Search

In Mantle Cell Lymphoma (MCL), the role of macrophages within the tumour microenvironment (TME) has recently gained attention due to their impact on prognosis and response to therapy. Despite their low absolute number in MCL tumour tissue, recent findings reveal an association between the levels of macrophages and prognosis, consistent with trends observed in other lymphoma subtypes. M2-like macrophages, identified by markers such as CD163, contribute to angiogenesis and suppression of the immune response. Clinical trials with MCL patients treated with chemoimmunotherapy and targeted treatments underscore the adverse impact of high levels of M2-like macrophages. Immunomodulatory drugs like lenalidomide reduce the levels of MCL-associated CD163 + macrophages and enhance macrophage phagocytic activity. Similarly, clinical approaches targeting the CD47 "don't eat me" signalling, in combination with the anti-CD20-antibody rituximab, demonstrate increased macrophage activity and phagocytosis of MCL tumour cells. Cell-based therapies such as chimeric antigen receptor (CAR) T-cell have shown promise but various challenges persist, leading to a potential interest in CAR-macrophages (CAR-M). When macrophages are recruited to the TME, they offer advantages including phagocytic function and responsiveness to microenvironment alterations, suggesting their potential as a manipulable and inducible alternative when CAR T-cell therapies fails in the complex landscape of MCL treatment., Competing Interests: IG has received support to the department from Jansen Cilag and Abbvie for educational purposes. IG participated in a real-world data project supported by Takeda with reimbursement to the department. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nylund, Nikkarinen, Ek and Glimelius.)

In Sweden, secondary prevention of fragility fractures through osteoporosis medication is directed by national guidelines. According to these, postmenopausal women and men who have suffered a fragility fracture should be assessed and pharmaceutical treatment of osteoporosis should always be considered. For the most serious fractures (hip and vertebral fractures), treatment can be initiated immediately. Despite this, previous studies have shown that the level of pharmaceutical treatment is low. In Sweden, osteoporosis drugs are predominantly administered by prescription, but about one-third of drugs are nowadays administered on-site in the health care system, which is not recorded in national registers. We have estimated the total amount of osteoporosis drugs through aggregated sales statistics. Our results show that medical treatment with osteoporosis drugs is still at low levels, covering approximately 5 percent of the population aged 70 or older, with clear differences between regions.

Objective: The effects of serotonin reuptake inhibition induced by antidepressants on ischemic stroke and its pathophysiology remain unclear despite the frequent use of antidepressants and high fatality of ischemic stroke. We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition., Design: Retrospective cohort study., Participants: The cohort consisted of older adult patients who were treated with antidepressants., Measurements: We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition using Korea's National Health Insurance System-Senior Cohort. Exposure to antidepressants was categorized by type (strong, intermediate, or weak serotonin reuptake inhibitors [SRIs]) and by the mean prescribed dose per day and treatment duration. The risk for the strong and intermediate SRIs group was compared with that of the weak SRIs group using a Cox proportional hazards regression model., Results: Of 97,411 were weak SRIs users, and 107,152 and 18,783 were users of strong and intermediate SRIs. The risk of ischemic stroke was 1.192- and 1.057-fold higher in strong and intermediate SRI users, respectively than in weak SRI users. Hazard ratios were increased in higher dose and shorter duration user groups. The risk increased 1.753-fold in strong SRI users with anticonvulsants and 1.387-fold in intermediate SRI users with PPIs., Conclusion: The use of strong and intermediate SRIs should be considered carefully in older adult patients, especially when high-dose antidepressants are prescribed even for a short duration., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Hospital length of stay (LoS) after a hip fracture likely mirrors health status; however, a too short hospitalization might increase the risk of readmission. In this national register-based study, we investigated the association between LoS after a hip fracture and the risk of readmissions., Methods: 73,551 patients with a first hip fracture between 2012 and 2019 were followed for 4 months after discharge. LoS was categorized by cubic splines and the association with readmissions was analyzed with Cox regression models., Results: The mean LoS was 11 ± 6 days and 25% of the study population had at least one readmission. Compared to the mean LoS of 9-12 days, there was a 18% decreased risk of readmission for LoS of 2-4 days (HR 0.82 [95% CI 0.77-0.87]) and 13% decrease for 5-8 days (HR 0.87 [95% CI 0.83-0.91]), when adjusting for sex, age, walking ability, ASA score, CCI, complications during hospitalization and living arrangements. For longer LoS, risk of readmission increased (13-23 days: HR 1.09 [95% CI 1.05-1.13] and 24 + days: HR 1.19 [95% CI 1.11-1.28]). The results were robust across sex, age, and living arrangements. The most common specific reasons for readmission were trauma/injury, cardiovascular and complications, and the proportions did not differ considerably between short and long LoS-categories., Conclusions: While a long LoS can be explained by the care need of the patient, a short LoS - compared to the average stay - does not increase the risk of readmission regardless of health status and hospital complications in a Swedish setting., (© 2023. The Author(s).)

Background: Fire seasons are longer, with more and larger wildfires, placing increased demands and risks on those fighting wildland fires. There are multiple agencies involved with fighting wildland fires and unique worksite conditions make meeting these workers' needs a challenge., Objective: The aim of the study is to develop and establish the effectiveness of a web-based safety and health program for those fighting wildland fires., Methods: This mixed methods project had 3 phases. The initial qualitative phase assessed the needs of 150 diverse firefighters through interviews and focus groups across 11 US sites to establish and prioritize program content. Interview transcripts were read for thematic content with iterative readings used to identify, code, and rank health and safety issues. The second phase used that information to build a comprehensive Total Worker Health program for those fighting wildfires. The program content was based on the qualitative interview data and consisted of 6 core and 8 elective 30-minute, web-based modules primarily done individually on a smartphone or computer. The final, third phase evaluated the program with a quantitative prospective proof-of-concept, usability, and effectiveness trial among wildland firefighter participants. Effectiveness was assessed with paired 2-tailed t tests for pre- and post-Likert agreement scale survey items, adjusted for multiple comparisons. In addition to assessing mean and SD at baseline and postsurvey, observed effect sizes were calculated (Cohen d). Usability and reaction to the program among firefighters who responded to postsurvey were also assessed., Results: The qualitative themes and subthemes were used to inform the program's content. For the effectiveness trial, 131 firefighters completed the presurvey, and 50 (38.2%) completed the postsurvey. The majority of the participants were White (n=123, 93.9%), male (n=117, 89.3%), with an average age of 41 (SD 12.9) years. Significant increases in knowledge and desired health and safety behaviors were found for both cancer (P<.001) and cardiovascular risk (P=.01), nutrition behaviors (P=.01), hydration or overheating (P=.001), binge drinking (P=.002), and getting medical checkups (P=.001). More than 80% (n=40) of postsurvey respondents agreed or strongly agreed that the program was easy to use and would recommend it to others., Conclusions: An innovative web-based safety and health promotion program for those fighting wildland fires was feasible, scalable, and usable. It improved the health and safety of those fighting wildland fires., Trial Registration: ClinicalTrials.gov NCT05753358; https://classic.clinicaltrials.gov/ct2/show/NCT05753358., (©Kerry Kuehl, Diane Elliot, Carol DeFrancesco, Wendy McGinnis, Susanna Ek, Bharti Garg. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 25.10.2023.)

