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• We report a patient with different coil-to-scalp distances over motor (11mm) and prefrontal (2mm) regions due to hairstyle. • 120 % MT dosing would have resulted in prefrontal E-fields equivalent to 180 % MT. • E-field dosing may mitigate over-stimulation and determined that only 71.3 % MT was needed in this case. [ABSTRACT FROM AUTHOR]

This review describes a new therapeutic landscape in the adjuvant treatment of resectable non-small cell lung cancer (NSCLC) and discusses the role of the surgeon in ensuring the best outcomes within this treatment paradigm. We conducted a narrative literature review using the search terms "non-small cell lung cancer" and "adjuvant" to identify randomized Phase III trials of systemic adjuvant therapy for NSCLC through March 17, 2022. We also searched ClinicalTrials.gov to identify ongoing trials of adjuvant immunotherapies and targeted therapies for NSCLC. Three recent randomized Phase III trials reported significant improvements in disease-free survival with adjuvant immune checkpoint inhibitors or targeted therapy in patients with resectable NSCLC: IMpower010 (atezolizumab vs best supportive care; NCT02486718), KEYNOTE-091 (PEARLS) (pembrolizumab vs placebo; NCT02504372), and ADAURA (osimertinib vs placebo; NCT02511106). Numerous other Phase III trials evaluating adjuvant immune checkpoint inhibitors and targeted therapies are currently underway, many of which demonstrate an evolution of trial design and end points for adjuvant therapy trials. This rapidly changing treatment landscape requires a shift in the role of the surgeon to facilitate appropriate biomarker screening for planning of the perioperative period and molecular testing of the surgical specimen to guide adjuvant therapy. After decades of stagnation in the management of NSCLC, recent results with immune checkpoint inhibitors and targeted therapies are ushering in a new era of precision medicine in the adjuvant treatment of early-stage NSCLC. Surgeons have an important role in facilitating multidisciplinary care in this rapidly evolving landscape. [ABSTRACT FROM AUTHOR]

The use of mechanical circulatory support (MCS) in lung transplantation has been steadily increasing over the prior decade, with evolving strategies for incorporating support in the preoperative, intraoperative, and postoperative settings. There is significant practice variability in the use of these techniques, however, and relatively limited data to help establish institutional protocols. The objective of the AATS Clinical Practice Standards Committee (CPSC) expert panel was to review the existing literature and establish recommendations about the use of MCS before, during, and after lung transplantation. The AATS CPSC assembled an expert panel of 16 lung transplantation physicians who developed a consensus document of recommendations. The panel was broken into subgroups focused on preoperative, intraoperative, and postoperative support, and each subgroup performed a focused literature review. These subgroups formulated recommendation statements for each subtopic, which were evaluated by the entire group. The statements were then developed via discussion among the panel and refined until consensus was achieved on each statement. The expert panel achieved consensus on 36 recommendations for how and when to use MCS in lung transplantation. These recommendations included the use of veno-venous extracorporeal membrane oxygenation (ECMO) as a bridging strategy in the preoperative setting, a preference for central veno-arterial ECMO over traditional cardiopulmonary bypass during the transplantation procedure, and the benefit of supporting selected patients with MCS postoperatively. Achieving optimal results in lung transplantation requires the use of a wide range of strategies. MCS provides an important mechanism for helping these critically ill patients through the peritransplantation period. Despite the complex nature of the decision making process in the treatment of these patients, the expert panel was able to achieve consensus on 36 recommendations. These recommendations should provide guidance for professionals involved in the care of end-stage lung disease patients considered for transplantation. [ABSTRACT FROM AUTHOR]

Neural oscillations in the primary motor cortex (M1) shape corticospinal excitability. Power and phase of ongoing mu (8–13 Hz) and beta (14–30 Hz) activity may mediate motor cortical output. However, the functional dynamics of both mu and beta phase and power relationships and their interaction, are largely unknown. Here, we employ recently developed real-time targeting of the mu and beta rhythm, to apply phase-specific brain stimulation and probe motor corticospinal excitability non-invasively. For this, we used instantaneous read-out and analysis of ongoing oscillations, targeting four different phases (0°, 90°, 180°, and 270°) of mu and beta rhythms with suprathreshold single-pulse transcranial magnetic stimulation (TMS) to M1. Ensuing motor evoked potentials (MEPs) in the right first dorsal interossei muscle were recorded. Twenty healthy adults took part in this double-blind randomized crossover study. Mixed model regression analyses showed significant phase-dependent modulation of corticospinal output by both mu and beta rhythm. Strikingly, these modulations exhibit a double dissociation. MEPs are larger at the mu trough and rising phase and smaller at the peak and falling phase. For the beta rhythm we found the opposite behavior. Also, mu power, but not beta power, was positively correlated with corticospinal output. Power and phase effects did not interact for either rhythm, suggesting independence between these aspects of oscillations. Our results provide insights into real-time motor cortical oscillation dynamics, which offers the opportunity to improve the effectiveness of TMS by specifically targeting different frequency bands. • Real-time EEG-TMS-induced MEPs show an opposing relationship for ongoing sensorimotor beta and mu oscillations. • MEP amplitudes are maximal at the peak-to-falling phase of the sensorimotor beta rhythm. • MEP amplitudes are maximal at the trough-to-rising phase of the sensorimotor mu rhythm. • Independent of phase, pre-TMS mu power, but not beta power, is positively correlated with MEP size. [ABSTRACT FROM AUTHOR]

