Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response.

BACKGROUND: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. OBJECTIVES: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. METHODS: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. RESULTS: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58% vs 22%), higher prevalence of gastrointestinal symptoms (58% vs 29%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV1/forced vital capacity (72% vs 81%), and lower diffusion capacity of the lung for carbon monoxide (68% vs 85% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. CONCLUSIONS: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.

The Incidence of Pulmonary Embolism in Hospitalized Non-ICU Patients with COVID-19 during the First Wave: A Multicenter Retrospective Cohort Study in the Netherlands.

INTRODUCTION: During the first COVID-19 outbreak in 2020 in the Netherlands, the incidence of pulmonary embolism (PE) appeared to be high in COVID-19 patients admitted to the intensive care unit (ICU). This study was performed to evaluate the incidence of PE during hospital stay in COVID-19 patients not admitted to the ICU. METHODS: Data were retrospectively collected from 8 hospitals in the Netherlands. Patients admitted between February 27, 2020, and July 31, 2020, were included. Data extracted comprised clinical characteristics, medication use, first onset of COVID-19-related symptoms, admission date due to COVID-19, and date of PE diagnosis. Only polymerase chain reaction (PCR)-positive patients were included. All PEs were diagnosed with computed tomography pulmonary angiography (CTPA). RESULTS: Data from 1,852 patients who were admitted to the hospital ward were collected. Forty patients (2.2%) were diagnosed with PE within 28 days following hospital admission. The median time to PE since admission was 4.5 days (IQR 0.0-9.0). In all 40 patients, PE was diagnosed within the first 2 weeks after hospital admission and for 22 (55%) patients within 2 weeks after onset of symptoms. Patient characteristics, pre-existing comorbidities, anticoagulant use, and laboratory parameters at admission were not related to the development of PE. CONCLUSION: In this retrospective multicenter cohort study of 1,852 COVID-19 patients only admitted to the non-ICU wards, the incidence of CTPA-confirmed PE was 2.2% during the first 4 weeks after onset of symptoms and occurred exclusively within 2 weeks after hospital admission.

Development and usability of a decision aid to initiate anti-osteoporosis medication treatment in patients visiting the fracture liaison service with a recent fracture.

This study describes the development of a decision aid (DA), aimed at supporting patients in their decision whether to start anti-osteoporosis medication. People with recent fractures or osteoporosis and health professionals were supportive of the DA initiative. An experimental study been started to assess (cost-)effectiveness of the DA. PURPOSE: At fracture liaison services (FLS), patients with a recent fracture ánd osteoporosis or a prevalent vertebral fracture are advised to start anti-osteoporosis medication (AOM). This study describes the development of a decision aid (DA) to support patients and healthcare providers (HCPs) in their decision about whether to start AOM. METHODS: The DA was developed according to International Patient Decision Aid Standards (IPDAS). A systematic procedure was chosen including scope, design, prototype development, and alpha testing. A previously developed DA for women with osteoporosis was used as a basis. Furthermore, input from literature searches, the Dutch guideline on management of osteoporosis, and from people with a fracture or osteoporosis was used. The updated DA was evaluated during alpha testing. RESULTS: The DA facilitates the decision of patients whether to initiate AOM treatment and provides information on fractures and osteoporosis, general risk factors that increase the likelihood of a subsequent fracture, the role of lifestyle, personalized risk considerations of a subsequent fracture with and without AOM treatment, and AOM options and their characteristics in an option grid. Alpha testing with 15 patients revealed that patient preferences and needs were adequately presented, and several suggestions for improvement (e.g. adding more specific information, simplifying terminology, improving icon use) were accounted for. Participants from the alpha testing recommended use of the DA during outpatient visits. CONCLUSION: Professionals and persons with osteoporosis were supportive of the proposed DA and its usability. The DA could help in a shared decision-making process between patients and HCPs.

Quantitative CT Evaluation of Bone Mineral Density in the Thoracic Spine on 18F-Fluorocholine PET/CT Imaging in Patients With Primary Hyperparathyroidism.