Background: Frailty is an age-related health condition affecting an estimated 18% of older adults in Europe and past evidence has shown a relationship between socioeconomic factors and frailty. We examined population frailty trends and the association between frailty and 5-year mortality by education tertiles and income quartiles at ages 75, 85 and 95 in Swedish registry data., Methods: All Swedish residents born in 1895-1945 and in the Total Population Register from 1990 to 2020 were included. Frailty was assessed with the Hospital Frailty Risk Score (HFRS), which sums 109 weighted International Classification of Diseases (ICD codes), collected from the National Patient Register., Results: Regardless of education and income, frailty increased over time, though the association between frailty and 5-year mortality remained stable. Particularly in earlier birth cohorts, although the highest education and income levels had the highest mean HFRS scores, the lowest education and income levels accounted for greater proportions among the frail. These trends varied slightly by sex and age. Men and women had similar levels of frailty, but frailty was more strongly associated with mortality among men., Conclusion: Over time, education and income levels were more equally represented among the frail population in more recent years. More equitable distribution over time may suggest improvement in health disparities, though more work is needed. The overall increase in frailty and unchanged association with mortality indicates that additional research is needed to better understand how to best support the growing ageing population. This would then support the long-term viability of the healthcare system., Competing Interests: Competing interests: AW receives payment from Janssen Pharmaceutica NV for a separate collaboration., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed toward the tumor immune microenvironment, where macrophages play an important role. In MCL, the presence of M2 macrophages defined by CD163 expression in diagnostic biopsies has been associated with a worse prognosis. An alternative way to assess the abundance of M2 macrophages is by measuring the level of soluble CD163 in serum (sCD163). We aimed to investigate the prognostic value of sCD163 in 131 patients with MCL. We found that high sCD163 at diagnosis was associated with shorter progression-free survival (PFS) and shorter overall survival (OS) in 81 patients who were newly diagnosed and subsequently treated with chemoimmunotherapy. The same was seen in a cohort of 50 patients with relapsed MCL that were mainly treated within the phase 2 Philemon-trial with rituximab, ibrutinib, and lenalidomide. In patients who were newly diagnosed and had low levels of sCD163, 5-year survival was 97%. There was a moderate correlation between sCD163 and tissue CD163. The association with a poor prognosis was independent of MCL international prognostic index, Ki67, p53 status, and blastoid morphology, as assessed in a multivariable Cox proportional hazards model. In this study, high sCD163 was associated with both shorter PFS and shorter OS, showing that high levels of the M2 macrophage marker sCD163 is an independent negative prognostic factor in MCL, both in the chemoimmunotherapy and ibrutinib/lenalidomide era. In addition, low sCD163 levels identify patients with MCL with a very good prognosis., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Correction professionals are a highly stressed workforce with heightened risks for depression, suicide, obesity, cardiovascular disease, and injury. These professionals, largely hidden from view, have received little study concerning means to improve their safety, health, and well-being. In other settings, mindfulness has resulted in lowered stress, along with other benefits. We hypothesized that a program that promoted mindfulness combined with more typical health and safety components could uniquely benefit corrections professionals., Objective: This project will assess a novel scalable, self-administered program to enhance the mindfulness, safety, and health of a vulnerable worker group., Methods: In partnership with the Oregon Department of Corrections, we are conducting a prospective quasi-experimental trial of a safety, health, and mindfulness program among 100 corrections professionals from 2 institutions. Survey and physiologic data will be collected at enrollment, upon weekly program completion (3 months), and at 9 months after enrollment. Primary outcome behaviors promoted by the program are being mindful, healthier eating, more physical activity, and greater restorative sleep. Secondary downstream benefits are anticipated in stress level, mood, positive feelings about the organization, vascular health, and cellular aging, along with job performance, injuries, and economic costs. Participants will meet in-person or in a Zoom-type meeting as 3- to 5-member coworker groups during their usual work hours for 30-minute sessions once a week for 12 weeks. The program uses self-guided web-based learning modules that include brief mindfulness practice, and it is accessible by smartphone, tablet, or laptop. Daily mindfulness practice is encouraged between sessions, which is facilitated by the study website and group format. The modules' structure emphasizes prerequisite knowledge, peer support, skill practice, self-monitoring, and enhancing self-efficacy for change. The program continues through self-directed use of the Headspace app following the 12 weekly sessions., Results: Participants are being enrolled, and the intervention is ready to launch., Conclusions: Although mindfulness training has gained traction for worker well-being, its usual format requires a skilled trainer, an initial retreat, and weekly 2-hour meetings for several weeks. The content is limited to mindfulness without safety or health promotion aspects. The need for skilled trainers and time commitment limits the scalability of the usual mindfulness interventions. The planned program is an innovative combination of technology, e-learning, and a group format to add mindfulness to a safety and health curriculum. If acceptable and effective, the format would facilitate its widespread use., Trial Registration: ClinicalTrials.gov NCT05608889; https://classic.clinicaltrials.gov/ct2/show/NCT05608889., International Registered Report Identifier (irrid): PRR1-10.2196/45535., (©Diane Elliot, Kerry Kuehl, Carol DeFrancesco, Wendy McGinnis, Susanna Ek, Allee Van Horne, Katherine Ginsberg Kempany. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.09.2023.)

This national register study investigated osteoporosis medication prescriptions for secondary fracture prevention among older Swedish adults. Although prescription proportions are increasing for both men and women, they remain low, especially among individuals aged 90 and older. Improved Fracture Liaison Services could increase the prescription proportions and should be bolstered., Purpose: Despite clear guidelines for secondary fracture prevention among older adults, it seems undertreatment persists. We aimed to describe secondary fracture prevention with medical osteoporosis treatment in the older Swedish population. Specifically, how prescription has changed over time and if these patterns differ in sociodemographic subgroups., Methods: Between 2007 and 2020, osteoporosis medication use was studied among all Swedish residents aged 70 and older who had a fragility fracture in the previous 5 years. Previous fragility fractures were defined as fractures of the humerus, wrist, hip, or vertebrae. Osteoporosis medication was defined as any prescription of bone-enhancing medications (including bisphosphonates and denosumab)., Results: Osteoporosis medication increased over the study period, especially among men. Prescription among individuals 90 + was consistently two- to threefold lower compared to 70-79- and 80-89-year-olds. In 2018-2020, 8-17% of women and 5-9% of men, depending on age, received osteoporosis medication. At the beginning of the study period, women with higher education were more likely to be prescribed osteoporosis medication, though this difference decreased over time. Prescription of vitamin D and/or calcium as the only treatment was more common than osteoporosis medications throughout the study period., Conclusion: Despite increasing prescription proportions, medical treatment for secondary fracture prevention remains low. In addition, it is more common to be prescribed vitamin D or calcium than osteoporosis medication after a fragility fracture, contrary to current guidelines. These results indicate that there is room for improvement for Fracture Liaison Services in Sweden., (© 2023. The Author(s).)

