Maternal risk factors for congenital vertebral formation and mixed defects: A population-based case-control study.

Background: The etiology and risk factors of congenital vertebral anomalies are mainly unclear in isolated cases. Also, there are no reports on the risk factors for different subgroups of vertebral anomalies. Therefore, we assessed and identified potential maternal risk factors for these anomalies and hypothesized that diabetes, other chronic diseases, smoking, obesity, and medication in early pregnancy would increase the risk of congenital vertebral anomalies. Methods: All cases with congenital vertebral anomalies were identified in the Finnish Register of Congenital Malformations from 1997 to 2016 for this nationwide register-based case-control study. Five matched controls without vertebral malformations were randomly selected. Analyzed maternal risk factors included maternal age, body mass index, parity, smoking, history of miscarriages, chronic diseases, and prescription drug purchases in early pregnancy. Results: The register search identified 256 cases with congenital vertebral malformations. After excluding 66 syndromic cases, 190 non-syndromic malformations (74 formation defects, 4 segmentation defects, and 112 mixed anomalies) were included in the study. Maternal smoking was a significant risk factor for formation defects (adjusted odds ratio 2.33, 95% confidence interval 1.21-4.47). Also, pregestational diabetes (adjusted odds ratio 8.53, 95% confidence interval 2.33-31.20) and rheumatoid arthritis (adjusted odds ratio 13.19, 95% confidence interval 1.31-132.95) were associated with mixed vertebral anomalies. Conclusion: Maternal pregestational diabetes and rheumatoid arthritis were associated with an increased risk of mixed vertebral anomalies. Maternal smoking increases the risk of formation defects and represents an avoidable risk factor for congenital scoliosis. Level of evidence: III.

Bone marrow metabolism is affected by body weight and response to exercise training varies according to anatomical location.

AIM: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole-body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight. METHODS: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co-twins 7.6 kg/m2 ; eight female pairs). Ten pairs completed the 6-month long training intervention. We measured lumbar vertebral and femoral BM insulin-stimulated glucose uptake (GU) using 18 F-FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers. RESULTS: At baseline, heavier co-twins had higher lumbar vertebral BM GU (p < .001) and lower bone turnover markers (all p < .01) compared with leaner co-twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole-body insulin sensitivity, aerobic capacity (both p < .05) and femoral BM GU (p = .008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p = .02), as GU tended to decrease in heavier co-twins (p = .06) while there was no change in leaner co-twins. CONCLUSIONS: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co-twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity.

Maternal Risk Factors for Congenital Vertebral Anomalies: A Population-Based Study.

BACKGROUND: The spectrum of congenital vertebral defects varies from benign lesions to severe, life-threatening conditions. The etiology and maternal risk factors remain mainly unclear in isolated cases. Hence, we aimed to assess and identify potential maternal risk factors for these anomalies. Based on previous studies, we hypothesized that maternal diabetes, smoking, advanced maternal age, obesity, chronic diseases, and medication used during the first trimester of pregnancy might increase the risk of congenital vertebral malformations. METHODS: We performed a nationwide register-based case-control study. All cases with vertebral anomalies (including live births, stillbirths, and terminations for fetal anomaly) were identified in the Finnish Register of Congenital Malformations from 1997 to 2016. Five matched controls from the same geographic region were randomly selected for each case. Analyzed maternal risk factors included age, body mass index (BMI), parity, smoking, history of miscarriages, chronic diseases, and prescription drugs dispensed during the first trimester of pregnancy. RESULTS: In total, 256 cases with diagnosed congenital vertebral anomalies were identified. After excluding 66 malformations associated with known syndromes, 190 nonsyndromic malformation cases were included. These were compared with 950 matched controls. Maternal pregestational diabetes was a significant risk factor for congenital vertebral anomalies (adjusted odds ratio [OR], 7.30 [95% confidence interval (CI), 2.53 to 21.09). Also, rheumatoid arthritis (adjusted OR, 22.91 [95% CI, 2.67 to 196.40]), estrogens (adjusted OR, 5.30 [95% CI, 1.57 to 17.8]), and heparins (adjusted OR, 8.94 [95% CI, 1.38 to 57.9]) were associated with elevated risk. In a sensitivity analysis using imputation, maternal smoking was also significantly associated with an elevated risk (adjusted OR, 1.57 [95% CI, 1.05 to 2.34]). CONCLUSIONS: Maternal pregestational diabetes and rheumatoid arthritis increased the risk of congenital vertebral anomalies. Also, estrogens and heparins, both of which are frequently used in assisted reproductive technologies, were associated with an increased risk. Sensitivity analysis suggested an increased risk of vertebral anomalies with maternal smoking, warranting further studies. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter variant: Fabry disease in Ostrobothnia (FAST) study.

