Search

Abstract Bone conduction implants enable patients to hear via vibrations transmitted to the skull. The main constraint of current bone conduction implants is their maximum output force level. Stimulating closer to the cochlea is hypothesized to increase efficiency and improve force transfer, addressing this limitation. This study evaluated stimulation at four positions in human cadaveric specimens: the cochlear promontory, the posterior wall of the outer ear canal, the lateral semi-circular canal, and the standard Bone-Anchored Hearing Aid (Baha) location. To assess potential hearing sensation, three objective measures were simultaneously recorded. For intracochlear pressure and promontory velocity, stimulating at the lateral semi-circular canal and promontory results in the highest response, with a gain of up to 20 dB. Ear canal pressure shows less conclusive results, with significant differences at only a few frequencies. These findings suggest that stimulation closer to the cochlea offers higher efficiency, which could benefit patients needing higher output force levels than currently available or those eligible for electro-vibrational stimulation, e.g. a cochlear implant combined with a bone conduction device.

Abstract Hope is a vital coping mechanism, enabling individuals to effectively confront life’s challenges. This study proposes a technique employing Natural Language Processing (NLP) tools like Linguistic Inquiry and Word Count (LIWC), NRC-emotion-lexicon, and vaderSentiment to analyze social media posts, extracting psycholinguistic, emotional, and sentimental features from a hope speech dataset. The findings of this study reveal distinct cognitive, emotional, and communicative characteristics and psycholinguistic dimensions, emotions, and sentiments associated with different types of hope shared in social media. Furthermore, the study investigates the potential of leveraging this data to classify different types of hope using machine learning algorithms. Notably, models such as LightGBM and CatBoost demonstrate impressive performance, surpassing traditional methods and competing effectively with deep learning techniques. We employed hyperparameter tuning to optimize the models’ parameters and compared their performance using both default and tuned settings. The results highlight the enhanced efficiency achieved through hyperparameter tuning for these models.

Abstract Potency assessment of monoclonal antibodies or corresponding biosimilars in cell-based assays is an essential prerequisite in biopharmaceutical research and development. However, cellular bioassays are still subject to limitations in sample throughput, speed, and often need costly reagents or labels as they are based on an indirect readout by luminescence or fluorescence. In contrast, whole-cell Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS) has emerged as a direct, fast and label-free technology for functional drug screening being able to unravel the molecular complexity of cellular response to pharmaceutical reagents. However, this approach has not yet been used for cellular testing of biologicals. In this study, we have conceived, developed and benchmarked a label-free MALDI-MS based cell bioassay workflow for the functional assessment of complement-dependent cytotoxicity (CDC) of Rituximab antibody. By computational evaluation of response profiles followed by subsequent m/z feature annotation via fragmentation analysis and trapped ion mobility MS, we identified adenosine triphosphate and glutathione as readily MS-assessable metabolite markers for CDC and demonstrate that robust concentration–response characteristics can be obtained by MALDI-TOF MS. Statistical assay performance indicators suggest that whole-cell MALDI-TOF MS could complement the toolbox for functional cellular testing of biopharmaceuticals.

IntroductionThe 2024 Voice AI Symposium, hosted by the Bridge2AI-Voice Consortium in Tampa, FL, featured two keynote speeches that addressed the intersection of voice AI, healthcare, ethics, and law. Dr. Rupal Patel and Dr. Nicholson Price provided insights into the advancements, applications, and challenges of AI-driven voice tools in healthcare. The symposium aimed to advance cross-disciplinary collaboration and establish frameworks for the ethical use of AI technologies in healthcare.MethodsThe keynote speeches, delivered on May 1st and 2nd, were 30 minutes each, followed by 10-minutes Q&A sessions. The audio was recorded and transcribed using Whisper (v7.13.1). Content summaries were generated with the aid of ChatGPT (v4.0), and the authors reviewed and edited the final transcripts to ensure accuracy and clarity.ResultsDr. Rupal Patel’s keynote, “Reflections and New Frontiers in Voice AI”, explored the potential of voice AI for early detection of health conditions, monitoring disease progression, and promoting non-invasive global health management. She highlighted innovative uses beyond traditional applications, such as examining menopause-related symptoms. Dr. Nicholson Price’s keynote, “Governance for Clinical Voice AI”, addressed the regulatory and ethical challenges posed by AI in healthcare. He stressed the need for context-aware systems and dynamic legal frameworks to address liability and accountability.ConclusionsThe 2024 Voice AI Symposium highlighted the transformative potential of voice AI for early detection, health monitoring, and reducing healthcare disparities. It also underscored the importance of dynamic governance to address the ethical and regulatory challenges of deploying AI in clinical settings.

BackgroundWhile the effectiveness of patient-reported outcome measures (PROMs) as an intervention to impact patient pathways has been established for cancer care, it is unknown for other indications. We assessed the cost-effectiveness of a PROM-based monitoring and alert intervention for early detection of critical recovery paths following hip and knee replacement.Methods and findingsThe cost-effectiveness analysis (CEA) is based on a multicentre randomised controlled trial encompassing 3,697 patients with hip replacement and 3,110 patients with knee replacement enrolled from 2019 to 2020 in 9 German hospitals. The analysis was conducted with a subset of 546 hip and 492 knee replacement cases with longitudinal cost data from 24 statutory health insurances. Patients were randomised 1:1 to a PROM-based remote monitoring and alert intervention or to a standard care group. All patients were assessed at 12-months post-surgery via digitally collected PROMs. Patients within the intervention group were additionally assessed at 1-, 3-, and 6-months post-surgery to be contacted in case of critical recovery paths. For the effect evaluation, a PROM-based composite measure (PRO-CM) was developed, combining changes across various PROMs in a single index ranging from 0 to 100. The PRO-CM included 6 PROMs focused on quality of life and various aspects of physical and mental health. The primary outcome was the incremental cost-effectiveness ratio (ICER). The intervention group showed incremental outcomes of 2.54 units PRO-CM (95% confidence interval (CI) [0.93, 4.14]; p = 0.002) for patients with hip and 0.87 (95% CI [-0.94, 2.67]; p = 0.347) for patients with knee replacement. Within the 12-months post-surgery period the intervention group had less costs of 376.43€ (95% CI [-639.74, -113.12]; p = 0.005) in patients with hip, and 375.50€ (95% CI [-767.40, 16.39]; p = 0.060) in patients with knee replacement, revealing a dominant ICER for both procedures. However, it remains unclear which step of the multistage intervention contributes most to the positive effect.ConclusionsThe intervention significantly improved patient outcomes at lower costs in patients with hip replacements when compared with standard care. Further it showed a nonsignificant cost reduction in knee replacement patients. This reinforces the notion that PROMs can be utilised as a cost-effective instrument for remote monitoring in standard care settings.Trial registrationRegistration: German Register for Clinical Studies (DRKS) under DRKS00019916.