Incidence and survival of breast cancer, the most common cancer among women, have been increasing, leaving survivors at risk of aging-related health conditions. In this matched cohort study, we examined frailty risk with the Hospital Frailty Risk Score among breast cancer survivors (n = 34,900) and age-matched comparison subjects (n = 290,063). Women born in 1935-1975, registered in the Swedish Total Population Register (1991-2015), were eligible for inclusion. Survivors had a first breast cancer diagnosis in 1991-2005 and survived ≥5 years after initial diagnosis. Death date was determined by linkage to the National Cause of Death Registry (through 2015). Cancer survivorship was weakly associated with frailty (subdistribution hazard ratio (SHR) = 1.04, 95% confidence interval (CI): 1.00, 1.07). In age-stratified models, those diagnosed at younger ages (<50 years) had higher risk of frailty (SHR = 1.12, 95% CI: 1.00, 1.24) than those diagnosed at ages 50-65 (SHR = 1.03, 95% CI: 0.98, 1.07) or >65 (SHR = 1.09, 95% CI: 1.02, 1.17) years. Additionally, there was increased risk of frailty for diagnoses in 2000 or later (SHR = 1.15, 95% CI: 1.09, 1.21) compared with before 2000 (SHR = 0.97, 95% CI: 0.93, 1.17). This supports work from smaller samples showing that breast cancer survivors have increased frailty risk, particularly when diagnosed at younger ages., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous disease, emphasizing the need for prognostic biomarkers. In this study we aimed at comparing the prognostic value of two RNA-based risk scores, circSCORE and MCL35, in 149 patients from the MCL2 (ISRCTN87866680) and MCL3 (NCT00514475) patient cohorts. Both risk scores provided significant stratification of high versus low risk for progression free survival (PFS) and overall survival (OS). The circSCORE retained significant prognostic value in adjusted multivariable Cox regressions for PFS, but not for OS. Furthermore, circSCORE added significant prognostic value to MIPI in the pooled cohort (MCL2 and MCL3) for PFS and OS, and for PFS in MCL3 alone, outperforming Ki67 and MCL35. We suggest a new, combined MIPI-circSCORE with improved prognostic value, and with potential for future clinical implementation, if validated in a larger, independent cohort.

The immune microenvironment of non-small cell lung cancer (NSCLC) is heterogeneous, which impedes the prediction of response to immune checkpoint inhibitors. We have mapped the expression of 49 proteins to spatial immune niches in 33 NSCLC tumors and report key differences in phenotype and function associated with the spatial context of immune infiltration. Tumor-infiltrating leukocytes (TIL), identified in 42% of tumors, had a similar proportion of lymphocyte antigens compared to stromal leukocytes (SL) but displayed significantly higher levels of functional, mainly immune suppressive, markers including PD-L1, PD-L2, CTLA-4, B7-H3, OX40L, and IDO1. In contrast, SL expressed higher levels of the targetable T-cell activation marker CD27, which increased with a longer distance to the tumor. Correlation analysis confirmed that metabolic-driven immune regulatory mechanisms, including ARG1 and IDO1, are present in the TIL. Tertiary lymphoid structures (TLS) were identified in 30% of patients. They displayed less variation in the expression profile and with significantly higher levels of pan lymphocyte and activation markers, dendritic cells, and antigen presentation compared to other immune niches. TLS also had higher CTLA-4 expression than non-structured SL, which may indicate immune dysfunction. Neither the presence of TIL nor TLS was associated with improved clinical outcomes. The apparent discrimination in functional profiles of distinct immune niches, independent of the overall level of leukocytes, illustrates the importance of spatial profiling to deconvolute how the immune microenvironment can dictate a therapeutic response and to identify biomarkers in the context of immunomodulatory treatment., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function., Competing Interests: Declaration of interests R.T.B. and B.N.F. are inventors on a U.S. patent (patent number: US11534423B2). R.T.B. is an inventor on a U.S. patent application (application number: 63/370,712). B.N.F. is a member of the Cell Reports advisory board., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies.

Introduction: Proton radiation therapy (PT) has become a treatment option alongside photon therapy (XRT) for lower-grade gliomas (LGG). In this single-institution retrospective study, we investigate the patient characteristics and treatment outcomes, including pseudo-progression (PsP), for LGG patients selected for PT., Method: Adult patients with grade 2-3 glioma consecutively treated with radiotherapy (RT) from May 2012 to December 2019 were retrospectively included in this cohort study. Tumor characteristics and treatment data were collected. The groups treated with PT and XRT were compared regarding treatment characteristics, side effects, occurrence of PsP, and survival outcomes. PsP was defined as new or growing lesions followed by either decrease or stabilization during a 12 month-period with no treatment., Results: Out of 143 patients meeting the inclusion criteria, 44 were treated with PT, 98 with XRT and one with mixed PT + XRT. The patients receiving PT were younger, had a lower tumor grade, more oligodendrogliomas and received a lower mean brain and brainstem dose. PsP was observed in 21 out of 126 patients, with no difference between XRT and PT ( p  = .38). The rate of fatigue in immediate connection to RT (zero to three months after) was higher for XRT than for PT ( p  = .016). The PT patients had a significantly better PFS and OS than the XRT patients ( p  = .025 and .035), but in multivariate analysis radiation modality was non-significant. Higher average dose to both brain and brainstem was associated with inferior PFS and OS ( p  < .001). Median follow-up time were 69 months and 26 months for XRT and PT patients, respectively., Conclusion: Contrary to previous studies, there was no difference in risk of PsP for XRT and PT. PT was associated with lower rates of fatigue <3 months after RT. The superior survival outcomes for PT indicates that the patients with the best prognosis were referred to PT.

The variable outcome to standard immunochemotherapy for mantle cell lymphoma (MCL) patients is a clinical challenge. Established risk factors, including high MCL International Prognostic Index (MIPI), high proliferation (Ki-67), non-classic (blastoid/pleomorphic) morphology, and mutated TP53, only partly identify patients in need of alternative treatment. Deepened understanding of biological factors that influence time to progression and relapse would allow for an improved stratification, and identification of novel targets for high-risk patients. We performed gene expression analyses to identify pathways and genes associated with outcome in a cohort of homogeneously treated patients. In addition to deregulated proliferation, we show that thermogenesis, fatty acid degradation and oxidative phosphorylation are altered in patients with poor survival, and that high expression of carnitine palmitoyltransferase 1A (CPT1A), an enzyme involved in fatty acid degradation, can specifically identify high-risk patients independent of the established high-risk factors. We suggest that complementary investigations of metabolism may increase the accuracy of patient stratification and that immunohistochemistry- based assessment of CPT1A can contribute to defining high-risk MCL.

