Living Well with Chronic Pain

A Chronic Pain Self-Management Program (CPSMP

Halo Excitation of 6^6He in Inelastic and Charge-Exchange Reactions

Four-body distorted wave theory appropriate for nucleon-nucleus reactions leading to 3-body continuum excitations of two-neutron Borromean halo nuclei is developed. The peculiarities of the halo bound state and 3-body continuum are fully taken into account by using the method of hyperspherical harmonics. The procedure is applied for A=6 test-bench nuclei; thus we report detailed studies of inclusive cross sections for inelastic $^6$He(p,p')$^6$He$^*$ and charge-exchange $^6$Li(n,p)$^6$He$^*$ reactions at nucleon energy 50 MeV. The theoretical low-energy spectra exhibit two resonance-like structures. The first (narrow) is the excitation of the well-known $2^+$ three-body resonance. The second (broad) bump is a composition of overlapping soft modes of multipolarities $1^-, 2^+, 1^+, 0^+$ whose relative weights depend on transferred momentum and reaction type. Inelastic scattering is the most selective tool for studying the soft dipole excitation mode.Comment: Submitted to Phys. Rev. C., 11 figures using eps

Reaction rate for two--neutron capture by 4^4He

Recent investigations suggest that the neutrino--heated hot bubble between the nascent neutron star and the overlying stellar mantle of a type--II supernova may be the site of the r--process. In the preceding $\alpha$--process building up the elements to $A \approx 100$, the $^4$He(2n,$\gamma$)$^6$He-- and $^6$He($\alpha$,n)$^9$Be--reactions bridging the instability gap at $A=5$ and $A=8$ could be of relevance. We suggest a mechanism for $^4$He(2n,$\gamma$)$^6$He and calculate the reaction rate within the $\alpha$+n+n approach. The value obtained is about a factor 1.6 smaller than the one obtained recently in the simpler direct--capture model, but is at least three order of magnitude enhanced compared to the previously adopted value. Our calculation confirms the result of the direct--capture calculation that under representative conditions in the $\alpha$--process the reaction path proceeding through $^6$He is negligible compared to $^4$He($\alpha$n,$\gamma$)$^9$Be.Comment: 13 pages, 4 postscript figures, to appear in "Zeitschrift f. Physik A", changed internet address and filename, the uuencoded postscript file including the figures is available at ftp://is1.kph.tuwien.ac.at/pub/ohu/twoneutron.u

Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour–stromal interactions: a report from the Children's Oncology Group

Relapse of Ewing sarcoma (ES) can occur months or years after initial remission, and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post‐therapy evaluation can be adjusted accordingly. For this study, we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumours in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non‐survivors were used to identify prognostic gene signatures. An independent cohort of tumours from the Euro‐Ewing cooperative group was similarly analysed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumours based on outcome. Supervised analysis of survivors versus non‐survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene‐specific enrichment analysis demonstrated that integrin and chemokine genes were associated with survival in tumours where stromal contamination was present. Tumours that did not harbour stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA‐based assays on archived bone tumour specimens. In addition, they reveal a key role for tumour stroma in determining ES prognosis. Future biological and clinical investigations should focus on elucidating the contribution of tumour:micro‐environment interactions on ES progression and response to therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111186/1/cjp29.pd

Transcriptional Regulation of T-Cell Lipid Metabolism: Implications for Plasma Membrane Lipid Rafts and T-Cell Function

It is well established that cholesterol and glycosphingolipids are enriched in the plasma membrane (PM) and form signalling platforms called lipid rafts, essential for T-cell activation and function. Moreover, changes in PM lipid composition affect the biophysical properties of lipid rafts and have a role in defining functional T-cell phenotypes. Here we review the role of transcriptional regulators of lipid metabolism including liver X receptors α/β (LXR/LXRβ), peroxisome proliferator-activated receptor γ (PPAR-γ), estrogen receptors α/β (ERα/β) and sterol regulatory element-binding proteins (SREBPs) in T-cells. These receptors lie at the interface between lipid metabolism and immune cell function and are endogenously activated by lipids and/or hormones. Importantly, they regulate cellular cholesterol, fatty acid, glycosphingolipid and phospholipid levels but are also known to modulate a broad spectrum of immune responses. The current evidence supporting a role for lipid metabolism pathways in controlling immune cell activation by influencing PM lipid raft composition in health and disease, and the potential for targeting lipid biosynthesis pathways to control unwanted T-cell activation in autoimmunity is reviewed