IntroductionThe 2024 Voice AI Symposium, presented by the Bridge2AI-Voice Consortium, featured deep-dive educational workshops conducted by experts from diverse fields to explore the latest advancements in voice biomarkers and artificial intelligence (AI) applications in healthcare. Through five workshops, attendees learned about topics including international standardization of vocal biomarker data, real-world deployment of AI solutions, assistive technologies for voice disorders, best practices for voice data collection, and deep learning applications in voice analysis. These workshops aimed to foster collaboration between academia, industry, and healthcare to advance the development and implementation of voice-based AI tools.MethodsEach workshop featured a combination of lectures, case studies, and interactive discussions. Transcripts of audio recordings were generated using Whisper (Version 7.13.1) and summarized by ChatGPT (Version 4.0), then reviewed by the authors. The workshops covered various methodologies, from signal processing and machine learning operations (MLOps) to ethical concerns surrounding AI-powered voice data collection. Practical demonstrations of AI-driven tools for voice disorder management and technical discussions on implementing voice AI models in clinical and non-clinical settings provided attendees with hands-on experience.ResultsKey outcomes included the discussion of international standards to unify stakeholders in vocal biomarker research, practical challenges in deploying AI solutions outside the laboratory, review of Bridge2AI-Voice data collection processes, and the potential of AI to empower individuals with voice disorders. Additionally, presenters shared innovations in ethical AI practices, scalable machine learning frameworks, and advanced data collection techniques using diverse voice datasets. The symposium highlighted the successful integration of AI in detecting and analyzing voice signals for various health applications, with significant advancements in standardization, privacy, and clinical validation processes.DiscussionThe symposium underscored the importance of interdisciplinary collaboration to address the technical, ethical, and clinical challenges in the field of voice biomarkers. While AI models have shown promise in analyzing voice data, challenges such as data variability, security, and scalability remain. Future efforts must focus on refining data collection standards, advancing ethical AI practices, and ensuring diverse dataset inclusion to improve model robustness. By fostering collaboration among researchers, clinicians, and technologists, the symposium laid a foundation for future innovations in AI-driven voice analysis for healthcare diagnostics and treatment.

INTRODUCTION: Quantifying antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neutralising antibodies may help to understand protection at the individual and population levels. Determination of neutralising antibodies using classical virus neutralisation tests (VNT) is considered the gold standard, but they are costly and time-intensive. Enzyme-linked immunosorbent assay (ELISA)-based surrogate VNTs (sVNT) or anti-SARS-CoV-2 spike protein receptor binding domain immunoglobulins (anti-S-RBD Ig) may be suitable alternatives to VNTs. We aimed to (a) explore the correlations between anti-S-RBD Ig, VNT, and sVNT measurements and (b) describe humoral immunity against SARS-CoV-2 after vaccination, natural infection, and vaccine breakthrough infection in healthy blood donors. METHODS: We measured total anti-SARS-CoV-2 Ig in 5714 serum samples from 2748 healthy individuals visiting the Swiss Red Cross Blood Donation Centre in Basel from 03/2020 to 04/2022. We used the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche) against the N- and S-receptor binding domain (RBD) proteins. In a subset of 548 samples from 123 donors, we conducted sVNTs against the Wuhan wild-type SARS-CoV-2 (SARS-CoV-2 Neutralizing Antibodies Detection Kit; Adipogen™). In 100 samples from 40 donors, we correlated sVNT and VNTs against the wild-type (D614G WU1) virus. Surveys were sent to the blood donors to collect data on their SARS-CoV-2 infection and vaccination status. Using this data, donors were categorised as “vaccination only”, “infection before vaccination”, “post-vaccine breakthrough infection”, and “natural infection only”. RESULTS: Our longitudinal observation study cohort consisted of 50.7% males with a median age of 31 years (range 18–75 y). Anti-SARS-CoV-2 N protein positivity rates per month indicate 57.1% (88/154) of the cohort was infected up to 04/2022. No differences in seropositivity were found between sexes, age groups, blood types (AB0 or RhD), and cytomegalovirus serostatus. We observed a high correlation between anti-S-RBD Ig and inhibition percentage (Spearman’s ρ = 0.92, Kendall’s τ = 0.77, p

The mortality of patients with MI has significantly decreased in recent decades, mainly due to early reperfusion therapy with a probability of surviving of more than 90% if the patient reaches the hospital [...]

Abstract We introduce a novel Natural Language Processing (NLP) task called guilt detection, which focuses on detecting guilt in text. We identify guilt as a complex and vital emotion that has not been previously studied in NLP, and we aim to provide a more fine-grained analysis of it. To address the lack of publicly available corpora for guilt detection, we created VIC, a dataset containing 4622 texts from three existing emotion detection datasets that we binarized into guilt and no-guilt classes. We experimented with traditional machine learning methods using bag-of-words and term frequency-inverse document frequency features, achieving a 72% f1 score with the highest-performing model. Our study provides a first step towards understanding guilt in text and opens the door for future research in this area.

Abstract A cochlear implant is a neuroprosthetic device that can restore speech perception for people with severe to profound hearing loss. Because of recent evolutions, a growing number of people with a cochlear implant have useful residual acoustic hearing. While combined electro-acoustic stimulation has been shown to improve speech perception for this group of people, some studies report limited adoption rates. Here, we present electro-vibrational stimulation as an alternative combined stimulation strategy that similarly targets the full cochlear reserve. This novel strategy combines the electrical stimulation by the cochlear implant with low-frequency bone conduction stimulation. In a first evaluation of electro-vibrational stimulation, speech perception in noise was assessed in 9 subjects with a CI and symmetrical residual hearing. We demonstrate a statistically significant and clinically relevant improvement for speech perception in noise of 1.9 dB signal-to-noise ratio. This effect was observed with a first prototype that provides vibrational stimulation to both ears with limited transcranial attenuation. Future integration of electro-vibrational stimulation into one single implantable device could ultimately allow cochlear implant users to benefit from their low-frequency residual hearing without the need for an additional insert earphone.

Recent years have seen a rapid increase in digital medicine research in an attempt to transform traditional healthcare systems to their modern, intelligent, and versatile equivalents that are adequately equipped to tackle contemporary challenges. This has led to a wave of applications that utilise AI technologies; first and foremost in the fields of medical imaging, but also in the use of wearables and other intelligent sensors. In comparison, computer audition can be seen to be lagging behind, at least in terms of commercial interest. Yet, audition has long been a staple assistant for medical practitioners, with the stethoscope being the quintessential sign of doctors around the world. Transforming this traditional technology with the use of AI entails a set of unique challenges. We categorise the advances needed in four key pillars: Hear, corresponding to the cornerstone technologies needed to analyse auditory signals in real-life conditions; Earlier, for the advances needed in computational and data efficiency; Attentively, for accounting to individual differences and handling the longitudinal nature of medical data; and, finally, Responsibly, for ensuring compliance to the ethical standards accorded to the field of medicine. Thus, we provide an overview and perspective of HEAR4Health: the sketch of a modern, ubiquitous sensing system that can bring computer audition on par with other AI technologies in the strive for improved healthcare systems.