Fabry disease (FD) is an X chromosome-linked, life-threatening lysosomal disease caused by one of more than 1000 currently known variants in the α-galactosidase A (GLA) gene. The follow-up part of the Fabry Disease in Ostrobothnia (FAST) study reports the long-term effect of enzyme replacement therapy (ERT) on a prospectively collected cohort of 12 patients, 4 males and 8 females, mean age 46 years (SD 16), with the classical variant c.679C > T p.Arg227Ter, which is one of the most common FD variants worldwide. In the natural history period of the FAST study, half of the patients in both sexes had at least one major event, of which 80% were of cardiac origin. During 5 years of ERT, four patients had a total of six major clinical events consisting of one silent ischemic stroke, three ventricular tachycardias and two increased left ventricular mass indexes. In addition, four patients developed minor cardiac events, four patients minor renal events, and one patient a minor neurological event. ERTs may delay but not prevent the progression of the disease in most patients with the variant Arg227Ter. This variant might be suitable for investigating the efficacy of second-generation ERTs compared to the currently used ERTs regardless of sex.

Cardiovascular morbidity following conventional therapy versus allogeneic hematopoietic stem cell transplantation after childhood, adolescent, and young adult leukemia in Finland.

Allogeneic hematopoietic stem cell transplantation (aHSCT) represents a therapeutic choice for high-risk and relapsed leukemia at a young age. In this retrospective population-based study, we evaluated cardiovascular complications after aHSCT (N = 272) vs conventional therapy (N = 1098) among patients diagnosed with acute lymphoblastic or acute myeloid leukemia below 35 years between 1985 and 2004. Additionally, siblings from a prior comparison group served as population controls (N = 39 217). Childhood leukemia and aHSCT was associated with a 16-fold HR for developing arterial hypertension (HR 16.8, 95%CI 1.5-185.5) compared with conventional therapy. A 2-fold HR for any cardiovascular complication was observed after AYA leukemia and aHSCT vs conventional treatment (HR 2.7, 95% CI 1.4-5.1). After AYA leukemia and aHSCT, the HR of cardiac arrhythmia was significantly elevated vs conventional therapy (HR 14.4, 95% CI 1.5-125.2). Moreover, after aHSCT in childhood, elevated hazard ratios (HRs) were found for cardiomyopathy/ cardiac insufficiency (HR 105.0, 95% CI 10.0-1100.0), cardiac arrhythmia, and arterial hypertension (HR 20.1, 95%CI 2.5-159.7 and HR 20.0, 95%CI 4.1-97.4) compared with healthy controls. After adolescent and young adult (AYA) leukemia and aHSCT, markedly increased HRs were observed for cardiac arrhythmia (HR 29.2, 95%CI 6.6-129.2), brain vascular thrombosis/ atherosclerosis and cardiomyopathy/cardiac insufficiency (HR 23.4, 95%CI 7.1-77.4 and HR 19.2, 95%CI 1.5-245.2) compared with healthy controls. As the cumulative incidence for cardiovascular complications rose during the follow-up of childhood and AYA leukemia patients, long-term cardiovascular surveillance is warranted to optimize the quality of life after childhood and AYA leukemia following both conventional treatment and aHSCT.

