An Update on the Six Recommendations from the 2012 IADMS Standard Measures Initiative: Assessing and Reporting Dancer Capacities, Risk Factors, and Injuries.

INTRODUCTION: In 2012, the Standard Measures Consensus Initiative (SMCI) of the International Association for Dance Medicine and Science (IADMS) presented 6 recommendations regarding dance injury surveillance, definitions of injury and exposure, dance-specific screening, risk reduction strategies, and collaborative data management. The aim was to standardize risk factor measurement and injury reporting by researchers in dance medicine and science. Since then, numerous reports on the recording and reporting of injury data in sport and performing arts have been published. METHODS: IADMS commissioned SMCI to update the 2012 recommendations, a process that involved 3 stages: (1) current field experts were invited to join SMCI, (2) SMCI members reviewed recent and relevant sport and performing arts literature, then drafted, discussed, and revised section updates, (3) IADMS invited individuals representing diverse backgrounds in the IADMS community to critically review drafted updates. The final update serves as a bridge from the 6 recommendations in the 2012 report to the current state of evidence. RESULTS: We continue to encourage use of dance injury surveillance systems and support that surveillance protocols be fit-for-purpose, and that failure to use clear and consistent injury definitions perpetuates a lack of rigor in dance injury research. Based on new evidence, we recommend that some aspects of injury surveillance be self-reported, that the choice of dance exposure measures be dependent on the research question, contextual factors, and type of injury/health problem(s) of interest, and that studies using dance-specific screening articulate specific objectives, validity, and reliability of each protocol. CONCLUSIONS: Future studies should focus on the development, implementation, and evaluation of strategies to minimize injury risk to improve consistency and rigor in data collection and research reporting on the health and wellness of dancer populations, thus facilitating a future dance injury consensus statement similar to recent statements published for sports and circus arts.

Prevalence of Abnormalities and Normal Variants in the Adolescent Knee on MRI in a Population-Based Cohort of 3800 Knees.

BACKGROUND: Many adolescents experience knee pain, and only some undergo detailed imaging. In this population, the prevalence of abnormalities and normal variants on magnetic resonance imaging (MRI) scans is unknown. PURPOSE: To investigate the prevalence of abnormalities and normal variants of the knee on MRI scans and their relationship with participant characteristics in the general young adolescent population. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: This study was part of an open population-based cohort study that focuses on health, growth, and development from fetal life until adulthood. Between 2017 and 2020, adolescents aged 12 to 15 years underwent MRI of both knees. These MRI scans were assessed in a standardized way for abnormalities and normal variants to determine their prevalence. Logistic regression was used to analyze the presence of abnormalities and normal variants in relation to sex, height, weight, body mass index-standard deviation (BMI-SD), and ethnicity. RESULTS: A total of 1910 participants (median age, 13.5 years; interquartile range, 13.4-13.7 years; 52% girls) were included in this study. Of them, 370 (19.4%) participants had at least 1 abnormality or normal variant. Bone marrow edema around the knee was the most prevalent finding, affecting 140 (7.3%) participants. In 107 (5.6%) participants, nonossifying fibromas were found. A total of 43 (2.3%) participants had characteristics of Osgood-Schlatter disease, 16 (0.8%) showed characteristics of Sinding-Larsen-Johansson syndrome, and osteochondritis dissecans was found in 13 (0.7%) participants. Variants such as discoid menisci were found in 40 (2.1%) participants and a bipartite patella in 21 (1.1%) participants. There were multiple associations between abnormalities or variants and participant characteristics, including bone marrow edema being more often present in boys (odds ratio [OR], 2.44; 95% CI, 1.69-3.52) and those with a lower BMI-SD (OR, 0.85; 95% CI, 0.73-0.98). Osgood-Schlatter and osteochondritis dissecans were more often present in boys (OR, 4.21 [95% CI, 2.01-8.85] and OR, 13.18 [95% CI, 1.71-101.58], respectively). Discoid menisci were associated with a non-Western ethnicity (OR, 2.06; 95% CI, 1.07-3.96) and higher BMI-SD (OR, 2.34; 95% CI, 1.76-3.11). CONCLUSION: Abnormalities and normal variants on MRI scans of the knees are common in adolescents. Physicians who are involved in the treatment of adolescents with knee pain need to be aware of this prevalence so that these children will not be overtreated or misdiagnosed.