INTRODUCTION: Measurement of bone mineral density (BMD) with quantitative CT (QCT) carries several advantages over other densitometric techniques, including superior assessment of the spine. As most QCT studies evaluated the lumbar spine, measurements of the thoracic spine are limited. We performed QCT analysis of the thoracic spine in a cohort of patients with primary hyperparathyroidism. MATERIALS AND METHODS: This study was a retrospective QCT analysis of the thoracic spine on 18F-fluorocholine PET/CT scans in patients with primary hyperparathyroidism patients between March 2018 and December 2022. Correlations between QCT-derived BMD or Hounsfield units (HU) and demographic data, laboratory parameters, results from histopathological examination after parathyroidectomy and results of DXA imaging were analyzed, when available. RESULTS: In 189 patients, mean QCT-derived BMD at the thoracic spine was 85.6 mg/cm3. Results from recent DXA were available in 122 patients. Mean thoracic QCT-derived BMD and HU were significantly correlated with DXA-derived BMD in lumbar spine, total hip and femoral neck and with the lowest T-score at DXA imaging. Only weak correlations were found with BMI or 18F-fluorocholine uptake, while no significant correlations were found with adenoma weight, PTH or calcium levels. CONCLUSION: Our study confirms correlation between QCT-derived BMD in the thoracic spine with age and DXA-derived BMD measurements within a population of patients with primary hyperparathyroidism. Establishment of reference BMD values for individual thoracic vertebrae, may allow direct osteoporosis classification on thoracic CT imaging.

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nation-wide cohort study.

BACKGROUND: Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. METHODS: A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013-2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. RESULTS: Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71-1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39-0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. CONCLUSION: SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

Bone Microarchitecture and Strength Changes During Teriparatide and Zoledronic Acid Treatment in a Patient with Pregnancy and Lactation-Associated Osteoporosis with Multiple Vertebral Fractures.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis, of which the pathogenesis and best treatment options are unclear. In this report, we describe the case of a 34-year old woman diagnosed with severe osteoporosis and multiple vertebral fractures after her first pregnancy, who was subsequently treated with teriparatide (TPTD) and zoledronic acid (ZA). We describe the clinical features, imaging examination, and genetic analysis. Substantial improvements were observed in areal and volumetric bone mineral density (BMD), microarchitecture, and strength between 7 and 40 months postpartum as assessed by dual-energy X-ray absorptiometry at the total hip and spine and by high-resolution peripheral quantitative CT at the distal radius and tibiae. At the hip, spine, and distal radius, these improvements were mainly enabled by treatment with TPTD and ZA, while at the distal tibiae, physiological recovery and postpartum physiotherapy due to leg pain after stumbling may have played a major role. Additionally, the findings show that, despite the improvements, BMD, microarchitecture, and strength remained severely impaired in comparison with healthy age- and gender-matched controls at 40 months postpartum. Genetic analysis showed no monogenic cause for osteoporosis, and it is suggested that PLO in this woman could have a polygenic origin with possible susceptibility based on familiar occurrence of osteoporosis.

The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus.

AIM: To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). METHODS: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. RESULTS: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. CONCLUSION: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.

Imminent fall risk after fracture.

RATIONALE: Adults with a recent fracture have a high imminent risk of a subsequent fracture. We hypothesise that, like subsequent fracture risk, fall risk is also highest immediately after a fracture. This study aims to assess if fall risk is time-dependent in subjects with a recent fracture compared to subjects without a fracture. METHODS: This retrospective matched cohort study used data from the UK Clinical Practice Research Datalink GOLD. All subjects ≥50 years with a fracture between 1993 and 2015 were identified and matched one-to-one to fracture-free controls based on year of birth, sex and practice. The cumulative incidence and relative risk (RR) of a first fall was calculated at various time intervals, with mortality as competing risk. Subsequently, analyses were stratified according to age, sex and type of index fracture. RESULTS: A total of 624,460 subjects were included; 312,230 subjects with an index fracture, matched to 312,230 fracture-free controls (71% females, mean age 70 ± 12, mean follow-up 6.5 ± 5 years). The RR of falls was highest in the first year after fracture compared to fracture-free controls; males had a 3-fold and females a 2-fold higher risk. This imminent fall risk was present in all age and fracture types and declined over time. A concurrent imminent fracture and mortality risk were confirmed. CONCLUSION/DISCUSSION: This study demonstrates an imminent fall risk in the first years after a fracture in all age and fracture types. This underlines the need for early fall risk assessment and prevention strategies in 50+ adults with a recent fracture.

