EACVI survey on radiation exposure in interventional echocardiography.

AIMS: The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey on radiation exposure in interventional echocardiography. The survey aimed to collect data on local practices for radioprotection in interventional echocardiography and to assess the awareness of echocardiography operators about radiation-related risks. METHODS AND RESULTS: A total of 258 interventional echocardiographers from 52 different countries (48% European) responded to the survey. One hundred twenty-two (47%) participants were women. Two-thirds (76%) of interventional echocardiographers worked in tertiary care/university hospitals. Interventional echocardiography was the main clinical activity for 34% of the survey participants. The median time spent in the cath-lab for the echocardiographic monitoring of structural heart procedures was 10 (5-20) hours/month. Despite this, only 28% of interventional echocardiographers received periodic training and certification in radioprotection and 72% of them did not know their annual radiation dose. The main adopted personal protection devices were lead aprons and thyroid collars (95% and 92% of use, respectively). Dedicated architectural protective shielding was not available for 33% of interventional echocardiographers. Nearly two-thirds of responders thought that the radiation exposure of interventional echocardiographers was higher than that of interventional cardiologists and 72% claimed for an improvement in the radioprotection measures. CONCLUSION: Radioprotection measures for interventional echocardiographers are widely variable across centres. Radioprotection devices are often underused by interventional echocardiographers, portending an increased radiation-related risk. International scientific societies working in the field should collaborate to endorse radioprotection training, promote reliable radiation dose assessment, and support the adoption of radioprotection shielding dedicated to interventional echocardiographers.

Ontogenetic changes in the body structure of the Arctic fish Leptoclinus maculatus.

Histological studies of the ontogenetic changes in Arctic marine fishes are often fragmented and incomplete. Here we present a comprehensive histological ontogenetic analysis of the daubed shanny (Leptoclinus maculatus) from the Arctic, characterizing its development as it undergoes a series of changes in the organ and tissue organization, especially during the postlarvae transition from the pelagic to benthic lifestyle. The thyroid, heart, digestive tract, liver, gonads, blood, and the lipid sac of the postlarvae at different developmental stages (L1-L5) were studied for the first time. We found that L. maculatus has structural characteristics of marine fish developing in cold, high-oxygen polar waters. We conclude that the presence of the lipid sac and the absence of distinguishable red blood cells in pelagic postlarvae are unique features of the daubed shanny most likely linked to its successful growth and development in the Arctic environment.

Comparative Study of Lipid Content in Leptoclinus maculatus Postlarvae from Kongsfjord and Rjipfjord, Svalbard Archipelago.

A comparative study of lipid profile of the daubed shanny Leptoclinus maculatus postlarvae from fjords of different domains (arctic-boreal Kongsfjord and high-arctic Rjipfjord) of Svalbard Archipelago waters in summer was performed. A more efficient accumulation of lipids in the fishes from Kongsfjord compared to Rjipfjord due to triacylglycerols and wax esters was established. These differences may be related mainly to the trophic conditions of the habitat (species composition, abundance, and availability of food items). The higher level of cholesterol esters than wax esters at the L1 stage of development of the daubed shanny postlarvae compared to older fishes pointed to their active feeding mainly on phytoplankton. The differences in the content of certain classes of phospholipids may indicate adaptive changes at the level of biomembranes, contributing to the maintenance of cell homeostasis in response to abiotic environmental factors, and reflect their additional intake with food at the early stages of fish development.

InterCarb: A Community Effort to Improve Interlaboratory Standardization of the Carbonate Clumped Isotope Thermometer Using Carbonate Standards.

Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

Patterns and resectability of colorectal cancer recurrences: outcome study within the COLOFOL trial.