The combination of PET and MRI is one of the recent advances of hybrid imaging. Yet to date, the adoption rate of PET/MRI systems has been rather slow. This seems to be partially caused by the high costs of PET/MRI systems and the need to verify an incremental benefit over PET/CT or sequential PET/CT and MRI. In analogy to PET/CT, the MRI part of PET/MRI was primarily used for anatomical imaging. Though this can be advantageous, for example in diseases where the superior soft tissue contrast of MRI is highly appreciated, the sole use of MRI for anatomical orientation lessens the potential of PET/MRI. Consequently, more recent studies focused on its multiparametric potential and employed diffusion weighted sequences and other functional imaging sequences in PET/MRI. This integration puts the focus on a more wholesome approach to PET/MR imaging, in terms of releasing its full potential for local primary staging based on multiparametric imaging and an included one-stop shop approach for whole-body staging. This approach as well as the implementation of computational analysis, in terms of radiomics analysis, has been shown valuable in several oncological diseases, as will be discussed in this review article. [ABSTRACT FROM AUTHOR]

Transcranial Magnetic Stimulation (TMS) is a widely used non-invasive brain stimulation method. However, its mechanism of action and the neural response to TMS are still poorly understood. Multi-scale modeling can complement experimental research to study the subcellular neural effects of TMS. At the macroscopic level, sophisticated numerical models exist to estimate the induced electric fields. However, multi-scale computational modeling approaches to predict TMS cellular and subcellular responses, crucial to understanding TMS plasticity inducing protocols, are not available so far. We develop an open-source multi-scale toolbox Neuron Modeling for TMS (NeMo-TMS) to address this problem. NeMo-TMS generates accurate neuron models from morphological reconstructions, couples them to the external electric fields induced by TMS, and simulates the cellular and subcellular responses of single-pulse and repetitive TMS. We provide examples showing some of the capabilities of the toolbox. NeMo-TMS toolbox allows researchers a previously not available level of detail and precision in realistically modeling the physical and physiological effects of TMS. • We developed a new toolbox (NeMo-TMS) to simulate the cellular and subcellular activity of single neurons in response to (repetitive) TMS. • TMS-induced electric fields from the macroscopic models are coupled with a morphologically realistic neuron model to simulate the membrane potential and the spiking pattern. • Membrane potentials are used to model the voltage-gated calcium dynamics important for understating neuronal plasticity. • All necessary codes can be found in an open-source repository (https://github.com/OpitzLab/NeMo-TMS). [ABSTRACT FROM AUTHOR]

Treatment of stage IIIA lung cancer remains controversial because it includes a very heterogeneous group of patients. The purpose of our study was to compare survival between stage IIIA subsets and to externally validate our results with another center's database. Patients with completely resected stage IIIA/B lung cancer were retrospectively analyzed. There were 424 patients with stage IIIA and 82 patients with stage IIIB (T3/4 N2) (study cohort). Stage IIIA was divided into 2 subsets according to the tumor localization and tumor size (T3 N1–T4 N0/1, IIIA-T group; n = 308) and the extension of nodal disease (T1/2 N2, IIIA-N2 group; n = 116). The study cohort results were used to create a model for stage IIIA patients, which was validated with another center's database (validation cohort). The multivariate analyses showed age, stage IIIB, and pN2 were independent negative prognostic factors (P <.0001). Survival at 5 years was 51.3% (median, 64 months) for patients in the IIIA-T group and was 25.7% (median, 31 months) in the IIIA-N2 patients (hazard ratio, 1.834; P <.0001). There was no statistical difference in survival between the IIIA-N2 and stage IIIB groups (25.7% vs 25.3%, P =.442). The created model was performed on patients in the validation cohort as a model IIIA-T (T3 N1–T4 N0/1, n = 139) and model IIIA-N2 (T1/2 N2, n = 104). Model IIIA-T patients had a statistically better survival rate than model IIIA-N2 patients (median, 62 months vs 37 months; hazard ratio, 1.707, P < 0.001). There is a prognostic difference between stage IIIA subgroups in lung cancer patients who undergo surgical treatment. [ABSTRACT FROM AUTHOR]