Characterizing Bone Phenotypes Related to Skeletal Fragility Using Advanced Medical Imaging.

PURPOSE OF REVIEW: Summarize the recent literature that investigates how advanced medical imaging has contributed to our understanding of skeletal phenotypes and fracture risk across the lifespan. RECENT FINDINGS: Characterization of bone phenotypes on the macro-scale using advanced imaging has shown that while wide bones are generally stronger than narrow bones, they may be more susceptible to age-related declines in bone strength. On the micro-scale, HR-pQCT has been used to identify bone microarchitecture phenotypes that improve stratification of fracture risk based on phenotype-specific risk factors. Adolescence is a key phase for bone development, with distinct sex-specific growth patterns and significant within-sex bone property variability. However, longitudinal studies are needed to evaluate how early skeletal growth impacts adult bone phenotypes and fracture risk. Metabolic and rare bone diseases amplify fracture risk, but the interplay between bone phenotypes and disease remains unclear. Although bone phenotyping is a promising approach to improve fracture risk assessment, the clinical availability of advanced imaging is still limited. Consequently, alternative strategies for assessing and managing fracture risk include vertebral fracture assessment from clinically available medical imaging modalities/techniques or from fracture risk assessment tools based on clinical risk factors. Bone fragility is not solely determined by its density but by a combination of bone geometry, distribution of bone mass, microarchitecture, and the intrinsic material properties of bone tissue. As such, different individuals can exhibit distinct bone phenotypes, which may predispose them to be more vulnerable or resilient to certain perturbations that influence bone strength.

What Is the Diagnostic Performance of Conventional Radiographs and Clinical Reassessment Compared With HR-pQCT Scaphoid Fracture Diagnosis?

BACKGROUND: Conventional radiographs and clinical reassessment are considered guides in managing clinically suspected scaphoid fractures. This is a unique study as it assessed the value of conventional radiographs and clinical reassessment in a cohort of patients, all of whom underwent additional imaging, regardless of the outcome of conventional radiographs and clinical reassessment. QUESTIONS/PURPOSES: (1) What is the diagnostic performance of conventional radiographs in patients with a clinically suspected scaphoid fracture compared with high-resolution peripheral quantitative CT (HR-pQCT)? (2) What is the diagnostic performance of clinical reassessment in patients with a clinically suspected scaphoid fracture compared with HR-pQCT? (3) What is the diagnostic performance of conventional radiographs and clinical reassessment combined compared with HR-pQCT? METHODS: Between December 2017 and October 2018, 162 patients with a clinically suspected scaphoid fracture presented to the emergency department (ED). Forty-six patients were excluded and another 25 were not willing or able to participate, which resulted in 91 included patients. All patients underwent conventional radiography in the ED and clinical reassessment 7 to 14 days later, together with CT and HR-pQCT. The diagnostic performance characteristics and accuracy of conventional radiographs and clinical reassessment were compared with those of HR-pQCT for the diagnosis of fractures since this was proven to be superior to CT scaphoid fracture detection. The cohort included 45 men and 46 women with a median (IQR) age of 52 years (29 to 67). Twenty-four patients with a median age of 44 years (35 to 65) were diagnosed with a scaphoid fracture on HR-pQCT. RESULTS: When compared with HR-pQCT, conventional radiographs alone had a sensitivity of 67% (95% CI 45% to 84%), specificity of 85% (95% CI 74% to 93%), positive predictive value (PPV) of 62% (95% CI 46% to 75%), negative predictive value (NPV) of 88% (95% CI 80% to 93%), and a positive and negative likelihood ratio (LR) of 4.5 (95% CI 2.4 to 8.5) and 0.4 (95% CI 0.2 to 0.7), respectively. Compared with HR-pQCT, clinical reassessment alone resulted in a sensitivity of 58% (95% CI 37% to 78%), specificity of 42% (95% CI 30% to 54%), PPV of 26% (95% CI 19% to 35%), NPV of 74% (95% CI 62% to 83%), as well as a positive and negative LR of 1.0 (95% CI 0.7 to 1.5) and 1.0 (95% CI 0.6 to 1.7), respectively. Combining clinical examination with conventional radiography produced a sensitivity of 50% (95% CI 29% to 71%), specificity of 91% (95% CI 82% to 97%), PPV of 67% (95% CI 46% to 83%), NPV of 84% (95% CI 77% to 88%), as well as a positive and negative LR of 5.6 (95% CI 2.4 to 13.2) and 0.6 (95% CI 0.4 to 0.8), respectively. CONCLUSION: The accuracy of conventional radiographs (80% compared with HR-pQCT) and clinical reassessment (46% compared with HR-pQCT) indicate that the value of clinical reassessment is limited in diagnosing scaphoid fractures and cannot be considered directive in managing scaphoid fractures. The combination of conventional radiographs and clinical reassessment does not increase the accuracy of these diagnostic tests compared with the accuracy of conventional radiographs alone and is therefore also limited in diagnosing scaphoid fractures. LEVEL OF EVIDENCE: Level II, diagnostic study.

