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Arian Ranjbar,1 Eilin Wermundsen Mork,1 Jesper Ravn,1 Helga Brøgger,2 Per Myrseth,2 Hans Peter Østrem,3 Harry Hallock2 1Medical Technology and E-Health, Akershus University Hospital, Lørenskog, Norway; 2Group Research and Development, DNV AS, Høvik, Norway; 3Business Assurance, DNV AS, Høvik, NorwayCorrespondence: Arian Ranjbar, Akershus University Hospital, Sykehusveien 25, 1478, Lørenskog, Norway, Tel +46700436768, Email arian.ranjbar@medisin.uio.noAbstract: Artificial intelligence (AI) provides a unique opportunity to help meet the demands of the future healthcare system. However, hospitals may not be well equipped to handle safe and effective development and/or procurement of AI systems. Furthermore, upcoming regulations such as the EU AI Act may enforce the need to establish new management systems, quality assurance and control mechanisms, novel to healthcare organizations. This paper discusses challenges in AI implementation, particularly potential gaps in current management systems (MS), by reviewing the harmonized standard for AI MS, ISO 42001, as part of a gap analysis of a tertiary acute hospital with ongoing AI activities. Examination of the industry agnostic ISO 42001 reveals a technical debt within healthcare, aligning with previous research on digitalization and AI implementation. To successfully implement AI with quality assurance in mind, emphasis should be put on the foundation and structure of the healthcare organizations, including both workforce and data infrastructure.Keywords: artificial intelligence, management systems, quality assurance, risk management, implementation

Introduction: This study aimed to evaluate the consistency of lung cancer case assessments across multidisciplinary team (MDT) sites in Denmark. The goal was to appraise the comparability of outcomes between hospitals in a real-world context., Methods: We prepared sixty comprehensive, fictitious lung cancer case stories, complete with images, and distributed them to the four primary lung cancer MDT conferences in Denmark. These cases were subsequently evaluated as had they been ordinary patients during regular MDT meetings. We compared the conclusions on assigned TNM stage and proposed treatment intent using Kappa statistics., Results: The consensus on assigned stage (Stages IA-B, IIA-B, IIIA-B, IV, and undetermined) corresponded to a Fleiss' Kappa-value of 0.62 (95% CI: 0.52-0.71). The overall assessment of curability, categorized as Curable, Incurable, and Undetermined, corresponded to a Kappa-value of 0.72 (CI: 0.61-0.84). However, for cases unanimously judged by all MDT sites to be Stage III, the concordance on treatment intent was poor, with an agreement coefficient of only 0.32 (95% CI: -0.27-0.97)., Conclusion: In detail, the level of agreement on assigned stages was less than desired. In consequence, comparative analyses of treatment results from different hospitals or centres may be prone to bias caused by systematic differences in stage assessment or intent of treatment. The least consensus was observed for cases in Stage III, indicating a need for quality improvement efforts to ensure a higher degree of consistency in MDT decisions., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. The study is based on fictitious case stories and associated imaging used in the study are fully and irrevocably anonymized. The Danish National Medical Research Ethics Committee (https://researchethics.dk/) waived the need for ethical approval and referred to the local Institutional Review Board at Aarhus University Hospital (IRB-AUH) for permission to access selected imaging for full and irrevocable anonymization and subsequent use in the study, for which permission was granted. The need for consent to participate was waived by IRB-AUH as it was deemed unnecessary for the intended use according to Danish national regulations (Danish Health Act, § 42 d (https://www.retsinformation.dk/eli/lta/2018/1286#P42d)). The use of fictitious case stories and fully and irrevocable anonymized data for research are permissible under Danish and European General Data Protection Regulation (the GPDR rules – REGULATION (EU) 2016/679 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 April 2016, article 26 (https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0679)). Consent for publication Not applicable. The study is based on fictitious case stories and fully and irrevocably anonymized images, the use of which is permissible under Danish and European GDPR rules as stated and explained above for ‘Ethics approval and consent to participate’. Competing interests The authors declare no competing interests. Authors information Each author is a senior consultant with extensive experience in lung cancer diagnostics at university hospitals or is conducting research into the function of MDT in lung cancer., (© 2024. The Author(s).)

