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Fragility fractures: proposal of the best practice through the fracture coordination units: the experience of Mexico.
Fragility fractures represent a health problem in Mexico and in the world. This paper reviews and puts forward the implementation of Fracture Liaison Services (FLS) as a feasible and cost-effective alternative in health institutions in our country through the identification, treatment, and follow-up of this type of fractures.
Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.
X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.
Immune response to COVID-19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T cell response.
Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID-19 vaccination. Using a prospective study of myeloma patients in UK Rudy Study cohort, we assessed humoral and Interferon gamma release assay (IGRA) cellular immune responses to COVID-19 vaccination post second COVID-19 vaccine administration. We report data from 214 adults with myeloma (n=204) or smouldering myeloma (n=10) who provided blood samples at least 3 weeks after second vaccine dose. Positive Anti-Spike antibody levels (> 50 IU/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative Anti-Spike protein antibody response. 95/158 (60.1%) patients produced positive results for both anti-Spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti-CD38/ anti-BCMA therapy and Pfizer-BioNTech (PB) vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.
Importance of Time Point-Specific Indirect Treatment Comparisons of Osteoporosis Treatments: A Systematic Literature Review and Network Meta-Analyses.
PURPOSE: The efficacy comparison of osteoporosis treatments can be hindered by the absence of head-to-head trials; instead, network meta-analyses (NMAs) have been used to determine comparative effectiveness. This study was the first to investigate the impact of time point-specific NMAs of osteoporosis treatments on variability in treatments' onset of action caused by their different mechanisms of actions and trial designs. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of treatments for postmenopausal women with osteoporosis, including romosozumab (ROMO), teriparatide (TPTD), abaloparatide (ABL), alendronate (ALN), risedronate (RIS), ibandronate (IB), zoledronic acid/zoledronate (ZOL), denosumab (DEN), and raloxifene (RLX), on at least 1 fracture or bone mineral density (BMD) outcome. Of 100 RCTs identified in 5 databases, 27 RCTs were included for NMAs of new vertebral, nonvertebral, and hip fracture outcomes at 12, 24, and 36 months, and 47 RCTs were included for NMAs of BMD outcomes at lumbar spine, total hip, and femoral neck to compare the relative efficacy of osteoporosis treatments. Quality of included studies was assessed using the Cochrane Risk of Bias tool. FINDINGS: For vertebral fractures, TPTD (83.63%), ABL (69.11%), and ROMO/ALN (78.70%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO/ALN had the highest probability (54.4%, 64.69%, and 90.29%, respectively) to be the most effective treatment for nonvertebral fractures at 12, 24, and 36 months. For hip fractures, ROMO/ALN (46.31%), ABL (61.1%), and DEN (55.21%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO had the highest probability (76.06%, 44.19%, and 51.78%, respectively) to be the most effective treatment for BMD outcomes at lumbar spine, total hip, and femoral neck. IMPLICATIONS: The importance of indirectly comparing available osteoporosis treatments using time point-specific NMAs was confirmed because indirect comparison results differed substantially across time points.
How to initiate and develop Fracture Liaison Services (FLS). Recommendations from the IOF Capture the Fracture® FLS Mentors in Brazil.
Expected number of fragility fractures in Brazil, raising the healthcare prioritization for interventions that reduce fracture risk. An FLS is dedicated to managing patient with fragility fracture to reduce risk of another fracture. We review FLSs cost-effectiveness and describe key components to effectively set up FLS in Brazil. PURPOSE: To create a guideline to show health professionals, hospital managers, and stakeholders in Brazil the importance of secondary fracture prevention and how to implement a Fracture Liaison Service. METHODS: We review the cost-effectiveness for FLSs in Brazil. We describe the key components needed to set up an effective FLS including methods for identification, investigation, treatment indication, including bone drugs, supplementation, physical activity, fall prevention, and monitoring. The staffing of FLSs, value of regional clinical networks and quality improvement are also described as a guide for healthcare professionals and decision makers in Brazil. RESULTS: An FLS is a service dedicated to identifying, assessing, recommending treatment, and monitoring patient who present with a fragility fracture reducing the risk of another fracture. FLS has been implemented in Brazil since 2012 overcoming a large geography and a complex health system. Even the limitations, restrictions, differences, and characteristics of each region, it is possible for health institutions to initiate an FLS, adapted to own available resources and meet the stages of identification, investigation, treatment, and monitoring. CONCLUSION: The peculiarity of the Brazilian healthcare system means FLS implementation needs to be tailored to local reality. However, even with limitations, any attempt to capture patients who suffer a fracture due to bone fragility is effective and reduces the risk of further fractures.