Association of Heart Rate Variability with Pulmonary Function Impairment and Symptomatology Post-COVID-19 Hospitalization.

The persistence of symptoms beyond three months after COVID-19 infection, often referred to as post-COVID-19 condition (PCC), is commonly experienced. It is hypothesized that PCC results from autonomic dysfunction with decreased vagal nerve activity, which can be indexed by low heart rate variability (HRV). The aim of this study was to assess the association of HRV upon admission with pulmonary function impairment and the number of reported symptoms beyond three months after initial hospitalization for COVID-19 between February and December 2020. Follow-up took place three to five months after discharge and included pulmonary function tests and the assessment of persistent symptoms. HRV analysis was performed on one 10 s electrocardiogram obtained upon admission. Analyses were performed using multivariable and multinomial logistic regression models. Among 171 patients who received follow-up, and with an electrocardiogram at admission, decreased diffusion capacity of the lung for carbon monoxide (DLCO) (41%) was most frequently found. After a median of 119 days (IQR 101-141), 81% of the participants reported at least one symptom. HRV was not associated with pulmonary function impairment or persistent symptoms three to five months after hospitalization for COVID-19.

Low-dose oral glucocorticoid therapy and risk of osteoporotic fractures in patients with rheumatoid arthritis: a cohort study using the Clinical Practice Research Datalink.

OBJECTIVES: Clinical trials have shown that low-dose glucocorticoid therapy in patients with RA reduces bone loss in hands or hip, but the effect on osteoporotic fractures is not yet clear. Therefore, we investigated the use of low-dose oral glucocorticoids and risk of osteoporotic fractures among patients with RA. METHODS: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (<6 months), recent (7-12 months) and past (>1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, adjusted for lifestyle parameters, comorbidities and comedications. Secondary analyses assessed osteoporotic fracture risk with a combination of average daily and cumulative doses of oral glucocorticoids. RESULTS: Among 15 123 patients with RA (mean age 68.8 years, 68% females), 1640 osteoporotic fractures occurred. Current low-dose oral glucocorticoid therapy (≤7.5 mg prednisolone equivalent dose/day) in patients with RA was not associated with overall risk of osteoporotic fractures (adjusted hazard ratio 1.14, 95% CI 0.98, 1.33) compared with past glucocorticoid use, but was associated with an increased risk of clinical vertebral fracture (adjusted hazard ratio 1.59, 95% CI 1.11, 2.29). Results remained unchanged regardless of a short-term or a long-term use of oral glucocorticoids. CONCLUSION: Clinicians should be aware that even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased.

The use of oral glucocorticoids and the risk of major osteoporotic fracture in patients with myasthenia gravis.