Abstract Atmospheric rivers (ARs) generate most of the economic losses associated with flooding in the western United States and are projected to increase in intensity with climate change. This is of concern as flood damages have been shown to increase exponentially with AR intensity. To assess how AR-related flood damages are likely to respond to climate change, we constructed county-level damage models for the western 11 conterminous states using 40 years of flood insurance data linked to characteristics of ARs at landfall. Damage functions were applied to 14 CMIP5 global climate models under the RCP4.5 “intermediate emissions” and RCP8.5 “high emissions” scenarios, under the assumption that spatial patterns of exposure, vulnerability, and flood protection remain constant at present day levels. The models predict that annual expected AR-related flood damages in the western United States could increase from $1 billion in the historical period to $2.3 billion in the 2090s under the RCP4.5 scenario or to $3.2 billion under the RCP8.5 scenario. County-level projections were developed to identify counties at greatest risk, allowing policymakers to target efforts to increase resilience to climate change.

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell–mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells’ pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

PurposeThis study aimed to examine the differences in the biofilms and physical deposits on Crawford stents compared to large-diameter stents.MethodsA prospective interventional study was performed on a series of patients undergoing external or endoscopic dacryocystorhinostomy (DCR) and endoluminal lacrimal duct recanalization (ELDR) with either Crawford or large-diameter stents. All the Crawford stents were retrieved at six weeks and the large-diameter ones at eight weeks following the surgical intervention. There was no evidence of post-operative infection in any of the patients. Following extubation, standard protocols of scanning electron microscopy were used to assess the biofilms and physical deposits on the stents.ResultsA total of 15 stents were studied. Of these, twelve were Crawford, and three were large-diameter stents. The Crawford stents were from two different manufacturers. All the stents demonstrated evidence of biofilm formation and physical deposits. The Crawford stents showed thin biofilms and sparse physical deposits, but there were no demonstrable differences amongst stents from different manufacturers. However, the deposits and biofilms were thicker and more extensive in the large-diameter stents than the Crawford ones. The biofilms from all stents showed the presence of polymicrobial communities within the exopolysaccharide matrix.ConclusionsThe present study found differences in biofilms and physical deposits between Crawford and large-diameter stents. These differences can be partly explained by stent duration, size, and their tissue interactions.

BackgroundAn enhanced recovery after surgery (ERAS) protocol is a multimodal and multi-professional strategy aiming to accelerate postoperative convalescence. Pre-, intra- and postoperative measures might furthermore reduce postoperative complications and hospital length of stay (LOS) in a cost-effective way. We hypothesized that our unique ERAS protocol leads to shorter stays on the intensive care unit (ICU) and a quicker discharge without compromising patient safety.MethodsThis retrospective single center cohort study compares data of n = 101 patients undergoing minimally invasive heart valve surgery receiving a comprehensive ERAS protocol and n = 111 patients receiving routine care. Hierarchically ordered primary endpoints are postoperative hospital length of stay (LOS), postoperative complications and ICU LOS.ResultsPatients risk profiles and disease characteristics were comparably similar. Age was relevantly different between the groups (56 (17) vs. 57.5 (13) years, p = 0.015) and therefore adjusted. Postoperative LOS was significantly lower in ERAS group (6 (2) days vs. 7 (1) days, pConclusionThe ERAS protocol for minimally invasive heart valve surgery is safe and feasible in an elective setting and leads to a quicker hospital discharge without compromising patient safety. However, further investigation in a randomized setting is needed.

Abstract Biometric identification techniques such as photo-identification require an array of unique natural markings to identify individuals. From 1975 to present, Bigg’s killer whales have been photo-identified along the west coast of North America, resulting in one of the largest and longest-running cetacean photo-identification datasets. However, data maintenance and analysis are extremely time and resource consuming. This study transfers the procedure of killer whale image identification into a fully automated, multi-stage, deep learning framework, entitled FIN-PRINT. It is composed of multiple sequentially ordered sub-components. FIN-PRINT is trained and evaluated on a dataset collected over an 8-year period (2011–2018) in the coastal waters off western North America, including 121,000 human-annotated identification images of Bigg’s killer whales. At first, object detection is performed to identify unique killer whale markings, resulting in 94.4% recall, 94.1% precision, and 93.4% mean-average-precision (mAP). Second, all previously identified natural killer whale markings are extracted. The third step introduces a data enhancement mechanism by filtering between valid and invalid markings from previous processing levels, achieving 92.8% recall, 97.5%, precision, and 95.2% accuracy. The fourth and final step involves multi-class individual recognition. When evaluated on the network test set, it achieved an accuracy of 92.5% with 97.2% top-3 unweighted accuracy (TUA) for the 100 most commonly photo-identified killer whales. Additionally, the method achieved an accuracy of 84.5% and a TUA of 92.9% when applied to the entire 2018 image collection of the 100 most common killer whales. The source code of FIN-PRINT can be adapted to other species and will be publicly available.

Background Inertial sensors hold the promise to objectively measure functional recovery after total knee (TKA) and hip arthroplasty (THA), but their value in addition to patient-reported outcome measures (PROMs) has yet to be demonstrated. This study investigated recovery of gait after TKA and THA using inertial sensors, and compared results to recovery of self-reported scores of pain and function. Methods PROMs and gait parameters were assessed before and at two and fifteen months after TKA (n = 24) and THA (n = 24). Gait parameters were compared with healthy individuals (n = 27) of similar age. Gait data were collected using inertial sensors on the feet, lower back, and trunk. Participants walked for two minutes back and forth over a 6m walkway with 180° turns. PROMs were obtained using the Knee Injury and Osteoarthritis Outcome Scores and Hip Disability and Osteoarthritis Outcome Score. Results Gait parameters recovered to the level of healthy controls after both TKA and THA. Early improvements were found in gait-related trunk kinematics, while spatiotemporal gait parameters mainly improved between two and fifteen months after TKA and THA. Compared to the large and early improvements found in of PROMs, these gait parameters showed a different trajectory, with a marked discordance between the outcome of both methods at two months post-operatively. Conclusion Sensor-derived gait parameters were responsive to TKA and THA, showing different recovery trajectories for spatiotemporal gait parameters and gait-related trunk kinematics. Fifteen months after TKA and THA, there were no remaining gait differences with respect to healthy controls. Given the discordance in recovery trajectories between gait parameters and PROMs, sensor-derived gait parameters seem to carry relevant information for evaluation of physical function that is not captured by self-reported scores.