Radium-223 dichloride treatment in metastatic castration-resistant prostate cancer in Finland: A real-world evidence multicenter study.

BACKGROUND: Radium-233 dichloride is an alpha emitter that specifically targets bone metastases in prostate cancer. Results of a previously reported phase III randomized trial showed survival benefit for radium-223 compared to best supportive care in castration-resistant prostate cancer (CRPC) with bone metastases. However, real-world data are also needed with wider inclusion criteria. METHODS: We report results of a retrospective multicenter study including all patients with metastatic CRPC treated with radium-223 in all five university hospitals in Finland since the introduction of the treatment. We identified 160 patients who had received radium-223 in Finland in 2014-2019. RESULTS: The median overall survival (OS) was 13.8 months (range 0.5-57 months), and the median real-world progression-free survival (rwPFS) was 4.9 months (range 0.5-29.8 months). Alkaline phosphatase (ALP) values within the normal range before and during the radium-223 treatment or the reduction of elevated ALP to normal range during treatment were associated with better OS when compared to elevated ALP values before and during treatment (p < 0.0001). High prostate-specific antigen (PSA) level (≥100 µg/L) before radium-223 treatment was associated with poor OS compared to low PSA level (<20 µg/L) (p = 0.0001). Most patients (57%) experienced pain relief. Pain relief indicated better OS (p = 0.002). Radium-223 treatment was well tolerated. Toxicity was mostly low grade. Only 12.5% of the patients had grade III-IV adverse events, most commonly anemia, neutropenia, leucopenia, and thrombocytopenia. CONCLUSION: Radium-223 was well tolerated in routine clinical practice, and most patients achieved pain relief. Pain relief, ALP normalization, lower baseline PSA, and PSA decrease during radium-223 treatment were prognostic for better survival. The efficacy of radium-223 in mCRPC as estimated using OS was comparable to earlier randomized trial in this retrospective real-world study. Our results support using radium-223 for mCRPC patients with symptomatic bone metastases even in the era of new-generation androgen receptor-targeted agents.

TSPO is a potential independent prognostic factor associated with cellular respiration and p16 in head and neck squamous cell carcinoma.

Background: Treatment resistance and relapse are common problems in head and neck squamous cell carcinoma (HNSCC). Except for p16, no clinically accepted prognostic biomarkers are available for HNSCC. New biomarkers predictive of recurrence and survival are crucial for optimal treatment planning and patient outcome. High translocator protein (TSPO) levels have been associated with poor survival in cancer, but the role of TSPO has not been extensively evaluated in HNSCC. Materials and methods: TSPO expression was determined in a large population-based tissue microarray cohort including 611 patients with HNSCC and evaluated for survival in several clinicopathological subgroups. A TCGA HNSCC cohort was used to further analyze the role of TSPO in HNSCC. Results: TSPO expression was downregulated in more aggressive tumors. Low TSPO expression associated with worse 5-year survival and was an independent prognostic factor for disease-specific survival. Subgroup analyses showed that low TSPO expression associated with worse survival particularly in p16-positive oropharyngeal cancer. In silico analyses supported the prognostic role of TSPO. Cellular respiration had the highest significance in pathway analyses for genes expressed positively with TSPO. Conclusion: Decreased TSPO expression associates with poor prognosis in HNSCC. TSPO is a prognostic biomarker in HNSCC to potentially guide treatment stratification especially in p16-positive oropharyngeal cancer.

Blood culture positivity in patients with acute appendicitis: A propensity score-matched prospective cohort study.

