Citations

Abstract Sweet's syndrome (SS) is a neutrophilic dermatosis characterised by the acute onset of erythematous papules or plaques and a constellation of symptoms including fever, leucocytosis, and histopathology demonstrating nodular, pustular, or diffuse infiltrate of neutrophils with marked papillary oedema. SS can be a manifestation of inflammatory bowel disease and often coincides with periods of disease flares. Only a few cases of SS associated with ulcerative colitis are reported in the literature, and no cases have involved pulmonary manifestations in the paediatric population. We present a case of a 14-year-old girl presenting with new onset ulcerative colitis requiring emergent colectomy with subsequent development of pulmonary SS. Treatment consisted of intravenous and oral corticosteroids and dapsone. SS should be considered in the differential diagnosis of prolonged fever with cutaneous involvement and systemic symptoms. Special consideration should be given to paediatric patients with extracutaneous manifestations, particularly pulmonary involvement.

Background:Waldenström Macroglobulinemia (WM) is a rare, indolent B‐cell lymphoplasmacytic malignancy. Patient outcomes are highly heterogeneous, with a proportion of patients surviving less than 5 years (short survivors) and another proportion that survive longer than 10 years. The laboratory parameters in the currently used International Prognostic Scoring System for WM (IPSSWM) include hemoglobin, serum IgM, platelet count, and serum β2‐microglobulin.Aims:We aim to identify unique patient characteristics and prognostic features associated with short survival in WM.Methods:The medical records of patients with active WM that were diagnosed at Mayo Clinic Rochester, Arizona, and Florida between January 1st, 1996 and December 31st, 2013 were reviewed. The patients with smoldering WM were excluded. Cohorts of patients who either survived ≤ 5 years (Short Survival Group) or those with an overall survival (OS) ≥ 10 years (Long Survival Group) from the diagnosis of active disease were compared. Survivors with a follow‐up of ≤ 5 years were not included in the analyses. Two‐sided Wilcoxon rank sum test and Chi square/Fisher's exact test were used to compare the continuous and categorical variables, respectively. The variables that were statistically significant on univariate analysis (P < 0.05) were included in a multivariate logisitic regression analysis.Results:Of 893 consecutively seen WM patients (median follow‐up of 9 years [95% CI 8.4–9.7]), we identified 387 patients who could be categorized into either the Short Survival Group (n = 171 patients, 44%) or the Long Survival Group (n = 216, 56%). The Short Survival Group had a median OS of 2.4 years (2.1–2.8) and median age at diagnosis of 73 years (42–93), while the Long Survival Group (n = 216, 56%) had a median OS of 18.9 years (16‐NR) and median age at diagnosis of 62 years (31–85). The baseline characteristics and significant findings between the two groups are listed in the Table. Parameters significant on univariate analysis included age >65 years, albumin < 3.5 g/dL, β2‐microglobulin >3 μg/ml, and LDH > upper limit of normal (ULN). On multivariate analysis, albumin <3.5 g/dL and LDH > ULN were independently associated with short survival. Among the Long Survivors, 60 (28%) patients survived 15 years or more.Summary/Conclusion:Lactate dehydrogenase above the ULN and serum albumin <3.5 g/dL are independent biomarkers of short survival in WM. The MYD88 L265P status and the size of serum IgM are not prognostic in WM. Our data suggest the need for simplification of the current staging system with the use of widely available markers: serum albumin and lactate dehydrogenase.image

