specific measure was more sensitive to changes in HRQOL than the generic instrument. These data suggest that CF-specific HRQOL improves with treatment for a PE with IV antibiotics. The noted statistically and clinically significant changes in the CFQ-respiratory scale indicate that the measure may be beneficial to pulmonary health care teams.

Occulocerebrocutaneous syndrome: a case report.

Occulocerebrocutaneous syndrome is a rare condition characterized by orbital cysts and skin tags. The presence of supernumerary teeth has not previously been associated with this syndrome. A primary supernumerary tooth with a permanent supernumerary successor was found in this case. This highlights the importance of very careful examination when assessing children with syndromes.

A multi-method assessment of treatment adherence for children with cystic fibrosis.

BACKGROUND: Adherence rates for chronic pediatric conditions are approximately 50%. The primary objective of the study was to assess rates of adherence using four different measurement methods for children with cystic fibrosis (CF). METHODS: Participants included 37 children with CF between 6 and 13 years of age and their primary caregivers. Adherence measures included parent and child self-reports, diary data, pharmacy refill history, and electronic monitors. RESULTS: Results suggested that rates of adherence varied by treatment component and across measurement methods. However, when examining more objective measures, rates of overall adherence were below 50% for children with CF, indicating generally poor adherence to the treatment regimen. For example, rates of adherence to enzyme medications, using electronic and diary measures, ranged from 27% to 46%. CONCLUSIONS: The multi-method measurement approach provided unique information regarding rates of adherence for each disease condition by type of treatment component. Accurately measuring rates of treatment adherence for children with CF is an important step in developing effective interventions to influence these behaviors.