Background and Purpose: The First-time Injurious Fall (FIF) screening tool was created to identify fall risk in community-living older men and women, who may be targets for primary preventive interventions. The FIF tool consists of 3 self-reported questions and 1 physical test (1-leg standing balance). The purpose of this study was to examine the predictive ability of the FIF tool and a modified FIF tool (in which 1-leg standing is replaced by self-reported balance) for first-time injurious falls., Methods: A cohort of 1194 community-living people 60 years and older from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), Sweden, was followed longitudinally for 5 years. Data on injurious falls were collected from registered data and were defined as receipt of care after a fall. The predictive ability of the FIF tool and the m-FIF tool was explored using Harrell's C statistic, stratified by sex., Results and Discussion: The injurious fall rate per 1000 person-years was 54.9 (95% CI: 47.22-63.78) for women and 36.3 (95% CI: 28.84-45.78) for men. The predictive ability for women and men according to Harrell's C statistic was 0.70 and 0.71 for the FIF tool and the m-FIF tool. The predictive ability was 0.70 and 0.69 for 1-leg standing, and 0.65 and 0.60 for self-reported balance problems., Conclusions: The m-FIF tool presented similar predictive ability as the FIF tool regarding first-time injurious falls. This finding could extend the usefulness of the tool to other settings, such as to electronic health (eHealth). A quickly and easily administered screening tool can help physical therapists to identify people with a high risk of falling who may need to undergo a more comprehensive fall risk assessment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Academy of Geriatric Physical Therapy, APTA.)

The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC., (© 2023. The Author(s).)

Background and Purpose: Waiting time to surgery is a modifiable risk factor in hip fracture surgery. However, there is no consensus regarding the acceptable duration of waiting time. We used the Swedish Hip Fracture Register RIKSHÖFT and 3 administrative registers to explore the association between time to surgery and adverse outcomes after discharge., Patients and Methods: 63,998 patients ≥ 65 years, admitted to a hospital between January 1, 2012, and August 31, 2017 were included. Time to surgery was divided into < 12, 12-24, and > 24 hours. Diagnoses investigated were atrial fibrillation/flutter (AF), congestive heart failure (CHF), pneumonia, and "acute ischemia" (a combination of stroke/intracranial bleeding, myocardial infarction, and acute kidney injury). Crude and adjusted survival analyses were performed. Time spent in hospital following the initial hospitalization was described for the 3 groups., Results: Waiting > 24 hours was associated with an increased risk of AF (HR 1.4, 95%CI 1.2-1.6), CHF (HR 1.3, CI 1.1-1.4) and "acute ischemia" (HR 1.2, CI 1.01-1.3). However, stratifying for ASA grade revealed that these associations were present only in patients with ASA 3-4. There was no association between waiting time and pneumonia after the initial hospitalization (HR 1.1, CI 0.97-1.2), but one was found with pneumonia during hospital stay OR 1.2 (CI 1.1-1.4). Time in hospital after the initial hospitalization was similar over the waiting time groups., Conclusion: The associations between waiting > 24 hours for hip fracture surgery and AF, CHF, and acute ischemia suggest that shorter waiting time may reduce adverse outcomes for the sicker patients.

Background: Aging is the primary risk factor for frailty, which is defined as an inability to respond to acute or chronic stressors. Individuals are living longer with greater multimorbidity, but there is a paucity of evidence examining frailty across birth cohorts and ages., Methods: We investigated frailty prevalence and its association with mortality at ages 75, 85, and 95 in the 1895-1945 birth cohorts in Sweden with data from population registries. Frailty was assessed with the Hospital Frailty Risk Score (HFRS)., Results: We observed that frailty increased with increasing age and that it has become more common in more recent birth cohorts. At age 75, the percent frail in the Total Population Register increased from 1.1% to 4.6% from birth cohorts 1915-1945, corresponding to calendar years 1990-2020. At age 85, the percentage of frail increased from 3.5% to 11.5% from birth cohorts 1905-1935, and at age 95 from birth cohorts 1895-1925, from 4.7% to 18.7%. Our results show that the increase was primarily driven by an increase in the distribution of individuals with scores in the highest quartile of HFRS, while the bottom 3 quartiles remained relatively stable across birth cohorts. Women accounted for a greater distribution of the overall population and frail population, though these disparities decreased over time. Despite increasing levels of frailty, the relationship between frailty and mortality did not change over time, nor did it differ by sex., Conclusion: Increased frailty with improved survival points to a chronic condition that could be intervened upon., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

In this study, we examined the impact of hip fractures on trajectories of home care, nursing home residence, and mortality among individuals aged 65 years or more and explored the impacts of living arrangements, cohabitation, frailty, and socioeconomic position on these trajectories. Based on a linkage of nationwide Swedish population registers, our study included 20,573 individuals with first hip fracture in 2014-2015. Care trajectories during the 2 years following the fracture were visualized and compared with those of 2 hip-fracture-free control groups drawn from the general population: age- and sex-matched controls and health-matched controls identified through propensity score matching. Multistate modeling was employed to identify sociodemographic and health-related factors associated with care trajectories among hip fracture patients. We found that hip fracture patients already had worse health than the general population before their fracture. However, when controlling for prefracture health, hip fractures still had a considerable impact on use of elder-care services and mortality. Comparisons with the health-matched controls suggest that hip fractures have an immediate, yet short-term, impact on care trajectories. Long-term care needs are largely attributable to poorer health profiles independent of the fracture itself. This emphasizes the importance of adequate comparison groups when examining the consequences of diseases which are often accompanied by other underlying health problems., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Schlieren photography is widely used for visualizing phenomena within transparent media. The technique, which comes in a variety of configurations, is based on detecting or extracting the degree to which light is deflected whilst propagating through a sample. To date, high-speed schlieren videography can only be achieved using high-speed cameras, thus limiting the frame rate of such configurations to the capabilities of the camera. Here we demonstrate, for the first time, optically multiplexed schlieren videography, a concept that allows such hardware limitations to be bypassed, opening up for, in principle, an unlimited frame rate. By illuminating the sample with a rapid burst of uniquely spatially modulated light pulses, a temporally resolved sequence can be captured in a single photograph. The refractive index variations are thereafter measured by quantifying the local phase shift of the superimposed intensity modulations. The presented results demonstrate the ability to acquire a series of images of flame structures at frame rates up to 1 Mfps using a standard 50 fps sCMOS camera., (© 2022. The Author(s).)

The genus Beaucarnea (Asparagaceae) has economic value as an ornamental plant but also has ecological importance. Nonetheless, habitat, physiological traits and growth parameters of this genus remain largely unknown. We characterized the environmental ranges of Beaucarnea inermis, B. gracilis and B. pliabilis; and screened for the presence of physiological adaptations to drought (biomass allocation, presence of crassulacean acid metabolism [CAM] and its effect on plant water use). We performed experiments in 3- and 5-year-old nursery-grown plants of the three species, measured dry mass accumulation in leaves/stems/roots and screened for CAM using gas exchange, titratable acidity and δ 13 C. We performed a second experiment on the water and light use responses of B. pliabilis under drought treatment. We found that B. gracilis was limited to xerophytic scrubs (precipitation >400 mm yr -1 ), while B. pliabilis and B. inermis (precipitation >500 and 700 mm year -1 , respectively) inhabited dry forests. Beaucarnea gracilis had the lowest dry mass and allocation to leaves, while B. inermis showed the opposite pattern. Only B. pliabilis exhibited small but significant acid fluctuations, characterized as weak CAM, along with high proline content. Acid concentration contributed in 2.7% of the daily carbon during the wet season but represented most of the carbon in the dry season, under closed stomata and had an important contribution to osmolality. Thus, CAM is described for the first time in the genus Beaucarnea, but was only present in one of three species, warranting exploration of this metabolism in the remaining species of this genus., (© 2022 Scandinavian Plant Physiology Society.)