Recognition of viral nucleic acids is one of the primary triggers for a type I interferon–mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger–containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease. [ABSTRACT FROM AUTHOR]

Improvement in ex vivo lung perfusion protocols could increase the number of donors available for transplantation and protect the lungs from primary graft dysfunction. We hypothesize that perfusate adsorption during ex vivo lung perfusion reconditions the allograft to ischemia–reperfusion injury after lung transplantation. Donor pig lungs were preserved for 24 hours at 4°C, followed by 6 hours of ex vivo lung perfusion according to the Toronto protocol. The perfusate was additionally adsorbed through a CytoSorb adsorber (CytoSorbents, Berlin, Germany) in the treatment group, whereas control lungs were perfused according to the standard protocol (n = 5, each). Ex vivo lung perfusion physiology and biochemistry were monitored. Upon completion of ex vivo lung perfusion, a left single lung transplantation was performed. Oxygenation function and lung mechanics were assessed during a 4-hour reperfusion period. The inflammatory response was determined during ex vivo lung perfusion and reperfusion. The cytokine concentrations in the perfusate were markedly lower with the adsorber, resulting in improved ex vivo lung perfusion physiology and biochemistry during the 6-hour perfusion period. Post-transplant dynamic lung compliance was markedly better during the 4-hour reperfusion period in the treatment group. Isolated allograft oxygenation function and dynamic compliance continued to be superior in the adsorber group at the end of reperfusion, accompanied by a markedly decreased local inflammatory response. Implementation of an additional cytokine adsorber has refined the standard ex vivo lung perfusion protocol. Furthermore, cytokine removal during ex vivo lung perfusion improved immediate post-transplant graft function together with a less intense inflammatory response to reperfusion in pigs. Further studies are warranted to understand the beneficial effects of perfusate adsorption during ex vivo lung perfusion in the clinical setting. [ABSTRACT FROM AUTHOR]

• Spontaneous pneumothorax due to COVID-19 may happen in never-ventilated patients. • Due to persistence, these pneumothoraces may need surgery for bulla resection. • Endothelitis as seen in other organs may contribute to prolonged healing. Patients with COVID-19 infection and severe lung parenchyma alterations may need mechanical ventilation with subsequent pneumothorax and eventually persistent air leak in case of pre-existing lung disease. This report presents the case of a never-ventilated 58 years old male patient without pre-existing, underlying lung disease demonstrating severe lung parenchyma changes due to COVID-19-pneumonia. He suffered from recurrent bilateral spontaneous pneumothoraces, which were successfully treated with bilateral thoracoscopy and resections of the destroyed lung areas. Notably, he has already been under treatment with anticoagulation due to portal thrombosis 8 years ago. Although especially know from patients under mechanical ventilation, this patient suffered from spontaneous pneumothorax without ever been ventilated. Probably due to the severe vascular inflammatory changes and focal endothelitis like also seen in other organs of COVID-19 patients, the pneumothorax may lead to a prolonged air leak, which needs surgical therapy. The patients pre-existing anticoagulation therapy may prevented him from a mere severe course. Early surgical therapy may be considered in COVID-19 patients with persistent air leak, even if not mechanically ventilated. Simultaneously, the role of early anticoagulation needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Medication plans are instruments used to document drug therapies, guide patients, and ensure medication safety. In Germany, patients who take at least 3 long-term medications are eligible to receive a medication plan. It has been statutory to use the federal standard layout (German: "Bundeseinheitlicher Medikationsplan") since April 2017.Objectives: This study explores the prevalence, availability, medication discrepancies, and conformance with statutory regulations of medication plans since the introduction of the format of the federal standard medication plan in Germany.Methods: Medication reconciliation was performed for hospitalized patients according to the Best Possible Medication History principle. The collected medication lists were analyzed for medication discrepancies and conformance with the statutory regulations. The medication discrepancies were (1) omitted drugs, (2) additional drugs, and (3) dosing errors.Results: After hospitalization, 524 patients taking drugs were included. The majority (n = 424 patients) were eligible for a medication plan. While 241 medication lists were present, only 24.1% (n = 58) matched the federal standard format. The mean number of drugs was 6.3 ± 3.6, with 3315 medications (3046 long-term and 269 as needed) reconciled totally. The 84 medication lists with omitted or additional drugs included 166 medication discrepancies upon 774 drugs listed. Of the 253 patients with dosing errors, 146 had a medication list. Inappropriate dosages were due to single dose (n = 195), daily dose (n = 225) or frequency of application (n = 255).Conclusion: Medication plans are valuable tools for patients and health care providers. This study shows that the introduced paper-based federal standard medication plan in Germany falls short of its expectations regarding availability and correctness. Switching to an electronic patient record system may overcome some of the current pitfalls. [ABSTRACT FROM AUTHOR]