BACKGROUND AND OBJECTIVE: The prevalence of bacteremia in acute appendicitis is unknown. We aimed to assess prevalence and predictive factors of bacteremia in adult patients with appendicitis. METHODS: In this prospective propensity score-matched cohort study, patients were recruited as part of one single-center prospective observational study assessing appendicitis microbiology in concurrence with two randomized controlled trials on non-operative treatment of uncomplicated acute appendicitis. All patients evaluated for enrollment in these three trials between April 2017 and December 2018 with both a confirmed diagnosis of appendicitis and available blood culture on admission were included in this study. Potential predictive factors of bacteremia (age, sex, body mass index (BMI), body temperature, C-reactive protein (CRP), leukocyte count, comorbidities, symptom duration, and appendicitis severity) were assessed. Prevalence of bacteremia was determined by all available blood cultures followed by propensity score matching using sex, age, BMI, CRP, leukocyte count, and body temperature of the patients without available blood culture. RESULTS: Out of the 815 patients with appendicitis, 271 patients had available blood culture and the prevalence of bacteremia was 12% (n = 33). Based on propensity score estimation, the prevalence of bacteremia in the whole prospective appendicitis cohort was 11.1%. Bacteremia was significantly more frequent in complicated acute appendicitis (15%; 29/189) compared with uncomplicated acute appendicitis (5%; 4/82) (p = 0.015). Male sex (p = 0.024) and higher body temperature (p = 0.0044) were associated with bacteremia. CONCLUSIONS: Estimated prevalence of bacteremia in patients with acute appendicitis was 11.1%. Complicated appendicitis, male sex, and higher body temperature were associated with bacteremia in acute appendicitis.

Bioactive glass granules versus standard autologous and allogeneic bone grafts: a randomized trial of 49 adult bone tumor patients with a 10-year follow-up.

BACKGROUND AND PURPOSE: As a synthetic bone void filler, bioactive glasses (BGs) may enhance angiogenesis and osteogenesis. In this randomized trial, we compared the clinical efficacy of BG granules and standard bone grafts in patients undergoing surgery for benign bone tumors. PATIENTS AND METHODS: 49 recruited patients were randomized to receive BG granules or undergo conventional bone grafting to fill defects following tumor removal. As the standard of care, small-sized defects were filled with autologous graft, and large-sized defects were filled with allogeneic graft. The primary endpoint was treatment success at 1 year, defined by no reoperation, no tumor recurrence, and no device-related adverse events. Secondary endpoints included patient-reported outcomes (Rand-36 and pain scores) and quantitative assessment of blood flow and metabolic activity by means of 18F-fluoride PET/CT imaging. As an off-trial group, 15 children and adolescents (age < 18 years) underwent tumor removal and BG-filling, without randomization. RESULTS: At 1-year, 21 of 25 BG-treated patients (risk estimate 0.84, 95% confidence interval [CI] 0.70-0.98) and 20 of 24 patients in the standard of care group (0.83, CI 0.68-0.98) met the criteria for treatment success. The groups had similar Rand-36 scores. In patients with small defects, BG filling was associated with shorter operative time and less postoperative pain at 1 month. In patients with large defects, blood flow was similar, but BG-filled defects showed higher metabolic activity than allograft-filled defects at 1-year. The survey of the postoperative period ≥10 years revealed no BG-related adverse events. INTERPRETATION: BG granules had similar overall rates of treatment success compared with autografts and allografts, but large-scale trials are needed for the confirmation of clinical equivalence. The extended metabolic activity confirms the expected cellular responses of osseointegrated BG granules.

Antibiotics versus placebo in adults with CT-confirmed uncomplicated acute appendicitis (APPAC III): randomized double-blind superiority trial.