Background and Purpose: Internal fixation (IF) has been the standard procedure for undisplaced femoral neck fractures (FNFs). However, there is a changing trend towards hip replacement (HR). Yet there is a knowledge gap regarding the benefits of this surgical method. We investigated functional outcomes in patients ≥ 70 years following HR compared to IF for undisplaced FNFs., Patients and Methods: Patients ≥ 70 years with undisplaced FNF registered in the Swedish National Hip Fracture Registry (SHR) who underwent either IF or HR (hemiarthroplasty [HA)] or total hip arthroplasty [THA]) were investigated in terms of 1-year survival and proportion of reoperation. In a subsample with 4-month follow-up data (n = 3,623), pain, changes in living status, and physical function were additionally analyzed., Results: 7,758 patients were included with a mean age of 85 years. 93% of the patients were operated on with IF, 5% with HA, and 2% with THA. Patients with THA more often lived independently and were able to walk outdoors, both before and after the hip fracture. The IF and HA groups were similar in baseline characteristics, and in functional and survival outcomes. The THA group had a 54% lower adjusted risk of 1-year mortality. The proportion of reoperations within 1 year was 9.5% for IF, 5.3% for HA, and 7% for THA., Interpretation: The pre-fracture difference in health and function between patients operated on with IF, HA, and THA maked it difficult to compare outcomes of the 2 methods. Decision on surgical method must be taken on an individual level, considering patients' well-being and allocation of resources.

Background: Hospital length of stay (LoS) is believed to be associated with higher mortality in hip fracture patients; however, previous research has shown conflicting results. We aimed to explore the association between LoS and 4-month mortality in different groups of hip fracture patients., Methods: The study population in this Swedish register-based cohort study was 47 811 patients 65 years or older with a first hip fracture during 2012-2016, followed up for 4 months after discharge. LoS was categorized by cubic splines, and the association between LoS and mortality was analyzed with Cox regression models, adjusted for sociodemographic- and health-related factors., Results: Mean LoS was 11.2 ± 5.9 days and 12.3% of the patients died within 4 months. Both a shorter and a longer LoS, compared to the reference 9-12 days, were associated with higher mortality (hazard ratio [95% confidence interval]): 2-4 days 2.15 (1.98-2.34), 5-8 days 1.58 (1.47-1.69), and 24+ days 1.29 (1.13-1.46). However, in fully adjusted models, only the association with a long LoS remained: 13-23 days 1.08 (1.00-1.17) and 24+ days 1.42 (1.25-1.61). Stratifying by living arrangement revealed that the increased risk for a short LoS was driven by the group living in care homes. For patients living at home, a short LoS was associated with lower risk: 0.65 (0.47-0.91) and 0.85 (0.74-0.98) for 2-4 and 5-8 days, respectively., Conclusions: A long LoS after a hip fracture is associated with increased 4-month mortality risk even after considering patient characteristics. The association between mortality and a short LoS, however, is explained by individuals coming from care homes (with higher mortality risk), being discharged early., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies., Aim: To pin-point biologically relevant changes in pre- and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients., Methods: Pre- and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points., Results: Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre- and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS)., Conclusion: We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

The longitudinal and multidisciplinary research project Malmö Youth Sport Study measured the sports results achieved by two cohorts of pupils using a variable named ACHIEVE, dividing the pupils into three categories (an elite group competing at the national or international level, a group competing at the district level, and a third group either not competing at all or below district level). This was assessed three and six years after baseline at age 13. An additional hypothetical measure, based on information from the athletes' trainers, predicted the category the pupils were expected to belong to after twelve years (age 25). Social variables related to the ACHIEVE variable are sex, socio-economic position of the parents, ethnicity, completed secondary sports school, sports capital, and quartile of birth. After three years, 28% of the pupils belonged to the elite group and after six years, 26%. Thirty-two and 48%, respectively, had abandoned their elite efforts. The elite group remained fairly stable over time but fewer girls than boys advanced to the elite group. The pupils at the school have a homogenous middle-class background. We found little evidence that socio-economic factors affected ACHIEVE. Nearly all parents had been engaged in sports, either competing or as coaches. On admission to the school, there was a pronounced relative age effect (RAE). This remained after three years as the age was significantly different between the three groups but was reduced after six years. According to the prognosis made by the coaches, the elite group would be considerably smaller when the subjects reached the age of 25. The RAE was again significant in the prognosis. A further follow-up when the subjects are 25 years old will reveal not only what proportion of subjects are actively competing, but also if they are engaged in recreational sports, to what extent the RAE is present, and how accurately coaches can predict success.

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158)., (© 2021. The Author(s).)

Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The incidences of pediatric scurvy has decreased substantially, particularly in developed countries, but there are still reports of it from developing countries. Unusual manifestations have led to delays in diagnosis and treatment. Nevertheless, there are few publications regarding misdiagnosis of scurvy. The objective is to determine dietary factors, clinical manifestations, laboratory and radiologic findings, treatment, and outcomes of scurvy cases. The occurrence of misdiagnosis and its associated factors are also explored., Method: The medical records of 0-18 year-old children from 2003 to 2016, diagnosed with scurvy, were included and reviewed. Clinical data, and data regarding feeding history, nutritional status, laboratory and radiologic findings, and misdiagnosis were collected. Univariate and logistic regression analysis were used for identification of the independent associated factors., Results: The study consisted of 106 children. The boys-to-girls ratio was 2.2:1, and their mean age was 44.65 months ± 30.50 months. The common manifestations were refusal to walk, tenderness, and swelling at the lower extremities. Four participants had unusual manifestations including proptosis and scalp hematoma. Low serum vitamin C level and abnormal radiologic findings were detected in most patients. All of them fully recovered after receiving vitamin C supplementation. Misdiagnosis was identified in 74 cases (69%). Logistic regression analysis revealed that temperature higher than or equal to 38 °C, participants aged 3 years or below, and swelling at lower extremities were independently associated with misdiagnosis (adjusted OR 5.91, 3.78, and 3.56 respectively)., Conclusions: Scurvy still exists, and misdiagnosis often occurs. Taking a careful medical history and conducting a physical examination are still the best way to diagnose scurvy., (© 2022 Japan Pediatric Society.)