Presentation of short-term results from the application of epiphysiodesis of the first ray as a method of treatment of adolescent hallux valgus. Material and method: The operative technique was introduced in USHATO in January 2018 like a operative procedure for treatment of mild and moderate deformity of adolescent hallux valgus (AHV). The technique includes percutaneous access to the growth zones in the area of ​​the first metatarsal bone and proximal phalanx and partial epiphysiodesis of the growth complex. The study presents 12 cases in 9 children with a mean age of 10.1 years (min. 5 years, max. 13 years). Most of the patients were female - 77.78%. According to the three-dimensional Stantrock classification and the HV severity classification, the twelve cases fell into group II-A and moderate severity. Three angular parameters hallux valgus angle(HVA), intra-metatarsal angle (IMA), distal-metatarsal articulation angle (DMAA), were used to monitor the results, and the measurements were performed preoperatively, intraoperatively and postoperatively. The American Orthopaedic Foot and Ankle Society (AOFAS), was used to report clinical outcomes. Results: Patients were followed up for a mean period of 17.58 months. For this period we do not established postoperative recurrences, and all cases remain in the same group according Stantrock classification and the HV severity classification. In the three monitored radiographic parameters we report clinical, but not statistical improvement: HVA by an average of 1.19°, IMA by an average of 0.55° and loss of correction in DMAA by 0.9°. For the follow-up period, we report a statistical improvement in the clinical parameters reported on the AOFAS scale (p

Objective: Evaluation the degree of complications in the surgical treatment of adolescent hallux valgus Material and method: The study examines 47 cases of surgically treated children with adolescent hallux valgus with a mean age of 14.3 years. Most of the patients were female - 93.75%. and the most affected is the right foot - 51.21%. For diagnosis and follow-up of the treatment result, X-ray methods were used with angular imaging measurements - hallux valgus angle (HVA) and intrametatarsal angle (IMA). Results: The mean follow-up period was 15.8 m. The mean preoperative angle of hallux valgus was 30.19 o and the mean preoperative intrametatarsal angle was 11.44o. In the final results we report a loss of correction of HVA on average to - 20.46 o (min 6.8 o max 38.2 o) and preservation of IM with an average value of 7.35 o. The Clavien Dindo classification was used to account of the postoperative complications. The recurrence rate reported at 10 months postoperatively were 15 cases or 31.91%. The following postoperative complications were reported for the follow-up period: avascular necrosis of the metatarsal head 1 year postoperatively and intraoperative fracture of the first metatarsal bone. Conclusions: Despite the many described surgical techniques, there are still no long-term indicative results for successfully used surgery. After processing our data and compare it with those of the world literature, we come to the conclusion that the rate of possible recurrence in the surgical treatment of AHV is high. The closure of the growth zone is confirmed as one of the criteria for the outcome of the treatment and the degree of postoperative recurrence of the deformity.

Presentation of short-term results from the application of epiphysiodesis of the first ray as a method of treatment of adolescent hallux valgus. Material and method: The operative technique was introduced in USHATO in January 2018 like a operative procedure for treatment of mild and moderate deformity of adolescent hallux valgus (AHV). The technique includes percutaneous access to the growth zones in the area of ​​the first metatarsal bone and proximal phalanx and partial epiphysiodesis of the growth complex. The study presents 12 cases in 9 children with a mean age of 10.1 years (min. 5 years, max. 13 years). Most of the patients were female - 77.78%. According to the three-dimensional Stantrock classification and the HV severity classification, the twelve cases fell into group II-A and moderate severity. Three angular parameters hallux valgus angle(HVA), intra-metatarsal angle (IMA), distal-metatarsal articulation angle (DMAA), were used to monitor the results, and the measurements were performed preoperatively, intraoperatively and postoperatively. The American Orthopaedic Foot and Ankle Society (AOFAS), was used to report clinical outcomes. Results: Patients were followed up for a mean period of 17.58 months. For this period we do not established postoperative recurrences, and all cases remain in the same group according Stantrock classification and the HV severity classification. In the three monitored radiographic parameters we report clinical, but not statistical improvement: HVA by an average of 1.19°, IMA by an average of 0.55° and loss of correction in DMAA by 0.9°. For the follow-up period, we report a statistical improvement in the clinical parameters reported on the AOFAS scale (p

Objective: Evaluation the degree of complications in the surgical treatment of adolescent hallux valgus Material and method: The study examines 47 cases of surgically treated children with adolescent hallux valgus with a mean age of 14.3 years. Most of the patients were female - 93.75%. and the most affected is the right foot - 51.21%. For diagnosis and follow-up of the treatment result, X-ray methods were used with angular imaging measurements - hallux valgus angle (HVA) and intrametatarsal angle (IMA). Results: The mean follow-up period was 15.8 m. The mean preoperative angle of hallux valgus was 30.19 o and the mean preoperative intrametatarsal angle was 11.44o. In the final results we report a loss of correction of HVA on average to - 20.46 o (min 6.8 o max 38.2 o) and preservation of IM with an average value of 7.35 o. The Clavien Dindo classification was used to account of the postoperative complications. The recurrence rate reported at 10 months postoperatively were 15 cases or 31.91%. The following postoperative complications were reported for the follow-up period: avascular necrosis of the metatarsal head 1 year postoperatively and intraoperative fracture of the first metatarsal bone. Conclusions: Despite the many described surgical techniques, there are still no long-term indicative results for successfully used surgery. After processing our data and compare it with those of the world literature, we come to the conclusion that the rate of possible recurrence in the surgical treatment of AHV is high. The closure of the growth zone is confirmed as one of the criteria for the outcome of the treatment and the degree of postoperative recurrence of the deformity.

Abstract Background Bone marrow mononuclear cells have been successfully utilized for numerous regenerative purposes. In the current study, patients suffering from erectile dysfunction (ED) unresponsive to phosphodiesterase 5 inhibitors were administered autologous bone marrow concentrate delivered intracavernously utilizing a point of care FDA cleared medical device. Methods A total of 40 patients were treated in the primary trial and 100 in the clinical registry, with the longest follow up of 12 months. Results Minimal treatment associated adverse effects where observed related to short term bruising at the site of harvest or injection. No long-term adverse events were noted related to the intervention. Mean improvements in IIEF-5 score were 2 in the Caverstem 1.0 low dose group, 3 in the high dose Caverstem 1.0 group and 9 in the Caverstem 2.0 group. Furthermore, improvements peaked by 3 months and maintained at 6 months follow-up. Conclusion These data support the safety and efficacy of point of care, minimally to non-manipulated, non-expanded bone marrow concentrate for the treatment of ED. Trial registration Funded by Creative Medical Health, Inc.; Clinicaltrials.gov number: NCT03699943; https://clinicaltrials.gov/ct2/show/NCT03699943?term=caverstem&rank=1 ; initially registered December 12, 2015.