Increased Usage of Doxycycline for Young Children With Lyme Disease

Background: The 2018 Infectious Disease Committee of the American Academy of Pediatrics stated that up to 3 weeks or less of doxycycline is safe in children of all ages. Our goal was to examine trends in doxycycline treatment for children with Lyme disease. Methods: We assembled a prospective cohort of children aged 1 to 21 years with Lyme disease who presented to one of eight participating Pedi Lyme Net centers between 2015 and 2023. We defined a Lyme disease case with an erythema migrans (EM) lesion or positive two-tier Lyme disease serology categorized by stage: early-localized (single EM lesion), early-disseminated (multiple EM lesions, cranial neuropathy, meningitis, and carditis), and late (arthritis). We compared doxycycline treatment by age and disease stage and used logistic regression to examine treatment trends. Results: Of the 1,154 children with Lyme disease, 94 (8.1%) had early-localized, 449 (38.9%) had early-disseminated, and 611 (53.0%) had late disease. Doxycycline treatment was more common for older children (83.3% ≥ 8 years vs. 47.1% \u3c 8 years; p \u3c 0.001) and with early-disseminated disease (77.2% early-disseminated vs. 52.1% early-localized or 62.1% late; p \u3c 0.001). For children under 8 years, doxycycline use increased over the study period (6.9% 2015 to 67.9% 2023; odds ratio by year, 1.45; 95% confidence interval, 1.34–1.58). Conclusion: Young children with Lyme disease are frequently treated with doxycycline. Prospective studies are needed to confirm the safety and efficacy of doxycycline in children younger than 8 years, especially for those receiving courses longer than 3 weeks

Radiographic pneumonia in young febrile infants presenting to the emergency department: secondary analysis of a prospective cohort study.

OBJECTIVE: The lack of evidence-based criteria to guide chest radiograph (CXR) use in young febrile infants results in variation in its use with resultant suboptimal quality of care. We sought to describe the features associated with radiographic pneumonias in young febrile infants. STUDY DESIGN: Secondary analysis of a prospective cohort study in 18 emergency departments (EDs) in the Pediatric Emergency Care Applied Research Network from 2016 to 2019. Febrile (≥38°C) infants aged ≤60 days who received CXRs were included. CXR reports were categorised as no, possible or definite pneumonia. We compared demographics, clinical signs and laboratory tests among infants with and without pneumonias. RESULTS: Of 2612 infants, 568 (21.7%) had CXRs performed; 19 (3.3%) had definite and 34 (6%) had possible pneumonias. Patients with definite (4/19, 21.1%) or possible (11/34, 32.4%) pneumonias more frequently presented with respiratory distress compared with those without (77/515, 15.0%) pneumonias (adjusted OR 2.17; 95% CI 1.04 to 4.51). There were no differences in temperature or HR in infants with and without radiographic pneumonias. The median serum procalcitonin (PCT) level was higher in the definite (0.7 ng/mL (IQR 0.1, 1.5)) vs no pneumonia (0.1 ng/mL (IQR 0.1, 0.3)) groups, as was the median absolute neutrophil count (ANC) (definite, 5.8 K/mcL (IQR 3.9, 6.9) vs no pneumonia, 3.1 K/mcL (IQR 1.9, 5.3)). No infants with pneumonia had bacteraemia. Viral detection was frequent (no pneumonia (309/422, 73.2%), definite pneumonia (11/16, 68.8%), possible pneumonia (25/29, 86.2%)). Respiratory syncytial virus was the predominant pathogen in the pneumonia groups and rhinovirus in infants without pneumonias. CONCLUSIONS: Radiographic pneumonias were uncommon in febrile infants. Viral detection was common. Pneumonia was associated with respiratory distress, but few other factors. Although ANC and PCT levels were elevated in infants with definite pneumonias, further work is necessary to evaluate the role of blood biomarkers in infant pneumonias

Increased usage of doxycycline for young children with Lyme disease

BackgroundThe 2018 Infectious Disease Committee of the American Academy of Pediatrics stated that up to 3 weeks or less of doxycycline is safe in children of all ages. Our goal was to examine trends in doxycycline treatment for children with Lyme disease.MethodsWe assembled a prospective cohort of children aged 1 to 21 years with Lyme disease who presented to one of eight participating Pedi Lyme Net centers between 2015 and 2023. We defined a Lyme disease case with an erythema migrans (EM) lesion or positive two-tier Lyme disease serology categorized by stage: early-localized (single EM lesion), early-disseminated (multiple EM lesions, cranial neuropathy, meningitis, and carditis), and late (arthritis). We compared doxycycline treatment by age and disease stage and used logistic regression to examine treatment trends.ResultsOf the 1,154 children with Lyme disease, 94 (8.1%) had early-localized, 449 (38.9%) had early-disseminated, and 611 (53.0%) had late disease. Doxycycline treatment was more common for older children (83.3% ≥ 8 years vs. 47.1% < 8 years; p < 0.001) and with early-disseminated disease (77.2% early-disseminated vs. 52.1% early-localized or 62.1% late; p < 0.001). For children under 8 years, doxycycline use increased over the study period (6.9% 2015 to 67.9% 2023; odds ratio by year, 1.45; 95% confidence interval, 1.34–1.58).ConclusionYoung children with Lyme disease are frequently treated with doxycycline. Prospective studies are needed to confirm the safety and efficacy of doxycycline in children younger than 8 years, especially for those receiving courses longer than 3 weeks

Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures