High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here, we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine ...corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016, and 1 retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4–11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6–30; median, 16 per 10 high-power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared with the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse and strong) cyclin D1 and BCOR staining. p53 staining was wild type in both components of all eight tumors tested. JAZF1-SUZ12 (n = 6), JAZF1-PHF1 (n = 3), EPC1-PHF1, (n = 1), or BRD8-PHF1 (n = 1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n = 4), II (n = 4), III (n = 1), and IV disease (n = 2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with five patients who died of disease 8–18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared with typical LGESS. Histologic high-grade transformation may herald aggressive behavior.
Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell ...multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
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•Reindeer antler velvet regenerates after wounding whereas back skin forms a scar•Fibroblasts direct site-specific immune cell recruitment and differentiation•Fibroblast fate reversion and absence of inflammatory signals enables regeneration•Obstructing fibroblast inflammatory signals enhances skin regeneration
The particular properties of reindeer antler velvet are leveraged here to identify which factors lead to scarring versus regenerative healing in mammalian skin, with relevance not only to reindeer, but also mouse and human systems.
role of the CD58 locus in multiple sclerosis De Jager, Philip L; Baecher-Allan, Clare; Maier, Lisa M ...
Proceedings of the National Academy of Sciences - PNAS,
03/2009, Letnik:
106, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the ...CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x 10⁻⁶, OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747G allele. This protective rs2300747G allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x 10⁻¹⁰) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4⁺CD25high regulatory T cells that are defective in subjects with MS.
Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source ...Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.
Background
The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain.
Objectives
To improve outcomes for people with ...chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services.
Design
The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies.
Setting
NHS, secondary care, primary care.
Participants
People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain.
Interventions
A care pathway for the management of people with pain at 3 months after knee replacement.
Main outcome measures
Patient-reported outcomes and cost-effectiveness over 12 months.
Data sources
Literature databases, the National Joint Registry, Hospital Episode Statistics, patient-reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events.
Review methods
Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis.
Results
In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre-operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m
2
and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri-operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13;
p =
0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08;
p =
0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation.
Limitations
Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome.
Conclusions
The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals.
Future work
Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors.
Study registration
All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361.
Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in
Programme Grants for Applied Research
; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.
McLaughlin crater is a 92‐km diameter complex crater that formed on Mars ~4 billion years ago. The resulting basin was the site of a large (~3,000 km2), deep (~500 m), voluminous (~1,500 km3) Martian ...lake circa 3.8 Ga. While there is strong evidence that hundreds of lakes have existed on Mars at some point during the same time period, the geology of McLaughlin crater is extraordinary for a number of reasons. Detailed spectral analyses show that the deep‐water sediments include detrital inputs of olivine and pyroxene, but the lake‐floor sediments include lithologies with abundant Fe‐rich, Mg‐bearing smectite, serpentine‐rich deposits, and ferrihydrite. For astrobiologists, this site provides a treasure trove of high‐priority targets. Serpentinization reactions are thought to have played a key role in abiogenesis on Earth, and within McLaughlin crater, deposits of subterranean and probably sublacustrine serpentinites are well preserved. In addition, delta sequences are well exposed throughout the east side of the basin; such deposits are endorsed by some as the highest priority targets for preservation of organics on Mars. Yet deep‐water turbidites, which might have flowed through hydrothermal environments, may be the most intriguing aspect of this geology. Such rapid sedimentation could have sequestered and preserved any potential organic materials for future exploration by a rover.
Plain Language Summary
Though Mars is cold, dry, and inhospitable today, it contains evidence for many dry lake beds—relics of an ancient climate that was at least episodically warmer and wetter. Considering that lakes can be an excellent environments for life on Earth, a common thread of Mars research has been to characterize the environmental conditions under which Martian lakes formed in order to better understand their implications for past habitability of the red planet. The goal of this work is to characterize the geology of McLaughlin crater, where a lake existed on Mars over 3.8 billion years ago. McLaughlin lake was vast, deep (~ 500 m), and probably long lived. Many characteristics of McLaughlin lake are unlike those seen in any other ancient lake basins on Mars. This lake contained a range of sedimentary environments including delta deposits, shallow‐water fan deposits, and deep‐water, fine‐grained materials. It is the only known place on Mars where fine‐grained, subaqueous “landslides” called turbidites are identified, and these are important because we know that such deposits can be sites of excellent preservation of organic matter on Earth (due to rapid burial).