Oral glucocorticoids may increase major osteoporotic fracture risk (MOF) in myasthenia gravis patients. To assess this risk, we performed a case-control study including all Danish patients with a MOF between 1995 and 2011. We also pooled our data with data from another study. We found no increased risk. Osteoporosis prevention remains advisable. PURPOSE/INTRODUCTION: The prolonged use of high doses of oral glucocorticoids (GCs), a common treatment in patients with myasthenia gravis (MG), may increase major osteoporotic fracture (MOF) risk. Previous epidemiological studies did not exclusively focus on patients with MG or had relatively few GC-exposed MG patients. Aims were to evaluate the risk of MOF in MG patients using oral GCs in a large study population and to perform a pooled analysis with data from previous work. METHODS: A population-based case-control study (1995-2011) was conducted using the Danish National Health Service. Cases had sustained a MOF, and controls had not. All were aged ≥ 18 years. Multivariate conditional logistic regression estimated odds ratios (ORs) among MG patients using oral GCs versus non-users. Adjustments were made for comorbidities and comedications. In the pooled analysis, results were pooled by the use of generic inverse variance methods, assuming a random-effects model. RESULTS: We identified 376,858 cases and 376,858 controls. MOF risk was not elevated in MG patients currently using oral GCs compared to MG patients not on oral GCs (ORadj.: 1.26 (95% CI 0.68-2.33)). The use of the highest cumulative dose of oral GCs (≥ 7 g) did not show an increased risk of MOF among MG patients (ORadj.: 2.00 (95% CI 0.90-4.44)). Our pooled analysis also showed no association between oral GC use and MOF risk. CONCLUSION: This study showed that oral GC use in patients with MG was not associated with increased risk of MOF in our case-control study and pooled analysis. Osteoporosis prevention in MG patients based on clinical guidelines remains advisable.

Incidence, hospitalization and mortality and their changes over time in people with a first ever diabetic foot ulcer.

AIMS: A diabetic foot ulcer (DFU) is a severe condition associated with morbidity and mortality. Population-based studies are rare and limited by access to reliable data. Without this data, efforts in primary prevention cannot be evaluated. Therefore, we examined the incidence and changes over time for the first DFU in people with diabetes. We also examined hospitalization and all-cause mortality and their changes over time. METHODS: From the UK primary care CPRD GOLD database (2007-2017), we identified 129,624 people with diabetes by a prescription for insulin or a non-insulin anti-diabetic drug. DFUs were identified using Read codes and expressed as incidence rates (IRs). Changes over time were described using Poisson and logistic regression and expressed as incidence rate ratios (IRRs) and odds ratios (ORs) respectively. RESULTS: The mean IR of first registered DFUs was 2.5 [95% CI: 2.1-2.9] per 1000 person-years for people with type 2 diabetes and 1.6 [1.3-1.9] per 1000 person-years for people with type 1. The IRs declined for people with type 2 diabetes (IRR per year: 0.97 [0.96-0.99]), while no changes were observed for people with type 1 diabetes (IRR per year: 0.96 [0.89-1.04]). Average hospitalization and 1-year mortality risk for people with type 2 diabetes were 8.2% [SD: 4.7] and 11.7% [SD: 2.2] respectively. Both declined over time (OR: 0.89 [0.84, 0.94] and 0.94 [0.89, 0.99]). CONCLUSION: The decline in all IRs, hospitalizations and mortality in people with type 2 diabetes suggests that prevention and care of the first DFU has improved for this group in primary care in the UK.

Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study.

BACKGROUND: Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA. METHODS: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7-12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications. RESULTS: Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use. CONCLUSIONS: There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.

High-Resolution Cone-Beam Computed Tomography is a Fast and Promising Technique to Quantify Bone Microstructure and Mechanics of the Distal Radius.

Obtaining high-resolution scans of bones and joints for clinical applications is challenging. HR-pQCT is considered the best technology to acquire high-resolution images of the peripheral skeleton in vivo, but a breakthrough for widespread clinical applications is still lacking. Recently, we showed on trapezia that CBCT is a promising alternative providing a larger FOV at a shorter scanning time. The goals of this study were to evaluate the accuracy of CBCT in quantifying trabecular bone microstructural and predicted mechanical parameters of the distal radius, the most often investigated skeletal site with HR-pQCT, and to compare it with HR-pQCT. Nineteen radii were scanned with four scanners: (1) HR-pQCT (XtremeCT, Scanco Medical AG, @ (voxel size) 82 µm), (2) HR-pQCT (XtremeCT-II, Scanco, @60.7 µm), (3) CBCT (NewTom 5G, Cefla, @75 µm) reconstructed and segmented using in-house developed software and (4) microCT (VivaCT40, Scanco, @19 µm-gold standard). The following parameters were evaluated: predicted stiffness, strength, bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), separation (Tb.Sp) and number (Tb.N). The overall accuracy of CBCT with in-house optimized algorithms in quantifying bone microstructural parameters was comparable (R2 = 0.79) to XtremeCT (R2 = 0.76) and slightly worse than XtremeCT-II (R2 = 0.86) which were both processed with the standard manufacturer's technique. CBCT had higher accuracy for BV/TV and Tb.Th but lower for Tb.Sp and Tb.N compared to XtremeCT. Regarding the mechanical parameters, all scanners had high accuracy (R2 [Formula: see text] 0.96). While HR-pQCT is optimized for research, the fast scanning time and good accuracy renders CBCT a promising technique for high-resolution clinical scanning.