BACKGROUND: Improvements in surgery, imaging, adjuvant treatment, and management of metastatic disease have led to modification of previous approaches regarding the risk of recurrence and prognosis in colorectal cancer. The aims of this study were to map patterns, risk factors, and the possibility of curative treatment of recurrent colorectal cancer in a multimodal setting. METHODS: This was a cohort study based on the COLOFOL trial population of patients who underwent radical resection of stage II or III colorectal cancer. The medical files of all patients with recurrence within 5 years after resection of the primary tumour were scrutinized. Follow-up time was 5 years after the first recurrence. Primary endpoints were cumulative incidence, site, timing, and risk factors for recurrence, and rate of potentially curative treatment. A secondary endpoint was survival. RESULTS: Of 2442 patients, 471 developed recurrences. The 5-year cumulative incidence was 21.4 (95 per cent c.i. 19.5 to 23.3) per cent. The median time to detection was 1.1 years after surgery and 87.3 per cent were detected within 3 years. Some 98.2 per cent of patients who had potentially curative treatment were assessed by a multidisciplinary tumour board. A total of 47.8 per cent of the recurrences were potentially curatively treated. The 5-year overall survival rate after detection was 32.0 (95 per cent c.i. 27.9 to 36.3) per cent for all patients with recurrence, 58.6 (51.9 to 64.7) per cent in the potentially curatively treated group and 7.7 (4.8 to 11.5) per cent in the palliatively treated group. CONCLUSION: Time to recurrence was similar to previous results, whereas the 21.4 per cent risk of recurrence was somewhat lower. The high proportion of patients who received potentially curative treatment, linked to a 5-year overall survival rate of 58.6 per cent, indicates that it is possible to achieve good results in recurrent colorectal cancer following multidisciplinary assessment.

Chemoradiation induces upregulation of immunogenic cell death-related molecules together with increased expression of PD-L1 and galectin-9 in gastric cancer.

Surgery alone or combined with chemo- and/or radiation therapy remains the primary treatment for gastric cancer (GC) to date and immunotherapeutic tools such as monoclonal antibodies are only slowly being implemented. This is partly due to the fact that the immune microenvironment in GC during chemoradiation and other treatment modalities is still poorly understood. 7 gastric cancer (GC) cell lines were tested for their response to chemoradiation using 5-FU in combination with X-ray irradiation. We conducted flow cytometric analysis to determine the cells' ability to undergo immunogenic cell death (ICD) and their expression of the two immunosuppressive proteins programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9). We evaluated the overall immunogenicity of two cell lines (MKN7, MKN74) in co-culture experiments with human monocyte-derived dendritic cells (Mo-DCs). Chemoradiation induces distinct responses in different GC cell lines. We observe ICD in vitro in all tested GC cell lines in the form of calreticulin (CRT) translocation to the plasma membrane. As a resistance mechanism, these cells also upregulated Gal-9 and PD-L1. Mo-DC maturation experiments showed that GCs provoked the maturation of Mo-DCs after chemoradiation in vitro. The addition of α-PD-L1 blocking antibody further enhanced the immunogenicity of these cells while improving DC viability. Blocking Tim-3, as the main receptor for Gal-9, had no such effect. Our findings suggest that the benefits of chemoradiation can substantially depend on tumor subtype and these benefits can be offset by induced immune evasion in GC. Combination treatment using checkpoint inhibitors could potentially lead to enhanced immune responses and yield better patient outcomes.

Extending the window for thrombolysis for treatment of acute ischaemic stroke during pregnancy: a review.

Historically, safety of intravenous recombinant tissue plasminogen activator (IV rt-PA) for the treatment of acute ischaemic stroke (AIS) is limited to use within 4.5 hours from symptom onset. Recent studies suggest the treatment window may be extended when patients have salvageable brain tissue on advanced neuroimaging. This paper describes a novel use of IV rt-PA for treatment of AIS in a pregnant patient within an extended-time window (>4.5 hours, and <9 hours) based on advanced neuroimaging with a favourable outcome. TWEETABLE ABSTRACT: Novel use of IV rt-PA for treatment of AIS in pregnancy within an extended-time window based on advanced imaging with a favourable outcome.

A prospective study evaluating the integration of a multifaceted evidence-based medicine curriculum into early years in an undergraduate medical school.

