Follow-up of intramyocardial bone marrow mononuclear cell transplantation beyond 10 years.

Bone marrow mononuclear cells (BMMCs) have been evaluated for their ability to improve cardiac repair and benefit patients with severe ischemic heart disease and heart failure. In our single-center trial in 2006-2011 we demonstrated the safety and efficacy of BMMCs injected intramyocardially in conjunction with coronary artery bypass surgery. The effect persisted in the follow-up study 5 years later. In this study, we investigated the efficacy of BMMC therapy beyond 10 years. A total of 18 patients (46%) died during over 10-years follow-up and 21 were contacted for participation. Late gadolinium enhancement cardiac magnetic resonance imaging (CMRI) and clinical evaluation were performed on 14 patients, seven from each group. CMRIs from the study baseline, 1-year and 5-years follow-ups were re-analyzed to enable comparison. The CMRI demonstrated a 2.1-fold larger reduction in the mass of late gadolinium enhancement values between the preoperative and the over 10-years follow-up, suggesting less scar or fibrosis after BMMC treatment (- 15.1%; 95% CI - 23 to - 6.7% vs. - 7.3%; 95% CI - 16 to 4.5%, p = 0.039), compared to placebo. No differences in mortality or morbidity were observed. Intramyocardially injected BMMCs may exert long-term benefits in patients with ischemic heart failure. This deserves further evaluation in patients who have received BMMCs in international clinical studies over two decades.

Smoking is a predictor of complications in all types of surgery: a machine learning-based big data study.

BACKGROUND: Machine learning algorithms are promising tools for smoking status classification in big patient data sets. Smoking is a risk factor for postoperative complications in major surgery. Whether this applies to all surgery is unknown. The aims of this retrospective cohort study were to develop a machine learning algorithm for clinical record-based smoking status classification and to determine whether smoking and former smoking predict complications in all surgery types. METHODS: All surgeries performed in a Finnish hospital district from 1 January 2015 to 31 December 2019 were analysed. Exclusion criteria were age below 16 years, unknown smoking status, and unknown ASA class. A machine learning algorithm was developed for smoking status classification. The primary outcome was 90-day overall postoperative complications in all surgeries. Secondary outcomes were 90-day overall complications in specialties with over 10 000 surgeries and critical complications in all surgeries. RESULTS: The machine learning algorithm had precisions of 0.958 for current smokers, 0.974 for ex-smokers, and 0.95 for never-smokers. The sample included 158 638 surgeries. In adjusted logistic regression analyses, smokers had increased odds of overall complications (odds ratio 1.17; 95 per cent c.i. 1.14 to 1.20) and critical complications (odds ratio 1.21; 95 per cent c.i. 1.14 to 1.29). Corresponding odds ratios of ex-smokers were 1.09 (95 per cent c.i. 1.06 to 1.13) and 1.09 (95 per cent c.i. 1.02 to 1.17). Smokers had increased odds of overall complications in all specialties with over 10 000 surgeries. ASA class was the most important complication predictor. CONCLUSION: Machine learning algorithms are feasible for smoking status classification in big surgical data sets. Current and former smoking predict complications in all surgery types.

Novel insights on association and reactivity of Bispectral Index, frontal electromyogram, and autonomic responses in nociception-sedation monitoring of critical care patients.

BACKGROUND: Assessing nociception and sedation in mechanically ventilated patients in the ICU is challenging, with few reliable methods available for continuous monitoring. Measurable cardiovascular and neurophysiological signals, such as frontal EEG, frontal EMG, heart rate, and blood pressure, have potential in sedation and nociception monitoring. The hypothesis of this explorative study is that derived variables from the aforementioned signals predict the level of sedation, as described by the Richmond Agitation-Sedation score (RASS), and respond to painful stimuli during critical care. METHODS: Thirty adult postoperative ICU patients on mechanical ventilation and receiving intravenous sedation, excluding patients with primary neurological disorders, head injury, or need for continuous neuromuscular blockage. Bispectral Index (BIS), EMG power (EMG), EMG-derived Responsiveness Index (RI), and averaged blood pressure variability (ARV) were tested against RASS measurements. The aforementioned variables together with blood pressure and Surgical Pleth Index (SPI) were explored before and after painful stimuli (for example bronchoscopy, or pleural puncture) at varying RASS levels, to test variable responsiveness. RESULTS: BIS, EMG, and RI predicted RASS levels with a prediction probability (PK) of 0.776 for BIS, 0.761 for EMG, and 0.763 for RI. In addition, BIS, EMG, and ARV demonstrated responsiveness to painful stimuli during deep sedation (RASS score ≤ -3). CONCLUSION: Variables derived from EEG and EMG are associated with sedation levels, as described by the RASS score. Furthermore, these variables, along with ARV, react with consistency to painful stimuli during deep sedation (RASS -5 to -3), offering novel tools for nociception-sedation monitoring of mechanically ventilated ICU patients requiring deep sedation.

Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery.

Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery. Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life. Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies. Trial Registration:ClinicalTrials.gov, identifier: NCT02672163.

Dramatic increase in serum trypsinogens, SPINK1 and hCGß in aortic surgery patients after hypothermic circulatory arrest.

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCGß, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCGß were observed in patients after HCA. This was accompanied by increased concentrations of S100ß and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.

Severe Complications of Laparoscopic and Conventional Appendectomy Reported to the Finnish Patient Insurance Centre.

BACKGROUND: Appendectomy is considered a safe operation, the related complications being minor. Negative exploration is an accepted procedure to avoid complications of appendicitis. Treatment with antibiotics is under debate as a primary treatment for appendicitis. The aim of this study was to collect and analyze detailed information on complications and morbidity related to appendectomy using the information of the nationwide Patient Insurance Association (PIA) database and to study the incidence of patient claims and compensated injuries related to appendectomy in Finland. METHODS: Patients' claims from 1990 to 2010 were collected from the PIA register. Complications were classified using the accordion severity grading system. Severe complications were selected for more detailed analyses. Laparoscopic and open surgeries were compared. Factors related to compensated claims were assessed. For statistical analysis, Fisher's exact test, logistic multivariate regression, and the Mann-Kendall function were used. RESULTS: Appendectomy complications leading to a patient insurance claim in Finland are rare (0.2 %). The rate of patients' claims after laparoscopic surgery was higher than after open surgery (p < 0.001), but the rate of compensated claims was equal. During the study period, complications after laparoscopic procedures more often led to additional surgery or organ failure (p = 0.03). Of the patients with a compensated injury, only 57 % had appendicitis. Preoperative computed tomography was used in only 6 % of these cases. CONCLUSIONS: Patient injuries and claims regarding severe complications after appendectomy are rare. The complications related to laparoscopic appendectomy were more severe than those of open surgery.

Increased risk of certain second primary malignancies in patients treated for well-differentiated thyroid cancer.

BACKGROUND: The objective was to evaluate the incidence of second primary malignancies (SPMs) in thyroid cancer patients compared to age- and gender-matched controls without thyroid cancer from the general population of the same region. METHODS: Tampere and Oulu University Hospitals treated 910 patients with well-differentiated thyroid cancer during 1981-2002. The Finnish cancer registry provided follow-up data for patients and controls (n = 4542) for an average of 16 years. The incidence of invasive malignancies per 10 000 person-years was calculated and compared between patients and controls. The follow-up period ended December 31st, 2011. RESULTS: Young patients <40 years [Rate Ratio (RR) 1.73, p = 0.037] and patients diagnosed since 1996 (RR 1.51, p = 0.029) had an increased incidence of SPMs. Patients had an increased risk of sarcomas and soft tissue tumours (RR 4.37, p = 0.004) and haematological and lymphatic malignancies (RR 1.87, p = 0.035), especially non-Hodgkin lymphomas (RR 2.78, p = 0.035). The overall incidence of SPMs was not statistically higher in patients (109 SPMs/910 patients vs. 500 SPMs/4542 controls, RR 1.12, p = 0.269). Most patients were radioiodine-treated (81 %). The risk of SPMs with low cumulative radioiodine doses was RR 0.94 (≤ 3.7 GBq, p = 0.650) and with high doses RR 1.37 (>3.7 GBq, p = 0.143). Cumulative radioiodine dose increased during the study period. CONCLUSIONS: The overall incidence of SPMs was not higher in patients than in controls. The incidence of SPMs in thyroid carcinoma patients was higher in patients <40 years old and patients diagnosed since 1996. The incidence of sarcomas and lymphomas was higher in patients than in controls.

APOE4 predicts amyloid-ß in cortical brain biopsy but not idiopathic normal pressure hydrocephalus.