The metamorphic core of the Betic-Rif orogenic chain (Alboran Domain) is made up of lower crustal rocks forming the envelope of the Ronda (Spain) and Beni Bousera (Morocco) peridotites. The deepest sections of the crustal envelopes are made of migmatitic granulites associated with diffuse acidic magmatic products, making these exposure and ideal site to investigate the textural and petrological connection between crustal anatexis and granite magmatism in the contintental crust. However, still debated is the timing of intracrustal emplacement of the peridotite bodies, with models proposing either Alpine (early Miocene) or Hercynian ages, and still uncertain is the linkage between peridotite emplacement and crustal anatexis. In this study, by combining rock textures with whole-rock geochemistry, metamorphic thermobarometry, the U-Pb zircon geochronology and the analysis of the garnet and zircon REE chemistry, we document the P-T-t evolution of the granulite facies migmatites that form the immediate envelope of the Beni Bousera peridotites of the Rif belt. A main episode of Permo-Carboniferous (ca. 300–290 Ma) deep crustal anatexis, melt extraction and migration is documented that we link to the crustal emplacement of the Beni Bousera peridotites during collapse of the Hercynian orogen. Correlation at a regional scale suggests that the Beni-Bousera section can be tentatively correlated with the pre-Alpine (Permo-Carboniferous) basement units tectonically interleaved within the orogenic structure of the Alpine chain. The results of this study provide ultimate constraints to reconstruct the tectono-metamorphic evolution of the Alboran Domain in the Western Mediterranean and impose re-assessment of the modes and rates through which Alpine orogenic construction and collapse occurred and operated in the region. Unlabelled Image • Hercynian granulite–granite suite preserved at the core of the Alboran Domain • Hercynian deep crustal anatexis linked to emplacement of the Alboran peridotites • The core of the Alboran Domain preserves a Hercynian crust-mantle coupling zone • Alboran Domain migmatites as part of the Hercynian basement of Mediterranean region [ABSTRACT FROM AUTHOR]

Community-supported agriculture (CSA), a model associated with the movement of Alternative Food Networks (AFN), is gaining increasing attention from citizens and in policy. Many studies have identified the economic benefits of CSA for farmers. Some of them explain the economic benefits by closer social ties and the reciprocal relationship between consumers and producers. Up until now, a systematic study taking into account all social and institutional features of the relationship between consumers and producers and assessing their relevance for farm economic stability has been missing. The objective of our research is to investigate, which consumer-producer interactions (CPI) are most relevant for economic stability of a farm. In our study, we extend and implement an analytical framework of CPI, describing areas of interaction (CPI domains) as well as organisational procedures and rules of relationship (CPI properties). We apply this framework to use CPI as independent rational criteria in an Analytic Hierarchy Process (AHP). An AHP is a mathematical method where experts evaluate different variables in pairs for each level of the hierarchical design. Our results show that CPI can be considered a key factor in CSA farm economic stability, because it could be seen as ways in which consumers empower the producer economically. In addition to consumer-producer interactions regarding classical production factors such as capital ('financing') and land, the surveyed experts identified the consideration of consumer needs regarding qualities and quantities of produce as a relevant stabilizing factor. From these results, we conclude direct collaboration with the consumers allows CSA farmers to gain greater independence from volatile markets, but increases their dependency on the shareholder group of consumers. • The paper introduces and explains the concept of consumer-producer interactions (CPI) in CSA. • The study assesses the relevance of CPI for the economic stability of CSA farms. • The paper introduces the AHP method. • The results of the Analytic Hierarchy Process (AHP) show different relevance of CPIs for economic stability. • Experts assessed CPIs regarding capital, land and addressing consumer needs as most important factors. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this manuscript is to provide a current concept review for the rehabilitative management of knee osteoarthritis (KOA) following regenerative medicine intervention. A proposed comprehensive regenerative rehabilitative program has been created, based on a literature review of the current best practices of rehabilitative methods and non-operative management in KOA patients with an emphasis on the goals of regenerative medicine: to optimize self-healing and functional tissue recovery. Regenerative medicine promotes regeneration and joint restoration by using blood-based procedures such as platelet rich plasma, stem cell and cell-based or tissue engineering. Regenerative medicine procedures are variable and lack of standardization in product preparation, administration, and different treatment protocols. The lack of standardization imposes challenges in regenerative rehabilitation. Over the last decade, there is growing evidence in regenerative medicine and its uses in non-operative management of various pathologies. Advances in regenerative medicine technologies brings radical innovations to establish new and effective rehabilitation protocols promoting restoration of function through tissue regeneration and repair optimizing the standard of care, specifically in rehabilitation when combined with regenerative protocols for patients with KOA is the most common degenerative disease in the knee and can affect any synovial joint in the body. It is a leading cause of disability affecting the quality of lives of millions of people world-wide. Conventional methods of mild to moderate KOA are focused on short-term symptomatic relief and do not promote joint homeostasis or regeneration of injured tissue. Regenerative medicine emphasizes a paradigm shift in patient-centered care promoting regeneration and joint restoration by using blood-based procedures such as platelet rich plasma, stem cell and cell-based or tissue engineering. The purpose of this current concept review is to outline a comprehensive post-regenerative rehabilitative program in the management of KOA based on the best available evidence. Our proposed regenerative rehabilitation program is intended to align the goals of regenerative medicine with the current, high-level evidence of non-operative management for KOA, to optimize self-healing and functional tissue recovery. [ABSTRACT FROM AUTHOR]