BACKGROUND: Non-operative management of uncomplicated acute appendicitis is an option, but omission of antibiotics from the regimen has not been tested. METHODS: A double-blind, placebo-controlled, superiority RCT in adults with CT-confirmed uncomplicated acute appendicitis was designed to compare placebo with antibiotics (intravenous ertapenem followed by oral levofloxacin and metronidazole). The primary endpoint was treatment success (resolution resulting in discharge without appendicectomy within 10 days); secondary outcomes included pain scores, complications, hospital stay, and return to work. RESULTS: From May 2017 to September 2020, 72 patients with a mean(s.d.) age of 37.5 (11.1) years were recruited at five hospitals. Six were excluded after randomization (5 early consent withdrawals, 1 randomization protocol violation), 35 were assigned to receive antibiotics, and 31 to receive placebo. Enrolment challenges (including hospital pharmacy resources in an acute-care surgery setting) meant that only the lowest sample size of three predefined scenarios was achieved. The 10-day treatment success rate was 87 (95 per cent c.i. 75 to 99) per cent for placebo and 97 (92 to 100) per cent for antibiotics. This clinical difference of 10 (90 per cent c.i. -0.9 to 21) per cent was not statistically different for the primary outcome (1-sided P = 0.142), and secondary outcomes were similar. CONCLUSION: The lack of antibiotic superiority statistically suggests that a non-inferiority trial against placebo is warranted in adults with CT-confirmed mild appendicitis. Registration number: EudraCT 2015-003634-26 (https://eudract.ema.europa.eu/eudract-web/index.faces), NCT03234296 (http://www.clinicaltrials.gov).

Appendicitis was the most common reason for emergency surgery, but we now know that mild and severe acute appendicitis are two different diseases. Severe appendicitis still necessitates removal of the appendix but antibiotics alone are an option for mild disease. This small study found that most cases of mild appendicitis to resolve even without antibiotics. Larger studies (more patients) would be needed to show that omitting antibiotics is safe and no worse than antibiotic therapy for milder acute appendicitis.

Individualised non-contrast MRI-based risk estimation and shared decision-making in men with a suspicion of prostate cancer: protocol for multicentre randomised controlled trial (multi-IMPROD V.2.0).

INTRODUCTION: European Association of Urology and UK National Institute for Health and Care Excellence guidelines recommend that all men with suspicions of prostate cancer should undergo prebiopsy contrast enhanced, that is, multiparametric prostate MRI. Subsequent prostate biopsies should also be performed if MRI is positive, that is, Prostate Imaging-Reporting and Data System (PI-RADS) scores 3-5. However, several retrospective post hoc analyses have shown that this approach still leads to many unnecessary biopsy procedures. For example, 88%-96% of men with PI-RADS, three findings are still diagnosed with clinically non-significant prostate cancer or no cancer at all. METHODS AND ANALYSIS: This is a prospective, randomised, controlled, multicentre trial, being conducted in Finland, to demonstrate non-inferiority in clinically significant cancer detection rates among men undergoing prostate biopsies post-MRI and men undergoing prostate biopsies post-MRI only after a shared decision based on individualised risk estimation. Men without previous diagnosis of prostate cancer and with abnormal digital rectal examination findings and/or prostate-specific antigen between 2.5 ug/L and 20.0 ug/L are included. We aim to recruit 830 men who are randomised at a 1:1 ratio into control (all undergo biopsies after MRI) and intervention arms (the decision to perform biopsies is based on risk estimation and shared decision-making). The primary outcome of the study is the proportion of men with clinically significant prostate cancer (Gleason 4+3 prostate cancer or higher). We will also compare the overall biopsy rate, benign biopsy rate and the detection of non-significant prostate cancer between the two study groups. ETHICS AND DISSEMINATION: The study (protocol V.2.0, 4 January 2021) was approved by the Ethics Committee of the Hospital District of Southwest Finland (IORG number: 0001744, IBR number: 00002216; trial number: 99/1801/2019). Participants are required to provide written informed consent. Full reports of this study will be submitted to peer-reviewed journals, mainly urology and radiology. TRIAL REGISTRATION NUMBER: NCT04287088; the study is registered at ClinicalTrials.gov.

Pulmonary manifestations and the effectiveness of enzyme replacement therapy in Fabry Disease with the p. Arg227Ter (p.R227*) mutation.