BACKGROUND: The importance of ensuring medical students are equipped with the skills to be able to practice evidence-based medicine (EBM) has been increasingly recognized in recent years. However, there is limited information on an effective EBM curriculum for undergraduate medical schools. This study aims to test the feasibility of integrating a multifaceted EBM curriculum in the early years of an undergraduate medical school. This was subsequently evaluated using the validated Fresno test and students' self-reported knowledge and attitudes as they progressed through the curriculum. METHODS: EBM was integrated horizontally and vertically into the curriculum into the first 2 years of undergraduate medical school. First year medical students were recruited to participate in the study. The 212-point Fresno test was administered along with a locally developed questionnaire at baseline before EBM teaching in year one and at the end of EBM teaching in year two. RESULTS: Thirty-one students participated at baseline and 55 students participated at the end of second year EBM teaching. For the 18 students who completed the Fresno at both time points, the average score increased by 38.7 marks (p < 0.001) after EBM teaching. Students felt confident in formulating clinical questions and in critically appraising journal articles after EBM teaching. EBM was perceived to be important to their future practice as a doctor and for improving patient outcomes at both time points. CONCLUSIONS: It has been feasible to integrate a multifaceted, EBM curriculum from the first year of an undergraduate medical program. Early evaluation of the curriculum using the Fresno test has shown a significant increase in students' EBM knowledge. The curriculum also demonstrated an increase in students' perceptions of the clinical relevance of EBM in their developing practice.

COVID 19 and manual therapy: international lessons and perspectives on current and future clinical practice and education.

BACKGROUND: The COVID-19 pandemic has altered clinical practice and education in manual therapy globally. Social distancing has limited in-person care and changed health-care provision. Education in manual therapy has moved to online platforms with in-person instruction restricted. The global impact on the clinical practice of manual therapy and education has to date not been explored. METHODS: a questionnaire survey methodology was used. A sample of convenience of global leaders in manual therapy practice and education received an electronic link to two surveys: one on clinical practice and one on education. Contributors could complete one or both surveys. RESULTS: Twenty-five surveys were received on clinical practice and 23 on education in manual therapy, representing the six major continents. Global themes in clinical practice demonstrated a sudden and dramatic shift away from patient contact, with limited modifications to manual therapy in patient care currently adopted. Themes in education were of a major shift to online learning, development of new modes of student instruction including video-based assessment and virtual case-based instruction. CONCLUSION: The international perspectives provided demonstrate a major change in manual therapy practice and education globally. Various approaches have been taken in practice and education without a uniform approach being demonstrated.

Milk osteopontin retains integrin-binding activity after in vitro gastrointestinal transit.

Osteopontin (OPN) is a multifunctional protein highly expressed in milk, where it is hypothesized to be involved in immunological signaling via the conserved Arg-Gly-Asp (RGD) integrin-binding sequence. Intervention studies have indicated beneficial effects of orally administered OPN in animal and human infants, but the mechanisms underlying these effects are not well described. To induce physiological effects, OPN must resist gastrointestinal transit in a bioactive form. In this study, we subjected bovine milk OPN to in vitro gastrointestinal transit, and characterized the generated fragments using monoclonal antibody and mass spectrometric analyses. We found that the fragment Trp27-Phe151 containing the integrin-binding RGD sequence resisted in vitro gastric digestion. This resistance was dependent on glycosylation of threonine residues near the integrin-binding sequence in both human and bovine milk OPN. Furthermore, the fragment Trp27-Phe151 retained the ability to interact with integrins in an RGD-dependent process. These results suggest a mechanism for how ingested milk OPN can induce physiological effects via integrin signaling in the intestine.

Pulseless electrical activity following traumatic cardiac arrest: Sign of life or death?