Abstract Objective Edema syndrome is highly prevalent but under researched in captive frogs around the world. The objective of the present study was to characterize at a basic microbiological and cytological level of the bacteria of the edema fluid of 20 individuals of the genus Gastrotheca to determine the presence of possible anaerobic and aerobic bacteria. Results Fourteen types of bacteria were identified in the edema fluid, 12 of them at the species level (Pasteurella haemolytica, Hafnia alvei, Enterobacter agglomerans, Aeromonas hydrophila, Pseudomonas fluorescens, Burkholderia pseudomallei, Salmonella arizonae, Enterobacter gergoviae, Enterobacter sakazakii, Yersinia enterocolitica, Klebsiella oxytoca, and Klebsiella ozaenae) and two at the genus level (Enterococcus spp. and Streptococcus spp.). The most frequently identified cells were lymphocytes (37.7% in females and 46.4% in males), erythrocytes (23.5% in females and 17.5% in males) and neutrophils (4.2% in females and 2.8% in males). Finally, no relationship was found between the data obtained and the sex of the individuals studied.

Abstract Daily precipitation in California has been projected to become less frequent even as precipitation extremes intensify, leading to uncertainty in the overall response to climate warming. Precipitation extremes are historically associated with Atmospheric Rivers (ARs). Sixteen global climate models are evaluated for realism in modeled historical AR behavior and contribution of the resulting daily precipitation to annual total precipitation over Western North America. The five most realistic models display consistent changes in future AR behavior, constraining the spread of the full ensemble. They, moreover, project increasing year-to-year variability of total annual precipitation, particularly over California, where change in total annual precipitation is not projected with confidence. Focusing on three representative river basins along the West Coast, we show that, while the decrease in precipitation frequency is mostly due to non-AR events, the increase in heavy and extreme precipitation is almost entirely due to ARs. This research demonstrates that examining meteorological causes of precipitation regime change can lead to better and more nuanced understanding of climate projections. It highlights the critical role of future changes in ARs to Western water resources, especially over California.

Medical faculties have the responsibility to train tomorrow's doctors and in a crisis face the challenge of delivering students into the workforce promptly and safely. Worldwide, medical faculties have faced unprecedented disruptions from viral outbreaks and pandemics including SARS, Ebola, H1N1 and COVID-19 which bring unique challenges. Currently there is worldwide disruption to medical faculties and medical education due to COVID-19. Despite close links with clinical medicine and the known risks of pandemics, many medical faculties have been caught off guard without pandemic planning in place, to deal with an exponential rise in infections and deaths, overwhelmed health services and widespread community risk of transmission. Assessing transmission risk of COVID-19 in teaching, clinical and community attachments and continuing medical education is paramount as medical faculties face subsequent pandemics waves. Consensus statements based on best available evidence and international expertise from medical faculties in Asia, Australia and Europe were developed to help guide the protection of staff and students, priorities on teaching activities and further educational development. Infection prevention, infection control, contact tracing and medical surveillance are detailed to minimise transmission and to enhance safety. Recommendations on teaching activities planning can enhance responsiveness of medical faculties to tackle subsequent waves of COVID-19 infection. A global approach and dialogue are encouraged.

BackgroundHospital readmissions place a major burden on patients and health care systems worldwide, but little is known about patterns and timing of readmissions in Germany.MethodsWe used German health insurance claims (AOK, 2011-2016) of patients ≥ 65 years hospitalized for acute myocardial infarction (AMI), heart failure (HF), a composite of stroke, transient ischemic attack, or atrial fibrillation (S/AF), chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, or osteoporosis to identify hospital readmissions within 30 or 90 days. Readmissions were classified into all-cause, specific, and non-specific and their characteristics were analyzed.ResultsWithin 30 and 90 days, about 14-22% and 27-41% index admissions were readmitted for any reason, respectively. HF and S/AF contributed most index cases, and HF and COPD accounted for most all-cause readmissions. Distributions and ratios of specific to non-specific readmissions were disease-specific with highest specific readmissions rates among COPD and AMI.ConclusionGerman claims are well-suited to investigate readmission causes if longer periods than 30 days are evaluated. Conditions closely related with the primary disease are the most frequent readmission causes, but multiple comorbidities among readmitted cases suggest that a multidisciplinary care approach should be implemented vigorously addressing comorbidities already during the index hospitalization.

Introduction International standards of care require the complete integration of psycho-oncological care into biomedical cancer treatment. The structured integrated, cross-sectoral psycho-oncological programme ‘isPO’ is aiming to ensure a provision of care in inpatient and outpatient settings according to a stepped-care approach. Up to now, psycho-oncological care is missing regulated and standardised processes to demonstrate the effectiveness. This study protocol describes the process and outcome evaluation that is conducted, along with the isPO study. The programme evaluation is aiming to proof effectiveness, explain potential discrepancies between expected and observed outcomes. Additionally, provide insight into the implementation process, as well as contextual factors that might promote or inhibit the dissemination and implementation of the stepped care programme will be gained. In addition to these measures, a cost–consequence analysis will provide further evidence aimed at integrating psycho-oncological care into primary healthcare.Methods and analysis The evaluation concept is based on a tripartite strategy consisting of a prospective, formative and summative evaluation. To capture all determinants, a concurrent mixed-method design is applied comprising qualitative (interviews and focus groups) and quantitative (standardised questionnaires) surveys of patients and healthcare providers. In addition, analysis of the psycho-oncological care data (isPO care data) and statutory health insurance claims data will be conducted. Primary and secondary data will complement one another (data linkage) to obtain a more comprehensive picture of the effectiveness and implementation of the complex intervention within the isPO study.Ethics and dissemination The study has been approved by the ethics committee of the Medical Faculty of the University of Cologne. For all collected data, the relevant national and European data protection regulations will be considered. All personal identifiers (eg, name, date of birth) will be pseudonymised. Dissemination strategies include annual reports as well as quality workshops for the organisations, the presentation of results in publications and on conferences, and public relations.Trial registration number DRKS00015326; Pre-results.

