搜索结果：castles

Professor Carolyn S.P. Lam is a senior consultant cardiologist at the National Heart Centre Singapore, where she founded Singapore's first women's heart clinic, and a tenured full professor at Duke-NUS Medical School. She is co-founder of Us2.ai, an award-winning startup applying artificial intelligence to echocardiography, with regulatory clearance across more than 35 countries. Her research spans heart failure with preserved ejection fraction, sex differences in cardiovascular disease, and Asian heart failure phenotypes. She is principal investigator of the ASIAN-HF registry and chairs several large international trials, including SURMOUNT-MMO, LIBREXIA-AF, HF-POLARIS, and CASTLE-HFpEF. She is co-chair of the 2024 KDIGO Controversies Conference and a leading voice on women's heart health and AI-enabled cardiovascular care.

Despite extensive research on the job demands-resources (JD-R) model, the interactions between personal resources and job demands remain insufficiently understood, particularly regarding their dual role in shaping perception and appraisal versus resource depletion. This study addresses this critical gap by exploring how mindfulness and psychological capital (PsyCap) operate within the JD-R framework. Specifically, we examined whether mindfulness and PsyCap alter individuals' perception and appraisal of job demands or, conversely, whether job demands deplete individuals' personal resources. The presented studies on employees experimentally manipulated quantitative, cognitive, and emotional demands to examine their interactions with personal resources. Testing the perception and appraisal effect in Study 1 (N = 253), self-efficacy and resilience predicted lower perceived demands and hindrance appraisals, while mindfulness predicted higher challenge appraisals and emotional demands. Testing the depleting effect in Study 2 (N = 207), quantitative and cognitive demands depleted self-efficacy, whereas emotional demands were associated with higher state mindfulness. Together, these studies reveal a complex seesaw effect, suggesting that specific demand types interact with particular resources to shape employees' work experiences. The findings highlight the need for tailored interventions that both cultivate personal resources and optimize the demand-resource balance to foster performance and well-being at work.

Immature teratoma (IT) of the ovary is an uncommon tumor with controversy regarding management. We aimed to review the characteristics, management and outcome of pure IT of the ovary in pediatric and adolescent females. A multicenter review was performed by 29 institutions participating in the Pediatric Surgical Oncology Research Collaborative of females aged 0-18 years with pure ovarian IT diagnosed between 2010 and 2022. Patients with additional malignant histology were excluded. We identified 127 females with pure ovarian IT with a mean age of 12 years. Most tumors were stage 1 and 2, and high-grade. Complete surgical staging was performed in 50% of patients and identified abnormal tissue, including IT, mature teratoma and gliomatosis at all sites sampled. Nineteen patients (16%) received chemotherapy. A total of 24 patients had a recurrence (9 multiple), 7 of whom had received postoperative chemotherapy. Nine recurrences were purely malignant, containing IT or yolk sac tumor and 19 patients had a benign recurrence Two-year recurrence-free survival was 82%, and there were 2 mortalities. In multivariable analysis, elevated serum alpha fetoprotein and preoperative tumor rupture were significantly associated with recurrence. Overall survival is excellent despite recurrence in 19% of patients. One third of recurrences were multiple, and mature teratoma was a common finding; therefore, surgical resection at recurrence is recommended. Surgical staging was incomplete in half of the patients. When controlling for confounding variables, AFP and preoperative tumor rupture remained associated with recurrence; however, grade, gliomatosis, and chemotherapy use are potentially important elements to consider in the management of these patients.

暂无摘要（点击查看详情）

Incendiary weapons (IW) have been used in 21st-century armed conflicts, causing severe burn injuries with lifelong physical and psychological consequences. Existing international law has shortcomings that have undermined its ability to adequately address the human cost of IW. While the harm from IW has been reported, limited standardized clinical data on their medical effects, in addition to high-quality evidence on treatment protocols, exist. No structured assessment of existing literature on this topic exists. This review seeks to address this gap. A scoping review was conducted to evaluate existing literature and identify evidence gaps regarding the medical effects and management of IW injuries in 21st-century armed conflict. A systematic search strategy was performed using standardized inclusion criteria. A standardized extraction form was used to capture data elements for description in both peer-reviewed and grey literature. Our search identified 14,050 records for screening across peer-reviewed and grey literature that were narrowed to 56 included reports. A total of 5565 patients were specifically reported to be affected by IW across 26 countries; however, there was a lack of homogeneous reporting across all categories of interest. Available reports described severe and multidimensional injuries with lack of consensus regarding both diagnosis and treatment of IW injuries. Available data regarding IW use, injury, and treatment are heterogeneous, limiting epidemiological analysis to inform care and practice guidelines. The described injuries raise the need for standardized data collection and focused training on IW care in conflict settings. Global databases to strengthen the evidence base on IW casualties are needed to enhance policy efforts, diagnosis and treatment standards, and trainings, which will in turn improve clinical performance.