BACKGROUND: Generally considered a sign of life, PEA is the most common arrhythmia encountered following pre-hospital traumatic cardiac arrest. Some recommend cardiac ultrasound (CUS) to determine cardiac wall motion (CWM) prior to terminating resuscitation efforts. This purpose of this study was to evaluate the outcomes of patients with traumatic cardiac arrest presenting with PEA, with and without CWM. METHODS: Trauma patients who underwent pre-hospital CPR were identified from the registries of two level-1 trauma centers. Pre-hospital management by emergency medical transport services was guided by advanced life support protocols. The on-duty trauma surgeon directed the resuscitations and performed or supervised CUS and determined CWM. RESULTS: Among 277 patients who underwent pre-hospital CPR, 110 patients had PEA on arrival to ED. 69 (62.7%) were injured by blunt mechanisms. Median CPR duration was 20.0 and 8.0 min for pre-hospital and ED, respectively. Sixty-three patients (22.7%) underwent resuscitative thoracotomy. One hundred seventy-two patients (62.1%) received CUS and of these 32 (18.6%) had CWM. CWM was significantly associated with survival to hospital admission (21.9% vs. 1.4%; P < 0.001); however, no patient with CUS survived to hospital discharge. Overall, only one patient with PEA on arrival survived to discharge. CONCLUSION: Following pre-hospital traumatic cardiac arrest, PEA on arrival portends death. Although CWM is associated with survival to admission, it is not associated with meaningful survival. Heroic resuscitative measures may be unwarranted for PEA following pre-hospital traumatic arrest, regardless of CWM.

Low frequency of septic arthritis after arthrocentesis and intra-articular glucocorticoid injection.

Objective: The aim of this study was to evaluate the risk of septic arthritis (SA) in patients who received an intra-articular (IA) glucocorticoid (GC) injection and to describe the characteristics of these patients. Methods: All patients undergoing IA procedures at the orthopaedic and rheumatological departments on the Danish island of Funen from January 2006 to December 2013 were identified in the central database and included by register extraction. Patients who developed a clinically inflamed joint and positive synovial fluid culture within 14 days after IA GC injection were considered as having SA. Retrospectively, data on age, gender, affected joint location, bacterial agent, pre-existing inflammatory disorder, and death within 30 days were extracted from the patient files. According to local recommendations, a non-touch sterile technique was used for IA procedures. Patients were informed about the risk of SA and advised to seek medical attention on suspicion of infection or lack of improvement. Results: In total, 22 370 IA procedures were performed. Among these, 14 118 GC injections and 8252 arthrocenteses were undertaken. Only 11 patients were diagnosed with SA (0.08%, 95% confidence interval 0.03-0.12). Risk factors for SA were male gender, age, and pre-existing joint disease. Conclusion: We found a low frequency of SA subsequent to IA GC injections. Older patients with pre-existing joint disease are at higher risk of developing SA.

Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion.

We aimed to identify factors influencing the sensitivity of perfusion imaging after an initial positive coronary computed tomography angiography (CCTA) using invasive coronary angiography (ICA) with conditional fractional flow reserve (FFR) as reference. Secondly we aimed to identify factors associated with revascularisation and to evaluate treatment outcome after ICA. We analysed 292 consecutive patients with suspected significant coronary artery disease (CAD) at CCTA, who underwent perfusion imaging with either cardiac magnetic resonance (CMR) or myocardial perfusion scintigraphy (MPS) followed by ICA with conditional FFR. Stratified analysis and uni- and multiple logistic regression analyses were performed to identify predictors of diagnostic agreement between perfusion scans and ICA and predictors of revascularisation. Myocardial ischemia evaluated with perfusion scans was present in 65/292 (22%) while 117/292 (40%) had obstructive CAD evaluated by ICA. Revascularisation rate was 90/292 (31%). The overall sensitivity for perfusion scans was 39% (30-48), specificity 89% (83-93), PPV 69% (57-80) and NPV 68% (62-74). Stratified analysis showed higher sensitivities in patients with multi-vessel disease at CCTA 49% (37-60) and typical chest pain 50% (37-60). Predictors of revascularisation were multi-vessel disease by CCTA (OR 3.51 [1.91-6.48]) and a positive perfusion scan (OR 4.69 [2.49-8.83]). The sensitivity for perfusion scans after CCTA was highest in patients with typical angina and multiple lesions at CCTA and predicted diagnostic agreement between perfusion scans and ICA. Abnormal perfusion and multi vessel disease at CCTA predicted revascularisation.