Knee Pain, Joint Loading, and Structural Abnormalities on MRI in 13-Year-Old Children in a Population-Based Birth Cohort.

BACKGROUND: Knee pain is a common problem in children and adolescents, and it often has a chronic character. PURPOSE: To examine the prevalence of knee pain in 13-year-old children and assess associations of knee pain with physical factors and the presence of structural abnormalities on magnetic resonance imaging (MRI). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Data from the Generation R Study, a population-based birth cohort, were used. Prevalence and characteristics of knee pain were assessed, using a pain mannequin, in children 13 years of age (N = 1849). Patient characteristics and data on physical activity were extracted from questionnaires. The body mass index standard deviation score and waist-hip ratio were calculated from objectively measured weight and height. Structural abnormalities were assessed by MRI. The differences between children with and without knee pain were also analyzed. RESULTS: A prevalence of 8.0% was found for knee pain in children, of which 92.3% persisted for >3 months (ie, chronic); 37.5% of the children experienced pain daily, and the pain was almost always located on the anterior side of the knee (98.6%). Higher body mass index standard deviation scores were seen in children with knee pain than in the children without knee pain. No differences in physical activity were seen between children with and without knee pain. Moreover, in children with knee pain compared with children without knee pain, characteristics of Osgood-Schlatter disease (6.8% vs 1.9%) and bipartite patella type 3 (4.7% vs 0.3%) were more often seen on MRI. CONCLUSION: This study shows that knee pain is a relatively frequent problem in children. It is almost always located on the anterior aspect, has a chronic character, and is often experienced daily. However, the possible implication of structural abnormalities on MRI in children with knee pain and the possible relationship with the development of future knee complaints are still unclear.

Remote Patient Monitoring and Machine Learning in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Dual Systematic Literature Review and Narrative Synthesis.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with high mortality, morbidity, and poor quality of life and constitute a substantial burden to patients and health care systems. New approaches to prevent or reduce the severity of AECOPD are urgently needed. Internationally, this has prompted increased interest in the potential of remote patient monitoring (RPM) and digital medicine. RPM refers to the direct transmission of patient-reported outcomes, physiological, and functional data, including heart rate, weight, blood pressure, oxygen saturation, physical activity, and lung function (spirometry), directly to health care professionals through automation, web-based data entry, or phone-based data entry. Machine learning has the potential to enhance RPM in chronic obstructive pulmonary disease by increasing the accuracy and precision of AECOPD prediction systems. OBJECTIVE: This study aimed to conduct a dual systematic review. The first review focuses on randomized controlled trials where RPM was used as an intervention to treat or improve AECOPD. The second review examines studies that combined machine learning with RPM to predict AECOPD. We review the evidence and concepts behind RPM and machine learning and discuss the strengths, limitations, and clinical use of available systems. We have generated a list of recommendations needed to deliver patient and health care system benefits. METHODS: A comprehensive search strategy, encompassing the Scopus and Web of Science databases, was used to identify relevant studies. A total of 2 independent reviewers (HMGG and CM) conducted study selection, data extraction, and quality assessment, with discrepancies resolved through consensus. Data synthesis involved evidence assessment using a Critical Appraisal Skills Programme checklist and a narrative synthesis. Reporting followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: These narrative syntheses suggest that 57% (16/28) of the randomized controlled trials for RPM interventions fail to achieve the required level of evidence for better outcomes in AECOPD. However, the integration of machine learning into RPM demonstrates promise for increasing the predictive accuracy of AECOPD and, therefore, early intervention. CONCLUSIONS: This review suggests a transition toward the integration of machine learning into RPM for predicting AECOPD. We discuss particular RPM indices that have the potential to improve AECOPD prediction and highlight research gaps concerning patient factors and the maintained adoption of RPM. Furthermore, we emphasize the importance of a more comprehensive examination of patient and health care burdens associated with RPM, along with the development of practical solutions.

Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review.

The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.

Single-arm, first-in-human feasibility study results for an ultra-low-cost insulin pump.