Anthropogenic nutrient enrichment and plant diversity loss reshape soil biodiversity, yet disentangling their individual and combined effects on key groups such as fungi and protists remains a major challenge. Here, we investigated soil microeukaryote communities using long-read amplicon rRNA gene sequencing in a temperate grassland experiment with 11 years of moderate NPK fertilization and manipulated plant diversity (1, 2, or 4 plant species). Our results indicate that fertilization generally had a stronger influence on microeukaryote communities than plant species richness. Fertilization altered the community composition of fungi and protists, with an increase in OTU richness by 20.8% and 52.7%, respectively, and shifted community dominance from fungi to protists. Plant diversity exclusively affected protists with a shift in community composition. Community changes were largely driven by increases in plant biomass (resulting from both fertilization and plant diversity), alongside higher soil phosphorus and lower soil pH, which were exclusively influenced by fertilization. Moreover, the experimental treatments exerted distinct effects on the different life strategies of fungi and protists. Fertilization enhanced fungal saprophytes (only richness), fungal animal pathogens, and protist consumers, whereas a decline in plant diversity increased phototrophic protists and decreased protist animal pathogens. Notably, fertilization and the decline in plant diversity together led to a cumulative increase in fungal plant pathogens. In conclusion, our results show that fertilization and reduced plant species richness exert distinct yet interacting effects on soil microeukaryotic communities. This highlights the need for integrated assessments of these two factors, rather than studying them in isolation, when evaluating global change effects.

暂无摘要（点击查看详情）

Psoriasis is a chronic immune-mediated inflammatory disease associated with systemic comorbidities, including gastrointestinal disorders. Emerging evidence supports a bidirectional gut-skin axis, with shared immunologic pathways involving the interleukin (IL)-23/IL-17 axis. Irritable bowel syndrome (IBS), traditionally considered a functional disorder, has also been linked to low-grade inflammation and cytokine dysregulation. We report a case of a 67-year-old man with moderate plaque and inverse psoriasis and longstanding IBS with diarrhea (IBS-D) who experienced complete resolution of gastrointestinal symptoms following treatment with risankizumab, an IL-23 inhibitor. Improvement in IBS symptoms began within weeks of therapy initiation and was sustained at follow-up, alongside complete skin clearance. No other changes in medications or lifestyle were identified. This case highlights a potential role of IL-23-mediated inflammation in IBS pathophysiology and suggests that targeted inhibition of the IL-23/IL-17 axis may benefit select patients with concurrent dermatologic and gastrointestinal disease.

Primary cicatricial alopecias are rare inflammatory disorders that disproportionately affect women and can cause permanent hair loss along with painful scalp symptoms. While their impact on quality of life has been described, comprehensive patient-reported data remain limited. To characterize symptoms, lifestyle disruption, and financial burden among women with central centrifugal cicatricial alopecia, lichen planopilaris, and frontal fibrosing alopecia. A nationwide cross-sectional survey was distributed via the Scarring Alopecia Foundation. Analyses included female respondents with self-reported centrifugal cicatricial alopecia, lichen planopilaris, or frontal fibrosing alopecia, stratified by subtype, hair loss severity, and symptom burden. Among 917 women, physical symptoms, lifestyle disruption, and disease-related spending were commonly reported. Burning and pain/tenderness were significantly associated with greater impairment in work productivity, daily activities, and treatment-related costs, while greater scalp involvement also corresponded to increased burden. However, this pattern did not hold among a small subset of completely bald respondents, suggesting that psychosocial burden increases with disease severity but may shift once a certain threshold is surpassed. Primary cicatricial alopecias impose substantial physical, psychosocial, and financial burden on women. These findings underscore the need for improved physician awareness and greater support for women managing this chronic, stigmatizing disease.