OBJECTIVE: To investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-ß (Aß) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimer's disease (AD). METHODS: 202 patients with presumed NPH were evaluated by intraventricular pressure monitoring and frontal cortical biopsy immunostained against Aß (134 semiquantified by Aß plaques/mm2). The 202 patients and 687 cognitively healthy individuals were genotyped for APOE. The final clinical diagnoses in a median follow-up of 3.9 years were: 113 iNPH (94 shunt responsive, 16 shunt non-responsive, three not shunted); 36 AD (12 mixed iNPH + AD); 53 others. RESULTS: The APOE genotypes distributed similarly in the 94 shunt responsive and 16 non-responsive iNPH patients and healthy controls. In multivariate analysis, the APOE4 allele correlated independently with Aß plaques in the cortical biopsies (OR 8.7, 95% CI 3.6 to 20, p<0.001). The APOE4 allele in presumed NPH predicted later AD as follows: sensitivity 61%; specificity 77%; positive predictive value 37%; negative predictive value 90%. CONCLUSION: In presumed NPH patients, APOE4 associates independently with the presence of Aß plaques in the frontal cortical biopsy. APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Our data further support the view that the iNPH syndrome is a distinct dementing disease. TRIAL REGISTRATION NUMBER: Kuopio NPH Registry (http://www.uef.fi/nph).

Detection of phase biaxiality in liquid crystals by use of the quadrupole shift in 131Xe NMR spectra.

An experimental method to unambiguously distinguish between uniaxial and biaxial liquid crystal phases is introduced. The method is based on the second order quadrupole shift (SOQS) observable in 131Xe NMR spectra of xenon dissolved in liquid crystals. It is shown that besides revealing the biaxiality, the 131Xe SOQS offers a novel method to determine the tilt angle in smectic C phases. As an example, the 131Xe SOQS in a ferroelectric liquid crystal is reported. It yields up a biaxial phase in between isotropic and smectic C phases.

A New Generation Prothrombin Time Method for INR.

Prothrombin time (PT) is the leading test for monitoring oral anticoagulation therapy (OAT). We sought to determine INR taking into account only active coagulation factors FII, FVII and FX without inhibition in patient plasmas and calibrator kits.We measured PT using a combined thromboplastin reagent. The calculation was based on a new PT method, which measures active coagulation factors (F II, F VII, FX) and corrects the errors caused by inactive coagulation factors.On this basis, an INR result with and without inhibition for individual patient samples was also calculated and applied to 200 plasma samples obtained from OAT patients. Conspicuous variation in inhibition between the four calibration kits was noted. The kinetics of this inhibition was closest to a noncompetitive pattern.The need of correction for INRs of single patients increases with higher INRs. At the same level of patient INRs the coagulation inhibiton varies markedly.It has been known that different thromboplastin reagents possess variable sensitivities, but this may depend on sensitivity in inactive coagulation factors. PT methods today measure the sum of active coagulation factors and inhibition of inactive coagulation factors. ISI calibrators contain variable amounts of inactive coagulation factors, which renders harmonisation of INR results.Application of the Acf-PT (INR(Acf)) presented in this work develops the PT methodology to measure the true coagulation activity in vivo for patient warfarin therapy without inhibition. INR(Inh) can evidently also be used for the diagnostics and follow-up of certain liver diseases.

A novel biodegradable biliary stent in the normal duct hepaticojejunal anastomosis: an 18-month follow-up in a large animal model.

Creating a well-functioning hepaticojejunostomy (HJ) anastomosis with nondilated bile ducts remains a challenge. Our aim was to study the use in a large animal model of a novel, braided polylactide barium sulfate biodegradable biliary stent (BDBS) without external connection and with no need for later removal. Fifty swine were randomly operated on for Roux-Y HJ with or without BDBS in the anastomosis, and followed up (dynamic biligraphy, x-ray, serum determinations, anastomosis inner diameter, and histology) for 1.5, 3, 6, 12, and 18 months. During the follow-up, one nonstented animal died because of anastomotic leakage. In x-ray BDBS was seen in place until 1.5 months in all of the stented animals. In the nonstented animals HJ anastomosis inner diameter was decreased at 18 months [6.3 (5.0-7.0) mm vs 7.4 (7.0-9.0) mm, p = 0.05] and liver clearance reduced at 12 and 18 months compared to stented animals. Serum liver values and liver and bile duct histology did not differ between the groups. We conclude that this novel BDBS is easy to insert into the HJ anastomosis with nondilated ducts. It is nontoxic, dissolves safely, and may be associated with a larger and better draining anastomosis at 18-month follow-up. These results encourage us to proceed to clinical studies.