BACKGROUND: Use of Continuous Subcutaneous Insulin Infusion (CSII) has been shown to improve glycemic outcomes in Type 1 Diabetes (T1D), but high costs limit accessibility. To address this issue, an inter-operable, open-source Ultra-Low-Cost Insulin Pump (ULCIP) was developed and previously shown to demonstrate comparable delivery accuracy to commercial models in standardised laboratory tests. This study aims to evaluate the updated ULCIP in-vivo, assessing its viability as an affordable alternative for those who cannot afford commercially available devices. METHODS: This first-in-human feasibility study recruited six participants with T1D. During a nine-hour inpatient stay, participants used the ULCIP under clinical supervision. Venous glucose, insulin, and ß-Hydroxybutyrate were monitored to assess device performance. RESULTS: Participants displayed expected blood glucose and blood insulin levels in response to programmed basal and bolus insulin dosing. One participant developed mild ketosis, which was treated and did not recur when a new pump reservoir was placed. All other participants maintained ß-Hydroxybutyrate < 0.6 mmol/L throughout. CONCLUSION: The ULCIP safely delivered insulin therapy to users in a supervised inpatient environment. Future work should focus on correcting a pump hardware issue identified in this trial and extending device capabilities for use in closed loop control. Longer-term outpatient studies are warranted. TRIAL REGISTRATION: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12623001288617) on the 11 December 2023.

Calculating toxic pressure for mixtures of endocrine disruptors.

Incidence of autoimmune disorders, birth defects, and neurological diseases rose over the past 50 years due to increasing variety and quantity of pollutants. To date, there appear few methods capable to evaluate and predict mixture effects by endocrine disruptors (EDs). For the first time, we have developed calculus to determine mixture effects by all kinds of EDs. Our method uses the golden ratio ϕ and draws from bifurcation and chaos theory. Using also the concept of molecular mimicry, we developed the equation: e f f e c t = 100 % 1 + e 5 · ∑ K i C i - n i ϕ 3 . We successfully tested the equation using a range of cohort studies and biomarkers, and for different pollutants like heavy metals, thyroid hormone mimickants, chromate/chlorate, etc. The equation is simple enough to use with only minor prior knowledge and understanding of basic algebra. The method is universal and calculation is data 'light', requiring only pollutant concentrations [C], potencies K and an integer n for endocrinal involvement. This study offers a comprehensive framework to assess the health effects of pollutant exposure across diverse populations, envisioning far-reaching impact, and presenting practical examples and insights.

Chimeric Viruses Enable Study of Antibody Responses to Human Rotaviruses in Mice.

The leading cause of gastroenteritis in children under the age of five is rotavirus infection, accounting for 37% of diarrhoeal deaths in infants and young children globally. Oral rotavirus vaccines have been widely incorporated into national immunisation programs, but whilst these vaccines have excellent efficacy in high-income countries, they protect less than 50% of vaccinated individuals in low- and middle-income countries. In order to facilitate the development of improved vaccine strategies, a greater understanding of the immune response to existing vaccines is urgently needed. However, the use of mouse models to study immune responses to human rotavirus strains is currently limited as rotaviruses are highly species-specific and replication of human rotaviruses is minimal in mice. To enable characterisation of immune responses to human rotavirus in mice, we have generated chimeric viruses that combat the issue of rotavirus host range restriction. Using reverse genetics, the rotavirus outer capsid proteins (VP4 and VP7) from either human or murine rotavirus strains were encoded in a murine rotavirus backbone. Neonatal mice were infected with chimeric viruses and monitored daily for development of diarrhoea. Stool samples were collected to quantify viral shedding, and antibody responses were comprehensively evaluated. We demonstrated that chimeric rotaviruses were able to efficiently replicate in mice. Moreover, the chimeric rotavirus containing human rotavirus outer capsid proteins elicited a robust antibody response to human rotavirus antigens, whilst the control chimeric murine rotavirus did not. This chimeric human rotavirus therefore provides a new strategy for studying human-rotavirus-specific immunity to the outer capsid, and could be used to investigate factors causing variability in rotavirus vaccine efficacy. This small animal platform therefore has the potential to test the efficacy of new vaccines and antibody-based therapeutics.