BACKGROUND: Fabry disease (FD) is caused by a defect in α-galactosidase A gene (GLA) which leads to a progressive accumulation of neutral shingolipids, mainly globotriaosylceramide and its metabolites in several organs. Pulmonary manifestations of FD mimic chronic obstructive pulmonary disease and are disproportionate to smoking status. The effect of enzyme replacement therapy (ERT) on pulmonary function is inconclusive. We studied the effect of ERT on pulmonary function in FD with a mutation p. Arg227Ter (p.R227*) which is one of the most common mutations causing classical FD in Finland and worldwide. METHODS: Patients were annually examined by multidisciplinary team. Based on the maximal pulmonary oxygen consumption at the baseline, either cardiopulmonary exercise test or combination of spirometry and 6-minute walking test were performed annually during 5-year follow-up. RESULTS: Four males and eight females met the criteria for ERT and were included in this study. Three of 12 patients had obstruction by GOLD criterion before ERT, and one had a borderline obstruction. In 5 years, five patients were classified as obstructive, although the real change in FEV1/FVC was unchanged in the whole cohort. Only one patient was an active smoker. CONCLUSION: In nonsmokers, pulmonary manifestations in classical FD are mild and might be stabilized by ERT.

Evaluation of [18F]F-DPA PET for Detecting Microglial Activation in the Spinal Cord of a Rat Model of Neuropathic Pain.

PURPOSE: Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ([18F]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats. PROCEDURES: Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post-injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using [18F]F-DPA or [11C]PK11195. Ex vivo biodistribution and PET imaging of the removed spinal cord were carried out with [18F]F-DPA. Sham-operated and PK11195-pretreated animals were also examined. RESULTS: Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with [18F]F-DPA compared with [11C]PK11195. Ex vivo PET imaging of the removed spinal cord showed [18F]F-DPA accumulation in the inflammation site, which was immunohistochemically confirmed to coincide with microglia activation. Pretreatment with PK11195 eliminated the uptake. The SUV values of in vivo [18F]F-DPA and [11C]PK11195 PET were not significantly increased in the lesion compared with the reference region, and were fivefold higher than the values obtained from the ex vivo data. Ex vivo biodistribution revealed a twofold higher [18F]F-DPA uptake in the vertebral body compared to that seen in the bone from the skull. CONCLUSIONS: [18F]F-DPA aided visualization of the spinal cord inflammation site in PSNL rats on ex vivo autoradiography and was superior to [11C]PK11195. In vivo [18F]F-DPA PET did not allow for visualization of tracer accumulation even using a high-spatial-resolution PET scanner. The main reason for this result was due to insufficient SUVs in the spinal cord region as compared with the background noise, in addition to a spillover from the vertebral body.

Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM-a prospective, randomized, single-centre, open-label study.

OBJECTIVES: Severe COVID-19 is associated with an imbalanced immune response. We hypothesized that patients with enhanced inflammation, as demonstrated by increased levels of certain inflammatory biomarkers, would benefit from interleukin-6 blockage. METHODS: Patients hospitalized with COVID-19, hypoxemia, and at least two of four markedly elevated markers of inflammation (interleukin-6, C-reactive protein, ferritin, and/or D-dimer) were randomized for tocilizumab (TCZ) plus standard of care (SoC) or SoC alone. The primary endpoint was clinical status at day 28 assessed using a seven-category ordinal scale, and the secondary endpoints included intensive care unit admission, respiratory support, and duration of hospital admission. RESULTS: Clinical status at day 28 was significantly better in patients who received TCZ in addition to SoC compared with those who received SoC alone (p = 0.037). By then, 93% of patients who received TCZ (n = 53 of 57) and 86% of control patients (n = 25 of 29) had been discharged from the hospital. In addition, 47% of TCZ patients (n = 27 of 57) and 24% of control patients (n = 7 of 29) had resumed normal daily activities. The median length of hospitalization was 9 days (interquartile range, 7-12) in the TCZ group and 12 days (interquartile range, 9-15) in the control group (p = 0.014). DISCUSSION: In patients hospitalized with COVID-19, hypoxemia, and elevated inflammation markers, administration of TCZ in addition to SoC was associated with significantly better clinical recovery by day 28 and a shorter hospitalization compared with SoC alone.