Bone stress injuries of the ankle and foot: an 86-month magnetic resonance imaging-based study of physically active young adults.

BACKGROUND: No comprehensive studies of bone stress injuries in the ankle and foot based on magnetic resonance imaging findings have been published. PURPOSE: Using magnetic resonance imaging findings to assess incidence, location, and type of bone stress injuries of the ankle and foot in military conscripts with ankle and/or foot pain. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients with ankle or foot pain, negative findings on plain radiography, and magnetic resonance images obtained of the ankle or foot were included in this 86-month study. Magnetic resonance images with bone stress injury findings were re-evaluated regarding location and injury type. Based on the number of conscripts within the hospital catchment area, the person-based incidence of bone stress injuries was calculated. RESULTS: One hundred thirty-one conscripts displayed 378 bone stress injuries in 142 ankles and feet imaged, the incidence being 126 per 100 000 person-years. This incidence represents the stress injuries not diagnosable with radiographs and requiring magnetic resonance images. Of injuries, 57.7% occurred in the tarsal and 35.7% in the metatarsal bones. Multiple bone stress injuries in 1 foot were found in 63% of the cases. The calcaneus and fifth metatarsal bone were usually affected alone. Injuries to the other bones of the foot were usually associated with at least 1 other stress injury. The talus and calcaneus were the most commonly affected single bones. High-grade bone stress injury (grade IV-V) with a fracture line on magnetic resonance images occurred in 12% (talus, calcaneus), and low-grade injury (grade I-III) presented only as edema in 88% of the cases. CONCLUSION: Multiple, various-stage bone stress injuries of the ankle and foot may occur simultaneously in physically active young adults. When considering injuries that were missed by plain radiographs but detected by magnetic resonance imaging, the bones most often affected were the tarsal bones, of which the talus and calcaneus were the most prominent single bones and most common locations for higher grade (IV-V) bone stress injuries. With use of magnetic resonance imaging, early detection and grading of bone stress injuries are available, which enable early and appropriate injury management.

Poor agreement among prothrombin time international normalized ratio methods: comparison of seven commercial reagents.

BACKGROUND: Prothrombin time (PT) has long been the most popular test for monitoring oral anticoagulation therapy. The International Normalized Ratio (INR) was introduced to overcome the problem of marked variation in PT results among laboratories and the various recommendations for patient care. According to this principle, all reagents should be calibrated to give identical results and the same patient care globally. This is necessary for monitoring of single patients and for application of the results of anticoagulation trials and guidelines to clinical practice. METHODS: We took blood samples from 150 patients for whom oral anticoagulation had been prescribed. Plasmas were separated and PTs determined by use of seven commercial reagents and four calibrator sets. The differences in results were assessed by plotting, for each possible pair of methods, the differences in INR values for each sample against the mean INR value (Bland-Altman difference plots). RESULTS: Mean results differed significantly (P <0.001) for 17 of 21 possible paired comparisons of methods. Only two pairs of methods produced very similar results when assessed for problems of substantial differences in INR values; a significant, systematic increase in the difference with INR; and a significant systematic increase in the variation in difference with increasing INR values. CONCLUSIONS: The agreement among several (and perhaps most) commercial INR methods is poor. The failure of current calibration strategies may severely compromise both the monitoring of individual patients and the application of oral anticoagulation guidelines and trial results to clinical practice.

Fatigue stress fractures of the sacrum: diagnosis with MR imaging.

The aim of this study was to describe the MRI findings and clinical observations in a fatigue stress fracture of the sacrum. In this retrospective study, 380 conscripts (53 women, 327 men; age range 18-29 years, mean age 20.7 years) who suffered from stress-related hip pain were studied with MRI of the pelvis. The findings of MRI were evaluated with regard to stress fracture of the sacrum. Thirty-one (8%) patients had MRI changes in signal intensity of the cranial part of the sacrum, extending to the first and second sacral foramina. The MRI changes in signal intensity were intermediate on T1-weighted images, and high on short tau inversion recovery or T2-weighted fat-suppressed images. A linear signal void fracture line was also seen. Multiple stress injuries to the pelvic bones were also seen in 7 of 31 (23%) patients. Five patients (16%) had bilateral sacral stress fracture. Fatigue sacral stress fractures appeared more commonly in women than in men ( p<0.001). During recovery time 20 of the 31 patients underwent control MRI, and fatty marrow conversion was seen in 8 (40%) cases as high signal intensity on T1-weighted images, which disappeared 5-6 months after the onset of symptoms. Fatigue sacral stress fractures are associated with stress-related hip pain. These fractures were more common in women than in men. Other stress injuries of the pelvis may be seen simultaneously with sacral stress fractures. Signal intensity of the sacrum was normal after 5-6 months.