Key Points
McLaughlin crater contained a deep, voluminous lake >3.8 Ga with features unlike any other known Martian paleolakes
Sedimentary units include delta deposits, turbidites, and deep‐water sediments; and hydrothermal deposits include serpentinites
Geochemical gradients occurred in a long‐lived lake that was in sustained communication with groundwater and subsurface environments
Viral videos of the detainment of undocumented immigrants in cages and police killings of unarmed citizens are two of the most pressing traumatic events facing adolescents of color. However, little ...is known about whether these online experiences are linked to mental health outcomes. This study examines the association between exposure to such events online and mental health in a sample of African American and Latinx adolescents.
Data were collected from a national sample of 302 African American and Latinx adolescents aged 11–19 years. Participants reported their exposure to traumatic events online (TEO), depressive symptoms, post-traumatic stress disorder (PTSD) symptoms, and other sociodemographics. Multiple regression analyses were conducted.
Analyses indicated a significant association between TEO and both PTSD symptoms and depressive symptoms, indicating that more frequent experiences of TEO were associated with higher levels of PTSD symptoms and depressive symptoms. In addition, regression analyses further indicated that girls reported higher PTSD and depressive symptoms than boys. Latinx participants also reported increased depressive symptoms.
This study extends recent research that suggests police killings, as well as viewing distressing news directed at members of one's own racial–ethnic group or those who share the same immigration status, are related to poor mental health outcomes. Researchers should also explore what protective factors may buffer youth against the outcomes typically associated with these events.
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) ...dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
•Treatment outcomes of 3328 NPC patient treated with IMRT in Hong Kong.•8 year local/regional control remained promising.•Confirmed benefits of concurrent chemotherapy with IMRT.•Additional ...chemotherapy onto backbone of concurrent chemo-irradiation warrants further investigation.•Various severe symptomatic complications after IMRT remained low.
To evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010.
Eligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed.
A total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure.
IMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT.
Objective(1) To estimate the pooled prevalence of multimorbidity in all age groups, globally. (2) To examine how measurement of multimorbidity impacted the estimated prevalence.MethodsIn this ...systematic review and meta-analysis, we conducted searches in nine bibliographic databases (PsycINFO, Embase, Global Health, Medline, Scopus, Web of Science, Cochrane Library, CINAHL and ProQuest Dissertations and Theses Global) for prevalence studies published between database inception and 21 January 2020. Studies reporting the prevalence of multimorbidity (in all age groups and in community, primary care, care home and hospital settings) were included. Studies with an index condition or those that did not include people with no long-term conditions in the denominator were excluded. Retrieved studies were independently reviewed by two reviewers, and relevant data were extracted using predesigned pro forma. We used meta-analysis to pool the estimated prevalence of multimorbidity across studies, and used random-effects meta-regression and subgroup analysis to examine the association of heterogeneous prevalence estimates with study and measure characteristics.Results13 807 titles were screened, of which 193 met inclusion criteria for meta-analysis. The pooled prevalence of multimorbidity was 42.4% (95% CI 38.9% to 46.0%) with high heterogeneity (I2 >99%). In adjusted meta-regression models, participant mean age and the number of conditions included in a measure accounted for 47.8% of heterogeneity in effect sizes. The estimated prevalence of multimorbidity was significantly higher in studies with older adults and those that included larger numbers of conditions. There was no significant difference in estimated prevalence between low-income or middle-income countries (36.8%) and high-income countries (44.3%), or between self-report (40.0%) and administrative/clinical databases (52.7%).ConclusionsThe pooled prevalence of multimorbidity was significantly higher in older populations and when studies included a larger number of baseline conditions. The findings suggest that, to improve study comparability and quality of reporting, future studies should use a common core conditions set for multimorbidity measurement and report multimorbidity prevalence stratified by sociodemographics.PROSPERO registration numberCRD42020172409.
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