Background:Ibrutinib is approved in Europe and the US for the treatment of Waldenstrom macroglobulinemia (WM) with a median progression‐free survival (PFS) measured on several years. As PFS is commonly used for drug approval by regulatory entities, there is an unmet need of reliable surrogate markers for PFS that could help accelerating such process. This is of importance with novel BTK inhibitors currently in clinical trials.Aims:We hypothesized that the depth of response at 6 months can be predictive of PFS in patients with WM treated with the BTK inhibitor ibrutinib.Methods:We evaluated our hypothesis in two separate cohorts of WM patients treated with ibrutinib. The learning cohort was composed by participants of two prospective clinical trials at Dana‐Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center and Stanford Cancer Center. The validation cohort was composed by consecutive WM patients treated with ibrutinib off clinical trial at DFCI and Mayo Clinic. Categorical responses at 6 months were assessed based on criteria from the 6thInternational Workshop for WM. PFS6 was defined as the time from the 6‐month response assessment until progression of disease or death from any cause. PFS6 curves were generated using the Kaplan‐Meier method and compared using the log‐rank test. Cox proportional hazard regression models were fitted for PFS6. Pvalues <0.05 were considered statistically significant.Results:The learning and validation cohorts were composed by 92 and 190 WM patients treated with ibrutinib, repsectively. There were no statistical differences between cohorts with regards to age, sex, serum IgM level, hemoglobin level, bone marrow involvement, prior treatment status, and MYD88 and CXCR4 mutational status (p>0.05 for all variables). The rates of partial response (PR) or better at 6 months in the learning and validation cohorts were 63% (54/86) and 72% (114/159), respectively (p = 0.15). The median PFS6 was not reached in the learning cohort and was 53 months (95% CI 44‐not reached) in the validation cohort. In the learning cohort, the median PFS6 for patients who attained a PR or better at 6 months was not reached, while for the patients who did not attained PR at 6 months was 48 months (95% CI 33‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 83% (95% CI 68–91%), while for patients who did not attained PR at 6 months was 58% (95% CI 33–76%) (Figure, left, log‐rank p = 0.02). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.37 (95% CI 0.16–0.87; p = 0.02).In the validation cohort, the median PFS6 for patients who attained a PR or better at 6 months was 53 months (95% CI 44‐not reached), while for the patients who did not attained PR at 6 months was 32 months (95% CI 22‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 79% (95% CI 67–87%), while for patients who did not attained PR at 6 months was 50% (95% CI 26–70%) (Figure, right, log‐rank p = 0.04). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.46 (95% CI 0.22–0.98; p = 0.04). Age, sex, serum IgM level, hemoglobin level, bone marrow involvement and prior treatment status were not prognostic of PFS6 in both cohorts.Summary/Conclusion:Attaining a PR or better at 6 months to ibrutinib is associated with longer median PFS and higher rates of 3‐year PFS in WM patients. Depth of response at 6 months could serve as a surrogate for PFS in clinical trials evaluating BTK inhibitors in WM patients.image

The surge in internet use for expression of personal thoughts and beliefs has made it increasingly feasible for the social Natural Language Processing (NLP) research community to find and validate associations between social media posts and mental health status . Cross-sectional and longitudinal studies of low-resourced social media data bring to fore the importance of real-time responsible Artificial Intelligence (AI) models for mental health analysis in native languages. Aiming at classifying research for social computing and tracking advances in the development of learning-based models, we propose a comprehensive survey on mental health analysis for social media and posit the need of analyzing low-resourced social media data for mental health . We first classify three components for computing on social media as: SM - data mining/natural language processing on social media , IA - integrated applications with social media data and user-network modeling, and NM - user and network modeling on social networks. To this end, we posit the need of mental health analysis in different languages of East Asia (e.g., Chinese, Japanese, Korean), South Asia (Hindi, Bengali, Tamil), Southeast Asia (Malay, Thai, Vietnamese), European languages (Spanish, French) and the Middle East (Arabic). Our comprehensive study examines available resources and recent advances in low-resourced languages for different aspects of SM, IA, and NM to discover new frontiers as potential field of research.

AbstractINTRODUCTIONThe implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A‐.METHODSWe evaluated 98 participants from the Mayo Clinic who were T+ and A‐. Participants were matched 2:1 to A‐ and T‐ cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups.RESULTSThe A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini‐Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale‐Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A‐T+ and CI A‐T+.DISCUSSIONA‐T+ participants show an association with lower cognitive performance.

Background Communication gaps, whether incomplete or fragmented communication, have been the cause of many disasters in human civilisation. Coordination of healthcare is directly related to proper communication and handoffs among multidisciplinary teams throughout multiple shifts during a patient’s hospitalisation. Local problem Patient surveys and direct patient feedback at Mayo Clinic Health System in Mankato, Minnesota, indicated that patient communication with physicians and nurses had declined in 2017 and 2018. Viewing this as an opportunity for improvement, our leadership initiated several changes to increase physician and nurse communication with patients, which resulted in no notable improvements. Methods A systematic quality improvement approach was implemented by using Six Sigma methodology. Stakeholders from multidisciplinary teams were assembled as the project team. The five steps of Six Sigma methodology (Define, Measure, Analyse, Improve and Control) were followed to create a quality improvement intervention. Intervention We developed a standardised and easy-to-use bedside team rounding tool to improve patient communication with physicians and nurses. Results Postintervention patient satisfaction top-box scores exceeded target improvements for both physician (from 78.5% to 82.0%, p<0.01) and nurse (from 80.5% to 83.1%, p=0.04) communication domains. Physicians had a 33-point increase in percentile rank (from 41st to 74th percentile rank), and nurses had a 25-point increase in percentile rank (from 59th to 84th percentile rank). This increase in communication ranked our institution at the top of national benchmark organisations. Conclusions Overwhelmingly positive patient feedback was achieved, and postintervention employee satisfaction was primarily positive when compared with preintervention satisfaction.