Short- and long-term prognostic factors associated with functional recovery in elderly patients with hip fracture: A systematic review.
This systematic review aimed to identify short- and long-term associated factors to functional recovery of elderly hip fracture patients after discharge. We identified 43 studies reporting 74 associated factors to functional recovery; most of them were biological, sociodemographic, or inherent factors to patients' baseline characteristics, including their pre-facture functional capacity. PURPOSE: This systematic review aimed to identify short- and long-term associated factors to functional recovery of elderly hip fracture patients after hospital discharge. We assessed the use of the hip fracture core-set and key-performance indicators for secondary fracture reduction. METHODS: A search was performed in seven electronic databases. Observational studies reporting predictors after usual care of elderly patients with hip fracture diagnoses receiving surgical or conservative treatment were included. Primary outcomes considered were part of the domains corresponding to functional capacity. RESULTS: Of 3873 references identified, and after the screening and selection process, 43 studies were included. Sixty-one functional measures were identified for ten functional outcomes, including BADLs, IADLs, ambulation, and mobility. Biological characteristics such as age, sex, comorbidities, cognitive status, nutritional state, and biochemical parameters are significantly associated. Determinants such as contact and size of social network and those related to institutional care quality are relevant for functional recovery at six and 12 months. Age, pre-fracture function, cognitive status, and complications continue to be associated five years after discharge. We found 74 associated factors to functional recovery of elderly hip fracture patients. Ten of the studies reported rehabilitation programs as suggested in KPI 9; none used the complete hip fracture core-set. CONCLUSION: Most of the associated factors for functional recovery of elderly hip fracture were biological, sociodemographic, or inherent factors to patients' baseline characteristics, including their pre-facture functional capacity. For the core-set and KPI's, we found an insufficient use and report. This study reports 61 different instruments to measure functional capacity. REGISTRATION NUMBER: PROSPERO (CRD42020149563).
Physical function and physical activity in adults with X-linked hypophosphatemia.
We described physical function and activity in UK adults with X-linked hypophosphatemia (XLH). Our data indicate that low physical activity and impaired mobility are common in adults with XLH. Deficits in lower limbs muscle power and functional capacity contribute to the loss of physical function in adults with XLH. INTRODUCTION: There is a dearth of literature on physical function and physical activity in adults with X-linked hypophosphatemia (XLH). We described muscle strength and power, functional capacity, mobility and physical activity level and explored the relationships among these variables in adults with XLH. METHODS: Participants were recruited as part of a UK-based prospective cohort study, the RUDY Study. They underwent a clinical visit and physical examination, including assessment of handgrip strength, jump power (mechanography), six-minute walk test (6MWT) and short physical performance battery (SPPB), and completed the International Physical Activity Questionnaire (IPAQ). Performance data were analysed using parametric and non-parametric tests, whereas correlations were assessed by univariate analysis. RESULTS: Twenty-six adults with XLH (50% males) with a mean age of 44 ± 16.1 years were recruited. Jump power and 6MWT distances (p
Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 With Clostridia and Insulin Sensitivity in Humans
Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22–producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22–related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales. This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22, and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.