Objective: This study aims to assess the ability of state-of-the-art machine learning algorithms to detect valvular heart disease (VHD) from digital heart sound recordings in a general population that includes asymptomatic cases and intermediate stages of disease progression., Methods: We trained a recurrent neural network to predict murmurs from heart sound audio using annotated recordings collected with digital stethoscopes from four auscultation positions in 2,124 participants from the Tromsø7 study. The predicted murmurs were used to predict VHD as determined by echocardiography., Results: The presence of aortic stenosis (AS) was detected with a sensitivity of 90.9%, a specificity of 94.5%, and an area under the curve (AUC) of 0.979 (CI: 0.963-0.995). At least moderate AS was detected with an AUC of 0.993 (CI: 0.989-0.997). Moderate or greater aortic and mitral regurgitation (AR and MR) were predicted with AUC values of 0.634 (CI: 0.565-703) and 0.549 (CI: 0.506-0.593), respectively, which increased to 0.766 and 0.677 when clinical variables were added as predictors. The AUC for predicting symptomatic cases was higher for AR and MR, 0.756 and 0.711, respectively. Screening jointly for symptomatic regurgitation or presence of stenosis resulted in an AUC of 0.86, with 97.7% of AS cases ( n  = 44) and all 12 MS cases detected., Conclusions: The algorithm demonstrated excellent performance in detecting AS in a general cohort, surpassing observations from similar studies on selected cohorts. The detection of AR and MR based on HS audio was poor, but accuracy was considerably higher for symptomatic cases, and the inclusion of clinical variables improved the performance of the model significantly., Competing Interests: Medsensio AS is a company that provides products for automatic detection of abnormal lung sounds. JR and MJ are employed by Medsensio. HM was working for Medsensio during this research project, and PW was employed for some time by Medsensio after the research project was mostly completed. JR, MJ, and LB owns shares in Medsensio. PW, HM, HS, MJ, TD, JR, SA, AD, JS, and LB have filed two patents for the algorithms outlined in this paper., (© 2024 Waaler, Malbye, Schirmer, Johnsen, Donnem, Ravn, Andersen, Davidsen, Aviles Solis, Stylidis and Bongo.)

Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular compartments is a limiting factor in their potency. Here, we synthesized splice-switching oligonucleotides (SSOs) previously developed to treat the rare disease erythropoietic protoporphyria. Using chemical ligation-quantitative polymerase chain reaction (CL-qPCR), we quantified the SSOs in cells and subcellular compartments following free uptake. To drive nuclear localization, we covalently conjugated nuclear localization signal (NLS) peptides to a lead 2'- O -methoxyethyl phosphorothioate SSO using thiol-maleimide chemistry. The conjugates and parent SSO displayed similar RNA target-binding affinities. CL-qPCR quantification of the conjugates in cells and subcellular compartments following free uptake revealed one conjugate with better nuclear accumulation relative to the parent SSO. However, compared to the parent SSO, which altered the splicing of the target pre-mRNA, the conjugates were inactive at splice correction under free uptake conditions in vitro . Splice-switching activity could be conferred on the conjugates by delivering them into cells via cationic lipid-mediated transfection or by treating the cells into which the conjugates had been freely taken up with chloroquine, an endosome-disrupting agent. Our results identify the major barrier to the activity of the peptide-oligonucleotide conjugates as endosomal entrapment., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Thanks to clinically newly introduced inhibitors of the mesenchymal-epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

Background: This article describes a scabies outbreak at a boarding school where failure of the first-line therapy was suspected., Case Presentation: A group of five students, two of whom were room-mates, presented with a varying degree of pruritic papular rash. Repeated treatments with permethrin monitored by the school nurse, in conjunction with a rigorous hygiene regimen, proved to be ineffective. Eventually all five students were prescribed a combination therapy consisting of permethrin and ivermectin. This treatment proved effective in all five students. Despite closely monitored treatment, monotherapy with permethrin failed in all five patients. We discuss whether the lack of response was due to failed application, inability to rid the home environment of mites, reinfection by unidentified infected individuals or increased tolerance to permethrin., Interpretation: Repeated therapeutic failure when permethrin was used under controlled conditions and documented mechanisms for increased tolerance may indicate the last possibility. We therefore call for additional research on this topic.