Background: Charlson Comorbidity Index (CCI) has been suggested to be associated with mortality in hip fracture patients, to the same extent as more expensive and time-consuming tools. However, even CCI might be too time-consuming in a clinical setting., Aim: To investigate whether the American Society of Anaesthesiologists score (ASA score), a simple grading from the anaesthesiologist's examination, is comparable with CCI in the association with 1-year mortality after a hip fracture., Methods: The study population was patients 60 + years registered in the Swedish Hip Fracture Registry with a first-time hip fracture between 1997 and 2017 (N = 165,596). The outcome was 1-year mortality, and the exposures were ASA score and CCI. The association between comorbidity and mortality was described with Kaplan-Meier curves and analyzed with Cox proportional hazards models., Results: The Kaplan-Meier curves showed a stepwise increase in mortality for increasing values of both ASA and CCI. The Hazard Ratios (HRs) for the highest ASA (4-5) were 3.8 (95% Confidence Interval 3.5-4.2) for women and 3.2 (2.8-3.6) for men in the fully adjusted models. Adjusted HRs for the highest CCI (4 +) were 3.6 (3.3-3.9) for women and 2.5 (2.3-2.7) for men. Reference was the lowest score value for both tools. The correlation between the tools was moderate., Conclusions: Both ASA and CCI show a similar stepwise association with 1-year mortality in hip fracture patients, despite measuring different factors and capturing different individuals at risk. Since the ASA score is already accessible for health care staff, it might be preferable to aid in prioritizing vulnerable hip fracture patients at risk of adverse outcomes., (© 2021. The Author(s).)

Midlife lipid levels are important predictors of cardiovascular diseases, yet their association with mortality in older adults is less clear. We aimed to (1) identify lipid profiles based on cholesterol, triglycerides, and apolipoproteins using cluster analysis, and (2) investigate how lipid profiles and lipid levels at different ages are associated with later-life all-cause and cardiovascular mortality. We used data from 98,270 individuals in the Swedish AMORIS cohort who had blood measurements between 1985-1996 and were followed until 2012. Over the follow-up (mean 18.0 years), 30,730 (31.3%) individuals died. Three lipid profiles were identified. Compared with reference profile, a high lipid profile (low ApoA-I and high total cholesterol (TC), triglycerides, ApoB, and ApoB/ApoA-I ratio) at ages 39-59 or 60-79 was associated with higher all-cause mortality. A high lipid profile at ≥ 80 years, however, did not confer higher mortality. For the specific markers, high TC (≥ 7.25 mmol/L) was associated with higher all-cause mortality in ages 39-59 but lower mortality in ages 60-79 and ≥ 80. Low ApoA-I (< 1.28 g/L) and high ApoB/ApoA-I ratio (≥ 1.18), on the other hand, were associated with higher cardiovascular mortality regardless of age at lipid measurement, highlighting their potential relevance for survival in both young and older individuals., (© 2021. The Author(s).)

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm that follows a heterogeneous clinical course. Recurrent mutations have been described, but their applicability in the clinical setting is currently limited. The main reasons are challenges in the sequencing of DNA retrieved from formalin-fixed tissue commonly used for tissue collection in clinical biobanks. In this study, we sequenced 77 samples from a population-based de novo MCL cohort to investigate the utility of targeted sequencing in guiding personalized treatment approaches. Tumors were genetically variable, and a similar genetic landscape as previous studies using non-formalin fixed samples was identified, with recurrent mutations including ATM, KMT2D, and TP53 . Novel alterations that can be considered actionable and/or indicative of treatment response were also identified. Our approach shows the potential benefits of using target sequencing of formalin fixed samples to facilitate treatment selection and individualized clinical decisions in MCL.

Fluorescence-based multispectral imaging of rapidly moving or dynamic samples requires both fast two-dimensional data acquisition as well as sufficient spectral sensitivity for species separation. As the number of fluorophores in the experiment increases, meeting both these requirements becomes technically challenging. Although several solutions for fast imaging of multiple fluorophores exist, they all have one main restriction; they rely solely on spectrally resolving either the excitation- or the emission characteristics of the fluorophores. This inability directly limits how many fluorophores existing methods can simultaneously distinguish. Here we present a snapshot multispectral imaging approach that not only senses the excitation and emission characteristics of the probed fluorophores but also all cross term combinations of excitation and emission. To the best of the authors' knowledge, this is the only snapshot multispectral imaging method that has this ability, allowing us to even sense and differentiate between light of equal wavelengths emitted from the same fluorescing species but where the signal components stem from different excitation sources. The current implementation of the technique allows us to simultaneously gather 24 different spectral images on a single detector, from which we demonstrate the ability to visualize and distinguish up to nine fluorophores within the visible wavelength range., (© 2021. The Author(s).)

Background: The impact of falls on cognitive function is unclear. We explored whether injurious falls are associated with cognitive decline in older adults, and evaluated the role of changes in psychological and physical health as mediators of such association., Methods: This prospective study involved 2267 community-dwelling participants in the Swedish National study on Aging and Care in Kungsholmen (≥60 years). Data on injurious falls (ie, falls requiring medical attention) during each 3-year time interval of follow-up were obtained from national registers. Assessment of cognitive function (Mini-Mental State Examination), depressive mood (Montgomery-Åsberg Depression Rating Scale), and physical performance (walking speed) were carried out every 3 or 6 years over a 12-year follow-up. The association between falls and cognition was estimated through linear mixed-effects models, and the mediating role of changes in depressive mood and physical performance was tested using mediation analysis., Results: After adjusting for potential confounders, individuals who experienced injurious falls had a greater annual decline in Mini-Mental State Examination in the subsequent time interval (β = -1.49, 95% CI: -1.84; -1.13), than those who did not. The association increased with the occurrence of ≥2 falls (β = -2.13, 95% CI: -2.70; -1.56). Worsening of walking speed and depressive mood explained around 26% and 8%, respectively, of the association between falls and cognitive decline., Conclusions: Injurious falls are associated with greater cognitive decline, and this association is partly mediated by worsening of physical performance and, in a lesser extent, of depressive mood. These findings suggest that physical deficits and low mood are potential therapeutic targets for mitigating the association between falls and cognitive decline., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: The functional consequences of injurious falls are well known. However, studies of the factors that can modify trajectories of disability after an injury from a fall are scarce., Aims: We aimed to investigate whether sociodemographic and health-related factors may impact this association., Methods: The study population consisted of 1426 community-dwelling older adults (≥ 60 years) from the SNAC-K cohort study in Stockholm, Sweden. Functional status over 12 years of follow-up was assessed using the number of limitations in basic and instrumental activities of daily living. Sex, cohabitation status, physical activity, and self-rated health were assessed at baseline. Injurious falls were defined as falls requiring healthcare and were assessed over 3 years starting at baseline. Data were analyzed using linear-mixed effects models., Results: The fastest increase in the number of disabilities was observed in those who had endured an injurious fall and were living alone (β coefficient = 0.408; p < 0.001), been physically inactive (β coefficient = 0.587; p < 0.001), and had poor self-rated health (β coefficient = 0.514; p < 0.001). The negative impact of these factors was more pronounced among fallers compared to non-fallers., Discussion: Living alone, being physically inactive, and having poor self-rated health magnifies the negative effect of an injurious fall on functional status. Among individuals who endure an injurious fall, the heterogeneity in long-term functional status is substantial, depending on the individuals' characteristics and behaviors., Conclusions: These findings emphasize the need for a person-centered approach in care provision and can guide secondary prevention within health care., (© 2020. The Author(s).)