Preclinical Aortic Atherosclerosis in Adolescents With Chronic Disease
BACKGROUND: Adolescents with chronic disease are often exposed to inflammatory, metabolic, and hemodynamic risk factors for early atherosclerosis. Since postmortem studies have shown that atherogenesis starts in the aorta, the CDACD (Cardiovascular Disease in Adolescents with Chronic Disease) study investigated preclinical aortic atherosclerosis in these adolescents. METHODS AND RESULTS: The cross-sectional CDACD study enrolled 114 adolescents 12 to 18 years old with chronic disorders including juvenile idiopathic arthritis, cystic fibrosis, obesity, corrected coarctation of the aorta, and healthy controls with a corrected atrial septal defect. Cardiovascular magnetic resonance was used to assess aortic pulse wave velocity and aortic wall thickness, as established aortic measures of preclinical atherosclerosis. Cardiovascular magnetic resonance showed a higher aortic pulse wave velocity, which reflects aortic stiffness, and higher aortic wall thickness in all adolescent chronic disease groups, compared with controls (P<0.05). Age (β=0.253), heart rate (β=0.236), systolic blood pressure (β=−0.264), and dias-tolic blood pressure (β=0.365) were identified as significant predictors for aortic pulse wave velocity, using multivariable linear regression analysis. Aortic wall thickness was predicted by body mass index (β=0.248) and fasting glucose (β=0.242), next to aortic lumen area (β=0.340). Carotid intima-media thickness was assessed using ultrasonography, and was only higher in adolescents with coarctation of the aorta, compared with controls (P<0.001). CONCLUSIONS: Adolescents with chronic disease showed enhanced aortic stiffness and wall thickness compared with con-trols. The enhanced aortic pulse wave velocity and aortic wall thickness in adolescents with chronic disease could indicate accelerated atherogenesis. Our findings underscore the importance of the aorta for assessment of early atherosclerosis, and the need for tailored cardiovascular follow-up of children with chronic disease.
Methodology for the development of National Multidisciplinary Management Recommendations using a multi-stage meta-consensus initiative.
BACKGROUND: Methods for developing national recommendations vary widely. The successful adoption of new guidance into routine practice is dependent on buy-in from the clinicians delivering day-to-day patient care and must be considerate of existing resource constraints, as well as being aspirational in its scope. This initiative aimed to produce guidelines for the management of head and neck squamous cell carcinoma of unknown primary (HNSCCUP) using a novel methodology to maximise the likelihood of national adoption. METHODS: A voluntary steering committee oversaw 3 phases of development: 1) clarification of topic areas, data collection and assimilation, including systematic reviews and a National Audit of Practice; 2) a National Consensus Day, presenting data from the above to generate candidate consensus statements for indicative voting by attendees; and 3) a National Delphi Exercise seeking agreement on the candidate consensus statements, including representatives from all 58 UK Head and Neck Multidisciplinary Teams (MDT). Methodology was published online in advance of the Consensus Day and Delphi exercise. RESULTS: Four topic areas were identified to frame guideline development. The National Consensus Day was attended by 227 participants (54 in-person and 173 virtual). Results from 7 new systematic reviews were presented, alongside 7 expert stakeholder presentations and interim data from the National Audit and from relevant ongoing Clinical Trials. This resulted in the generation of 35 statements for indicative voting by attendees which, following steering committee ratification, led to 30 statements entering the National Delphi exercise. After 3 rounds (with a further statement added after round 1), 27 statements had reached 'strong agreement' (n = 25, 2, 0 for each round, respectively), a single statement achieved 'agreement' only (round 3), and 'no agreement' could be reached for 3 statements (response rate 98% for each round). Subsequently, 28 statements were adopted into the National MDT Guidelines for HNSCCUP. CONCLUSIONS: The described methodology demonstrated an effective multi-phase strategy for the development of national practice recommendations. It may serve as a cost-effective model for future guideline development for controversial or rare conditions where there is a paucity of available evidence or where there is significant variability in management practices across a healthcare service.
Broad and strong memory CD4 + and CD8 + T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients.
COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.
T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.
Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.