The EFSA Panel on Food Additives and Flavourings (FAF) evaluated the genotoxic potential of two flavouring substances, 2-phenylcrotonaldehyde [FL-no: 05.062] and 5-methyl-2-phenylhex-2-enal [FL-no: 05.099] from subgroup 3.3 of FGE.19, in the Flavouring Group Evaluation 216 revision 3 (FGE.216Rev3). In FGE.216Rev2, the Panel concluded that the use of the flavouring [FL-no: 05.062] at the reported use levels in several food categories would raise a concern for aneugenicity and requested substance-specific data for the other related compounds [FL-no: 05.099, 05.100, 05.175 and 05.222]. New data were provided only for [FL-no: 05.062 and 05.099]. For [FL-no: 05.062], the results of a new plasma analysis of the exposed animals were considered to be sufficient to rule out a concern for systemic aneugenicity of the substance. However, the data available do not overrule the concern for aneugenicity of 2-phenylcrotonaldehyde at the site of contact, where the concentrations will be maximal, taking into account that the positive findings in the in vitro micronucleus (MN) assay were seen only in the absence of metabolic activation. Therefore, in line with the principles described in the EFSA Scientific Committee guidance on aneugenicity, the Panel compared the lowest concentration resulting in aneugenicity in the in vitro MN assay (20 μg/mL) with the reported use levels of 2-phenylcrotonaldehyde [FL-no: 05.062] in food (up to 2 mg/kg) and noted that they are one order of magnitude below the concentration for which an aneugenic effect was observed in the in vitro MN assay. Based on this comparison, the Panel concluded that the use of the flavouring substance [FL-no: 05.062] in foods, including beverages, would not raise a concern for aneugenicity if the use levels were not greater than 2 mg/kg or mg/L. For [FL-no: 05.099], based on the new data available, the Panel concluded that there is no concern for genotoxicity.

Risankizumab (RZB) is an approved injectable IL-23 inhibitor with demonstrated high levels of skin clearance, and icotrokinra (ICO) is an oral IL-23 receptor blocker recently approved for the treatment of moderate-to-severe plaque psoriasis. In the absence of head-to-head trials, this study uses matching-adjusted indirect comparison (MAIC) to compare RZB with ICO in the treatment of adult patients with moderate-to-severe psoriasis. Individual patient data from phase 3 RZB trials and summary data from published ICO phase 3 trials were used in this MAIC through week 52. Risk differences between RZB and ICO placebo-adjusted response rates (anchored) were assessed for&#x2009;&#x2265;&#x2009;75%,&#x2009;&#x2265;&#x2009;90%, and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90, and PASI 100) and Investigator's Global Assessment (IGA) of 0 and 0/1 (IGA 0 and IGA 0/1) every 4&#xa0;weeks up to week 16. Risk differences between RZB and ICO unadjusted response rates (unanchored) at weeks 24 and 52, along with confidence intervals and P-values, are also presented. At 16&#xa0;weeks, the PBO-adjusted response rates (RZB versus ICO) were 80.6% versus 61.7%, with a risk difference (RD) of 18.9% (95% CI 11.5, 26.4; P&#x2009;<&#x2009;0.001) for PASI 75; 71.4% versus 49.9% (RD: 21.5%; 95% CI 15.6, 27.4; P&#x2009;<&#x2009;0.001) for PASI 90; 42.3% versus 29.4% (RD: 13.0%; 95% CI 7.9, 18.0; P&#x2009;<&#x2009;0.001) for PASI 100; 77.8% versus 58.4% (RD: 19.4%; 95% CI 12.4, 26.3; P&#x2009;<&#x2009;0.001) for IGA 0/1; and 41.6% versus 33.9% (RD: 7.7%; 95% CI 2.3, 13.0; P&#x2009;<&#x2009;0.05) for IGA 0. Results were consistent in the unanchored analysis at weeks 24 and 52. In this analysis, adult patients with moderate-to-severe psoriasis treated with RZB demonstrated greater clinical efficacy as early as week 4 or 8, and through week 52 compared with ICO. This study compared two medicines for moderate-to-severe psoriasis: risankizumab, which is already approved and in use by patients, and icotrokinra, a recently approved oral medicine. There are currently no direct comparison studies, so an indirect comparison was used to compare results from separate clinical trials on each medicine. Clear skin was assessed using measures such as the degree of improvement (&#x2265;&#x2009;75%,&#x2009;&#x2265;&#x2009;90%, or 100%) and doctors&#x2019; assessments. The results showed that at all assessed time points, patients treated with risankizumab were more likely to have clearer skin than patients treated with icotrokinra. For example, 71.4% of patients treated with risankizumab achieved at least 90% skin improvement, compared with 49.9% of patients treated with icotrokinra at week 16, and similar differences were observed at other levels of improvement and timepoints up to week 52. Overall, this indirect comparison found that more patients treated with risankizumab achieved clearer skin compared with patients treated with icotrokinra.