Early detection of hospitalized patients with COVID-19 at high risk of clinical deterioration: Utility of emergency department shock index.

BACKGROUND: The COVID-19 outbreak has put an unprecedented strain on Emergency Departments (EDs) and other critical care resources. Early detection of patients that are at high risk of clinical deterioration and require intensive monitoring, is key in ED evaluation and disposition. A rapid and easy risk-stratification tool could aid clinicians in early decision making. The Shock Index (SI: heart rate/systolic blood pressure) proved useful in detecting hemodynamic instability in sepsis and myocardial infarction patients. In this study we aim to determine whether SI is discriminative for ICU admission and in-hospital mortality in COVID-19 patients. METHODS: Retrospective, observational, single-center study. All patients ≥18 years old who were hospitalized with COVID-19 (defined as: positive result on reverse transcription polymerase chain reaction (PCR) test) between March 1, 2020 and December 31, 2020 were included for analysis. Data were collected from electronic medical patient records and stored in a protected database. ED shock index was calculated and analyzed for its discriminative value on in-hospital mortality and ICU admission by a ROC curve analysis. RESULTS: In total, 411 patients were included. Of all patients 249 (61%) were male. ICU admission was observed in 92 patients (22%). Of these, 37 patients (40%) died in the ICU. Total in-hospital mortality was 28% (114 patients). For in-hospital mortality the optimal cut-off SI ≥ 0.86 was not discriminative (AUC 0.49 (95% CI: 0.43-0.56)), with a sensitivity of 12.3% and specificity of 93.6%. For ICU admission the optimal cut-off SI ≥ 0.57 was also not discriminative (AUC 0.56 (95% CI: 0.49-0.62)), with a sensitivity of 78.3% and a specificity of 34.2%. CONCLUSION: In this cohort of patients hospitalized with COVID-19, SI measured at ED presentation was not discriminative for ICU admission and was not useful for early identification of patients at risk of clinical deterioration.

Improvement of osteoporosis Care Organized by Nurses: ICON study - Protocol of a quasi-experimental study to assess the (cost)-effectiveness of combining a decision aid with motivational interviewing for improving medication persistence in patients with a recent fracture being treated at the fracture liaison service.

BACKGROUND: Given the health and economic burden of fractures related to osteoporosis, suboptimal adherence to medication and the increasing importance of shared-decision making, the Improvement of osteoporosis Care Organized by Nurses (ICON) study was designed to evaluate the effectiveness, cost-effectiveness and feasibility of a multi-component adherence intervention (MCAI) for patients with an indication for treatment with anti-osteoporosis medication, following assessment at the Fracture Liaison Service after a recent fracture. The MCAI involves two consultations at the FLS. During the first consultation, a decision aid is will be used to involve patients in the decision of whether to start anti-osteoporosis medication. During the follow-up visit, the nurse inquires about, and stimulates, medication adherence using motivational interviewing techniques. METHODS: A quasi-experimental trial to evaluate the (cost-) effectiveness and feasibility of an MCAI, consisting of a decision aid (DA) at the first visit, combined with nurse-led adherence support using motivational interviewing during the follow-up visit, in comparison with care as usual, in improving adherence to oral anti-osteoporosis medication for patients with a recent fracture two Dutch FLS. Medication persistence, defined as the proportion of patients who are persistent at one year assuming a refill gap < 30 days, is the primary outcome. Medication adherence, decision quality, subsequent fractures and mortality are the secondary outcomes. A lifetime cost-effectiveness analysis using a model-based economic evaluation and a process evaluation will also be conducted. A sample size of 248 patients is required to show an improvement in the primary outcome with 20%. Study follow-up is at 12 months, with measurements at baseline, after four months, and at 12 months. DISCUSSION: We expect that the ICON-study will show that the MCAI is a (cost-)effective intervention for improving persistence with anti-osteoporosis medication and that it is feasible for implementation at the FLS. TRIAL REGISTRATION: This trial has been registered in the Netherlands Trial Registry, part of the Dutch Cochrane Centre (Trial NL7236 (NTR7435)). Version 1.0; 26-11-2020.