Background: The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression., Methods: A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group., Results: In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4., Conclusions: The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

Intrathoracic splenosis is a rare diagnosis that is usually made after an invasive procedure. Most cases report concomitant rupture of the spleen and left hemidiaphragm with autotransplantation of splenic tissue into the left hemithorax. We report a case of intrathoracic splenosis with no evidence of diaphragmatic rupture. The mechanism may be explained by hematogenous spread. The patient underwent video-assisted thoracoscopic surgery for diagnosis, which could have been avoided if splenosis was suspected., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We applied deep learning to create an algorithm for breathing phase detection in lung sound recordings, and we compared the breathing phases detected by the algorithm and manually annotated by two experienced lung sound researchers. Our algorithm uses a convolutional neural network with spectrograms as the features, removing the need to specify features explicitly. We trained and evaluated the algorithm using three subsets that are larger than previously seen in the literature. We evaluated the performance of the method using two methods. First, discrete count of agreed breathing phases (using 50% overlap between a pair of boxes), shows a mean agreement with lung sound experts of 97% for inspiration and 87% for expiration. Second, the fraction of time of agreement (in seconds) gives higher pseudo-kappa values for inspiration (0.73-0.88) than expiration (0.63-0.84), showing an average sensitivity of 97% and an average specificity of 84%. With both evaluation methods, the agreement between the annotators and the algorithm shows human level performance for the algorithm. The developed algorithm is valid for detecting breathing phases in lung sound recordings.

Locked nucleic acid based antisense oligonucleotides (LNA-ASOs) can reach their intracellular RNA targets without delivery modules. Functional cellular uptake involves vesicular accumulation followed by translocation to the cytosol and nucleus. However, it is yet unknown how many LNA-ASO molecules need to be delivered to achieve target knock down. Here we show by quantitative fluorescence imaging combined with LNA-ASO microinjection into the cytosol or unassisted uptake that ∼105 molecules produce >50% knock down of their targets, indicating that a substantial amount of LNA-ASO escapes from endosomes. Microinjected LNA-ASOs redistributed within minutes from the cytosol to the nucleus and remained bound to nuclear components. Together with the fact that RNA levels for a given target are several orders of magnitude lower than the amounts of LNA-ASO, our data indicate that only a minor fraction is available for RNase H1 mediated reduction of target RNA. When non-specific binding sites were blocked by co-administration of non-related LNA-ASOs, the amount of target LNA-ASO required was reduced by an order of magnitude. Therefore, dynamic processes within the nucleus appear to influence the distribution and activity of LNA-ASOs and may represent important parameters for improving their efficacy and potency.

Different types of oxidized cellulose have been used for haemorrhage control in thoracic surgery, abdominal surgery and neurosurgery. Oxidized resorbable cellulose (Gelita-cel) is a new haemostatic agent. Once saturated with blood, it swells and makes a gelatinous mass that formats as a fibrin clot. We have performed a prospective observational cohort study of patients operated for lung cancer or suspected lung cancer using Gelita-cel as a haemostatic agent. Between October 2010 and April 2012, 477 patients were operated in our department for lung cancer. Gelita-cel was used in 200 patients due to minor intraoperative haemorrhage after lymph node resection from Stations 2 to 11. During follow-up for lung cancer, computed tomography, which was performed 4-60 months after the primary operation, showed enlarged lymph nodes in the mediastinum in 16 patients. Endoscopic bronchial ultrasonographic biopsies of the lymph nodes showed foreign body material and granulomatous inflammation, and no sign of lung cancer recurrence. Gelita-cel has a high risk of causing granuloma and should not be used as a haemostatic agent in thoracic surgery.

Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Current standard-of-care therapies only rarely lead to a functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss following treatment. The goal for next generation CHB therapies is to achieve a higher rate of functional cure with finite treatment duration. To address this urgent need, we are developing liver-targeted single-stranded oligonucleotide (SSO) therapeutics for CHB based on the locked nucleic acid (LNA) platform. These LNA-SSOs target hepatitis B virus (HBV) transcripts for RNase-H-mediated degradation. Here, we describe a HBV-specific LNA-SSO that effectively reduces intracellular viral mRNAs and viral antigens (HBsAg and HBeAg) over an extended time period in cultured human hepatoma cell lines that were infected with HBV with mean 50% effective concentration (EC 50 ) values ranging from 1.19 to 1.66 μM. To achieve liver-specific targeting and minimize kidney exposure, this LNA-SSO was conjugated to a cluster of three N-acetylgalactosamine (GalNAc) moieties that direct specific binding to the asialoglycoprotein receptor (ASGPR) expressed specifically on the surface of hepatocytes. The GalNAc-conjugated LNA-SSO showed a strikingly higher level of potency when tested in the AAV-HBV mouse model as compared with its non-conjugated counterpart. Remarkably, higher doses of GalNAc-conjugated LNA-SSO resulted in a rapid and long-lasting reduction of HBsAg to below the detection limit for quantification, i.e., by 3 log10 (p < 0.0003). This antiviral effect depended on a close match between the sequences of the LNA-SSO and its HBV target, indicating that the antiviral effect is not due to non-specific oligonucleotide-driven immune activation. These data support the development of LNA-SSO therapeutics for the treatment of CHB infection., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented., Methods: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine., Results: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035-0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030-0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis., Conclusions: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

Objectives: Lung cancer is the most common cause of cancer-related deaths worldwide. Survival is highly dependent on surgery. Video-assisted thoracoscopic surgery (VATS) is increasingly chosen over open thoracotomy (OT) because of the possible benefits of the minimally invasive approach. Consequently, our aim was to compare the 30-day morbidity and mortality for lung cancer patients operated by VATS lobectomy or lobectomy by OT., Method: Data were obtained from prospective national and regional databases, including patients who underwent lobectomy for lung cancer in the eastern part of Denmark from 1 January 2005 to 31 December 2011. All patients operated before 2009 were re-staged according to the latest International Association for the Study of Lung Cancer lung cancer classification. Patient characteristics, comorbidities, pathology and operative data were assessed using an independent samples t-test, Pearson's χ(2), Fisher's exact test and Mann-Whitney test. Morbidity was assessed using multinomial logistic regression adjusted for gender, age, cancer stage, forced expiratory volume in 1 s (FEV1), year of surgery and Charlson comorbidity score., Results: In total, 1379 patients underwent lobectomy, 785 patients via VATS and 594 patients via thoracotomy. The two groups were similar in gender and FEV1. The patients operated by VATS were older (P < 0.001), and had a lower Charlson comorbidity score (P = 0.034), higher frequency of adenocarcinomas (P < 0.001) and lower cancer stage (P < 0.001). Among the VATS patients, 285 (36.3%) and among the thoracotomy patients, 288 (48.5%) had minor complications (P < 0.001); and 157 (20.0%) VATS patients and 212 (35.7%) thoracotomy patients had major complications (P < 0.001). The 30-day mortality rate was 1% in the VATS group and 1.5% in the thoracotomy group (P = 0.47). Multinomial logistic regression analysis showed that the prevalence of both minor [odds ratio (OR) = 1.51; 95% confidence interval (Cl) = 1.18-1.96] and major complications (OR = 1.91, 95% Cl = 1.44-2.53) was significantly higher for patients who underwent lobectomy via thoracotomy compared with VATS., Conclusion: Patients undergoing lobectomy via VATS were less likely to have at least one minor complication within the first 30 postoperative days and less likely to have at least one major complication, compared with patients operated by thoracotomy. These findings remained after adjusting for gender, age, FEV1, cancer stage, year of surgery and Charlson comorbidity score., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background/aim: We recently reported that miR-126 is down-regulated in malignant pleural mesothelioma (MPM) and can be combined into a 4-microRNA-classifier that can accurately diagnose MPM with high sensitivity and specificity. Herein we analyzed the epigenetic regulation of miR-126 and its host gene EGF-like domain, multiple 7 (EGFL7)., Materials and Methods: Resected formalin-fixed paraffin-embedded MPM tissues from 29 patients, 14 patient-matched non-neoplastic pleura (NNP) specimens, 5 MPM diagnostic biopsies (DB), and 5 samples of pneumothorax-induced benign reactive mesothelial proliferation (PTHX) were analyzed. miR-126 and EGFL7 mRNA were quantified by RT-qPCR. CpG-islands' methylation in the EGFL7 promoter was analyzed using methylation-specific PCR and in the MIR126-containing intron 7 was quantified by pyrosequencing., Results: Relative to NNP, EGFL7 was under-expressed more than 4-fold in MPM (p<0.001). EGFL7 mRNA and miR-126 levels correlated in MPM (p<0.01) and NNP (p<0.001). The EGFL7 promoter region was hypermethylated in 69% of MPM and 80% of DB samples, but not in NNP and PTHX samples. EGFL7 promoter hypermethylation was associated with epithelioid histology (p<0.05) and reduced patient-survival (p<0.05)., Conclusion: In MPM, DNA-hypermethylation down-regulates miR-126 and its host gene EGFL7, therefore is a poor prognostic factor, and may represent a future therapeutic target for de-methylating strategies re-establishing EGFL7 and miR-126 expression., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Despite extensive research, the debate continues as to the optimal way of guiding intraoperative and postoperative fluid therapy. In 2009 we changed our institutional guideline for perioperative fluid therapy in patients undergoing extrapleural pneumonectomy (EPP) and implemented the use of central venous oxygen saturation and intended low urine output to guide therapy in the early postoperative period. Here we evaluate the consequences of our changes., Methods: Retrospective, observational study of 30 consecutive patients undergoing EPP; 18 who had surgery before and 12 who had surgery after the changes. Data were collected from patient files and from institutional databases. Outcome measures included: Volumes of administered fluids, fluid balances, length of stays and postoperative complications. Dichotomous variables were compared with Fisher's exact test, whereas continuous variables were compared with Student's unpaired t-test or the Wilcoxon Two-Sample Test depending on the distribution of data., Results: The applied changes significantly reduced the volumes of administered fluids, both in the intraoperative (p = 0.01) and the postoperative period (p = 0.04), without increasing the incidence of postoperative complications. Mean length of stay in the intensive care unit (LOSI) was reduced from three to one day (p = 0.04) after the changes., Conclusion: The use of clinical parameters to balance fluid restriction and a sufficient circulation in patients undergoing EPP was associated with a reduction in mean LOSI without increasing the incidence of postoperative complications. Due to methodological limitations these results are only hypothesis generating.