The X-linked Allan-Herndon-Dudley syndrome (AHDS) is characterized by severely impaired psychomotor development and is caused by mutations in the SLC16A2 gene encoding the thyroid hormone transporter MCT8 (monocarboxylate transporter 8). By targeting exon 3 of SLC16A2 using CRISPR/Cas9 with single-stranded oligodeoxynucleotides as homology-directed repair templates, we introduced the AHDS patient missense variant G401R and a novel knock-out deletion variant (F400Sfs*17) into the male healthy donor hiPSC line BIHi001-B. We successfully generated cerebral organoids from these genome-edited lines, demonstrating the utility of the novel lines for modelling the effects of MCT8-deficency on human neurodevelopment. [ABSTRACT FROM AUTHOR]

• Leaching of cathode materials from LIBs from varied sources. • Selective electrochemical recoveries of Cu and Mn. • Highly pure recovery products. Lithium-ion batteries (LIBs) are a tremendous achievement in the current energy storage landscape. However, there is an increasing demand for their implementation due to a variety of applications, such as mobile devices and a growing market of electric vehicles. Hence, the recycling of end-of-life batteries is one of the ways to satisfy the need for manufacturing new ones; however, this is challenging due to the lack of sustainable and efficient methods on a large scale. Electrochemical methods are widely used in the production of metals and alloys, therefore constituting a promising way for the recovery of critical metals present in cathode materials in LIBs. In this work, cathode materials have been collected from used LIBs from different sources and leached altogether with sulphuric acid and hydrogen peroxide. The resulting solution was treated electrochemically by applying a constant potential of -0.5 V for 20 h, which promoted the selective separation of copper and manganese at the cathode and anode sides, respectively. Complete and selective recoveries of Cu and Mn were proved by ICP-OES methods, while the purity of the obtained products was assessed by XRD, XPS and SEM-EDS analysis. This investigation presents a great potential for the implementation of an electrochemical treatment to recover valuable metals in pure and ready to reuse form from spent LIBs, which can be easily scaled-up as an alternative to current non-green recovery processes. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Lung volume reduction surgery (LVRS) has been proven to be a successful procedure and can be performed with low mortality when defined selection criteria are met. We hypothesized good outcome and low mortality after LVRS for selected patients with severe hyperinflation and nonhomogeneous morphology even when diffusion capacity of the lung for carbon monoxide (D lco) is less than 20%. Methods The study included all patients scheduled for LVRS between March 2005 and May 2014 with a preoperative D lco of less than 20%. Postoperative 90-day mortality was the primary end point. Secondary end points were postoperative lung function and surgical morbidity at 3, 6, and 12 months. Results Included were 33 patients with a median forced expiratory volume in 1 second of 23% (interquartile range, 19% to 28%), a median diffusion capacity of 15% (interquartile range, 13% to 18%), and a median hyperinflation of 76% (residual volume–to–total lung capacity ratio of 70% to 76%). Mean follow-up was 44.8 months (range, 10 to 141 months). Heterogeneous emphysema was present in 26 patients, and 7 showed intermediately heterogeneous morphology. Sixteen procedures were bilateral, and 31 were performed by video-assisted thoracoscopic surgery. The 90-day mortality was 0%. Median forced expiratory volume in 1 second percentage predicted at 3 months increased from 23% to 29% ( p < 0.001). Median D lco increased from 15% to 24% ( p < 0.001), and median hyperinflation decreased from 76% to 63% ( p < 0.001). A prolonged air leak exceeding 7 days occurred in 16 patients (48.5%), and 6 required reoperation for fistula closure. The 7 patients with intermediately heterogeneous emphysema showed a median increase in forced expiratory volume in 1 second from 20% preoperatively to 28% postoperatively ( p = 0.028). Conclusions Selected patients with severely impaired D lco of less than 20% can cautiously be considered as potential candidates if hyperinflation is severe and the lungs show areas with advanced destruction as targets for resection. [ABSTRACT FROM AUTHOR]