Comparison of reprojected bone SPECT/CT and planar bone scintigraphy for the detection of bone metastases in breast and prostate cancer.

OBJECTIVE: The aim of this study was to compare reprojected bone SPECT/CT (RBS) against planar bone scintigraphy (BS) in the detection of bone metastases in breast and prostate cancer patients. METHODS: Twenty-six breast and 105 prostate cancer patients with high risk for bone metastases underwent 99mTc-HMDP BS and whole-body SPECT/CT, 1.5-T whole-body diffusion-weighted MRI and 18F-NaF or 18F-PSMA-1007 PET/CT within two prospective clinical trials (NCT01339780 and NCT03537391). Consensus reading of all imaging modalities and follow-up data were used to define the reference standard diagnosis. The SPECT/CT data were reprojected into anterior and posterior views to produce RBS images. Both BS and RBS images were independently double read by two pairs of experienced nuclear medicine physicians. The findings were validated against the reference standard diagnosis and compared between BS and RBS on the patient, region and lesion levels. RESULTS: All metastatic patients detected by BS were also detected by RBS. In addition, three metastatic patients were missed by BS but detected by RBS. The average patient-level sensitivity of two readers for metastases was 75% for BS and 87% for RBS, and the corresponding specificity was 79% for BS and 39% for RBS. The average region-level sensitivity of two readers was 64% for BS and 69% for RBS, and the corresponding specificity was 96% for BS and 87% for RBS. CONCLUSION: Whole-body bone SPECT/CT can be reprojected into more familiar anterior and posterior planar images with excellent sensitivity for bone metastases, making additional acquisition of planar BS unnecessary.

Association between bone mineral metabolism and vascular calcification in end-stage renal disease.

BACKGROUND: Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism. METHODS: Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 - L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score. RESULTS: This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured. CONCLUSIONS: The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042 . Date of registration is 17/11/2016.

Diagnostic accuracy using low-dose versus standard radiation dose CT in suspected acute appendicitis: prospective cohort study.

BACKGROUND: Contrast-enhanced CT is the reference standard used in diagnostic imaging for acute appendicitis in adults. The radiation dose has been of concern. This study aimed to assess whether a lower radiation dose would affect the diagnostic accuracy of CT. METHODS: This was a prospective single-centre cohort study of patients (aged over 16 years) with suspected appendicitis evaluated for enrolment in concurrent APPAC II-III trials. The diagnostic accuracy of contrast-enhanced low- and standard-dose CT was compared with study protocols guiding imaging based on BMI; this enabled direct CT imaging comparison only in patients with a BMI below 30 kg/m2. The on-call CT diagnosis was compared with the final clinical diagnosis. RESULTS: Among all 856 patients investigated, the accuracy of low-dose (454 patients) and standard-dose (402 patients) CT in identifying patients with and without appendicitis was 98·0 and 98·5 per cent respectively. In patients with a BMI under 30 kg/m2, respective values were 98·2 per cent (434 patients) and 98·6 per cent (210 patients) (P = 1·000). The corresponding accuracy for differentiating between uncomplicated and complicated acute appendicitis was 90·3 and 87·6 per cent in all patients, and 89·8 and 88·4 per cent respectively among those with a BMI below 30 kg/m2 (P = 0·663). The median radiation dose in the whole low- and standard-dose CT groups was 3 and 7 mSv respectively. In the group with BMI below 30 kg/m2, corresponding median doses were 3 and 5 mSv (P < 0·001). CONCLUSION: Low- and standard-dose CT were accurate both in identifying appendicitis and in differentiating between uncomplicated and complicated acute appendicitis. Low-dose CT was associated with a significant radiation dose reduction, suggesting that it should be standard clinical practice at least in patients with a BMI below 30 kg/m2.