Background: Activated microglia play a complex role in neuroinflammation associated with acute ischaemic stroke. As a potential target for anti-inflammatory therapy, it is crucial to understand the association between intensity, extent and the clinical outcome of a stroke. The 18-kDa translocator protein is a marker of cerebral microglial activation and of macrophage infiltration after damage to the brain. It can be imaged by positron emission tomography. Therefore, the recently developed radiopharmaceutical [18F]-GE180 was used in patients after a mild to moderate stroke and compared with [11C]-(R)-PK11195, which has already been established in research but cannot be used in routine clinical settings because of its very short half-life. Objectives: Objectives for phase 1 were to evaluate the tolerability of positron emission tomography scanning, to assess the technical feasibility of imaging the 18-kDa translocator protein using [18F]-GE180 as radiopharmaceutical, to compare [18F]-GE180 with [11C]-(R)-PK11195 as reference. Objectives for phase 2 were examining the relation of positron emission tomography imaging with clinical outcome, magnetic resonance imaging and systemic inflammation. However, the study was ended after phase 1 because of the results obtained in that phase and did not enter phase 2. Methods: Ten participants (aged 24–89 years, median 68 years) (eight male and two female) with a history of recent ischaemic stroke of mild to moderate severity (modified Rankin scale score of 2–3) in the middle cerebral artery territory were scanned 18 to 63 days (median 34.5 days) after the stroke by magnetic resonance imaging (Philips 1.5 T; Philips, Amsterdam, the Netherlands), [18F]-GE180 (200 MBq, 30-minute dynamic scan) and [11C]-(R)-PK11195 (740 MBq, 60-minute dynamic scan) positron emission tomography (Siemens HRRT; Siemens, Munich, Germany). The two positron emission tomography scans were performed on 2 separate days (mean 3.4 days apart). Five patients were randomised to receive the [18F]-GE180 scan at the first session and five patients were randomised to receive it at the second session. Participants were genotyped for the rs6971 18-kDa translocator protein polymorphism, which is known to affect binding of [18F]-GE180 but not of [11C]-(R)-PK11195. All positron emission tomography and magnetic resonance data sets were co-registered with T1-weighted magnetic resonance image scans. Binding of [18F]-GE180 was compared with [11C]-(R)-PK11195 for the infarct and contralateral reference regions. Spearman’s rank-order correlation was used to compare tracers, t-tests to compare patient subgroups. Results: Tolerability of scans was rated as 4.36 (range 4–5) out of a maximum of 5 by participants, and there were no serious adverse events. There was a close correlation between [18F]-GE180 and [11C]-(R)-PK11195 (r = 0.79 to 0.84). The 18-kDa translocator protein polymorphism had a significant impact on the uptake of [18F]-GE180, which was very low in normal cortex. Ischaemic lesions with contrast enhancement on magnetic resonance as an indicator of blood–brain barrier damage showed a significantly higher uptake of [18F]-GE180 than the lesions without enhancement, even in low-affinity binders. Conclusions: [18F]-GE180 was safe and well tolerated. However, strong dependency of uptake on blood–brain barrier damage and a genetic 18-kDa translocator protein polymorphism, as well as a high contribution of vascular signal to the uptake and evidence of non-specific binding in ischaemic lesions with blood–brain barrier damage, limits the clinical applicability of [18F]-GE180 as a diagnostic marker of neuroinflammation. Limitations: As the study was ended after phase 1, this was only a small pilot trial. Further studies are warranted to fully understand the influence of blood–brain barrier damage on positron emission tomography microglia imaging. Trial registration: Registered as a clinical trial with EudraCT 2014-000591-26. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 1. See the NIHR Journals Library website for further information. It was also supported by GE Healthcare (Chicago, IL, USA) by free production and delivery of [18F]-GE180 and by supply of regulatory documents (Investigational Medical Product Dossier, Investigator’s Brochure). There was partial support by the European Commission (INMiND, grant #278850) and the NIHR Sheffield Biomedical Research Centre.

Introduction The optimal duration of dual anti-platelet therapy (DAPT) following percutaneous coronary intervention (PCI) is still a matter of debate. Biomarkers may help to identify patients who will benefit from extended DAPT. The aim of the study was to test the interaction between lipid parameters and platelet function in patients with coronary artery disease (CAD) on DAPT. Material and methods Overall, 58 patients on DAPT were prospectively included following PCI in stable CAD. Platelet markers, i.e. mean platelet volume (MPV), platelet distribution width (PDW), fraction of reticulated thrombocytes (RT) and ADP-induced multiple electrode aggregometry (MEA), as well as serum lipids, i.e. high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG) and remnant cholesterol (RC), were assessed after intake of a maintenance dose of ASA and P2Y12 inhibitor. Results A significant inverse correlation was found for HDL-C levels and markers of platelet activation: MPV (r = –0.351, p = 0.009), PDW (r = –0.391, p = 0.003), fraction of RT (r = –0.402, p = 0.003) and ADP-induced MEA (r = –0.345, p = 0.011). Only a weak or no association was found between other lipid parameters and platelet markers. After multivariable adjustment, HDL-C levels served as a strong and significant predictor of MPV (95% CI: –0.039 to –0.009; p = 0.002), PDW (95% CI: –0.094 to –0.034; p < 0.0001), RT (95% CI: –0.107 to –0.031; p = 0.001) and MEA (95% CI: –0.540 to –0.170; p < 0.0001), while TG, LDL-C, RC and TC were not significantly associated with platelet function. Conclusions Within lipid parameters, only HDL-C levels are strongly associated with markers of platelet activation in CAD patients on DAPT. Accordingly, detection of dyslipidemia might indicate the need for prolongation of DAPT.

Abstract Background A patent microvascular anastomosis is of paramount importance in free tissue transfer. Anastomotic coupler devices provide an alternative to technically demanding hand-sewn venous anastomosis. Various advantages of these devices have been discussed but previous systematic reviews had methodological flaws or did not perform a meta-analysis. This review aims to evaluate the quality of the evidence and quantify the efficacy and safety of venous couplers compared to hand-sewn anastomosis. Methods A PRISMA-compliant systematic review and meta-analysis will be performed. A comprehensive search strategy has been developed and will be applied to the databases MEDLINE and Embase from inception to October 2018. All clinical studies using anastomotic coupler devices for venous anastomoses in free tissue transfer will be eligible for inclusion. Screening of studies and data extraction will be performed independently by two authors. Our primary outcome is anastomotic venous thrombosis. Secondary outcomes will include time to complete the venous anastomosis, tearing of veins, anastomotic leakage, flap loss/failure and fiscal outcomes. The risk of bias for included studies will be assessed by using the ROBINS-I tool, and recommendations based on the evidence will be made using the GRADE approach. Descriptive statistical analyses will be used and if two or more studies report the same outcome, data will be pooled for comparative analysis. A direct comparison meta-analysis will be performed if possible. Discussion There has been no comparison of coupled and hand-sewn venous anastomoses using a robust and validated methodology preceded by a protocol and performing meta-analysis. Included studies are expected to be mainly observational and prone to bias; however, there is value in summarising the evidence, assessing its risk of bias and performing meta-analysis to guide clinicians. By using a broad approach including all types of flaps, we foresee inherent differences regarding the unit of analysis and different anatomic sites. This will limit the validity of our conclusions but is unavoidable. We will seek unpublished data from authors and perform subgroup analysis where appropriate. Limitations and areas of uncertainty will be discussed to guide future research. Systematic review registration PROSPERO CRD42018110111