Legionella pneumophila is a facultative intracellular bacterium which can cause a severe pneumonia called Legionnaires' disease after inhalation of contaminated water droplets and replication in alveolar macrophages. The innate immune system is generally able to sense and −in most cases- control L. pneumophila infection. Comorbidities and genetic risk factors, however, can compromise the immune system and high infection doses might overwhelm its capacity, thereby enabling L. pneumophila to grow and disseminate inside the lung. The innate immune system mediates sensing of L. pneumophila by employing e.g. NOD-like receptors (NLRs), Toll-like receptors (TLRs), as well as the cGAS/STING pathway to stimulate death of infected macrophages as well as production of proinflammatory cytokines and interferons (IFNs). Control of pulmonary L. pneumophila infection is largely mediated by inflammasome-, TNFα- and IFN-dependent macrophage-intrinsic resistance mechanisms. This article summarizes the current knowledge of innate immune responses to L. pneumophila infection in general, and of macrophage-intrinsic defense mechanisms in particular. [ABSTRACT FROM AUTHOR]

Objective As large registries show an increased risk for lung transplant recipients aged 60 years or more, few single centers report favorable outcomes for carefully selected older recipients without providing essential details. The purpose of our study was to determine variables that influence survival in the elderly. Methods All adult bilateral first lung transplants between January 2000 and December 2014 were divided in 2 groups: those aged less than 60 years (N = 223) and those aged 60 years or more (N = 83). The Charlson-Deyo Index determined recipient comorbidities. The Oto Donor Score assessed donor lung quality. Results Recipients aged 60 years or more had a significant lower median survival compared with their younger counterparts (48 vs 112 months, respectively, P < .001). Recipient age was as an exponentially increasing univariate risk factor for mortality. By adjusting for variables in multivariate analysis, this trend was nonsignificant. The displacing variables were idiopathic pulmonary fibrosis (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.0-2.2), Charlson-Deyo Index 2 or greater (HR, 1.3; 95% CI, 1.0-1.8), systemic hypertension (HR, 1.7; 95% CI, 1.2-2.6), gastroesophageal reflux (HR, 1.9; 95% CI, 1.1-3.1), diverticulosis (HR, 1.7; 95% CI, 1.0-2.7), and an Oto Donor Score 8 or greater (HR, 1.5; 95% CI, 1.1-2.0). All of these risk factors were significantly more likely to occur in recipients aged 60 years or more, except for a tendency for high Charlson-Deyo Index. Conclusions The comorbidity profile, underlying disease, and donor lung quality appear to be more important than age in reducing long-term survival. Older age serves as a marker for a complex constellation of factors that might be considered the relative or absolute contraindication to lung transplantation rather than age, per se. [ABSTRACT FROM AUTHOR]

Background Transcranial direct current stimulation (tDCS) can polarize the cortex of the human brain. Objective/Hypothesis We sought to verify the hypothesis that posterior-anterior (PA) but not anterior-posterior (AP) tDCS of primary motor cortex (M1) produces cooperative effects with corticospinal plasticity induced by paired associative stimulation of the supplementary motor area (SMA) to M1 projection (PAS SMA→M1 ) in a highly controlled experimental design. Methods Three experimental conditions were tested in a double-blinded, randomized crossover design in 15 healthy adults: Navigated PAS SMA→M1 during PA-tDCS (35 cm 2 electrodes, anode 3 cm posterior to M1 hand area, cathode over contralateral frontopolar cortex, 1 mA, 2 × 5 min) or AP-tDCS (reversed polarity), or sham-tDCS. Effects were analyzed over 120 min post-intervention by changes of motor evoked potential (MEP) amplitude in a hand muscle. Results There was no significant effect of tDCS on PAS SMA→M1 induced plasticity in the repeated-measures ANOVA. However, post-hoc within-subject contrasts revealed a significant tDCS with PAS SMA→M1 interaction. This was explained by PA-tDCS and AP-tDCS modifying the PAS SMA→M1 effect into the same direction in 13/15 subjects (87%, p = 0.004 for deviation from equality). Sizes of the PA-tDCS and AP-tDCS effects were correlated (r s = 0.53, p = 0.044). A control experiment demonstrated that PA-tDCS and AP-tDCS alone (without PAS SMA→M1 ) had no effect on MEP amplitude. Conclusions Data point to unidirectional tDCS effects on PAS SMA→M1 induced plasticity irrespective of tDCS polarity, in contrast to our hypothesis. We propose that radial symmetry of cortical columns, gyral geometry of motor cortex, and cooperativity of plasticity induction can explain the findings. [ABSTRACT FROM AUTHOR]