Patient-Reported Outcomes After Intramedullary Nailing of Oncologic Impending or Pathologic Fractures With Carbon Fiber or Titanium Implant.

INTRODUCTION: Despite the benefits of intramedullary nailing (IMN) of impending or pathologic fractures in oncologic patients, literature on patient-reported outcomes (PROs) is scarce in patients treated with carbon fiber (CF) nails. Our study compared postoperative PROs after IMN with CF or titanium implants. METHODS: We conducted a retrospective propensity score-matched cohort study of patients treated at our institution with CF or titanium nails for impending or pathologic fractures from metastatic bone disease. Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (SF) Physical, Mental, and Physical Function 10a scores were collected. Pain was assessed using visual analog scale (VAS). Absolute and differential scores were compared between groups. RESULTS: We included 207 patients, 51 treated with CF and 156 with titanium nails. One month postoperatively, patients had a one-point decrease in the pain VAS score while PROMIS scores did not improve. At 3 months, PROMIS SF Physical and SF 10a scores improved from preoperative values. Six months postoperatively, median PROMIS SF Physical, SF Mental, and SF 10a scores were higher than preoperative scores. Absolute and differential PROMIS and pain VAS scores were similar between groups at the 6-month and 1-year marks. CONCLUSION: Patient-reported outcomes were similar after intramedullary nailing with either CF or titanium implants.

Annotation-preserving machine translation of English corpora to validate Dutch clinical concept extraction tools.

OBJECTIVE: To explore the feasibility of validating Dutch concept extraction tools using annotated corpora translated from English, focusing on preserving annotations during translation and addressing the scarcity of non-English annotated clinical corpora. MATERIALS AND METHODS: Three annotated corpora were standardized and translated from English to Dutch using 2 machine translation services, Google Translate and OpenAI GPT-4, with annotations preserved through a proposed method of embedding annotations in the text before translation. The performance of 2 concept extraction tools, MedSpaCy and MedCAT, was assessed across the corpora in both Dutch and English. RESULTS: The translation process effectively generated Dutch annotated corpora and the concept extraction tools performed similarly in both English and Dutch. Although there were some differences in how annotations were preserved across translations, these did not affect extraction accuracy. Supervised MedCAT models consistently outperformed unsupervised models, whereas MedSpaCy demonstrated high recall but lower precision. DISCUSSION: Our validation of Dutch concept extraction tools on corpora translated from English was successful, highlighting the efficacy of our annotation preservation method and the potential for efficiently creating multilingual corpora. Further improvements and comparisons of annotation preservation techniques and strategies for corpus synthesis could lead to more efficient development of multilingual corpora and accurate non-English concept extraction tools. CONCLUSION: This study has demonstrated that translated English corpora can be used to validate non-English concept extraction tools. The annotation preservation method used during translation proved effective, and future research can apply this corpus translation method to additional languages and clinical settings.

Shared Vision for Improving Outcomes for Serious Fungal Diseases: Report of a Patient, Caregiver, and Clinician Summit.

Background: Recently, increasing focus on patient input into research and healthcare improvements has fostered expanded patient-centered advocacy efforts. This first pan-fungal disease summit, part of the MYCology Advocacy, Research, & Education effort, brought together patients, caregivers, and mycology experts to better document patient experiences with invasive fungal disease (IFD) and establish priorities for mycology education, advocacy, and research. Methods: Patients who had suffered from IFD, their caregivers, clinicians, industry representatives, government officials, and patient advocacy professionals were invited. Patients and caregivers shared their stories and struggles with IFD. Breakout sessions separated mycology experts from patients and caregivers for further discussions to identify commonalities and perceived gaps and to formulate recommendations. The 2 groups then reconvened to develop consensus recommendations. Results: IFD patients and their caregivers shared experiences reflecting the typically lengthy prediagnosis, acute treatment, long-term treatment, and posttreatment recovery stages of IFD. They reported substantial physical, psychological, and financial burdens associated with the IFD experience, particularly related to delayed diagnoses. They reaffirmed a need for coordinated patient-centered education, peer support, and advocacy to document the burden of serious fungal infections. Mycology experts discussed strategies to address gaps in the mycology field, such as insufficient training, inadequate workforce support, and a need to partner more with patient groups. Conclusions: A summit involving patients with IFD, family caregivers, and mycology experts identified a substantial nonclinical burden of disease associated with IFD. Patients and mycology experts prioritized several goals for education, advocacy, and research to raise awareness of IFD and improve outcomes.

Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Talaromyces marneffei, Coccidioides species, and Paracoccidioides species-a systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal pathogen priority list. This systematic review aimed to evaluate the epidemiology and impact of infections caused by Talaromyces marneffei, Coccidioides species, and Paracoccidioides species. PubMed and Web of Sciences databases were searched to identify studies published between 1 January 2011 and 23 February 2021 reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 25, 17, and 6 articles were included for T. marneffei, Coccidioides spp. and Paracoccidioides spp., respectively. Mortality rates were high in those with invasive talaromycosis and paracoccidioidomycosis (up to 21% and 22.7%, respectively). Hospitalization was frequent in those with coccidioidomycosis (up to 84%), and while the duration was short (mean/median 3-7 days), readmission was common (38%). Reduced susceptibility to fluconazole and echinocandins was observed for T. marneffei and Coccidioides spp., whereas >88% of T. marneffei isolates had minimum inhibitory concentration values ≤0.015 µg/ml for itraconazole, posaconazole, and voriconazole. Risk factors for mortality in those with talaromycosis included low CD4 counts (odds ratio 2.90 when CD4 count <200 cells/µl compared with 24.26 when CD4 count <50 cells/µl). Outbreaks of coccidioidomycosis and paracoccidioidomycosis were associated with construction work (relative risk 4.4-210.6 and 5.7-times increase, respectively). In the United States of America, cases of coccidioidomycosis increased between 2014 and 2017 (from 8232 to 14 364/year). National and global surveillance as well as more detailed studies to better define sequelae, risk factors, outcomes, global distribution, and trends are required.

Fusarium species,Scedosporium species, and Lomentospora prolificans: A systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.

Factors associated with skeletal-related events in patients with bone metastatic melanoma: A retrospective study of 481 patients.

OBJECTIVES: Metastatic bone disease is estimated to develop in up to 17% of patients with melanoma, compromising skeleton integrity resulting in skeletal-related events (SREs), which impair quality of life and reduce survival. The objective of the study was to investigate (1) the proportion of melanoma patients developing SREs following diagnosis of bone metastasis and (2) the predictors for SREs in this patient cohort. METHODS: Four hundred and eighty-one patients with bone metastatic melanoma from two tertiary centers in the United States from 2008 to 2018 were included. The primary outcome was 90-day and 1-year occurrence of a SRE, including pathological fractures of bones, cord compression, hypercalcemia, radiotherapy, and surgery. Fine-Gray regression analysis was performed for overall SREs and pathological fracture, with death as a competing risk. RESULTS: By 1-year, 52% (258/481) of patients experienced SREs, and 28% (137/481) had a pathological fracture. At 90-day, lytic lesions, bone pain, elevated calcium and absolute lymphocyte, and decreased albumin and hemoglobin were associated with higher SRE risk. The same factors, except for decreased hemoglobin, were shown to predict development of SREs at 1-year. CONCLUSION: The high incidence of SREs and pathological fractures warrants vigilance using the identified factors in this study and preventative measures during clinical oncological care.

Remineralization Rate of Lytic Lesions of the Spine in Multiple Myeloma Patients Undergoing Radiation Therapy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: In general, Multiple Myeloma (MM) patients are treated with systemic therapy including chemotherapy. Radiation therapy can have an important supportive role in the palliative management of MM-related osteolytic lesions. Our study aims to investigate the degree of radiation-induced remineralization in MM patients to gain a better understanding of its potential impact on bone mineral density and, consequently, fracture prevention. Our primary outcome measure was percent change in bone mineral density measured in Hounsfield Units (Δ% HU) between pre- and post-radiation measurements, compared to non-targeted vertebrae. METHODS: We included 119 patients with MM who underwent radiotherapy of the spine between January 2010 and June 2021 and who had a CT scan of the spine at baseline and between 3-24 months after radiation. A linear mixed effect model tested any differences in remineralization rate per month (ßdifference) between targeted and non-targeted vertebrae. RESULTS: Analyses of CT scans yielded 565 unique vertebrae (366 targeted and 199 non-targeted vertebrae). In both targeted and non-targeted vertebrae, there was an increase in bone density per month (ßoverall = .04; P = .002) with the largest effect being between 9-18 months post-radiation. Radiation did not cause a greater increase in bone density per month compared to non-targeted vertebrae (ßdifference = .67; P = .118). CONCLUSION: Our results demonstrate that following radiation, bone density increased over time for both targeted and non-targeted vertebrae. However, no conclusive evidence was found that targeted vertebrae have a higher remineralization rate than non-targeted vertebrae in patients with MM.