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p&#x2009;<&#x2009;0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p&#x2009;<&#x2009;0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

暂无摘要（点击查看详情）

Metastatic uveal melanoma (mUM) is a rare, aggressive malignancy with limited therapeutic options in the metastatic setting. Tebentafusp (IMCgp100) is an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), targeting gp100 in HLA-A*0201+ patients. Tebentafusp has demonstrated an overall survival (OS) benefit in clinical trials, usually without marked radiographic tumor regression. We describe a mUM patient who was treated with tebentafusp for more than two years and achieved durable stable disease on imaging but passed away due to sudden cardiac death. Autopsy examination revealed extensive tumor necrosis and dense immune cell infiltration within metastatic liver lesions with minimally viable tumor, providing direct evidence of robust immune activation in the tumor microenvironment. This case highlights the potential for T cell bispecifics to induce profound anti-tumor effects that are not fully captured by conventional radiographic assessment, underscoring the need for integrated clinical, pathologic, and imaging evaluation in this setting.

暂无摘要（点击查看详情）

Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMBSHH). Comparison of these therapies in large molecularly defined iMBSHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies. In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMBSHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMBSHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS). Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMBSHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMBSHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-na&#xef;ve iMBSHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMBSHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MBSHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-na&#xef;ve PFS findings were validated in a re-evaluation of smaller historical trials cohorts. Our findings show that iMBSHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMBSHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that often requires long-term therapy for effective management. Several biologics have been approved for treating patients with moderate-to-severe AD, but, to date, no head-to-head trials comparing these biologics have been completed. Although long-term data from individual trials have been published, the differences in trial design prevent direct comparisons across treatments and therefore only indirect comparisons, such as matching-adjusted indirect comparisons (MAICs), should be used to compare efficacy endpoints. MAICs utilize individual patient data from one trial, adjusted to match the summary statistics for relevant demographic and disease characteristics with those of an aggregate comparator trial. Available published phase 3 clinical trial data on the long-term efficacy of approved biologics for the treatment of moderate-to-severe AD were reviewed to provide an overview of the key differences in trial design for AD biologics, and the implications of these differences for comparing efficacy. Available published MAIC analyses of clinical trial data were reviewed to provide further insights into the long-term efficacy of approved biologics for the treatment of moderate-to-severe AD. Six long-term combination therapy and monotherapy trials were summarized and assessed, revealing substantial differences in trial design that prevent efficacy comparisons of AD biologics. Three available MAIC analyses comparing trials of biologics for AD were reviewed and critically assessed, revealing important considerations for robust MAIC analyses and highlighting the limitations and advantages of MAIC analyses in the absence of head-to-head trial data. Although any interpretation of indirect treatment comparisons should be made with caution, anchored MAIC remains a valuable and methodologically appropriate tool for comparative assessment when direct head-to-head evidence is unavailable. Available MAIC analyses indicate comparable long-term efficacy among three widely-used biologics-tralokinumab, dupilumab, and lebrikizumab-in the treatment of moderate-to-severe AD.

Eosinophilia with multi-organ infiltration is rarely reported in dogs. Successful treatment of previous cases has relied on a combination of prednisolone and hydroxyurea. A 15-month-old, intact, male Border terrier was presented at a referral hospital with a 6-month history of recurrent, acute episodic abdominal pain, trembling, vomiting, soft feces, and persistent marked eosinophilia. Computed tomography (CT) disclosed abdominal lymphadenomegaly, and cytological evaluation of fine needle aspirates indicated eosinophilic and neutrophilic pyogranulomatous lymphadenitis. Biopsy samples of jejunal and iliac lymph nodes, liver, and jejunum were obtained during exploratory celiotomy and showed marked eosinophilic infiltration with no inciting cause identifiable on histological examination. The dog was successfully managed with dietary modification alone, using a gluten-free hydrolyzed diet (Pro Plan Veterinary Diets HA Hypoallergenic, Purina, York, United Kingdom). The role of dietary modification should be considered in dogs presenting with acute gastrointestinal clinical signs and marked circulating and tissue eosinophilia when other causes are ruled out.

暂无摘要（点击查看详情）