Background: Transgender persons face barriers to health care including discrimination and lack of awareness by professionals. This study aimed to describe transgender persons' experiences of encounters with healthcare staff., Methods: Participants were recruited through postings in social media and on websites targeting people identifying as transgender. Through an online form, 21 people identifying as transgender provided written self-reports. These were analysed using a method for inductive qualitative content analysis. The study was conducted in Sweden in 2018., Results: The results describe transgender persons' experiences and perceptions of encounters with healthcare staff in one theme: treat me with respect, and three main categories: accept me for who I am; treat me according to my needs; and meet me with competence., Conclusions: Healthcare professionals can contribute in restoring and upholding transgender people's trust in health care by accepting their identity and focusing on their healthcare needs while also being informed about transgender people's needs and realities. A key point in this is recognising transgender person's vulnerability to violations of dignity in relation to health care., (© 2020 The Authors. Scandinavian Journal of Caring Sciences published by John Wiley & Sons Ltd on behalf of Nordic College of Caring Science.)

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3 + T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1·97, 95% confidence interval (CI) 1·18-3·25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163 + cells (continuously, HR 1·51, 95% CI 1·03-2·23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3 + cells (HR 3·22, 95% CI 1·40-7·43) and CD163 + cells (HR 6·09, 95% CI 1·84-20·21), independent of sex and MIPI. When combined a higher frequency of CD163 + macrophages and PD-L1 + cells or high CD163 + macrophages and FoxP3 + regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Hip fractures are common and severe conditions among older individuals, associated with high mortality, and the Nordic countries have the highest incidence rates globally. With this study, we aim to present a comprehensive picture of trends in hip fracture incidence and survival in the older Swedish population stratified by education, birth country, and comorbidity level., Methods: This study is based on a linkage of several population registers and included the entire population over the age of 60 living in Sweden. We calculated age-standardized incidence rates for first and recurrent hip fractures as well as age-standardized proportions of patients surviving 30 and 365 days through the time period 1998 to 2017. We calculated all outcomes for men and women in the total population and in each population stratum., Results: Altogether, we observed 289,603 first hip fractures during the study period. Age-standardized incidence rates of first and recurrent fractures declined among men and women in the total population and in each educational-, birth country-, and comorbidity group. Declines in incidence were more pronounced for recurrent than for first fractures. Approximately 20% of women and 30% of men died within 1 year of their first hip fracture. Overall, survival proportions remained constant throughout the study period but improved when taking into account comorbidity level., Conclusions: Hip fracture incidence has declined across the Swedish population, but mortality after hip fracture remained high, especially among men. Hip fracture patients constitute a vulnerable population group with increasing comorbidity burden and high mortality risk., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research., (© 2021 Afanasyeva et al.)

Background: Response to modern treatment strategies, which combine cytotoxic compounds with immune stimulatory agents and targeted treatment is highly variable among MCL patients. Thus, providing prognostic and predictive markers for risk adapted therapy is warranted and molecular information that can help in patient stratification is a necessity. In relapsed MCL, biopsies are rarely available and molecular information from tumor tissue is often lacking. Today, the main tool to access risk is the MCL international prognostic index (MIPI), which does not include detailed biological information of relevance for different treatment options. To enable continuous monitoring of patients, non-invasive companion diagnostic tools are needed which can further reduce cost and patient distress and enable efficient measurements of biological markers., Methods: We have assessed if serum-based protein profiling can identify immune related proteins that stratify relapsed MCL patients based on risk. Overall, 371 scFv targeting 158 proteins were assessed using an antibody microarray platform. We profiled patients (n = 44) who had been treated within the MCL6-Philemon trial combining targeted and immune-modulatory treatment., Results: The downstream processing led to the identification of the relapsed immune signature (RIS) consisting of 11 proteins with potential to stratify patients with long and short overall survival (OS). Moreover, in this population, MIPI alone failed to separate high, intermediate and low risk patients, but a combined index based on MIPI together with RIS, MIPI ris , showed improved performance and significantly stratified all three risk groups based on OS., Conclusions: Our results show that addition of biological parameters to previous prognostic indices improves patient stratification among patients treated with BTK inhibitor triplet combination, particularly, in the identification of an extreme high risk group.

Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3·1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: The First-time Injurious Fall (FIF) screening tool was created to identify fall risk in community-living older adults who may benefit from primary preventive interventions. The aim of this study was to evaluate the predictive performance of the FIF tool in 2 cohorts of older adults., Design: Longitudinal cohort study., Setting and Participants: The Swedish National Study on Aging and Care in Skåne (SNAC-S) and Blekinge (SNAC-B), Sweden. Community-living people aged ≥60 years (n = 2766)., Methods: Nurses and physicians collected data in the 2 cohorts through interviews and testing. Data on injurious falls were collected from register data and were defined as receipt of care after a fall. The FIF tool, consisting of 3 questions and 1 balance test, was examined in relation to injurious falls for up to 5 years of follow-up using Cox proportional hazards models. The predictive performance of the FIF tool was further explored using Harrell C statistic and Youden cut-off for sensitivity and specificity., Results: The hazard ratios (HRs) of an injurious fall in the high-risk group for women and men were 3.80 (95% confidence interval [CI] 2.53, 5.73) and 5.10 (95% CI 2.57, 10.12) in SNAC-S and 4.45 (95% CI 1.86, 10.61) and 32.58 (95% CI 4.30, 247.05) in SNAC-B compared with those in the low risk group. The sensitivity and specificity of the Youden cut-off point (3 or higher for high-risk) were 0.64 and 0.69 for women and 0.68 and 0.69 for men in SNAC-S, and 0.64 and 0.74 for women and 0.94 and 0.68 for men in SNAC-B. The predictive values (Harrell C statistic) for the scores for women and men were 0.73 and 0.74 in SNAC-S and 0.72 and 0.89 in SNAC-B., Conclusions and Implications: Our results suggest that the FIF tool is a valid tool to use for prediction of first-time injurious falls in community-living older adults., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Frequency recognition algorithm for multiple exposures (FRAME) is a single-exposure imaging technique that can be used for ultrafast videography, achieved through rapid illumination with spatially modulated laser pulses. To date, both the limit in sequence length as well as the relation between sequence length and image quality are unknown for FRAME imaging. Investigating these questions requires a flexible optical arrangement that has the capability of reaching significantly longer image sequences than currently available solutions. In this paper we present a new type of FRAME setup that fulfills this criteria. The setup relies only on (i) a diffractive optical element, (ii) an imaging lens and (iii) a digital micromirror device to generate a modulated pulse train with sequence lengths ranging from 2 to 1024 image frames. To the best of the authors' knowledge, this is the highest number of temporally resolved frames imaged in a single-exposure.