Introduction Respiratory failure requiring endotracheal intubation accounts for a significant proportion of intensive care unit (ICU) admissions. Little attention has been paid to the laryngeal consequences of endotracheal intubation. Acute laryngeal injury (ALgI) after intubation occurs at the mucosal interface of the endotracheal tube and posterior larynx and although not immediately manifest at extubation, can progress to mature fibrosis, restricted glottic mobility and clinically significant ventilatory impairment. A recent prospective observational study has shown that >50% of patients intubated >24 hours in an ICU develop ALgI. Strikingly, patients with AlgI manifest significantly worse subjective breathing at 12 weeks. Current ALgI treatments are largely surgical yet offer a marginal improvement in symptoms. In this study, we will examine the ability of a postextubation medical regime (azithromycin and inhaled budesonide) to improve breathing 12 weeks after ALgI.Methods and analysis A prospective, single-centre, double-blinded, randomised, control trial will be conducted at Vanderbilt Medical Center. Participants will be recruited from adult patients in ICUs. Participants will undergo a bedside flexible nasolaryngoscopy for the identification of ALgI within 72 hours postextubation. In addition, participants will be asked to complete peak expiratory flow measurements immediately postintubation. Patients found to have ALgI will be randomised to the placebo control or medical therapy group (azithromycin 250 mg and budesonide 0.5 mg for 14 days). Repeat peak expiratory flow, examination of the larynx and patient-reported Clinical COPD (chronic obstructive pulmonary disease) Questionnaire, Voice Handicap Index and 12-Item Short Form Health Survey questionnaires will be conducted at 12 weeks postextubation. Consented patients will also have patient-specific, disease-specific and procedure-specific covariates abstracted from their medical record.Ethics and dissemination The Institutional Review Board (IRB) Committee of the Vanderbilt University Medical Center has approved this protocol (IRB #171066). The findings of the trial will be disseminated through peer-reviewed journals, national and international conferences.Trial registration number NCT03250975

We specify a Bayesian, geoadditive Stochastic Frontier Analysis (SFA) model to assess hospital performance along the dimensions of resources and quality of stroke care in German hospitals. With 1,100 annual observations and data from 2006 to 2013 and risk-adjusted patient volume as output, we introduce a production function that captures quality, resource inputs, hospital inefficiency determinants and spatial patterns of inefficiencies. With high relevance for hospital management and health system regulators, we identify performance improvement mechanisms by considering marginal effects for the average hospital. Specialization and certification can substantially reduce mortality. Regional and hospital-level concentration can improve quality and resource efficiency. Finally, our results demonstrate a trade-off between quality improvement and resource reduction and substantial regional variation in efficiency.

Many studies showed that biological (e.g., gaze-shifts or hand movements) and non-biological stimuli (e.g., arrows or moving points) redirect attention. Biological stimuli seem to be more suitable than non-biological to perform this task. However, the question remains if biological stimuli do have different influences on redirecting attention and if this property is dependent on how we react to those stimuli. In two separate experiments, participants interact either with a biological or a non-biological stimulus (experiment 1), or with two biological stimuli (gaze-shifts, hand movements)(experiment 2) to which they responded with two different actions (saccade, button press), either in a congruent or incongruent manner. Results from experiment 1 suggest that interacting with the biological stimulus lead to faster responses, compared to the non-biological stimulus, independent of the response type. Results from experiment 2 show longer reaction times when the depicted stimulus was not matching the response type (e.g., reacting with hand movements to a moving object or gaze-shift) compared to a matching condition, while especially the gaze-following condition (reacting with a gaze shift to a perceived gaze shift) led to the fastest responses. These results suggest that redirecting attention is not only dependent on the perceived stimulus but also on the way how those stimuli are responded to.

Pulmonary hypertension (PH) is characterized by the increase of the mean pulmonary arterial pressure in the lung circulation. Despite the large number of experimental and clinical studies conducted on pulmonary hypertension, there is no comprehensive work that analyzed the global research activity on PH so far. We retrieved the bibliometric data of the publications on pulmonary hypertension for two periods from the Web of science database. Here, we set the first investigation period from 1900 to 2007 (t1) due to the cited half life of articles and the relating difficulties to interpret the citation parameters. The second evaluation period (t2) covers the time interval from 2008 onwards including the year 2015. The data were analyzed and processed to density-equalizing maps using the NewQIS platform. A total number of 18,986 publications were identified in t1 that come from 85 countries. The US published the highest number of publications (n = 7,290), followed by the UK, Germany, Japan and France. In t2 19,676 items could be found worked out by 130 countries. The raking started just the same with the USA as most publishing nation with 7,127 publications on PH, followed by the UK and Germany. Japan fell back on 6th place, whereas China came into view on the 5th position. Analyzing the average citation rate as a parameter for research quality, Mexico reached the highest value in t1 and Ireland in t2. While, the country specific h-index underlined the leading position of the US research in both evaluation periods again. The average number of international collaboration items was expanding from none in 1978 to 530 items in 2015 with the USA as the country with the highest number of collaboration articles. The present study is the first large scale density-equalizing mapping and scientometric analysis of global PH research activity. Our data draw a sketch of the global research architecture in this field, indicating a need for specific research programs in countries with a lower human development index.

The pathophysiology underlying postural instability in Parkinson's disease is poorly understood. The frequent co-existence with freezing of gait raises the possibility of shared pathophysiology. There is evidence that dysfunction of brainstem structures contribute to freezing of gait. Here, we evaluated whether dysfunction of these structures contributes to postural instability as well. Brainstem function was assessed by studying the StartReact effect (acceleration of latencies by a startling acoustic stimulus (SAS)).We included 25 patients, divided in two different ways: 1) those with postural instability (HY = 3, n = 11) versus those without (HY

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.

BACKGROUND:Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. METHODS:Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS:Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin. CONCLUSION:Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β(1) may represent a mechanism for the promotion of fibrogenesis in IPF.