Obesity leads to impairments in the morphology and organization of human skeletal muscle lipid droplets and mitochondrial networks, which are resolved with gastric bypass surgery-induced improvements in insulin sensitivity.

AIMS: Skeletal muscle lipid stores and mitochondrial function have been appointed as key players in obesity-induced insulin resistance. However, there are conflicting reports in the literature based on in vitro quantitative measurements. Here, we test the hypothesis that it is not the quantity but the quality that matters. METHODS: This study combines quantitative and qualitative structural measurements of lipid stores and mitochondrial dynamics in skeletal muscle from lean subjects, and subjects with morbid obesity, with and without type 2 diabetes, before and after gastric bypass surgery. RESULTS: The structural organization of muscle mitochondrial networks in type II muscle fibres from subjects with morbid obesity is impaired. In addition, the amount of skeletal muscle perilipin 2 protein per intramyocellular lipid is reduced in subjects with morbid obesity, resulting in qualitative alterations in perilipin 2 coat around some lipid droplets. Gastric bypass surgery-induced weight loss and insulin resistance remission were associated with decreases in intramyocellular lipid stores and, qualitative improvements in lipid droplets' morphology, perilipin 2 coat and mitochondrial dynamics. CONCLUSION: Morbid obesity leads to severe qualitative alterations of both skeletal muscle lipid stores and mitochondrial networks. The degree of structural improvements after gastric bypass surgery was proportional to the improvements in whole body insulin sensitivity, suggesting an association between these events.

Diagnosing coronary artery disease after a positive coronary computed tomography angiography: the Dan-NICAD open label, parallel, head to head, randomized controlled diagnostic accuracy trial of cardiovascular magnetic resonance and myocardial perfusion scintigraphy.

Aims: Perfusion scans after coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD) may reduce unnecessary invasive coronary angiographies (ICAs). However, the diagnostic accuracy of perfusion scans after primary CCTA is unknown. The aim of this study was to determine the diagnostic accuracy of cardiac magnetic resonance (CMR) and myocardial perfusion scintigraphy (MPS) against ICA with fractional flow reserve (FFR) in patients suspected of CAD by CCTA. Methods and results: Included were consecutive patients (1675) referred to CCTA with symptoms of CAD and low/intermediate risk profile. Patients with suspected CAD based on CCTA were randomized 1:1 to CMR or MPS followed by ICA with FFR. Obstructive CAD was defined as FFR ≤ 0.80 or > 90% diameter stenosis by visual assessment. After initial CCTA, 392 patients (23%) were randomized; 197 to CMR and 195 to MPS. Perfusion scans and ICA were completed in 292 patients (CMR 148, MPS 144). Based on the ICA, 117/292 (40%) patients were classified with CAD. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for CMR were 41%, 95% CI [28-54], 84% [75-91], 62% [45-78], and 68% [58-76], respectively. For the MPS group 36% [24-50], 94% [87-98], 81% [61-93], and 68% [59-76], respectively. Conclusion: Patients with low/intermediate CAD risk and a positive CCTA scan represent a challenge to perfusion techniques indicated by the low sensitivity of both CMR and MPS with FFR as a reference. The mechanisms underlying this discrepancy need further investigation.

Prior fragility fracture and risk of incident ischaemic cardiovascular events: results from UK Biobank.