Implementing Interventions for Women and Youth with Traumatic Brain Injury at Transition from Custodial Settings: A Call to Action.

Traumatic brain injury (TBI) is a serious public health concern and overrepresented among justice-involved populations. An emerging area of research focuses on the complex, interrelated and unmet health and social needs of justice-involved women and youth with TBI. Evidence of these needs continues to grow, yet the health and justice systems continue to underperform in supporting the health and social care of justice-involved women and youth. This commentary is a call to action to begin to redress these gaps. We first provide an overview of the needs of women and youth with TBI that affect their transition from custody to community, including those related to victimization, trauma, mental health, substance use, and homelessness. We then highlight the current gaps in knowledge and practice with respect to interventions for women and youth with TBI at transition from custody. The available evidence for the impact of interventions on people with head injury who are justice-involved is sparse, especially studies of interventions focused on women and youth. We conclude with a call for implementation science studies to support translation from research to practice, emphasizing that researchers, practitioners, policy makers, and women and youth at transition should collaborate to develop, implement, and evaluate accommodations and interventions for TBI. To have meaningful, positive impacts on the systems that serve these women and youth, interdisciplinary service delivery approaches should aim to prevent, raise awareness, identify, and provide timely support and services for the varied needs of women and youth with TBI in transition.

Cytokine biomarkers of exacerbations in sputum from Chronic Obstructive Pulmonary Disease patients: a prospective cohort study.

BACKGROUND: We determined the relationships between cytokine expression in sputum and clinical data to characterise and understand Chronic Obstructive Pulmonary Disease (COPD) exacerbations in COPD patients. METHODS: We measured 30 cytokines in 936 sputum samples, collected at stable state (ST) and exacerbation (EX) visits from 99 participants in the Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) study (NCT01360398, www.clinicaltrials.gov). We determined their longitudinal expression and examined differential expression based on disease status or exacerbation type. RESULTS: Of the cytokines, 17 were suitable for analysis. As for disease states, in EX sputum samples, IL-17A, TNF-α, IL-1ß, and IL-10 were significantly increased compared to ST sputum samples, but a logistic mixed model could not predict disease state. As for exacerbation types, bacteria-associated exacerbations showed higher expression of IL-17A, TNF-α, IL-1ß, and IL-1α. IL-1α, IL-1ß, and TNF-α were identified as suitable biomarkers for bacteria-associated exacerbation. Bacteria-associated exacerbations also formed a cluster separate from other exacerbation types in principal component analysis. CONCLUSIONS: Measurement of cytokines in sputum from COPD patients could help identify bacteria-associated exacerbations based on increased concentrations of IL-1α, IL-1ß, or TNF-α. This finding may provide a point-of-care assessment to distinguish a bacterial exacerbation of COPD from other exacerbation types.

Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

BACKGROUND: The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. METHODS: With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. RESULTS: We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. CONCLUSIONS: We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

Nuclear receptor Nur77 regulates immunomechanics of macrophages.

Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While cellular mechanics have been implicated in inflammation, the contribution of Nur77 to these mechanical processes remains elusive. Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. To establish the potential correlation of Nur77 with cellular mechanics, we compared bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Nur77-deficient (Nur77-KO) mice and employed cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis assays, and RNA-sequencing. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent in vitro experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics. Our findings suggest that immune regulation by Nur77 may be partially mediated through alterations in cellular mechanics, highlighting a potential avenue for therapeutic targeting.