Objectives: We aimed to examine to what extent blood pressure (BP) components are associated with injurious falls in older adults, and whether the possible associations differ by functional status (indicated by physical and cognitive impairment at baseline)., Methods: This prospective cohort study included 3055 community-living participants of the Swedish National study on Aging and Care in Kungsholmen (aged ≥60 years). At baseline (2001-2004), we measured systolic BP (SBP) and diastolic BP (DBP), mean arterial pressure, pulse pressure (PP), and orthostatic hypotension. Physical function was assessed using tests of balance, chair stands, and walking speed. Cognitive function was assessed with the Mini-Mental State Examination. Injurious falls leading to inpatient or outpatient care during 3 and 10 years of follow-up were identified via patient registers. Data were analyzed using flexible parametric survival models adjusted for potential confounders., Results: During the 10-year follow-up period in people without functional impairment, the multi-adjusted hazard ratios (HR) of injurious falls were 1.77 (95% CI 1.02-3.07) for having SBP <130 mmHg, 1.73 (95% CI 1.05-2.83) for having SBP ≥160 mmHg (vs. 130-139), and 1.46 (1.05-2.02) for having higher tertile of PP (vs. lower tertile). During the 3-year follow-up period in people with functional impairment, the multi-adjusted HR of injurious falls was 1.91 (95% CI 1.17-3.13) for having SBP <130 mmHg (vs. 130-139) and 0.74 (0.59-0.94) for having higher tertile of PP (vs. lower tertile). There was no significant association between BP components and injurious falls either in people without functional impairment during the 3-year follow-up period, or in people with functional impairment during the 10-year follow-up period., Conclusions: This large-scale Swedish study provides evidence that the associations between some specific components of BP and risk of injurious falls in older adults vary by functional status. This supports the view that a personalized approach to blood pressure management depending on functional status among older adults might be warranted in clinical settings., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Previous studies showed that peak expiratory flow (PEF) is associated with health-related outcomes in advanced age, but the extent to which it may be related to falls risk remains unclear. We aimed to detect the association between PEF and injurious falls in older adults and to explore the role of cognitive and physical deficits in this association., Design: Prospective study with a 6-year follow-up., Setting and Participants: The study involves 2234 community-dwelling older adults with no history of pulmonary disease., Methods: For each study participant, we assessed the PEF at baseline, expressed as standardized residual (SR) percentile and derived from the normalization of residuals between the measured and predicted PEF values (based on individual age, sex, and body height); incident injurious falls over 6 years, from Hospital Discharge Diagnosis; and physical and cognitive functioning at the baseline and at 3- and 6-year follow-ups by evaluating walking speed, balance, chair stand, and Mini-Mental State Examination, respectively., Results: Over the follow-up, 232 individuals experienced injurious falls. Cox models indicated 7% higher risk of falls per each 10th reduction in PEF SR-percentile. The risk of injurious falls increased by more than twice for those who had PEF SR-percentile <10th as for values of 80th-100th (hazard ratio = 2.31, 95% confidence interval: 1.41-3.76). Physical deficits mediated 63% of the total effect of PEF on falls risk., Conclusions and Implications: Our findings suggest that low PEF is associated with higher risk of injurious falls in older adults, and most of this association is explained by balance or muscular strength deficits., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

The relationship between birth quarter distribution and physiological characteristics related to athletic skills, in adolescent sport academy students has not been fully investigated. In a cross-sectional study, we recruited 86 boys and 52 girls aged 12-14 years during their first term at a sport academy school. We measured body size, cardiac size, pulmonary function, body composition, lower body power, cardiorespiratory fitness parameters, and running endurance by standard methods and analyzed these estimates in relation to birth quarter by ANOVA. Birth quarter distribution in our cohort was compared with birth quarter distribution in the same ages in the whole of Sweden and analyzed by logistic regression. The academy had an overrepresentation of students born in the first quartile of the year compared to those born in the last quartile (odds ratio 2.3 (95% CI: 1.1-4.7)). When comparing the physiological characteristics between birth quarters, uniformity is prominent since out of 26 performed physiological and anthropometric tests only four showed statistically significant group differences. We thus believe that the selection process to the sport academy favours athletes with higher chronological age, i.e., a so-called relative age effect is present., Competing Interests: The authors declare that they have no conflict interests.

Objectives: The aim of this study was to create a screening tool to predict first-time injurious falls in community-living older men and women., Design: Longitudinal cohort study between 2001 and 2009., Setting: The Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), Sweden., Participants: Community-living older adults (n = 2808; 1750 women and 1058 men) aged ≥60 years (mean age 73, standard deviation 10.3)., Measurements: The outcome was injurious falls within 5 years from baseline survey. Data on the risk factors for falls were collected through interviews, clinical examinations, and tests at baseline. Several previously established fall risk factors were identified for the development of the screening tool. The tool was formulated based on the β coefficients from sex-specific multivariate Cox proportional hazards models. The discriminative power was assessed using Harrell C statistic., Results: Old age, living alone, being dependent in instrumental activities of daily living, and impaired balance were the factors included in the final score of the First Injurious Fall (FIF) screening tool. The predictive values (Harrell C statistic) for the scores were 0.75 for women and 0.77 for men. The sensitivity and specificity at the Youden cut-off points were 0.69 and 0.70 for women, and 0.72 and 0.71 for men., Conclusions and Implications: The FIF screening tool for first injurious fall in older persons consists of 3 questions and a physical test (5-second 1-leg standing balance with eyes open). Quick and easy to administer, it could be ideal for use in primary care or public health to identify older men and women at high fall risk, who may benefit from primary preventive interventions., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The Bruton's Tyrosine Kinase (BTK)-inhibitor ibrutinib is highly active in mantle cell lymphoma (MCL) but may inhibit response to anti-CD20 antibody as previously shown in CLL models. We investigated how antibody-dependent cellular cytotoxicity (ADCC) induced by type I/II anti-CD20 antibodies was affected by treatment with ibrutinib in MCL. Furthermore, we investigated if lenalidomide, a potential sensitizer to anti-CD20 treatment, could prevent an inhibitory effect of ibrutinib., Methods: Anti-CD20 (rituximab/obinutuzumab) opsonized MCL cell lines were co-cultured with ibrutinib (± lenalidomide)-exposed effector cells, and analyzed for evaluation of cell death., Results: Cell death induced by rituximab was reduced with 75% at 0.5 µM ibrutinib and with 52% at 0.1 µM ibrutinib when induced by obinutuzumab, even by addition of lenalidomide. Moreover, obinutuzumab was associated with higher rate of cell death compared to rituximab., Conclusion: Ibrutinib negatively affects anti-CD20 induced cell death in MCL, not reversed by lenalidomide. Explorations of sequential administration and selective BTK-inhibitors may reveal the optimal combination of novel agents in MCL., Competing Interests: Competing interestsAA-L; CF; SE: no competing interests; Mats Jerkeman: Research support from Celgene, Janssen, Gilead, Abbvie.