Gaussian scale mixtures are constructed as Gaussian processes with a random variance. They have non-Gaussian marginals and can exhibit asymptotic dependence unlike Gaussian processes, which are asymptotically independent except in the case of perfect dependence. In this paper, we study the extremal dependence properties of Gaussian scale mixtures and we unify and extend general results on their joint tail decay rates in both asymptotic dependence and independence cases. Motivated by the analysis of spatial extremes, we propose flexible yet parsimonious parametric copula models that smoothly interpolate from asymptotic dependence to independence and include the Gaussian dependence as a special case. We show how these new models can be fitted to high threshold exceedances using a censored likelihood approach, and we demonstrate that they provide valuable information about tail characteristics. In particular, by borrowing strength across locations, our parametric model-based approach can also be used to provide evidence for or against either asymptotic dependence class, hence complementing information given at an exploratory stage by the widely used nonparametric or parametric estimates of the χ and χ ̄ coefficients. We demonstrate the capacity of our methodology by adequately capturing the extremal properties of wind speed data collected in the Pacific Northwest, US. [ABSTRACT FROM AUTHOR]

Tide pools habitats are naturally exposed to a high degree of environmental variability. The consequences of living in these extreme habitats are not well established. In particular, little it is known about of the effects of hypercanic seawater (i.e. high p CO 2 levels) on marine vertebrates such as intertidal pool fish. The aim of this study was to evaluate the effects of increased p CO 2 on the physiology and behavior in juveniles of the intertidal pool fish Girella laevifrons . Two nominal p CO 2 concentrations (400 and 1600 μatm) were used. We found that exposure to hypercapnic conditions did not affect oxygen consumption and absorption efficiency. However, the lateralization and boldness behavior was significantly disrupted in high p CO 2 conditions. In general, a predator-risk cost of boldness is assumed, thus the increased occurrence of shy personality in juvenile fishes may result in a change in the balance of this biological interaction, with significant ecological consequences. [ABSTRACT FROM AUTHOR]

Inclusive education of pupils with special educational needs (SEN) has become a global trend. However, a considerable number of studies have shown that mere enrolment in mainstream classrooms is not enough to support the social participation of pupils with SEN. These children are at risk of experiencing difficulties in their involvement with peers at school. Thus, the question arises of how social participation can be fostered in mainstream classrooms. A systematic review of 35 studies was conducted to investigate which interventions are effective in inclusive mainstream preschool and elementary classrooms. Teaching interaction strategies to typically developing pupils, group activities in the academic context (cooperative learning and peer-tutoring), support groups for pupils with SEN, and training paraprofessionals to facilitate social interactions, were found to improve the social participation of pupils with SEN in general education classrooms. Nevertheless, there is need for more intervention studies implementing a variety of strategies and including different groups of pupils with SEN. [ABSTRACT FROM AUTHOR]

Specific risk factors for suicide among female prisoners were examined using an exhaustive sample of all suicides in German prisons between 2000 and 2013. The rate of prison suicide was lower among female (53,5/100,000) than among male prisoners (101/100,000). Differences between the genders regarding the various risk factors for prison suicide are few. Significant differences were observed only for bullying among men and higher percentages of drug withdrawal syndrome among women. Factors specific to the prison setting that contribute to suicide risk in incarcerated women should be examined. [ABSTRACT FROM AUTHOR]

Background Extracorporeal life support (ECLS) as a bridge to lung retransplantation has been reported only anecdotally. Thus, we analyzed combined data from our center with pooled data from published studies to identify selection criteria for this advanced therapy. Methods Four patients at our center were bridged on ECLS to lung retransplantation. Patient data were retrospectively retrieved from electronic records. The MEDLINE database was searched using the PubMed engine and yielded 13 relevant studies that included a minimum of 3 patients bridged to lung retransplantation, and four studies described detailed data on 17 patients. Patient data from our center (n = 4) were pooled with data from the MEDLINE database (n = 17) and analyzed. Results Of 21 patients, 3 (14%) died on ECLS awaiting retransplantation, and 18 (86%) underwent retransplantation after a median of 37 months (range, 0 to 168 months) after primary transplantation. Type of ECLS was extracorporeal carbon dioxide removal (ECCO2R) in 4, venovenous extracorporeal membrane oxygenation (ECMO) in 7, venoarterial ECMO in 5, or was not mentioned in 2. The 90-day postoperative mortality was 28%. Overall 1-year survival was 48%. Patients bridged to retransplantation with ECCO2R/venovenous ECMO ( p = 0.05) or on awake ECMO ( p = 0.06) showed strong trends toward better survival in univariate analysis. Univariate and multivariate analysis identified a longer intertransplant interval as a statistically significant favorable prognostic factor. In a selected subgroup of patients (awake ECCO2R/venovenous ECMO support and intertransplant interval >2 years), 1-year survival reached 67%. Conclusions Despite limited overall 1-year survival for patients bridged with ECLS to lung retransplantation, careful patient selection may yield an acceptable 1-year survival of 67%. [ABSTRACT FROM AUTHOR]