Malignant pleural mesothelioma (MPM) is difficult to distinguish from reactive mesothelial proliferations (RMPs). It is uncertain whether miRNAs are useful biomarkers for differentiating MPM from RMPs. Thus, we screened with a quantitative RT-PCR (RT-qPCR)-based platform the expression of 742 miRNAs in formalin-fixed, paraffin-embedded, preoperative diagnostic biopsy samples, surgically resected MPM specimens previously treated with chemotherapy, and corresponding non-neoplastic pleura (NNP), from five patients. miR-126, miR-143, miR-145, and miR-652 were significantly down-regulated (≥twofold) in resected MPM and/or chemotherapy-naïve diagnostic tumor biopsy samples. The miRNA expression pattern was validated by RT-qPCR in a cohort of 40 independent MPMs. By performing binary logistic regression on the RT-qPCR data for the four miRNAs, the established four-miRNA classifier differentiated MPM from NNP with high sensitivity and specificity (area under the curve, 0.96; 95% CI, 0.92-1.00). The classifier's optimal logit(P) value of 0.62 separated NNP and MPM samples with a sensitivity of 0.95 (95% CI, 0.89-1.00), a specificity of 0.93 (95% CI, 0.87-0.99), and an overall accuracy of 0.94 (95% CI, 0.88-1.00). The level of miR-126 in MPM was inversely correlated with that of the known target, the large neutral amino acid transporter, small subunit 1 (r = -0.38; 95% CI, -0.63 to -0.06). Overall, these results indicate that these four miRNAs may be suitable biomarkers for distinguishing MPM from RMPs., (Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Malignant disease's ability to metastasize remains one of the major obstacles when treating patients with cancer. The change from loco-regional to systemic disease usually renders the patient beyond surgical treatment, as local treatment with surgery in a systemic disease is usually considered without benefit. However, numerous retrospective studies have demonstrated that resection of metastases limited to the lungs may be associated with prolonged survival. No prospective, randomized studies have been published, and most series compare highly selected patients with historical data for unresected patients. In this article, we discuss the current status on pulmonary metastasectomy. Preoperative assessment and selection of surgical candidates is covered. The different surgical strategies including surgical approach, unilateral versus bilateral exploration, lymph node dissection, and repeat surgery are discussed. Finally, we review some of the common tumors that metastasize to the lungs, the role of metastasectomy in their treatment and the prognostic factors with impact on survival., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Chronic pain complaints after thoracic surgery represent a significant clinical problem in 25-60% of patients. Results from thoracic and other surgical procedures suggest multiple pathogenic mechanisms that include pre-, intra-, and postoperative factors. This review attempts to analyse the methodology and systematics of the studies on the post-thoracotomy pain syndrome (PTPS) after lung cancer surgery in adults, in order to clarify the relative role of possible pathogenic factors and to define future strategies for prevention. Literature published from 2000 to 2008 together with studies included in previous systematic reviews was searched recursively using PubMed and OVID by combining three categories of search terms. The available data have major inconsistencies in collection of pre-, intra- and postoperative data that may influence PTPS, thereby hindering precise conclusions as well as preventive and treatment strategies. However, intercostal nerve injury seems to be the most important pathogenic factor. Since there is a general agreement on the clinical relevance of PTPS, a proposal for design of future trials is presented.