Early warning scores to assess the probability of critical illness in patients with COVID-19.

OBJECTIVE: Validated clinical risk scores are needed to identify patients with COVID-19 at risk of severe disease and to guide triage decision-making during the COVID-19 pandemic. The objective of the current study was to evaluate the performance of early warning scores (EWS) in the ED when identifying patients with COVID-19 who will require intensive care unit (ICU) admission for high-flow-oxygen usage or mechanical ventilation. METHODS: Patients with a proven SARS-CoV-2 infection with complete resuscitate orders treated in nine hospitals between 27 February and 30 July 2020 needing hospital admission were included. Primary outcome was the performance of EWS in identifying patients needing ICU admission within 24 hours after ED presentation. RESULTS: In total, 1501 patients were included. Median age was 71 (range 19-99) years and 60.3% were male. Of all patients, 86.9% were admitted to the general ward and 13.1% to the ICU within 24 hours after ED admission. ICU patients had lower peripheral oxygen saturation (86.7% vs 93.7, p≤0.001) and had a higher body mass index (29.2 vs 27.9 p=0.043) compared with non-ICU patients. National Early Warning Score 2 (NEWS2) ≥ 6 and q-COVID Score were superior to all other studied clinical risk scores in predicting ICU admission with a fair area under the receiver operating characteristics curve of 0.740 (95% CI 0.696 to 0.783) and 0.760 (95% CI 0.712 to 0.800), respectively. NEWS2 ≥6 and q-COVID Score ≥3 discriminated patients admitted to the ICU with a sensitivity of 78.1% and 75.9%, and specificity of 56.3% and 61.8%, respectively. CONCLUSION: In this multicentre study, the best performing models to predict ICU admittance were the NEWS2 and the Quick COVID-19 Severity Index Score, with fair diagnostic performance. However, due to the moderate performance, these models cannot be clinically used to adequately predict the need for ICU admission within 24 hours in patients with SARS-CoV-2 infection presenting at the ED.

The Prevalence of Celiac Disease in a Fracture Liaison Service Population.

Celiac disease (CD) is a known risk factor for osteoporosis and fractures. The prevalence of CD in patients with a recent fracture is unknown. We therefore systematically screened patients at a fracture liaison service (FLS) to study the prevalence of CD. Patients with a recent fracture aged ≥ 50 years were invited to VieCuri Medical Center's FLS. In FLS attendees, bone mineral density (BMD) and laboratory evaluation for metabolic bone disorders and serological screening for CD was systematically evaluated. If serologic testing for CD was positive, duodenal biopsies were performed to confirm the diagnosis CD. Data were collected in 1042 consecutive FLS attendees. Median age was 66 years (Interquartile range (IQR) 15), 27.6% had a major and 6.9% a hip fracture, 26.4% had osteoporosis and 50.8% osteopenia. Prevalent vertebral fractures were found in 29.1%. CD was already diagnosed in two patients (0.19%), one still had a positive serology. Three other patients (0.29%) had a positive serology for CD (one with gastro-intestinal complaints). In two of them, CD was confirmed by duodenal histology (0.19%) and one refused further evaluation. The prevalence of biopsy-proven CD was therefore 0.38% (4/1042) of which 0.19% (2/1042) was newly diagnosed. The prevalence of CD in patients with a recent fracture at the FLS was 0.38% and within the range of reported prevalences in the Western-European population (0.33-1.5%). Newly diagnosed CD was only found in 0.19%. Therefore, standard screening for CD in FLS patients is not recommended.