The oxygen (δ(18)O) and carbon (δ(13)C) isotope compositions of bioapatite from skeletal remains of fossil mammals are well-established proxies for the reconstruction of palaeoenvironmental and palaeoclimatic conditions. Stable isotope studies of modern analogues are an important prerequisite for such reconstructions from fossil mammal remains. While numerous studies have investigated modern large- and medium-sized mammals, comparable studies are rare for small mammals. Due to their high abundance in terrestrial ecosystems, short life spans and small habitat size, small mammals are good recorders of local environments.The δ(18)O and δ(13)C values of teeth and bones of seven sympatric modern rodent species collected from owl pellets at a single locality were measured, and the inter-specific, intra-specific and intra-individual variations were evaluated. Minimum sample sizes to obtain reproducible population δ(18)O means within one standard deviation were determined. These parameters are comparable to existing data from large mammals. Additionally, the fractionation between coexisting carbonate (δ(18)O(CO3)) and phosphate (δ(18)O(PO4)) in rodent bioapatite was determined, and δ(18)O values were compared to existing calibration equations between the δ(18)O of rodent bioapatite and local surface water (δ(18)O(LW)). Specific calibration equations between δ(18)O(PO4) and δ(18)O(LW) may be applicable on a taxonomic level higher than the species. However, a significant bias can occur when bone-based equations are applied to tooth-data and vice versa, which is due to differences in skeletal tissue formation times. δ(13)C values reflect the rodents' diet and agree well with field observations of their nutritional behaviour.Rodents have a high potential for the reconstruction of palaeoenvironmental conditions by means of bioapatite δ(18)O and δ(13)C analysis. No significant disadvantages compared to larger mammals were observed. However, for refined palaeoenvironmental reconstructions a better understanding of stable isotope signatures in modern analogous communities and potential biases due to seasonality effects, population dynamics and tissue formation rates is necessary.

The high biological production of the California Current System (CCS) results from the seasonal development of equatorward alongshore winds that drive coastal upwelling. While several climatic fluctuation patterns influence the dynamics and biological productivity of the CCS, including the El Niño-Southern Oscillation (ENSO), the Pacific Decadal Oscillation index (PDO) and the North Pacific Gyre Oscillation (NPGO), the mechanisms of interaction between climatic oscillations and the CCS upwelling dynamics have remained obscure. Here, we use Singular Spectral Analysis (SSA) to reveal, for the first time, low-frequency concordance between the time series of climatic indices and upwelling intensity along the coast of western North America. Based on energy distributions in annual, semiannual and low-frequency signals, we can divide the coast into three distinct regions. While the annual upwelling signal dominates the energy spectrum elsewhere, low-frequency variability is maximal in the regions south of 33°N. Non-structured variability associated with storms and turbulent mixing is enhanced at northerly locations. We found that the low-frequency signal is significantly correlated with different climatic indices such as PDO, NPGO and ENSO with the correlation patterns being latitude-dependent. We also analyzed the correlations between this upwelling variability and sea surface temperature (SST) and sea level pressure (SLP) throughout the North Pacific to visualize and interpret the large-scale teleconnection dynamics in the atmosphere that drive the low-frequency coastal winds. These results provide new insights into the underlying mechanisms connecting climatic patterns with upwelling dynamics, which could enhance our prediction and forecast capabilities of the effects of future oceanographic and climatic variability in the CCS.

An incomplete understanding of the nature of heterogeneity within stem cell populations remains a major impediment to the development of clinically effective cell-based therapies. Transcriptional events within a single cell are inherently stochastic and can produce tremendous variability, even among genetically identical cells. It remains unclear how mammalian cellular systems overcome this intrinsic noisiness of gene expression to produce consequential variations in function, and what impact this has on the biologic and clinical relevance of highly 'purified' cell subgroups. To address these questions, we have developed a novel method combining microfluidic-based single cell analysis and information theory to characterize and predict transcriptional programs across hundreds of individual cells. Using this technique, we demonstrate that multiple subpopulations exist within a well-studied and putatively homogeneous stem cell population, murine long-term hematopoietic stem cells (LT-HSCs). These subgroups are defined by nonrandom patterns that are distinguishable from noise and are consistent with known functional properties of these cells. We anticipate that this analytic framework can also be applied to other cell types to elucidate the relationship between transcriptional and phenotypic variation.

The Raf/ERK (Extracellular Signal Regulated Kinase) signal transduction pathway controls numerous cellular processes, including growth, differentiation, cellular transformation and senescence. ERK activation is thought to involve complex spatial and temporal regulation, to achieve a high degree of specificity, though precisely how this is achieved remains to be confirmed. We report here that prolonged activation of a conditional form of c-Raf-1 (BXB-ER) leads to profound changes in the level and distribution of a heterochromatic histone mark. In mouse fibroblasts, the heterochromatic trimethylation of lysine 9 in histone H3 (H3K9Me3) is normally confined to pericentromeric regions. However, following ERK activation a genome-wide redistribution of H3K9Me3 correlates with loss of the histone modification from chromocentres and the appearance of numerous punctuate sites throughout the interphase nucleus. These epigenetic changes during interphase correlate with altered chromosome structure during mitosis, where robust H3K9Me3 signals appear within telomeric heterochromatin. This pattern of heterochromatinization is distinct from previously described oncogene induced senescence associated heterochromatin foci (SAHF), which are excluded from telomeres. The H3K9Me3 histone mark is known to bind the major heterochromatin protein HP1 and we show that the alterations in the distribution of this histone epistate correlate with redistribution of HP1β throughout the nucleus. Interestingly while ERK activation is fully reversible, the observed chromatin changes induced by epigenetic modifications are not reversible once established. We describe for the first time a link from prolonged ERK activation to stable changes in genome organization through redistribution of heterochromatic domains involving the telomeres. These epigenetic changes provide a possible mechanism through which prolonged activation of Raf/ERK can lead to growth arrest or the induction of differentiation, senescence and cancer.

Directional migration of transmigrated leukocytes to the site of injury is a central event in the inflammatory response. Here, we present an in vivo chemotaxis assay enabling the visualization and quantitative analysis of subtype-specific directional motility and polarization of leukocytes in their natural 3D microenvironment. Our technique comprises the combination of i) semi-automated in situ microinjection of chemoattractants or bacteria as local chemotactic stimulus, ii) in vivo near-infrared reflected-light oblique transillumination (RLOT) microscopy for the visualization of leukocyte motility and morphology, and iii) in vivo fluorescence microscopy for the visualization of different leukocyte subpopulations or fluorescence-labeled bacteria. Leukocyte motility parameters are quantified off-line in digitized video sequences using computer-assisted single cell tracking. Here, we show that perivenular microinjection of chemoattractants [macrophage inflammatory protein-1alpha (MIP-1alpha/Ccl3), platelet-activating factor (PAF)] or E. coli into the murine cremaster muscle induces target-oriented intravascular adhesion and transmigration as well as polarization and directional interstitial migration of leukocytes towards the locally administered stimuli. Moreover, we describe a crucial role of Rho kinase for the regulation of directional motility and polarization of transmigrated leukocytes in vivo. Finally, combining in vivo RLOT and fluorescence microscopy in Cx3CR1(gfp/gfp) mice (mice exhibiting green fluorescent protein-labeled monocytes), we are able to demonstrate differences in the migratory behavior of monocytes and neutrophils.Taken together, we propose a novel approach for investigating the mechanisms and spatiotemporal dynamics of subtype-specific motility and polarization of leukocytes during their directional interstitial migration in vivo.