Objectives: Extrapleural pneumonectomy (EPP) in MPM may be confined with both morbidity and mortality and careful preoperative staging identifying resectable patients is important. Staging is difficult and the accuracy of preoperative CT scan, 18F-FDG PET/CT scan (PET/CT), and mediastinoscopy is unclear. The objectives were to compare these staging techniques to each other and to surgical-pathological findings., Methods: Patients had epithelial subtype MPM, age

Background: In April 2004, the Norwegian Institute of Public Health was notified about an outbreak of a respiratory illness among participants on a cultural-historical theme tour to Central America. One patient was examined in a Swedish hospital where the clinician suspected histoplasmosis, which later was verified by serology and by culture of Histoplasma capsulatum. In order to describe the outbreak and identify the possible source of infection, a clinical and epidemiological study was conducted., Material and Methods: A questionnaire on symptoms, treatment and participation in various activities was sent to all the tour participants. Reminders were sent by e-mail. In addition, some participants underwent a more detailed clinical examination., Results: 19 of the 21 travellers completed the questionnaire. All travellers had visited several caves inhabited by bats in El Salvador and Guatemala. During the last 10 days of the journey, 16 of the respondents (84%) acquired a respiratory illness that lasted for more than 3 weeks. The diagnosis was confirmed by serology in 8 of the 14 tested cases. Antibacterial therapy was given to 11 patients and antifungal therapy to 3 patients. Only one patient was hospitalised., Interpretation: The described outbreak of histoplasmosis was probably caused by exposure to Histoplasma capsulatum during a visit in bat-infested caves. Due to the increasing popularity of adventure and theme travels, this disease may become more frequent in our population. The condition should be considered in travellers with prolonged respiratory illness after visits to caves or other closed environments with little circulation of air that are potentially contaminated with bat or bird droppings. Persons with immunosuppression may develop severe illness, and should consider avoiding places with increased risk.

Anterior tibial translation was measured in six patients with anterior cruciate ligament insufficiency. The tests were done in 15, 45, and 90 degrees of knee flexion, partly with activated quadriceps or hamstrings, and partly with subjects wearing a 4-point functional DonJoy brace. The translation was evaluated with a computerized electrogoniometer (Acufex KSS). The anterior tibial translation was significantly reduced by use of the hamstrings in all three degrees of knee flexion. The effect of the 4-point brace was only significant in 15 and 45 degrees of flexion. The quadriceps did not reduce the anterior tibial translation.

The reaction of 15 functionally unstable ankles to sudden inversion was described by monitoring muscle activity, joint motion, and alternation of the body center of pressure. The results were compared with those of 15 stable controls. Stable and unstable subjects showed a similar reaction pattern to sudden inversion: first, a peripheral reflex action, namely, a contraction of the peronei counteracting the ankle inverting momentum, and, then, a centrally elicited pattern, namely, a flexion of the hip, knee, and ankle relieving the vertical pressure on the ankle and producing ankle eversion. Unstable subjects did not show a defect in their central processing of afferent input. In contrast, a prolonged reaction time (median 84 msec compared with 69 msec in stable subjects) suggested a partial deafferentation of the reflex stabilization of the ankle and substantiated the theory of a proprioceptive deficit being responsible for ankle instability.