Background: Metacarpophalangeal (MCP) joint arthritis is common secondary to a variety of inflammatory, degenerative, and traumatic causes. Although MCP arthroplasty is more common for the second to fifth digits, primary arthrodesis can be used for high-demand patients with arthritis or unsalvageable fractures of the MCP joint. There has been limited recent studies on the outcomes of these patients. Methods: A retrospective review of 38 fingers in 27 patients with primary arthrodesis from 1990 to 2020 was conducted. The major outcomes were complications, reoperations, radiographic union, and time to union. Patient-reported outcomes including the Michigan Hand Outcomes Questionnaire and a questionnaire specific to the operative MCP joint were collected. Results: Rate of radiographic union was 84% including revisions. The average time to union was 3.6 months. Rates of complications, reoperation, and amputation were 26%, 16%, and 7%, respectively. Arthrodesis as part of emergent trauma reconstruction was significantly more likely to result in reoperation (50% vs 7%) and complication (63% vs 17%) than chronic arthritis. Patient-reported outcomes were fair to good with improvement in pain (79%), function (66%), and appearance (40%). Sixty-six percent (66%) of patients were satisfied with their surgery, and 73% would repeat the surgery. Conclusion: Arthrodesis for unsalvageable MCP fractures was associated with higher rates of reoperation and complication than inflammatory or degenerative arthritis. Excluding emergent trauma, MCP fusion was reliable with a reoperation rate of 7% and a modest complication rate of 17%. Patients rated reasonable levels of satisfaction and willingness to repeat the procedure despite complications.

The initial excitement generated more than two decades ago by the discovery of drugs targeting fatty acid synthase (FASN)‐catalyzed de novo lipogenesis for cancer therapy was short‐lived. However, the advent of the first clinical‐grade FASN inhibitor (TVB‐2640; denifanstat), which is currently being studied in various phase II trials, and the exciting advances in understanding the FASN signalome are fueling a renewed interest in FASN‐targeted strategies for the treatment and prevention of cancer. Here, we provide a detailed overview of how FASN can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape and organ‐specific metastatic potential. We then present a variety of FASN‐targeted therapeutic approaches that address the major challenges facing FASN therapy. These include limitations of current FASN inhibitors and the lack of precision tools to maximize the therapeutic potential of FASN inhibitors in the clinic. Rethinking the role of FASN as a signal transducer in cancer pathogenesis may provide molecularly driven strategies to optimize FASN as a long‐awaited target for cancer therapeutics.

Abstract Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.g., lipids, nucleic acids, proteins), and that can have biological functions within and beyond the CNS. Thus, CSF EVs likely serve as both mediators of and contributors to communication in the CNS. Accordingly, their potential as biomarkers for CNS diseases has stimulated much excitement for and attention to CSF EV research. However, studies on CSF EVs present unique challenges relative to EV studies in other biofluids, including the invasive nature of CSF collection, limited CSF volumes and the low numbers of EVs in CSF as compared to plasma. Here, the objectives of the International Society for Extracellular Vesicles CSF Task Force are to promote the reproducibility of CSF EV studies by providing current reporting and best practices, and recommendations and reporting guidelines, for CSF EV studies. To accomplish this, we created and distributed a world‐wide survey to ISEV members to assess methods considered ‘best practices’ for CSF EVs, then performed a detailed literature review for CSF EV publications that was used to curate methods and resources. Based on responses to the survey and curated information from publications, the CSF Task Force herein provides recommendations and reporting guidelines to promote the reproducibility of CSF EV studies in seven domains: (i) CSF Collection, Processing, and Storage; (ii) CSF EV Separation/Concentration; (iii) CSF EV Size and Number Measurements; (iv) CSF EV Protein Studies; (v) CSF EV RNA Studies; (vi) CSF EV Omics Studies and (vii) CSF EV Functional Studies.