Early restrictive fluid balance is associated with lower hospital mortality independent of acute disease severity in critically ill patients on CRRT.

Fluid overload (FO) with coincident acute kidney injury has been associated with increased mortality. However, it is unclear whether FO is an independent determinant of mortality for disease severity. We aimed to explore whether the development of fluid balance (FB) during the first 72 h of continuous renal replacement therapy (CRRT) is independently associated with hospital mortality. All patients admitted to a single centre ICU requiring CRRT for at least 24 h between years 2010-2019 were included. Extracted data included patient demographics and clinical parameters including daily cumulative fluid balance (FBcum), lactate, SOFA score and vasoactive requirement at the initiation and during the first 72 h of CRRT. 399 patients were included in the analysis. Hospital survivors had a significantly lower FBcum at CRRT initiation compared to non-survivors (median 1382 versus 3265 ml; p = 0.003). Hourly fluid balance per bodyweight (FBnet) was lower in survivors at 0-24, 24-48 and 48-72 h after initiation of CRRT (p < 0.008 for all comparisons). In the survival analysis (analyzed with counting process model) significant time-dependent explanatory variables for hospital mortality were FBnet (per ml/kg/h: HR: 1.319, 95% CI 1.038-1.677, p = 0.02), lactate (HR: 1.086, 95% CI 1.030-1.145, p = 0.002) and SOFA score (per ml/kg/h: HR: 1.084, 95% CI 1.025-1.146, p = 0.005) during the first 72 h of CRRT. Even after careful adjustment for repeated measures of disease severity, FBnet during the first 72 h of CRRT remains independently associated with hospital mortality, in critically ill patients with AKI.

Pregabalin and Persistent Postoperative Pain Following Posterior Spinal Fusion in Children and Adolescents: A Randomized Clinical Trial.

BACKGROUND: Surgical correction of spinal deformity requires major surgical intervention with extensive manipulation of the spine and neural elements. Persistent postoperative pain affects patient quality of life and can also cause financial burden for patient families and for society. We aimed to investigate the effect of perioperative pregabalin on the incidence of persistent pain following instrumented spinal fusion. METHODS: We conducted a randomized, double-blinded, and placebo-controlled single-center clinical trial. Adolescents and children 10 to 21 years old with a spinal deformity who were scheduled for pedicle screw instrumentation and fusion were randomized into either the pregabalin or placebo group. Patients received 2 mg/kg of pregabalin or a placebo twice daily preoperatively and for 5 days postoperatively. The duration of follow-up was 2 years. The primary outcomes were cumulative opioid consumption during the first 48 hours postoperatively and the incidence of persistent postoperative pain over the course of the 2-year follow-up. RESULTS: Sixty-four of 77 eligible patients were enrolled in the study, with all patients completing the 2-year follow-up. Thirty-three patients were randomized into the pregabalin group and 31 into the placebo group. There was no significant difference in cumulative 48-hour opioid consumption between the study groups. The Scoliosis Research Society 24-Item Questionnaire pain domain score improved significantly, from a mean value of 3.8 in both groups to 4.3 in the pregabalin and 4.0 in the placebo group at 2 years postoperatively, with no differences between the study groups at any time point (p = 0.317). The Scoliosis Research Society total scores of the study groups were similar (p = 0.678). Back pain, as measured with use of a visual analogue scale, improved significantly (p = 0.001) with no significant differences at any time point (preoperatively and 6 months, 1 year, and 2 years postoperatively). CONCLUSIONS: Perioperative pregabalin does not reduce postoperative opioid consumption or the incidence of persistent postoperative pain following instrumented posterior spinal fusion for spinal deformities in an adolescent population. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.