Fatigue stress injuries of the pelvic bones and proximal femur: evaluation with MR imaging.

The purpose of this study was to determine the prevalence and the distribution as well as male/female differences in patients with hip or pelvic pain based on MRI results. Three hundred forty consecutive conscripts (45 women, 295 men; age range 18-29 years; mean age 20.7 years) suffering from stress-related hip, buttock or groin pain took part in the study. All 340 patients underwent MR imaging. Radiographic data were available for 215 patients. Two radiologists interpreted the images by consensus. In MRI 174 stress injuries were diagnosed in 137 patients (32 women, 105 men). The incidence of bone stress injuries in women was significantly higher than that in men ( p<0.0001). One hundred five of the injuries (60%) were related to the proximal femur, 70 (67%) to the neck, 34 (32%) to the proximal shaft, and one (1%) to the head. Sixty-nine of the 174 stress injuries (40%) concerned the pelvic bones: sacrum 28 (41%); inferior pubic ramus 34 (49%); superior pubic ramus 3 (4%); iliac bone 3 (4%); and acetabulum 1 (1%). In 31 of the 174 cases (18%) symptoms were contralateral to MR findings. Thirty-three of the 137 patients (24%) had multiple bone stress injuries, 29 had two bone stress injuries and 4 patients had three. The sensitivity of radiography was 37%, specificity 79%, accuracy 60%, positive predictive value 59% and negative predictive value 61%. The kappa value for agreement between radiography and MRI was poor (0.17, p=0.0008). Patients suffering from stress-related hip pain MRI revealed bone stress injuries in 40%; of these, 60% were located in the proximal femur and 40% in the pelvic bones. For accurate diagnosis of bone stress injuries, and to ensure appropriate treatment, the entire pelvis and both proximal femurs should be studied simultaneously by means of MRI.

Evaluation of stress-related anterior lower leg pain with magnetic resonance imaging and intracompartmental pressure measurement.

The purpose of this work was to evaluate stress-related anterior lower leg pain with clinical examination, magnetic resonance imaging, and measurement of anterior tibial compartment pressure findings. All medical data were gathered from 24 conscripts with stress-related anterior lower leg pain. Twenty exhibited bilateral symptoms. In 22 of the 44 cases, the intracompartmental pressure was pathological. Symptoms were exhibited for longer periods by patients with chronic exertional compartment syndrome (CECS) than by other patients (p < 0.01). At rest, magnetic resonance imaging revealed no abnormal findings in the soft tissues of the legs but showed bone abnormalities in 35 symptomatic legs. Thirty-three exhibited bone stress injuries, and two exhibited leg traction periostitis. On magnetic resonance imaging, there was no difference in bone findings between patients with and without CECS (p > 0.05). Stress-related anterior lower leg pain can be related to CECS, bone stress injury, and traction periostitis. Clinical diagnosis is unreliable. CECS and bone stress injury or traction periostitis can occur separately or together.

MR imaging of fatigue stress injuries to bones: intra- and interobserver agreement.

The aim of this study was to determine the validity of MR imaging (MRI) in the assessment of stress-related injuries to bone.MR images of 50 military recruits (8 females and 42 males; 18-27 (mean 20) years of age) were retrospectively evaluated twice for stress injuries to bone by 4 radiologists (2 musculoskeletal radiologists, 2 radiology residents). Coronal T1-weighed (T1W) and STIR images, as well as axial and coronal T2-weighted (T2W) fat-suppressed images were taken using a 1.0T scanner. Rates for sensitivity, specificity, and accuracy of MRI of the stress-related injuries were calculated. Intraobserver and interobserver agreement was determined with kappa statistics. Rates for MRI sensitivity were 27-96%, for specificity 65-100%, and for diagnostic accuracy 58-97%. Lowest rates were seen when reading T1W images and highest when reading STIR images. Readers showed moderate to excellent intraobserver agreement (kappa 0.75-0.95). Interobserver agreement was fair to excellent (kappa 0.41-0.91), and the lowest values were seen in the interpretation of T1W images. Normal findings could be differentiated from various grades of stress injury to bone.MRI is a valid means of revealing the presence of stress injuries to bone and their staging. Observer agreement is good to excellent when using T2W images and STIR images, while T1W images are of lesser value.