In the large UK Biobank population-based cohort, we found that amongst men, but not women, prior fragility fracture was associated with increased risk of admission with ischaemic heart disease. INTRODUCTION: We aimed to investigate the relationship between prior fracture and risk of incident ischaemic cardiovascular events in a UK population-based cohort. METHODS: UK Biobank is a large prospective cohort comprising 502,637 men and women aged 40-69 years, with detailed baseline assessment. History of fracture was self-reported, and details of hospital admissions for ischaemic heart disease (IHD) (ICD-10:I20-I25) were obtained through linkage to UK Hospital Episode Statistics. Cox proportional hazards models were used to investigate the prospective relationships between prior fracture and hospital admission for men and women, controlling for age, BMI, smoking, alcohol, educational level, physical activity, systolic blood pressure, calcium and vitamin D use, ankle spacing-width, heel BUA and HRT use (women). RESULTS: Amongst men, a fragility fracture (hip, spine, wrist or arm fracture resulting from a simple fall) within the previous 5 years was associated with a 35% increased risk of IHD admission (fully adjusted HR 1.35; 95%CI 1.00, 1.82; p = 0.047), with the relationship predominantly driven by wrist fractures. Associations with hospitalisation for angina in men were similar in age-adjusted models [HR1.54; 95%CI: 1.03, 2.30), p = 0.037], but did not remain statistical significant after full adjustment [HR 1.64; 95%CI: 0.88, 3.07); p = 0.121]. HRs for admission with angina were lower in women, and neither age- nor fully adjusted relationships attained statistical significance. CONCLUSIONS: Prior fragility fracture is an independent risk factor for incident ischaemic cardiovascular events in men. Further work may clarify whether this association is causal or represents shared risk factors, but these findings are likely to be of value in risk assessment of both osteoporosis and cardiovascular disease.

Drug response prediction in high-risk multiple myeloma.

A Drug Response Prediction (DRP) score was developed based on gene expression profiling (GEP) from cell lines and tumor samples. Twenty percent of high-risk patients by GEP70 treated in Total Therapy 2 and 3A have a progression-free survival (PFS) of more than 10years. We used available GEP data from high-risk patients by GEP70 at diagnosis from Total Therapy 2 and 3A to predict the response by the DRP score of drugs used in the treatment of myeloma patients. The DRP score stratified patients further. High-risk myeloma with a predicted sensitivity to melphalan by the DRP score had a prolonged PFS, HR=2.4 (1.2-4.9, P=0.014) and those with predicted sensitivity to bortezomib had a HR 5.7 (1.2-27, P=0.027). In case of predicted sensitivity to bortezomib, a better response to treatment was found (P=0.022). This method may provide us with a tool for identifying candidates for effective personalized medicine and spare potential non-responders from suffering toxicity.

The role of the P2X7 receptor on bone loss in a mouse model of inflammation-mediated osteoporosis.

In inflammatory autoimmune diseases, bone loss is frequent. In most cases, secondary osteoporosis is caused by treatment with systemic glucocorticoid. However, the pathogenesis behind the bone loss is presumed multifactorial. We aimed to elucidate the role of the P2X7 receptor on bone mineral density (BMD), microarchitecture, and bone strength in a standardized mouse model of inflammation-mediated osteoporosis (IMO). In total 146 mice completed our protocol, 70 wild type (WT) mice and 76 P2X7 -/- (knockout, KO). BMD at the femur and spine decreased significantly from baseline to day 20 in the WT IMO mice (p < 0.01). In the WT vehicle, KO vehicle and KO IMO, no significant BMD changes were found. Bone strength showed a lower mid-shaft max strength (p = 0.038) and also a non-significant trend towards lower strength at the femoral neck of the WT IMO group. Trabecular bone volume fraction (BV/TV) and connectivity density (CD) after 20 days were significantly decreased in the WT IMO group (p = 0.001). In contrast, the WT vehicle and KO vehicle, BV/TV and CD did no change at 20 days. Cortical bone revealed no significant microarchitectural changes after 20 days in the WT IMO group, whereas the total cortical area increased significantly in WT vehicle and KO IMO after 20 days (5.2% and 8.8%, respectively). In conclusion, the P2X7 receptor KO mice did not respond to inflammation with loss of BMD whereas the WT mice had a significant loss of BMD, bone strength and trabecular microarchitecture, demonstrating a role for the P2X7 receptor in inflammatory bone loss.