This study examines the status and exploitation level of 31 northern European stocks targeted by fisheries certified by the Marine Stewardship Council (MSC) as being sustainable and well managed. In the first year of certification, 11 stocks (52% of stocks with available data) were exploited above the maximum sustainable level and four stocks (16% of stocks with available data) were outside of safe biological limits. MSC states that it certifies sub-standard stocks because they will improve once they are in their program. However, after a duration of certification of one to ten years (average four years), no significant changes in fishing pressure or stock size were detected. In the last certified year with available data, seven stocks (44% of stocks with available data) were subject to overfishing and five stocks (21% of stocks with available data) were outside of safe biological limits. Certification should guarantee that fishing quotas are set correctly and are enforced. However, in 11 stocks quotas were set 20–60% above the level that fishers were taking, whereas in three stocks landings exceeded quotas by 30–50%. The study concludes that MSC should change its rules such that overfishing or unsafe stock sizes lead to immediate suspension of certification and that no certification is issued in the first place for a stock that is already in such a situation. [ABSTRACT FROM AUTHOR]

We tackle the modeling of threshold exceedances in asymptotically independent stochastic processes by constructions based on Laplace random fields. Defined as mixtures of Gaussian random fields with an exponential variable embedded for the variance, these processes possess useful asymptotic properties while remaining statistically convenient. Univariate Laplace distribution tails are part of the limiting generalized Pareto distributions for threshold exceedances. After normalizing marginal distributions in data, a standard Laplace field can be used to capture spatial dependence among extremes. Asymptotic properties of Laplace fields are explored and compared to the classical framework of asymptotic dependence. Multivariate joint tail decay rates are slower than for Gaussian fields with the same covariance structure; hence they provide more conservative estimates of very extreme joint risks while maintaining asymptotic independence. Statistical inference is illustrated on extreme wind gusts in the Netherlands where a comparison to the Gaussian dependence model shows a better goodness-of-fit. In this application we fit the well-adapted Weibull distribution, closely related to the Laplace distribution, as univariate tail model. [ABSTRACT FROM AUTHOR]

Surgical treatment of locally advanced non–small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials. A total of 197 patients with T3/T4 non–small cell lung cancer of 368 patients with stage III non–small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters. Patients' median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P <.001), but pretreatment N2 extension (177/197) showed no impact on overall survival. Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status. [Display omitted] [ABSTRACT FROM AUTHOR]

In this work, we develop a constructive modeling framework for extreme threshold exceedances in repeated observations of spatial fields, based on general product mixtures of random fields possessing light or heavy-tailed margins and various spatial dependence characteristics, which are suitably designed to provide high flexibility in the tail and at sub-asymptotic levels. Our proposed model is akin to a recently proposed Gamma–Gamma model using a ratio of processes with Gamma marginal distributions, but it possesses a higher degree of flexibility in its joint tail structure, capturing strong dependence more easily. We focus on constructions with the following three product factors, whose different roles ensure their statistical identifiability: a heavy-tailed spatially-dependent field, a lighter-tailed spatially-constant field, and another lighter-tailed spatially-independent field. Thanks to the model's hierarchical formulation, inference may be conveniently performed based on Markov chain Monte Carlo methods. We leverage the Metropolis adjusted Langevin algorithm (MALA) with random block proposals for latent variables, as well as the stochastic gradient Langevin dynamics (SGLD) algorithm for hyperparameters, in order to fit our proposed model very efficiently in relatively high spatio-temporal dimensions, while simultaneously censoring non-exceedances of the threshold and performing spatial prediction at multiple sites. The censoring mechanism is applied to the spatially independent component, such that only univariate cumulative distribution functions have to be evaluated. We explore the theoretical properties of our model, and illustrate the proposed methodology by simulation and application to daily precipitation data from North–Eastern Spain measured at nearly 100 stations over the period 2011–2020. [ABSTRACT FROM AUTHOR]